Geometric target margin strategy of proton craniospinal irradiation for pediatric medulloblastoma.

In proton craniospinal irradiation (CSI) for skeletally immature pediatric patients, a treatment plan should be developed to ensure that the dose is uniformly delivered to all vertebrae, considering the effects on bone growth balance. The technical (t) clinical target volume (CTV) is conventionally set by manually expanding the CTV from the entire intracranial space and thecal sac, based on the physician's experience. However, there are differences in contouring methods among physicians. Therefore, we aimed to propose a new geometric target margin strategy. Nine pediatric patients with medulloblastoma who underwent proton CSI were enrolled. We measured the following water equivalent lengths for each vertebra in each patient: body surface to the dorsal spinal canal, vertebral limbus, ventral spinal canal and spinous processes. A simulated tCTV (stCTV) was created by assigning geometric margins to the spinal canal using the measurement results such that the vertebral limb and dose distribution coincided with a margin assigned to account for the uncertainty of the proton beam range. The stCTV with a growth factor (correlation between body surface area and age) and tCTV were compared and evaluated. The median values of each index for cervical, thoracic and lumber spine were: the Hausdorff distance, 9.14, 9.84 and 9.77 mm; mean distance-to-agreement, 3.26, 2.65 and 2.64 mm; Dice coefficient, 0.84, 0.81 and 0.82 and Jaccard coefficient, 0.50, 0.60 and 0.62, respectively. The geometric target margin setting method used in this study was useful for creating an stCTV to ensure consistent and uniform planning.

Assessment of changes in vessel area during needle manipulation in microvascular anastomosis using a deep learning-based semantic segmentation algorithm: A pilot study.

Appropriate needle manipulation to avoid abrupt deformation of fragile vessels is a critical determinant of the success of microvascular anastomosis. However, no study has yet evaluated the area changes in surgical objects using surgical videos. The present study therefore aimed to develop a deep learning-based semantic segmentation algorithm to assess the area change of vessels during microvascular anastomosis for objective surgical skill assessment with regard to the "respect for tissue." The semantic segmentation algorithm was trained based on a ResNet-50 network using microvascular end-to-side anastomosis training videos with artificial blood vessels. Using the created model, video parameters during a single stitch completion task, including the coefficient of variation of vessel area (CV-VA), relative change in vessel area per unit time (ΔVA), and the number of tissue deformation errors (TDE), as defined by a ΔVA threshold, were compared between expert and novice surgeons. A high validation accuracy (99.1%) and Intersection over Union (0.93) were obtained for the auto-segmentation model. During the single-stitch task, the expert surgeons displayed lower values of CV-VA (p < 0.05) and ΔVA (p < 0.05). Additionally, experts committed significantly fewer TDEs than novices (p < 0.05), and completed the task in a shorter time (p < 0.01). Receiver operating curve analyses indicated relatively strong discriminative capabilities for each video parameter and task completion time, while the combined use of the task completion time and video parameters demonstrated complete discriminative power between experts and novices. In conclusion, the assessment of changes in the vessel area during microvascular anastomosis using a deep learning-based semantic segmentation algorithm is presented as a novel concept for evaluating microsurgical performance. This will be useful in future computer-aided devices to enhance surgical education and patient safety.

Probability of normal tissue complications for hematologic and gastrointestinal toxicity in postoperative whole pelvic radiotherapy for gynecologic malignancies using intensity-modulated proton therapy with robust optimization.

