Improved Mass Spectrometry-based methods reveal abundant propionylation and tissue specific histone propionylation profiles.

Histone post-translational modifications (PTMs) have crucial roles in a multitude of cellular processes, and their aberrant levels have been linked with numerous diseases, including cancer. Although histone PTM investigations have focused so far on methylations and acetylations, alternative long-chain acylations emerged as new dimension, as they are linked to cellular metabolic states and affect gene expression through mechanisms distinct from those regulated by acetylation. Mass spectrometry (MS) is the most powerful, comprehensive and unbiased method to study histone PTMs. However, typical MS-based protocols for histone PTM analysis do not allow identification of naturally occurring propionylation and butyrylation. Here, we present improved state-of-the-art sample preparation and analysis protocols to quantitate these classes of modifications. After testing different derivatization methods coupled to protease digestion, we profiled common histone PTMs and histone acylations in seven mouse tissues and human normal and tumor breast clinical samples, obtaining a map of propionylations and butyrylations found in different tissue contexts. A quantitative histone PTM analysis also revealed a contribution of histone acylations in discriminating different tissues, also upon perturbation with antibiotics, and breast cancer samples from the normal counterpart. Our results show that profiling only classical modifications is limiting and highlight the importance of using sample preparation methods that allows the analysis of the widest possible spectrum of histone modifications, paving the way for deeper insights into their functional significance in cellular processes and disease states.

Detection and quantification of the histone code in the fungal genus Aspergillus.

In eukaryotes, the combination of different histone post-translational modifications (PTMs) - the histone code - impacts the chromatin organization as compact and transcriptionally silent heterochromatin or accessible and transcriptionally active euchromatin. Although specific histone PTMs have been studied in fungi, an overview of histone PTMs and their relative abundance is still lacking. Here, we used mass spectrometry to detect and quantify histone PTMs in three fungal species belonging to three distinct taxonomic sections of the genus Aspergillus (Aspergillus niger, Aspergillus nidulans (two strains), and Aspergillus fumigatus). We overall detected 23 different histone PTMs, including a majority of lysine methylations and acetylations, and 23 co-occurrence patterns of multiple histone PTMs. Among those, we report for the first time the detection of H3K79me1, H3K79me2, and H4K31ac in Aspergilli. Although all three species harbour the same PTMs, we found significant differences in the relative abundance of H3K9me1/2/3, H3K14ac, H3K36me1 and H3K79me1, as well as the co-occurrence of acetylation on both K18 and K23 of histone H3 in a strain-specific manner. Our results provide novel insights about the underexplored complexity of the histone code in filamentous fungi, and its functional implications on genome architecture and gene regulation.

Role of diffusion-weighted MRI in recurrent rectal cancer treated with carbon ion radiotherapy.

Aim: To evaluate the association between pretreatment diffusion-weighted MRI (DW-MRI) and 12-month radiological response in locally recurrent rectal cancer treated with carbon ion radiotherapy. Methods: Histogram analysis was performed on pretreatment DW-MRI for patients re-irradiated with carbon ion radiotherapy for local recurrence of rectal cancer. Results: A total of 17 patients were enrolled in the study. Pretreatment DW-MRI b-value of 1000 s/mm2 (b1000) and apparent diffusion coefficient (ADC) lesion median values for 1-year nonresponders (six patients) and responders (11 patients) demonstrated a median (interquartile of median values) of 62.5 (23.9) and 34.0 (13.0) and 953.0 (277.0) and 942.5 (339.0) µm2/s, respectively. All b1000 histogram features (h-features) and ADC h-kurtosis showed statistically significant differences, whereas only b1000 h-median, b1000 h-interquartile range and ADC h-kurtosis demonstrated remarkable diagnostic accuracy. Conclusion: DW-MRI showed promising results in predicting carbon ion radiotherapy outcome in local recurrence of rectal cancer, particularly with regard to b1000 h-median, b1000 h-interquartile range and ADC h-kurtosis.

