Testicular cancer is a rare but curable male malignancy. Seminoma represents the majority of germ cell tumors and is considered radiation sensitive. Radiation treatment plays a role in adjuvant therapy after orchiectomy of stage I, IIA, and IIB seminomas. Radiation dose de-escalation has been effective in preventing tumor recurrences while also limiting acute and long-term toxicities. However, long-term risks, including the prevailing concern of secondary malignancy risk, between adjuvant radiation and chemotherapy play a role in recommendations. Ongoing work continues to be performed to reduce radiation field and dose in combination with chemotherapy while still maintaining excellent outcomes.

UNASSIGNED: Pediatric low-grade gliomas (pLGG) are the most common brain tumor in children and encompass a wide range of histologies. Treatment may pose challenges, especially in those incompletely resected or those with multiple recurrence or progression.
UNASSIGNED: We report the clinical course of a girl diagnosed with pilocytic astrocytoma and profound hydrocephalus at age 12 years treated with subtotal resection, vinblastine chemotherapy, and focal proton radiotherapy. After radiotherapy the tumor increased in enhancement temporarily with subsequent resolution consistent with pseudoprogression. Despite improvement in imaging and radiographic local control, the patient continues to have challenges with headaches, visual and auditory concerns, stroke-like symptoms, and poor quality of life.
UNASSIGNED: pLGG have excellent long-term survival; thus, treatments should focus on maintaining disease control and limiting long-term toxicities. Various treatment options exist including surgery, chemotherapy, targeted agents, and radiation therapy. Given the morbidity associated with pLGG, individualized treatment approaches are necessary, with a multi-disciplinary approach to care focused on minimizing treatment side effects, and promoting optimal quality of life for patients.

Skull-base chordomas are aggressive tumors with a propensity for recurrence/progression. Even with standard of care (SoC), 5-year recurrence rates are variable (19%-54%). This high recurrence/progression rate correlates with increased morbidity and mortality. We sought to analyze a multicenter cohort of skull base chordomas to identify predictors of progression in patients receiving SoC.
The [Blinded]-Neurosurgery data registry was queried for skull base chordomas treated from 2008-2020. Patients with the histopathologic diagnosis of chordoma were included. The cohort was composed of patients with preoperative and postoperative magnetic resonance imaging. Tumor volume and radiologic characteristics were obtained from axial T2 sequences using a Digital Imaging and Communications in Medicine viewer. Survival analysis was performed using Kaplan-Meier method, and time-to-event multivariate regression was performed to identify independent predictors of progression.
The cohort included 195 patients, of which 66 patients met inclusion criteria; median age was 44, and 28 (42%) were females. Fifty-four (82%) received SoC, 7 (11%) resection only, and 5 (8%) radiotherapy only. Median preoperative and postoperative tumor volumes were 11.55 cm3 (0.33-54.89) and 0.34 cm3 (0-42.52), respectively. Recurrence rate with SoC was 37%. Postoperative tumor volume (P = 0.010) correlated with progression. A postoperative volume of >4.9 cm3 (P = 0.044), ≤81.3% of tumor resection (P = 0.02), and lower-clivus location (P < 0.005) correlated with decreased time to progression.
Skull base chordomas can be challenging to resect. Even though maximal resection and radiotherapy improve rate of tumor progression, many of these lesions eventually recur. We have identified a postoperative tumor volume of ≥4.9 cm3 and extent of resection of ≤81.3% in this cohort as predictors of progression in patients receiving SoC.

UNASSIGNED: The benefit of combining immunotherapy with photon irradiation has been shown pre-clinically and clinically. This current pre-clinical study was designed to investigate the anti-tumour action of combining immunotherapy with protons.
UNASSIGNED: Male CDF1 mice, with a C3H mammary carcinoma inoculated on the right rear foot, were locally irradiated with single radiation doses when tumours reached 200mm3. Radiation was delivered with an 83-107MeV pencil scanning proton beam in the centre of a 3 cm spread out Bragg peak. Following irradiation (day 0), mice were injected intraperitoneal with anti-CTLA-4, anti-PD-1, or anti-PD-L1 (10 mg/kg) twice weekly for two weeks. Endpoints were tumour growth time (TGT3; time to reach 3 times treatment volume) or local tumour control (percent of mice showing tumour control at 90 days). A Student\'s T-test (tumour growth) or Chi-squared test (tumour control) were used for statistical analysis; significance levels of p < 0.05.
UNASSIGNED: Untreated tumours had a mean (± 1 S.E.) TGT3 of 4.6 days (± 0.4). None of the checkpoint inhibitors changed this TGT3. A linear increase in TGT3 was seen with increasing radiation doses (5-20 Gy), reaching 17.2 days (± 0.7) with 20 Gy. Anti-CTLA-4 had no effect on radiation doses up to 15 Gy, but significantly enhanced 20 Gy; the TGT3 being 23.0 days (± 1.3). Higher radiation doses (35-60 Gy) were investigated using a tumour control assay. Logit analysis of the dose response curve, resulted in a TCD50 value (radiation dose causing 50% tumour control; with 95% confidence intervals) of 48 Gy (44-53) for radiation only. This significantly decreased to 43 Gy (38-49) when mice were treated with anti-CTLA-4. Neither anti-PD-1 nor anti-PD-L1 significantly affected tumour control.
UNASSIGNED: Checkpoint inhibitors enhanced the response of this C3H mammary carcinoma to proton irradiation. However, this enhancement depended on the checkpoint inhibitor and radiation dose.