This retrospective treatment-planning study was conducted to determine whether intensity-modulated proton therapy with robust optimization (ro-IMPT) reduces the risk of acute hematologic toxicity (H-T) and acute and late gastrointestinal toxicity (GI-T) in postoperative whole pelvic radiotherapy for gynecologic malignancies when compared with three-dimensional conformal radiation therapy (3D-CRT), intensity-modulated X-ray (IMXT) and single-field optimization proton beam (SFO-PBT) therapies. All plans were created for 13 gynecologic-malignancy patients. The prescribed dose was 45 GyE in 25 fractions for 95% planning target volume in 3D-CRT, IMXT and SFO-PBT plans and for 99% clinical target volume (CTV) in ro-IMPT plans. The normal tissue complication probability (NTCP) of each toxicity was used as an in silico surrogate marker. Median estimated NTCP values for acute H-T and acute and late GI-T were 0.20, 0.94 and 0.58 × 10-1 in 3D-CRT; 0.19, 0.65 and 0.24 × 10-1 in IMXT; 0.04, 0.74 and 0.19 × 10-1 in SFO-PBT; and 0.06, 0.66 and 0.15 × 10-1 in ro-IMPT, respectively. Compared with 3D-CRT and IMXT plans, the ro-IMPT plan demonstrated significant reduction in acute H-T and late GI-T. The risk of acute GI-T in ro-IMPT plan is equivalent with IMXT plan. The ro-IMPT plan demonstrated potential clinical benefits for reducing the risk of acute H-T and late GI-T in the treatment of gynecologic malignances by reducing the dose to the bone marrow and bowel bag while maintaining adequate dose coverage to the CTV. Our results indicated that ro-IMPT may reduce acute H-T and late GI-T risk with potentially improving outcomes for postoperative gynecologic-malignancy patients with concurrent chemotherapy.

Prostatic urinary tract visualization with super-resolution deep learning models.

In urethra-sparing radiation therapy, prostatic urinary tract visualization is important in decreasing the urinary side effect. A methodology has been developed to visualize the prostatic urinary tract using post-urination magnetic resonance imaging (PU-MRI) without a urethral catheter. This study investigated whether the combination of PU-MRI and super-resolution (SR) deep learning models improves the visibility of the prostatic urinary tract. We enrolled 30 patients who had previously undergone real-time-image-gated spot scanning proton therapy by insertion of fiducial markers. PU-MRI was performed using a non-contrast high-resolution two-dimensional T2-weighted turbo spin-echo imaging sequence. Four different SR deep learning models were used: the enhanced deep SR network (EDSR), widely activated SR network (WDSR), SR generative adversarial network (SRGAN), and residual dense network (RDN). The complex wavelet structural similarity index measure (CW-SSIM) was used to quantitatively assess the performance of the proposed SR images compared to PU-MRI. Two radiation oncologists used a 1-to-5 scale to subjectively evaluate the visibility of the prostatic urinary tract. Cohen's weighted kappa (k) was used as a measure of agreement of inter-operator reliability. The mean CW-SSIM in EDSR, WDSR, SRGAN, and RDN was 99.86%, 99.89%, 99.30%, and 99.67%, respectively. The mean prostatic urinary tract visibility scores of the radiation oncologists were 3.70 and 3.53 for PU-MRI (k = 0.93), 3.67 and 2.70 for EDSR (k = 0.89), 3.70 and 2.73 for WDSR (k = 0.88), 3.67 and 2.73 for SRGAN (k = 0.88), and 4.37 and 3.73 for RDN (k = 0.93), respectively. The results suggest that SR images using RDN are similar to the original images, and the SR deep learning models subjectively improve the visibility of the prostatic urinary tract.

Medical Radiation Exposure Reduction in PET via Super-Resolution Deep Learning Model.

In positron emission tomography (PET) imaging, image quality correlates with the injected [18F]-fluorodeoxyglucose (FDG) dose and acquisition time. If image quality improves from short-acquisition PET images via the super-resolution (SR) deep learning technique, it is possible to reduce the injected FDG dose. Therefore, the aim of this study was to clarify whether the SR deep learning technique could improve the image quality of the 50%-acquisition-time image to the level of that of the 100%-acquisition-time image. One-hundred-and-eight adult patients were enrolled in this retrospective observational study. The supervised data were divided into nine subsets for nested cross-validation. The mean peak signal-to-noise ratio and structural similarity in the SR-PET image were 31.3 dB and 0.931, respectively. The mean opinion scores of the 50% PET image, SR-PET image, and 100% PET image were 3.41, 3.96, and 4.23 for the lung level, 3.31, 3.80, and 4.27 for the liver level, and 3.08, 3.67, and 3.94 for the bowel level, respectively. Thus, the SR-PET image was more similar to the 100% PET image and subjectively improved the image quality, as compared to the 50% PET image. The use of the SR deep-learning technique can reduce the injected FDG dose and thus lower radiation exposure.