Carbon ion radiotherapy is a form of advanced radiotherapy that is especially suitable for radioresistant and/or difficult-to-irradiate tumors. In case of recurrence of rectal cancer after pelvic photon beam radiotherapy, carbon ion radiotherapy may be an option. In this study, the authors looked at the potential role of specific MRI sequences performed before treatment to predict response to carbon ion radiotherapy. If confirmed in a larger prospective cohort, the findings of this study may drive clinical decisions toward a more tumor- and patient-tailored therapeutic approach.

Current Status and Future Directions of Proton Therapy for Head and Neck Carcinoma.

The growing interest in proton therapy (PT) in recent decades is justified by the evidence that protons dose distribution allows maximal dose release at the tumor depth followed by sharp distal dose fall-off. But, in the holistic management of head and neck cancer (HNC), limiting the potential of PT to a mere dosimetric advantage appears reductive. Indeed, the precise targeting of PT may help evaluate the effectiveness of de-escalation strategies, especially for patients with human papillomavirus associated-oropharyngeal cancer (OPC) and nasopharyngeal cancer (NPC). Furthermore, PT could have potentially greater immunogenic effects than conventional photon therapy, possibly enhancing both the radiotherapy (RT) capability to activate anti-tumor immune response and the effectiveness of immunotherapy drugs. Based on these premises, the aim of the present paper is to conduct a narrative review reporting the safety and efficacy of PT compared to photon RT focusing on NPC and OPC. We also provide a snapshot of ongoing clinical trials comparing PT with photon RT for these two clinical scenarios. Finally, we discuss new insights that may further develop clinical research on PT for HNC.

Technical note: Radiological clinical equivalence for phantom materials in carbon ion therapy.

PURPOSE: As carbon ion radiotherapy increases in use, there are limited phantom materials for heterogeneous or anthropomorphic phantom measurements. This work characterized the radiological clinical equivalence of several phantom materials in a therapeutic carbon ion beam. METHODS: Eight materials were tested for radiological material-equivalence in a carbon ion beam. The materials were computed tomography (CT)-scanned to obtain Hounsfield unit (HU) values, then irradiated in a monoenergetic carbon ion beam to determine relative linear stopping power (RLSP). The corresponding HU and RLSP for each phantom material were compared to clinical carbon ion calibration curves. For absorbed dose comparison, ion chamber measurements were made in the center of a carbon ion spread-out Bragg peak (SOBP) in water and in the phantom material, evaluating whether the material perturbed the absorbed dose measurement beyond what was predicted by the HU-RLSP relationship. RESULTS: Polyethylene, solid water (Gammex and Sun Nuclear), Blue Water (Standard Imaging), and Techtron HPV had measured RLSP values that agreed within ±4.2% of RLSP values predicted by the clinical calibration curve. Measured RLSP for acrylic was 7.2% different from predicted. The agreement for balsa wood and cork varied between samples. Ion chamber measurements in the phantom materials were within 0.1% of ion chamber measurements in water for most materials (solid water, Blue Water, polyethylene, and acrylic), and within 1.9% for the rest of the materials (balsa wood, cork, and Techtron HPV). CONCLUSIONS: Several phantom materials (Blue Water, polyethylene, solid water [Gammex and Sun Nuclear], and Techtron HPV) are suitable for heterogeneous phantom measurements for carbon ion therapy. Low density materials should be carefully characterized due to inconsistencies between samples.

Is motherhood still possible after pelvic carbon ion radiotherapy? A promising combined fertility-preservation approach.

INTRODUCTION: Preserving the endocrine and reproductive function in young female cancer patients undergoing pelvic radiation is a significant challenge. While the photon beam radiation's adverse effects on the uterus and ovaries are well established, the impact of pelvic carbon ion radiotherapy on women's reproductive function is largely unexplored. Strategies such as oocyte cryopreservation and ovarian transposition are commonly recommended for safeguarding future fertility. METHODS: This study presents a pioneering case of successful pregnancy after carbon ion radiotherapy for locally advanced sacral chondrosarcoma. RESULTS: A multidisciplinary approach facilitated the displacement of ovaries and uterus before carbon ion radiotherapy, resulting in the preservation of endocrine and reproductive function. CONCLUSION: The patient achieved optimal oncological response and delivered a healthy infant following the completion of cancer treatment.