Objective. To develop a metaphase chromosome model representing the complete genome of a human lymphocyte cell to support microscopic Monte Carlo (MMC) simulation-based radiation-induced DNA damage studies.Approach. We first employed coarse-grained polymer physics simulation to obtain a rod-shaped chromatid segment of 730 nm in diameter and 460 nm in height to match Hi-C data. We then voxelized the segment with a voxel size of 11 nm per side and connected the chromatid with 30 types of pre-constructed nucleosomes and 6 types of linker DNAs in base pair (bp) resolutions. Afterward, we piled different numbers of voxelized chromatid segments to create 23 pairs of chromosomes of 1-5μm long. Finally, we arranged the chromosomes at the cell metaphase plate of 5.5μm in radius to create the complete set of metaphase chromosomes. We implemented the model in gMicroMC simulation by denoting the DNA structure in a four-level hierarchical tree: nucleotide pairs, nucleosomes and linker DNAs, chromatid segments, and chromosomes. We applied the model to compute DNA damage under different radiation conditions and compared the results to those obtained with G0/G1 model and experimental measurements. We also performed uncertainty analysis for relevant simulation parameters.Main results. The chromatid segment was successfully voxelized and connected in bps resolution, containing 26.8 mega bps (Mbps) of DNA. With 466 segments, we obtained the metaphase chromosome containing 12.5 Gbps of DNA. Applying it to compute the radiation-induced DNA damage, the obtained results were self-consistent and agreed with experimental measurements. Through the parameter uncertainty study, we found that the DNA damage ratio between metaphase and G0/G1 phase models was not sensitive to the chemical simulation time. The damage was also not sensitive to the specific parameter settings in the polymer physics simulation, as long as the produced metaphase model followed a similar contact map distribution.Significance. Experimental data reveal that ionizing radiation induced DNA damage is cell cycle dependent. Yet, DNA chromosome models, except for the G0/G1 phase, are not available in the state-of-the-art MMC simulation. For the first time, we successfully built a metaphase chromosome model and implemented it into MMC simulation for radiation-induced DNA damage computation.

To evaluate the dosimetric data, early toxicity, and patient-reported cosmetic outcomes in breast cancer patients treated with adjuvant proton-based radiotherapy (RT) after breast-conserving surgery.
We performed a retrospective review of our institutional database to identify breast cancer patients treated with breast-conserving surgery followed by proton-based RT from 2015 to 2020. Patient-reported cosmetic outcomes were graded as excellent, good, fair, or poor. Early toxicity outcomes were graded by the treating physician during treatment. Dose-volume histograms were reviewed to obtain dosimetry data.
We identified 21 patients treated with adjuvant proton-based RT. Median whole breast dose delivered was 46.8 Gy (range, 40.0-50.4 Gy). Target volumes included the regional lymph nodes in 17 patients (81%). Seventeen patients (81%) received a lumpectomy boost. The median planning target volume V95 was 94% (range, 77%-100%), V100 71% (range, 60%-97%), V110 2% (range 0%-18%), and median max point dose was 115% (range, 105%-120%). The median ipsilateral breast V105 was 367.3 cc (range, 0-1172 cc) and V110 was 24.1 cc (range, 0-321.3 cc). Grade 2 and 3 dermatitis occurred in 62% and 14% of patients, respectively. Grade 2 and 3 pain was reported by 33% and 10% of patients, respectively. Median follow-up at the time of cosmetic evaluation was 27 months (range, 5-42 months). Four patients (21%) reported fair cosmetic outcome and 15 patients (79%) reported good or excellent cosmetic outcome. No poor cosmesis was reported.
Adjuvant proton-based radiotherapy after breast-conserving surgery is well tolerated with acceptable rates of acute toxicities and a high rate of good-to-excellent patient-reported cosmetic outcomes.