Dosimetric advantages of daily adaptive strategy in IMPT for high-risk prostate cancer.

PURPOSE: To evaluate the dosimetric advantages of daily adaptive radiotherapy (DART) in intensity-modulated proton therapy (IMPT) for high-risk prostate cancer by comparing estimated doses of the conventional non-adaptive radiotherapy (NART) that irradiates according to an original treatment plan through the entire treatment and the DART that uses an adaptive treatment plan generated by using daily CT images acquired before each treatment. METHODS: Twenty-three patients with prostate cancer were included. A treatment plan with 63 Gy (relative biological effectiveness (RBE)) in 21 fractions was generated using treatment planning computed tomography (CT) images assuming that all patients had high-risk prostate cancer for which the clinical target volume (CTV) needs to include prostate and the seminal vesicle (SV) in our treatment protocol. Twenty-one adaptive treatment plans for each patient (total 483 data sets) were generated using daily CT images, and dose distributions were calculated. Using a 3 mm set-up uncertainty in the robust optimization, the doses to the CTV, prostate, SV, rectum, and bladder were compared. RESULTS: Estimated accumulated doses of NART and DART in the 23 patients were 60.81 ± 3.47 Gy (RBE) and 63.24 ± 1.04 Gy (RBE) for CTV D99 (p < 0.01), 62.99 ± 1.28 Gy (RBE) and 63.43 ± 1.33 Gy (RBE) for the prostate D99 (p = 0.2529), and 59.07 ± 5.19 Gy (RBE) and 63.17 ± 1.04 Gy (RBE) for SV D99 (p < 0.001). No significant differences were observed between NART and DART in the estimated accumulated dose for the rectum and bladder. CONCLUSION: Compared with the NART, DART was shown to be a useful approach that can maintain the dose coverage to the target without increasing the dose to the organs at risk (OAR) using the 3 mm set-up uncertainty in the robust optimization in patients with high-risk prostate cancer.

A treatment planning study of urethra-sparing intensity-modulated proton therapy for localized prostate cancer.

BACKGROUND AND PURPOSE: Urethra-sparing radiation therapy for localized prostate cancer can reduce the risk of radiation-induced genitourinary toxicity by intentionally underdosing the periurethral transitional zone. We aimed to compare the clinical impact of a urethra-sparing intensity-modulated proton therapy (US-IMPT) plan with that of conventional clinical plans without urethral dose reduction. MATERIALS AND METHODS: This study included 13 patients who had undergone proton beam therapy. The prescribed dose was 63 GyE in 21 fractions for 99% of the clinical target volume. To compare the clinical impact of the US-IMPT plan with that of the conventional clinical plan, tumor control probability (TCP) and normal tissue complication probability (NTCP) were calculated with a generalized equivalent uniform dose-based Lyman-Kutcher model using dose volume histograms. The endpoints of these model parameters for the rectum, bladder, and urethra were fistula, contraction, and urethral stricture, respectively. RESULTS: The mean NTCP value for the urethra in US-IMPT was significantly lower than that in the conventional clinical plan (0.6% vs. 1.2%, p < 0.05). There were no statistically significant differences between the conventional and US-IMPT plans regarding the mean minimum dose for the urethra with a 3-mm margin, TCP value, and NTCP value for the rectum and bladder. Additionally, the target dose coverage of all plans in the robustness analysis was within the clinically acceptable range. CONCLUSIONS: Compared with the conventional clinically applied plans, US-IMPT plans have potential clinical advantages and may reduce the risk of genitourinary toxicities, while maintaining the same TCP and NTCP in the rectum and bladder.

Cost-effectiveness analysis using lifetime attributable risk of proton beam therapy for pediatric medulloblastoma in Japan.