The first real-world study on the role of carbon ion radiotherapy for oligo-metastatic, persistent, or recurrent (MPR) ovarian/fallopian tube cancer.

Introduction: In the multidisciplinary management of oligometastatic, persistent, or recurrent (MPR) ovarian cancer, radiotherapy (RT) is becoming a more and more worthwhile treatment to potentially improve the chronicity of the disease. Particle beam RT has proved to be effective in several gynecological malignancies, but so far no data are available for ovarian cancer. Material and Methods: This is a real-world, retrospective, bi-institutional, single-arm study aimed to assess the effectiveness and the safety of carbon ion RT (CIRT) in this setting. The co-first endpoints are 1-year and 2-year actuarial local control (LC) rates and the objective response rate (ORR) defined on a "per lesion" basis. The secondary endpoint was toxicity. Actuarial outcomes were evaluated using the Kaplan-Meier method while potential predictors were explored using the Log-rank test. Bi-variable logistic regression was employed in the analysis of factors predicting the complete response on a per-lesion basis. Results: 26 patients accounting for a total of 36 lesions underwent CIRT with a total median dose of 52.8 Gy[RBE] (range: 39-64 Gy[RBE]). Five patients received CIRT for re-irradiation. No concomitant systemic therapies were administered during CIRT. Within 12 months after the treatment, 17 lesions (47 %) achieved complete response while 18 (50 %) obtained a partial response with an ORR of 97 %. The achievement of a complete response is related to the dose per fraction (>4.2 Gy[RBE], p = 0.04) and total dose (>52,8 Gy[RBE], p = 0.05). The 1-year LC was 92 % and the 2-year LC was 83 %, according to the achievement of a CR (p = 0.007) and GTV ≤ 14 cm3 (p = 0.024). No grade > 3 toxicities were recorded both in naïve and re-irradiated patients. PARP-i and anti-VEGF seemed not to exacerbate the risk of severe toxicities. Conclusions: CIRT was effective and safe in MPR ovarian cancers, even in the case of re-irradiation. Largest cohort studies and longer follow-up are needed to confirm these data.

Characterization of a flat-panel detector for 2D dosimetry in scanned proton and carbon ion beams.

PURPOSE: To fully characterize the flat panel detector of the new Sphinx Compact device with scanned proton and carbon ion beams. MATERIALS AND METHODS: The Sphinx Compact is designed for daily QA in particle therapy. We tested its repeatability and dose rate dependence as well as its proportionality with an increasing number of particles and potential quenching effect. Potential radiation damage was evaluated. Finally, we compared the spot characterization (position and profile FWHM) with our radiochromic EBT3 film baseline. RESULTS: The detector showed a repeatability of 1.7% and 0.9% for single spots of protons and carbon ions, respectively, while for small scanned fields it was inferior to 0.2% for both particles. The response was independent from the dose rate (difference from nominal value < 1.5%). We observed an under-response due to quenching effect for both particles, mostly for carbon ions. No radiation damage effects were observed after two months of weekly use and approximately 1350 Gy delivered to the detector. Good agreement was found between the Sphinx and EBT3 films for the spot position (central-axis deviation within 1 mm). The spot size measured with the Sphinx was larger compared to films. For protons, the average and maximum differences over different energies were 0.4 mm (3%) and 1 mm (7%); for carbon ions they were 0.2 mm (4%) and 0.4 mm (6%). CONCLUSIONS: Despite the quenching effect the Sphinx Compact fulfills the requirements needed for constancy checks and could represent a time-saving tool for daily QA in scanned particle beams.

Synthetic CT in Carbon Ion Radiotherapy of the Abdominal Site.