Hippocampal avoidance (HA) has been shown to preserve cognitive function in adult patients with cancer treated with whole-brain radiation therapy for brain metastases. However, the feasibility of HA in pediatric patients with brain tumors has not been explored because of concerns of increased risk of relapse in the peri-hippocampal region. Our aim was to determine patterns of recurrence and incidence of peri-hippocampal relapse in pediatric patients with medulloblastoma (MB).
We identified pediatric patients with MB treated with protons between 2002 and 2016 and who had recurrent disease. To estimate the risk of peri-hippocampal recurrence, three hippocampal zones (HZs) were delineated corresponding to ≤5 mm (HZ-1), 6 to 10 mm (HZ-2), and >10 mm (HZ-3) distance of the recurrence from the contoured hippocampi. To determine the feasibility of HA, three standard-risk patients with MB were planned using either volumetric-modulated arc therapy (VMAT) or intensity-modulated proton therapy (IMPT) plans.
Thirty-eight patients developed a recurrence at a median of 1.6 years. Of the 25 patients who had magnetic resonance imaging of the recurrence, no patients failed within the hippocampus and only two patients failed within HZ-1. The crude incidence of peri-hippocampal failure was 8%. Both HA-VMAT and HA-IMPT plans were associated with significantly reduced mean dose to the hippocampi (p < .05). HA-VMAT and HA-IMPT plans were associated with decreased percentage of the third and lateral ventricles receiving the prescription craniospinal dose of 23.4 Gy.
Peri-hippocampal failures are uncommon in pediatric patients with MB. Hippocampal avoidance should be evaluated in a prospective cohort of pediatric patients with MB.
In this study, the patterns of disease recurrence in patients with a pediatric brain tumor known as medulloblastoma treated with proton radiotherapy were examined. The majority of failures occur outside of an important structure related to memory formation called the hippocampus. Hippocampal sparing radiation plans using proton radiotherapy were generated and showed that dose to the hippocampus was able to be significantly reduced. The study provides the rationale to explore hippocampal sparing in pediatric medulloblastoma in a prospective clinical trial.

The role of multiparametric MRI (mp-MRI) for postproton radiation evaluation is unclear. In this pilot study, we characterize the mp-MRI features using the Prostate Imaging-Reporting and Data System (PI-RADS) for recurrent prostate cancer (PCa) following proton radiation therapy.
After obtaining IRB approval, we identified 163 consecutive cases who underwent MRI-fusion prostate biopsy at our institution from November 2017 to May 2020. This study evaluated patients with prostate cancer (PCa) with biochemical recurrence following proton radiation. Patients were excluded if they had grossly metastatic disease, metal fragments, implanted devices, or with surgically removed prostates. The mpMRI studies were reviewed in depth and scored by 2 fellowship-trained radiologists. Following MRI-fusion biopsy of lesions of interest (LOI), slides were read by fellowship-trained pathologists.
We found 14 patients with 16 lesions who met the study inclusion criteria. The median age was 69 years (range 57-79) and median time to biochemical recurrence was 7.3 years (range 3-13). On post-treatment imaging, decreases in prostate size and diffusely decreased T2 signal intensity were observed, making the use of apparent diffusion coefficient (ADC) and early enhancement at dynamic contrast enhanced (DCE) imaging often necessary for diagnosis of disease recurrence. We identified a total of 16 lesions with PIRADS scores of 3 or higher. Of these lesions, there were 5 PIRADS 3 lesions (4/5 (80%) without prostate cancer), 7 PIRADS 4-5 lesions (6 (86%) had high risk Pca), and 4 lesions with unassigned PIRADS scores (100% had high risk cancers). Among the MRI variables, diffusion weighted imaging (DWI) heterogeneity had the strongest association with recurrence of PCa (P < 0.001).
Results of our pilot study showed that the PIRADS scoring system in the postproton radiation therapy setting has some correlations with prostate cancer recurrence; However, the clinical value of these findings are unclear. While definitive PIRADS categorization of lesions demonstrated expected frequency of cancer consistent with the scoring system, all unassigned lesions also harbored malignancy suggesting a cautious approach to PIRADS scoring system in postproton radiation setting. The findings from this study may be validated using a larger cohort.

The increased use of proton therapy has led to the need of better understanding the cellular mechanisms involved. The aim of this study was to investigate the effects induced by the accelerated proton beam in hepatocarcinoma cells. An existing facility in IFIN-HH, a 3 MV Tandetron™ accelerator, was used to irradiate HepG2 human hepatocarcinoma cells with doses between 0 and 3 Gy. Colony formation was used to assess the influence of radiation on cell long-term replication. Also, the changes induced at the mitochondrial level were shown by increased ROS and ATP levels as well as a decrease in the mitochondrial membrane potential. An increased dose has induced DNA damages and G2/M cell cycle arrest which leads to caspase 3/7 mediated apoptosis and senescence induction. Finally, the morphological and ultrastructural changes were observed at the membrane level and the nucleus of the irradiated cells. Thus, proton irradiation induces both morphological and functional changes in HepG2 cells.

Pathological complete response (pCR) has been correlated with overall survival in several cancer entities including colorectal cancer. Novel total neoadjuvant treatment (TNT) in rectal cancer has achieved pathological complete response in one-third of the patients. To define better treatment options for nonresponding patients, we used patient-derived organoids (PDOs) as avatars of the patient\'s tumor to apply both photon- and proton-based irradiation as well as single and combined chemo(radio)therapeutic treatments. While response to photon and proton therapy was similar, PDOs revealed heterogeneous responses to irradiation and different chemotherapeutic drugs. Radiotherapeutic response of the PDOs was significantly correlated with their ability to repair irradiation-induced DNA damage. The classical combination of 5-FU and irradiation could not sensitize radioresistant tumor cells. Ataxia-telangiectasia mutated (ATM) kinase was activated upon radiation, and by inhibition of this central sensor of DNA damage, radioresistant PDOs were resensitized. The study underlined the capability of PDOs to define nonresponders to irradiation and could delineate therapeutic approaches for radioresistant patients.