Compared to conventional X-ray therapy, proton beam therapy (PBT) has more clinical and physical advantages such as irradiation dose reduction to normal tissues for pediatric medulloblastoma. However, PBT is expensive. We aimed to compare the cost-effectiveness of PBT for pediatric medulloblastoma with that of conventional X-ray therapy, while focusing on radiation-induced secondary cancers, which are rare, serious and negatively affect a patient's quality of life (QOL). Based on a systematic review, a decision tree model was used for the cost-effectiveness analysis. This analysis was performed from the perspective of health care payers; the cost was estimated from medical fees. The target population was pediatric patients with medulloblastoma below 14 years old. The time horizon was set at 7.7 years after medulloblastoma treatment. The primary outcome was the incremental cost-effectiveness ratio (ICER), which was defined as the ratio of the difference in cost and lifetime attributable risk (LAR) between conventional X-ray therapy and PBT. The discount rate was set at 2% annually. Sensitivity analyses were performed to model uncertainty. Cost and LAR in conventional X-ray therapy and PBT were Japanese yen (JPY) 1 067 608 and JPY 2436061 and 42% and 7%, respectively. The ICER was JPY 3856398/LAR. In conclusion, PBT is more cost-effective than conventional X-ray therapy in reducing the risk of radiation-induced secondary cancers in pediatric medulloblastoma. Thus, our constructed ICER using LAR is one of the valid indicators for cost-effectiveness analysis in radiation-induced secondary cancer.

First experimental results of gated proton imaging using x-ray fluoroscopy to detect a fiducial marker.

Increasing numbers of proton imaging research studies are being conducted for accurate proton range determination in proton therapy treatment planning. However, there is no proton imaging system that deals with motion artifacts. In this study, a gated proton imaging system was developed and the first experimental results of proton radiography (pRG) were obtained for a moving object without motion artifacts. A motion management system using dual x-ray fluoroscopy for detecting a spherical gold fiducial marker was introduced and the proton beam was gated in accordance with the motion of the object. To demonstrate the performance of the gated proton imaging system, gated pRG images of a moving phantom were acquired experimentally, and the motion artifacts clearly were diminished. Also, the factors causing image deteriorations were evaluated focusing on the new gating system developed here, and the main factor was identified as the latency (with a maximum value of 93 ms) between the ideal gating signal according to the actual marker position and the actual gating signal. The possible deterioration due to the latency of the proton imaging system and proton beam irradiation was small owing to appropriate setting of the time structure.

Visualizing the urethra by magnetic resonance imaging without usage of a catheter for radiotherapy of prostate cancer.

The urethra position may shift due to the presence/absence of the catheter. Our proposed post-urination-magnetic resonance imaging (PU-MRI) technique is possible to identify the urethra without catheter. We aimed to verify the inter-operator difference in contouring the urethra by PU-MRI. The mean values of the evaluation indices of dice similarity coefficient, mean slice-wise Hausdorff distance, and center coordinates were 0.93, 0.17 mm, and 0.36 mm for computed tomography, and 0.75, 0.44 mm, and 1.00 mm for PU-MRI. Therefore, PU-MRI might be useful for identifying the prostatic urinary tract without using a urethral catheter. Clinical trial registration: Hokkaido University Hospital for Clinical Research (018-0221).

Are simple verbal instructions sufficient to ensure that bladder volume does not deteriorate prostate position reproducibility during spot scanning proton therapy?