The generation of synthetic CT for carbon ion radiotherapy (CIRT) applications is challenging, since high accuracy is required in treatment planning and delivery, especially in an anatomical site as complex as the abdomen. Thirty-nine abdominal MRI-CT volume pairs were collected and a three-channel cGAN (accounting for air, bones, soft tissues) was used to generate sCTs. The network was tested on five held-out MRI volumes for two scenarios: (i) a CT-based segmentation of the MRI channels, to assess the quality of sCTs and (ii) an MRI manual segmentation, to simulate an MRI-only treatment scenario. The sCTs were evaluated by means of similarity metrics (e.g., mean absolute error, MAE) and geometrical criteria (e.g., dice coefficient). Recalculated CIRT plans were evaluated through dose volume histogram, gamma analysis and range shift analysis. The CT-based test set presented optimal MAE on bones (86.03 ± 10.76 HU), soft tissues (55.39 ± 3.41 HU) and air (54.42 ± 11.48 HU). Higher values were obtained from the MRI-only test set (MAEBONE = 154.87 ± 22.90 HU). The global gamma pass rate reached 94.88 ± 4.9% with 3%/3 mm, while the range shift reached a median (IQR) of 0.98 (3.64) mm. The three-channel cGAN can generate acceptable abdominal sCTs and allow for CIRT dose recalculations comparable to the clinical plans.

Consensus guide on CT-based prediction of stopping-power ratio using a Hounsfield look-up table for proton therapy.

BACKGROUND AND PURPOSE: Studies have shown large variations in stopping-power ratio (SPR) prediction from computed tomography (CT) across European proton centres. To standardise this process, a step-by-step guide on specifying a Hounsfield look-up table (HLUT) is presented here. MATERIALS AND METHODS: The HLUT specification process is divided into six steps: Phantom setup, CT acquisition, CT number extraction, SPR determination, HLUT specification, and HLUT validation. Appropriate CT phantoms have a head- and body-sized part, with tissue-equivalent inserts in regard to X-ray and proton interactions. CT numbers are extracted from a region-of-interest covering the inner 70% of each insert in-plane and several axial CT slices in scan direction. For optimal HLUT specification, the SPR of phantom inserts is measured in a proton beam and the SPR of tabulated human tissues is computed stoichiometrically at 100 MeV. Including both phantom inserts and tabulated human tissues increases HLUT stability. Piecewise linear regressions are performed between CT numbers and SPRs for four tissue groups (lung, adipose, soft tissue, and bone) and then connected with straight lines. Finally, a thorough but simple validation is performed. RESULTS: The best practices and individual challenges are explained comprehensively for each step. A well-defined strategy for specifying the connection points between the individual line segments of the HLUT is presented. The guide was tested exemplarily on three CT scanners from different vendors, proving its feasibility. CONCLUSION: The presented step-by-step guide for CT-based HLUT specification with recommendations and examples can contribute to reduce inter-centre variations in SPR prediction.

Investigating pathological epigenetic aberrations by epi-proteomics.

Epigenetics includes a complex set of processes that alter gene activity without modifying the DNA sequence, which ultimately determines how the genetic information common to all the cells of an organism is used to generate different cell types. Dysregulation in the deposition and maintenance of epigenetic features, which include histone posttranslational modifications (PTMs) and histone variants, can result in the inappropriate expression or silencing of genes, often leading to diseased states, including cancer. The investigation of histone PTMs and variants in the context of clinical samples has highlighted their importance as biomarkers for patient stratification and as key players in aberrant epigenetic mechanisms potentially targetable for therapy. Mass spectrometry (MS) has emerged as the most powerful and versatile tool for the comprehensive, unbiased and quantitative analysis of histone proteoforms. In recent years, these approaches-which we refer to as "epi-proteomics"-have demonstrated their usefulness for the investigation of epigenetic mechanisms in pathological conditions, offering a number of advantages compared with the antibody-based methods traditionally used to profile clinical samples. In this review article, we will provide a critical overview of the MS-based approaches that can be employed to study histone PTMs and variants in clinical samples, with a strong focus on the latest advances in this area, such as the analysis of uncommon modifications and the integration of epi-proteomics data into multi-OMICs approaches, as well as the challenges to be addressed to fully exploit the potential of this novel field of research.

Lower-Neck Sparing Using Proton Therapy in Patients with Uninvolved Neck Nasopharyngeal Carcinoma: Is It Safe?