Objectives: The purpose of this study is to investigate whether verbal instructions are sufficient for bladder volume (BV) control not to deteriorate prostate position reproducibility in image-guided spot scanning proton therapy (SSPT) for localized prostate cancer. Methods: A total of 268 treatment sessions in 12 consecutive prostate cancer patients who were treated with image-guided SSPT with fiducial markers were retrospectively analyzed. In addition to strict rectal volume control procedures, simple verbal instructions to void urine one hour before the treatment were used here. The BV was measured by a Bladder Scan just before the treatment, and the prostate motion was measured by intraprostatic fiducial markers and two sets of X-ray fluoroscopy images. The correlation between the BV change and prostate motion was assessed by linear mixed-effects models and systematic and random errors according to the reproducibility of the BV. Results: The mean absolute BV change during treatment was from -98.7 to 86.3 ml (median 7.1 ml). The mean absolute prostate motion of the patients in the left-right direction was -1.46 to 1.85 mm; in the cranial-caudal direction it was -6.10 to 3.65 mm, and in the anteroposterior direction -1.90 to 5.23 mm. There was no significant relationship between the BV change and prostate motion during SSPT. The early and late genitourinary and gastrointestinal toxicity was minimal with a minimum follow up of 4.57 years. Conclusions: Simple verbal instructions about urination was suggested to be sufficient to control the BV not to impact on the prostate motion and clinical outcomes in image-guided SSPT. Careful attention to BV change is still needed when the seminal vesicle is to be treated. Advances in knowledge: Our data demonstrated that there was no apparent relationship between BV changes and prostate position reproducibility and simple verbal instruction about urination could be sufficient for image-guided SSPT.

Potential benefits of adaptive intensity-modulated proton therapy in nasopharyngeal carcinomas.

PURPOSE: To investigate potential advantages of adaptive intensity-modulated proton beam therapy (A-IMPT) by comparing it to adaptive intensity-modulated X-ray therapy (A-IMXT) for nasopharyngeal carcinomas (NPC). METHODS: Ten patients with NPC treated with A-IMXT (step and shoot approach) and concomitant chemotherapy between 2014 and 2016 were selected. In the actual treatment, 46 Gy in 23 fractions (46Gy/23Fx.) was prescribed using the initial plan and 24Gy/12Fx was prescribed using an adapted plan thereafter. New treatment planning of A-IMPT was made for the same patients using equivalent dose fractionation schedule and dose constraints. The dose volume statistics based on deformable images and dose accumulation was used in the comparison of A-IMXT with A-IMPT. RESULTS: The means of the Dmean of the right parotid gland (P < 0.001), right TM joint (P < 0.001), left TM joint (P < 0.001), oral cavity (P < 0.001), supraglottic larynx (P = 0.001), glottic larynx (P < 0.001), , middle PCM (P = 0.0371), interior PCM (P < 0.001), cricopharyngeal muscle (P = 0.03643), and thyroid gland (P = 0.00216), in A-IMPT are lower than those of A-IMXT, with statistical significance. The means of, D0.03cc , and Dmean of each sub portion of auditory apparatus and D30% for Eustachian tube and D0.5cc for mastoid volume in A-IMPT are significantly lower than those of A-IMXT. The mean doses to the oral cavity, supraglottic larynx, and glottic larynx were all reduced by more than 20 Gy (RBE = 1.1). CONCLUSIONS: An adaptive approach is suggested to enhance the potential benefit of IMPT compared to IMXT to reduce adverse effects for patients with NPC.

Proton dose calculation based on converting dual-energy CT data to stopping power ratio (DEEDZ-SPR): a beam-hardening assessment.

To achieve an accurate stopping power ratio (SPR) prediction in particle therapy treatment planning, we previously proposed a simple conversion to the SPR from dual-energy (DE) computed tomography (CT) data via electron density and effective atomic number (Z eff) calibration (DEEDZ-SPR). This study was conducted to carry out an initial implementation of the DEEDZ-SPR conversion method with a clinical treatment planning system (TPS; VQA, Hitachi Ltd., Tokyo) for proton beam therapy. Consequently, this paper presents a proton therapy plan for an anthropomorphic phantom to evaluate the stability of the dose calculations obtained by the DEEDZ-SPR conversion against the variation of the calibration phantom size. Dual-energy x-ray CT images were acquired using a dual-source CT (DSCT) scanner. A single-energy CT (SECT) scan using the same DSCT scanner was also performed to compare the DEEDZ-SPR conversion with the SECT-based SPR (SECT-SPR) conversion. The scanner-specific parameters necessary for the SPR calibration were obtained from the CT images of tissue substitutes in a calibration phantom. Two calibration phantoms with different sizes (a 33 cm diameter phantom and an 18 cm diameter phantom) were used for the SPR calibrations to investigate the beam-hardening effect on dosimetric uncertainties. Each set of calibrated SPR data was applied to the proton therapy plan designed using the VQA TPS with a pencil beam algorithm for the anthropomorphic phantom. The treatment plans with the SECT-SPR conversion exhibited discrepancies between the dose distributions and the dose-volume histograms (DVHs) of the 33 cm and 18 cm phantom calibrations. In contrast, the corresponding dose distributions and the DVHs obtained using the DEEDZ-SPR conversion method coincided almost perfectly with each other. The DEEDZ-SPR conversion appears to be a promising method for providing proton dose plans that are stable against the size variations of the calibration phantom and the patient.

Quantitative analysis of treatments using real-time image gated spot-scanning with synchrotron-based proton beam therapy system log data.

A synchrotron-based real-time image gated spot-scanning proton beam therapy (RGPT) system with inserted fiducial markers can irradiate a moving tumor with high accuracy. As gated treatments increase the beam delivery time, this study aimed to investigate the frequency of intra-field adjustments corresponding to the baseline shift or drift and the beam delivery efficiency of a synchrotron-based RGPT system. Data from 118 patients corresponding to 127 treatment plans and 2810 sessions between October 2016 and March 2019 were collected. We quantitatively analyzed the proton beam delivery time, the difference between the ideal beam delivery time based on a simulated synchrotron magnetic excitation pattern and the actual treatment beam delivery time, frequency corresponding to the baseline shift or drift, and the gating efficiency of the synchrotron-based RGPT system according to the proton beam delivery machine log data. The mean actual beam delivery time was 7.1 min, and the simulated beam delivery time in an ideal environment with the same treatment plan was 2.9 min. The average difference between the actual and simulated beam delivery time per session was 4.3 min. The average frequency of intra-field adjustments corresponding to baseline shift or drift and beam delivery efficiency were 21.7% and 61.8%, respectively. Based on our clinical experience with a synchrotron-based RGPT system, we determined the frequency corresponding to baseline shift or drift and the beam delivery efficiency using the beam delivery machine log data. To maintain treatment accuracy within ± 2.0 mm, intra-field adjustments corresponding to baseline shift or drift were required in approximately 20% of cases. Further improvements in beam delivery efficiency may be realized by shortening the beam delivery time.

Analysis of treatment process time for real-time-image gated-spot-scanning proton-beam therapy (RGPT) system.

We developed a synchrotron-based real-time-image gated-spot-scanning proton-beam therapy (RGPT) system and utilized it to clinically operate on moving tumors in the liver, pancreas, lung, and prostate. When the spot-scanning technique is linked to gating, the beam delivery time with gating can increase, compared to that without gating. We aim to clarify whether the total treatment process can be performed within approximately 30 min (the general time per session in several proton therapy facilities), even for gated-spot-scanning proton-beam delivery with implanted fiducial markers. Data from 152 patients, corresponding to 201 treatment plans and 3577 sessions executed from October 2016 to June 2018, were included in this study. To estimate the treatment process time, we utilized data from proton beam delivery logs during the treatment for each patient. We retrieved data, such as the disease site, total target volume, field size at the isocenter, and the number of layers and spots for each field, from the treatment plans. We quantitatively analyzed the treatment process, which includes the patient load (or setup), bone matching, marker matching, beam delivery, patient unload, and equipment setup, using the data obtained from the log data. Among all the cases, 90 patients used the RGPT system (liver: n = 34; pancreas: n = 5; lung: n = 4; and prostate: n = 47). The mean and standard deviation (SD) of the total treatment process time for the RGPT system was 30.3 ± 7.4 min, while it was 25.9 ± 7.5 min for those without gating treatment, excluding craniospinal irradiation (CSI; head and neck: n = 16, pediatric: n = 31, others: n = 15); for CSI (n = 11) with two or three isocenters, the process time was 59.9 ± 13.9 min. Our results demonstrate that spot-scanning proton therapy with a gating function can be achieved in approximately 30-min time slots.