Undifferentiated carcinoma of the nasopharynx (NPC) is a rare disease, which usually occurs in the Asian population. Due to its anatomic location, it is characterised by rich lymph node drainage and has a high incidence of cervical node metastasis. However, cervical nodal metastasis commonly involves retropharyngeal nodes and level II nodes, followed by level III nodes. In recent years, innovations in terms of systemic treatments and radiotherapy techniques have improved oncological outcome and treatment-related toxicities. Therefore, there is a growing interest in de-intensification strategies of reducing volumes and treatment-related side effects, especially in patients with NPC with N0-N1-stage disease. Proton therapy could represent a valid alternative to Intensity Modulated Radiotherapy (IMRT) in the management of NPC in this setting. With this Commentary, we aim to explore the feasibility of Intensity Modulated Proton Therapy (IMPT) in upper-neck irradiation of NPC N1-stage disease. We selected an NPC patient with N1 disease and compared the original IMRT plan with the IMPT plan in terms of dosimetric parameters. IMPT offers a minimal dosimetric advantage over IMRT in the bilateral lower-neck sparing. Clinical trials are needed to evaluate the significance of these proposed suggestions and their applicability in non-endemic areas.

Dosimetric validation of a GPU-based dose engine for a fast in silico patient-specific quality assurance program in light ion beam therapy.

BACKGROUND: With rapid evolutions of fast and sophisticated calculation techniques and delivery technologies, clinics are almost facing a daily patient-specific (PS) plan adaptation, which would make a conventional experimental quality assurance (QA) workflow unlikely to be routinely feasible. Therefore, in silico approaches are foreseen by means of second-check independent dose calculation systems possibly handling machine log-files. PURPOSE: To validate the in-house developed GPU-dose engine, FRoG, for light ion beam therapy (protons and carbon ions) as a second-check independent calculation system and to integrate machine log-file analysis into the patient-specific quality assurance (PSQA) program. METHODS: Spot sizes, depth-dose distributions, and absolute dose calibrations were configured into FRoG and a set of nine regular-shaped targets in combination with more than 170 clinical treatment fields were tested against pinpoint ionization chamber measurements. Both the treatment planning system DICOM RTplans and machine treatment log-files were used as input for the dose kernel in water, and a 3D local γ (1 mm/2%) index was used as the main evaluation metric. RESULTS: Calculated configuration data matched experimental measurements with submillimetric agreement. For regular-shaped targets, the unsigned average relative difference between calculated and measured dose values was less than 2% for both protons and carbon ions. The mean γ passing rate (PR) was around 98% for both particle species. For clinical treatment beams, DICOM-based recalculations showed a γ-PR more than 99% for both particle species. The same level of agreement was preserved for protons when moving to log-file-based recalculations. A score of around 95% was registered for carbon ion beams, once excluding low-quality machine log-files. Unsigned average relative difference against acquired data was less than 2% also for real clinical beams. CONCLUSIONS: FRoG was proven as an accurate and reliable tool for PSQA in scanning light ion beam therapy. The proposed method allows for an extremely efficient workflow, without compromising the quality of the plan verification procedure.

Investigating the use of virtual 4DCT from 4DMRI in gated carbon ion radiation therapy of abdominal tumors.