The urethral position may shift due to urethral catheter placement in the treatment planning for prostate radiation therapy.

PURPOSE: To determine the best method to contour the planning organ at risk volume (PRV) for the urethra, this study aimed to investigate the displacement of a Foley catheter in the urethra with a soft and thin guide-wire. METHODS: For each patient, the study used two sets of computed tomography (CT) images for radiation treatment planning (RT-CT): (1) set with a Foley urethral catheter (4.0 mm diameter) plus a guide-wire (0.46 mm diameter) in the first RT-CT and (2) set with a guide-wire alone in the second CT recorded 2 min after the first RT-CT. Using three fiducial markers in the prostate for image fusion, the displacement between the catheter and the guide-wire in the prostatic urethra was calculated. In 155 consecutive patients treated between 2011 and 2017, 5531 slices of RT-CT were evaluated. RESULTS: Assuming that ≥3.0 mm of difference between the catheter and the guide-wire position was a significant displacement, the urethra with the catheter was displaced significantly from the urethra with the guide-wire alone in > 20% of the RT-CT slices in 23.2% (36/155) of the patients. The number of patients who showed ≥3.0 mm anterior displacement with the catheter in ≥20% RT-CT slices was significantly larger at the superior segment (38/155) than at the middle (14/155) and inferior segments (18/155) of the prostatic urethra (p < 0.0167). CONCLUSIONS: The urethral position with a Foley catheter is different from the urethral position with a thin and soft guide-wire in a significant proportion of the patients. This should be taken into account for the PRV of the urethra to ensure precise radiotherapy such as in urethra-sparing radiotherapy.

Physical and biological impacts of collimator-scattered protons in spot-scanning proton therapy.

To improve the penumbra of low-energy beams used in spot-scanning proton therapy, various collimation systems have been proposed and used in clinics. In this paper, focused on patient-specific brass collimators, the collimator-scattered protons' physical and biological effects were investigated. The Geant4 Monte Carlo code was used to model the collimators mounted on the scanning nozzle of the Hokkaido University Hospital. A systematic survey was performed in water phantom with various-sized rectangular targets; range (5-20 cm), spread-out Bragg peak (SOBP) (5-10 cm), and field size (2 × 2-16 × 16 cm2 ). It revealed that both the range and SOBP dependences of the physical dose increase had similar trends to passive scattering methods, that is, it increased largely with the range and slightly with the SOBP. The physical impact was maximized at the surface (3%-22% for the tested geometries) and decreased with depth. In contrast, the field size (FS) dependence differed from that observed in passive scattering: the increase was high for both small and large FSs. This may be attributed to the different phase-space shapes at the target boundary between the two dose delivery methods. Next, the biological impact was estimated based on the increase in dose-averaged linear energy transfer (LETd ) and relative biological effectiveness (RBE). The LETd of the collimator-scattered protons were several keV/µm higher than that of unscattered ones; however, since this large increase was observed only at the positions receiving a small scattered dose, the overall LETd increase was negligible. As a consequence, the RBE increase did not exceed 0.05. Finally, the effects on patient geometries were estimated by testing two patient plans, and a negligible RBE increase (0.9% at most in the critical organs at surface) was observed in both cases. Therefore, the impact of collimator-scattered protons is almost entirely attributed to the physical dose increase, while the RBE increase is negligible.

Clinical experience of craniospinal intensity-modulated spot-scanning proton therapy using large fields for central nervous system medulloblastomas and germ cell tumors in children, adolescents, and young adults.