PURPOSE: To generate virtual 4DCT from 4DMRI with field of view (FOV) extended to the entire involved patient anatomy, in order to evaluate its use in carbon ion radiation therapy (CIRT) of the abdominal site in a clinical scenario. MATERIALS AND METHODS: The virtual 4DCT was generated by deforming a reference CT in order to (1) match the anatomy depicted in the 4DMRI within its FOV, by calculating deformation fields with deformable image registration to describe inter-fractional and breathing motion, and (2) obtain physically plausible deformation outside of the 4DMRI FOV, by propagating and modulating the previously obtained deformation fields. The implemented method was validated on a digital anthropomorphic phantom, for which a ground truth (GT) 4DCT was available. A CIRT treatment plan was optimized at the end-exhale reference CT and the RBE-weighted dose distribution was recalculated on both the virtual and GT 4DCTs. The method estimation error was quantified by comparing the virtual and GT 4DCTs and the corresponding recomputed doses. The method was then evaluated on 8 patients with pancreas or liver tumors treated with CIRT using respiratory gating at end-exhale. The clinical treatment plans adopted at the National Center for Oncological Hadrontherapy (CNAO, Pavia, Italy) were considered and the dose distribution was recomputed on all respiratory phases of the planning and virtual 4DCTs. By comparing the two datasets and the corresponding dose distributions, the geometrical and dosimetric impact of organ motion was assessed. RESULTS: For the phantom, the error outside of the 4DMRI FOV was up to 4.5mm, but it remained sub-millimetric in correspondence to the target within the 4DMRI FOV. Although the impact of motion on the target D95% resulted in variations ranging from 22% to 90% between the planned dose and the doses recomputed on the GT 4DCT phases, the corresponding estimation error was ≤2.2%. In the patient cases, the variation of the baseline tumor position between the planning and the virtual end-exhale CTs presented a median (interquartile range) value of 6.0 (4.9) mm. For baseline variations larger than 5mm, the tumor D95% variation between the plan and the dose recomputed on the end-exhale virtual CT resulted larger than 10%. Median variations higher than 10% in the target D95% and gastro-intestinal OARs D2% were quantified at the end-inhale, whereas close to the end-exhale phase, limited variations of relevant dose metrics were found for both tumor and OARs. CONCLUSIONS: The negligible impact of the geometrical inaccuracy in the estimated anatomy outside of the 4DMRI FOV on the overall dosimetric accuracy suggests the feasibility of virtual 4DCT with extended FOV in CIRT of the abdominal site. In the analyzed patient group, inter-fractional variations such as baseline variation and breathing variability were quantified, demonstrating the method capability to support treatment planning in gated CIRT of the abdominal site.

The role of multiple anatomical scenarios in plan optimization for carbon ion radiotherapy of pancreatic cancer.

PURPOSE /OBJECTIVE: To quantify benefits of robust optimization on multiple 4DCT acquisitions combined with off-line treatment adaptation for neoadjuvant carbon ion therapy (CIRT) of pancreatic cancer. MATERIAL/METHODS: For 10 previously treated patients, 4DCTs were acquired around -15 (CTPlan), -5 (RE1), -1 (RE2) and +6 (RE3) days from RT start. Treatment plans were newly optimized to a dose prescription of 38.4 Gy(RBE) (8 fractions) with a constraint of 38 Gy(RBE) to 1% of the gastrointestinal organs at risk volume (D1%). Three strategies were tested: (A) robust optimization on CTPlan maximum exhale (0Ex) with 3 mm set-up, 3% range uncertainty, including 30%-inhale; (B) addition of the RE1-0Ex scenario; (C) plan recalculation at each REi and adaptation (RPi) according to deviation thresholds from clinical goals. The cumulative variation of target coverage and GI-OARs doses was evaluated. Duodenum contours of all 4DCTs of each patient were registered on CTPlan-0Ex. The capacity of pre-RT acquisitions to predict duodenum position was investigated by computing the intersection of contours at CTplan, RE1, or their union, with respect to subsequent 4DCTs and the CTV, coupled with increasing margin. RESULTS: (A) No recalculation exceeded the D1% constraint. (B) The inclusion of RE1-0Ex in the optimization problem improved inter-fraction robustness on a patient-specific basis, but was non-significant on average. (C) Half of the plans would be re-optimized to recover target coverage and/or minimize duodenum dose, at least once. A significant difference was observed between pre-RT duodenum contours when intersecting subsequent contours, either with a margin expansion. CONCLUSION: Anatomical variations highlighted at multiple REi proved that a fast and efficient online adaptation is essential to optimize treatment quality of CIRT for pancreatic cancer.

A Patient Selection Approach Based on NTCP Models and DVH Parameters for Definitive Proton Therapy in Locally Advanced Sinonasal Cancer Patients.