The outcomes of intensity-modulated proton craniospinal irradiation (ipCSI) are unclear. We evaluated the clinical benefit of our newly developed ipCSI system that incorporates two gantry-mounted orthogonal online X-ray imagers with a robotic six-degrees-of-freedom patient table. Nine patients (7-19 years old) were treated with ipCSI. The prescribed dose for CSI ranged from 23.4 to 36.0 Gy (relative biological effectiveness) in 13-20 fractions. Four adolescent and young adult (AYA) patients (15 years or older) were treated with vertebral-body-sparing ipCSI (VBSipCSI). Myelosuppression following VBSipCSI was compared with that of eight AYA patients treated with photon CSI at the same institution previously. The mean homogeneity index (HI) in the nine patients was 0.056 (95% confidence interval: 0.044-0.068). The mean time from the start to the end of all beam delivery was 37 min 39 s ± 2 min 24 s (minimum to maximum: 22 min 49 s - 42 min 51 s). The nadir white blood cell, hemoglobin, and platelet levels during the 4 weeks following the end of the CSI were significantly higher in the VBSipCSI group than in the photon CSI group (P = 0.0071, 0.0453, 0.0024, respectively). The levels at 4 weeks after the end of CSI were significantly higher in the VBSipCSI group than in the photon CSI group (P = 0.0023, 0.0414, 0.0061). Image-guided ipCSI was deliverable in a reasonable time with sufficient HI. Using VBSipCSI, AYA patients experienced a lower incidence of serious acute hematological toxicity than AYA patients treated with photon CSI.

NTCP modeling analysis of acute hematologic toxicity in whole pelvic radiation therapy for gynecologic malignancies - A dosimetric comparison of IMRT and spot-scanning proton therapy (SSPT).

PURPOSE: This treatment planning study was conducted to determine whether spot scanning proton beam therapy (SSPT) reduces the risk of grade ⩾3 hematologic toxicity (HT3+) compared with intensity modulated radiation therapy (IMRT) for postoperative whole pelvic radiation therapy (WPRT). METHODS AND MATERIALS: The normal tissue complication probability (NTCP) of the risk of HT3+ was used as an in silico surrogate marker in this analysis. IMRT and SSPT plans were created for 13 gynecologic malignancy patients who had received hysterectomies. The IMRT plans were generated using the 7-fields step and shoot technique. The SSPT plans were generated using anterior-posterior field with single field optimization. Using the relative biological effectives (RBE) value of 1.0 for IMRT and 1.1 for SSPT, the prescribed dose was 45Gy(RBE) in 1.8Gy(RBE) per fractions for 95% of the planning target volume (PTV). The homogeneity index (HI) and the conformity index (CI) of the PTV were also compared. RESULTS: The bone marrow (BM) and femoral head doses using SSPT were significantly lower than with IMRT. The NTCP modeling analysis showed that the risk of HT3+ using SSPT was significantly lower than with IMRT (NTCP=0.04±0.01 and 0.19±0.03, p=0.0002, respectively). There were no significant differences in the CI and HI of the PTV between IMRT and SSPT (CI=0.97±0.01 and 0.96±0.02, p=0.3177, and HI=1.24±0.11 and 1.27±0.05, p=0.8473, respectively). CONCLUSION: The SSPT achieves significant reductions in the dose to BM without compromising target coverage, compared with IMRT. The NTCP value for HT3+ in SSPT was significantly lower than in IMRT.

Aldehyde oxidase 1 gene is regulated by Nrf2 pathway.

Aldehyde oxidase is a member of the molybd-flavo enzyme family that catalyzes the hydroxylation of heterocycles and the oxidation of aldehydes into corresponding carboxylic acids. Aldehyde oxidase-1 (AOX1) is highly expressed in liver and is involved in the oxidation of a variety of aldehydes and nitrogenous heterocyclic compounds, including anti-cancer and immunosuppressive drugs. However, the physiological substrates of AOX1 have not been identified, and it was unknown how the expression of AOX1 is regulated. Here, we found that the AOX1 gene is regulated by the Nrf2 pathway. Two Nrf2 binding consensus elements (antioxidant responsive element, ARE) are located in the 5' upstream region of the rat AOX1 gene. Molecular analyses using reporter transfection analysis, EMSA, and ChIP analysis show that Nrf2 binds to and strongly activates the rat AOX1 gene.