(1) Background: In this work, we aim to provide selection criteria based on normal tissue complication probability (NTCP) models and additional explanatory dose-volume histogram parameters suitable for identifying locally advanced sinonasal cancer patients with orbital invasion benefitting from proton therapy. (2) Methods: Twenty-two patients were enrolled, and two advanced radiation techniques were compared: intensity modulated proton therapy (IMPT) and photon volumetric modulated arc therapy (VMAT). Plans were optimized with a simultaneous integrated boost modality: 70 and 56 Gy(RBE) in 35 fractions were prescribed to the high risk/low risk CTV. Several endpoints were investigated, classified for their severity and used as discriminating paradigms. In particular, when NTCP models were already available, a first selection criterion based on the delta-NTCP was adopted. Additionally, an overall analysis in terms of DVH parameters was performed. Furthermore, a second selection criterion based on a weighted sum of the ΔNTCP and ΔDVH was adopted. (3) Results: Four patients out of 22 (18.2%) were suitable for IMPT due to ΔNTCP > 3% for at least one severe toxicity, 4 (18.2%) due to ΔNTCP > 20% for at least three concurrent intermediate toxicities and 16 (72.7%) due to the mixed sum of ΔNTCP and ΔDVH criterion. Since, for some cases, both criteria were contemporary fulfilled, globally 17/22 patients (77.3%) would benefit from IMPT. (4) Conclusions: For this rare clinical scenario, the use of a strategy including DVH parameters and NTCPs when comparing VMAT and IMPT is feasible. We showed that patients affected by sinonasal cancer could profit from IMPT compared to VMAT in terms of optical and central nervous system organs at risk sparing.

Time-resolved MRI for off-line treatment robustness evaluation in carbon-ion radiotherapy of pancreatic cancer.

PURPOSE: In this study, we investigate the use of magnetic resonance imaging (MRI) for the clinical evaluation of gating treatment robustness in carbon-ion radiotherapy (CIRT) of pancreatic cancer. Indeed, MRI allows radiation-free repeated scans and fast dynamic sequences for time-resolved (TR) imaging (cine-MRI), providing information on inter- and intra-fraction cycle-to-cycle variations of respiratory motion. MRI can therefore support treatment planning and verification, overcoming the limitations of the current clinical standard, that is, four-dimensional computed tomography (4DCT), which describes an "average" breathing cycle neglecting breathing motion variability. METHODS: We integrated a technique to generate a virtual CT (vCT) from 3D MRI with a method for 3D reconstruction from 2D cine-MRI, to produce TR vCTs for dose recalculations. For eight patients, the method allowed evaluating inter-fraction variations at end-exhale and intra-fraction cycle-to-cycle variability within the gating window in terms of tumor displacement and dose to the target and organs at risk. RESULTS: The median inter-fraction tumor motion was in the range 3.33-12.16 mm, but the target coverage was robust (-0.4% median D95% variation). Concerning cycle-to-cycle variations, the gating technique was effective in limiting tumor displacement (1.35 mm median gating motion) and corresponding dose variations (-3.9% median D95% variation). The larger exposure of organs at risk (duodenum and stomach) was caused by inter-fraction motion, whereas intra-fraction cycle-to-cycle dose variations were limited. CONCLUSIONS: This study proposed a method for the generation of TR vCTs from MRI, which enabled an off-line evaluation of gating treatment robustness and suggested its feasibility to support treatment planning of pancreatic tumors in CIRT.

Proton Radiation Therapy for Nasopharyngeal Cancer Patients: Dosimetric and NTCP Evaluation Supporting Clinical Decision.

(1) Background: we proposed an integrated strategy to support clinical allocation of nasopharyngeal patients between proton and photon radiotherapy. (2) Methods: intensity-modulated proton therapy (IMPT) plans were optimized for 50 consecutive nasopharyngeal carcinoma (NPC) patients treated with volumetric modulated arc therapy (VMAT), and differences in dose and normal tissue complication probability (ΔNTCPx-p) for 16 models were calculated. Patient eligibility for IMPT was assessed using a model-based selection (MBS) strategy following the results for 7/16 models describing the most clinically relevant endpoints, applying a model-specific ΔNTCPx-p threshold (15% to 5% depending on the severity of the complication) and a composite threshold (35%). In addition, a comprehensive toxicity score (CTS) was defined as the weighted sum of all 16 ΔNTCPx-p, where weights follow a clinical rationale. (3) Results: Dose deviations were in favor of IMPT (ΔDmean ≥ 14% for cord, esophagus, brainstem, and glottic larynx). The risk of toxicity significantly decreased for xerostomia (-12.5%), brain necrosis (-2.3%), mucositis (-3.2%), tinnitus (-8.6%), hypothyroidism (-9.3%), and trismus (-5.4%). There were 40% of the patients that resulted as eligible for IMPT, with a greater advantage for T3-T4 staging. Significantly different CTS were observed in patients qualifying for IMPT. (4) Conclusions: The MBS strategy successfully drives the clinical identification of NPC patients, who are most likely to benefit from IMPT. CTS summarizes well the expected global gain.

High-dose hypofractionated pencil beam scanning carbon ion radiotherapy for lung tumors: Dosimetric impact of different spot sizes and robustness to interfractional uncertainties.

PURPOSE: The robustness against setup and motion uncertainties of gated four-dimensional restricted robust optimization (4DRRO) was investigated for hypofractionated carbon ion radiotherapy (CIRT) of lung tumors. METHODS: CIRT plans of 9 patients were optimized using 4DRRO strategy with 3 mm setup errors, 3% density errors and 3 breathing phases related to the gate window. The prescription was 60 Gy(RBE) in 4 fractions. Standard spots (SS) were compared to big spots (BS). Plans were recalculated on multiple 4DCTs acquired within 3 weeks from treatment simulation and rigidly registered with planning images using bone matching. Warped dose distributions were generated using deformable image registration and accumulated on the planning 4DCTs. Target coverage (D98%, D95% and V95%) and dose to lung were evaluated in the recalculated and accumulated dose distributions. RESULTS: Comparable target coverage was obtained with both spot sizes (p = 0.53 for D95%). The mean lung dose increased of 0.6 Gy(RBE) with BS (p = 0.0078), still respecting the dose constraint of a 4-fraction stereotactic treatment for the risk of radiation pneumonitis. Statistically significant differences were found in the recalculated and accumulated D95% (p = 0.048 and p = 0.024), with BS showing to be more robust. Using BS, the average degradations of the D98%, D95% and V95% in the accumulated doses were -2.7%, -1.6% and -1.5%. CONCLUSIONS: Gated 4DRRO was highly robust against setup and motion uncertainties. BS increased the dose to healthy tissues but were more robust than SS. The selected optimization settings guaranteed adequate target coverage during the simulated treatment course with acceptable risk of toxicity.

An MRI framework for respiratory motion modelling validation.

INTRODUCTION: Respiratory motion models establish a correspondence between respiratory-correlated (RC) 4-dimensional (4D) imaging and respiratory surrogates, to estimate time-resolved (TR) 3D breathing motion. To evaluate the performance of motion models on real patient data, a validation framework based on magnetic resonance imaging (MRI) is proposed, entailing the use of RC 4DMRI to build the model, and on both (i) TR 2D cine-MRI and (ii) additional 4DMRI data for testing intra-/inter-fraction breathing motion variability. METHODS: Repeated MRI data were acquired in 7 patients with abdominal lesions. The considered model relied on deformable image registration (DIR) for building the model and compensating for inter-fraction baseline variations. Both 2D and 3D validation were performed, by comparing model estimations with the ground truth 2D cine-MRI and 4DMRI respiratory phases, respectively. RESULTS: The median DIR error was comparable to the voxel size (1.33 × 1.33 × 5 mm3 ), with higher values in the presence of large inter-fraction motion (median value: 2.97 mm). In the 2D validation, the median estimation error on anatomical landmarks' position resulted below 4 mm in every scenario, whereas in the 3D validation it was 1.33 mm and 4.21 mm when testing intra- and inter-fraction motion, respectively. The range of motion described in the cine-MRI was comparable to the motion of the building 4DMRI, being always above the estimation error. Overall, the model performance was dependent on DIR error, presenting reduced accuracy when inter-fraction baseline variations occurred. CONCLUSIONS: Results suggest the potential of the proposed framework in evaluating global motion models for organ motion management in MRI-guided radiotherapy.