Robot-assisted system for non-invasive wide-range flexible eye positioning and tracking in particle radiotherapy.

Particle (proton, carbon ion, or others) radiotherapy for ocular tumors is highly dependent on precise dose distribution, and any misalignment can result in severe complications. The proposed eye positioning and tracking system (EPTS) was designed to non-invasively position eyeballs and is reproducible enough to ensure accurate dose distribution by guiding gaze direction and tracking eye motion. Eye positioning was performed by guiding the gaze direction with separately controlled light sources. Eye tracking was performed by a robotic arm with cameras and a mirror. The cameras attached to its end received images through mirror reflection. To maintain a light weight, certain materials, such as carbon fiber, were utilized where possible. The robotic arm was controlled by a robot operating system. The robotic arm, turntables, and light source were actively and remotely controlled in real time. The videos captured by the cameras could be annotated, saved, and loaded into software. The available range of gaze guidance is 360° (azimuth). Weighing a total of 18.55 kg, the EPTS could be installed or uninstalled in 10 s. The structure, motion, and electromagnetic compatibility were verified via experiments. The EPTS shows some potential due to its non-invasive wide-range flexible eye positioning and tracking, light weight, non-collision with other equipment, and compatibility with CT imaging and dose delivery. The EPTS can also be remotely controlled in real time and offers sufficient reproducibility. This system is expected to have a positive impact on ocular particle radiotherapy.

Combined, yet separate: cocktails of carriers (not drugs) for actinium-225 α-particle therapy of solid tumors expressing moderate-to-low levels of targetable markers.

Alpha-particle radionuclide-antibody conjugates are being clinically evaluated against solid tumors even when they moderately express the targeted markers. At this limit of lower tumor-absorbed doses, to maintain efficacy, the few(er) intratumorally delivered alpha-particles need to traverse/hit as many different cancer cells as possible. We complement antibody-radioconjugate therapies with a separate nanocarrier delivering a fraction of the same total injected radioactivity to tumor regions geographically different than those affected by targeting antibodies; these carrier-cocktails collectively distribute the alpha-particle emitters better. METHODS: The efficacy of actinium-225 delivered by our carrier-cocktails was assessed in vitro and on mice with orthotopic MDA-MB-436 and/or MDA-MB-231 triple-negative breast cancers and/or an ectopic BxPC3 pancreatic cancer. Cells/tumors were chosen to express low-to-moderate levels of HER1, as model antibody-targeted marker. RESULTS: Independent of cell line, antibody-radioconjugates were most lethal on cell monolayers. On spheroids, with radii greater than alpha-particles' range, carrier-cocktails improved killing efficacy (p < 0.0500). Treatment with carrier-cocktails decreased the MDA-MB-436 and MDA-MB-231 orthotopic tumor volumes by 73.7% and 72.1%, respectively, relative to treatment with antibody-radioconjugates alone, at same total injected radioactivity; these carrier-cocktails completely eliminated formation of spontaneous metastases vs. 50% and 25% elimination in mice treated with antibody-radioconjugates alone. In BxPC3 tumor-bearing mice, carrier-cocktails increased the median survival to 25-26 days (in male-female animals) vs. 20-21 days of mice treated with antibody-radioconjugates alone (vs. 17 days for non-treated animals). Survival with carrier-cocktail radiotherapy was further prolonged by pre-injecting low-dose, standard-of-care, gemcitabine (p = 0.0390). CONCLUSION: Tumor-agnostic carrier-cocktails significantly enhance the therapeutic efficacy of existing alpha-particle radionuclide-antibody treatments.

Novel concept of "sequential particle radiotherapy" with atezolizumab plus bevacizumab for hepatocellular carcinoma with portal vein tumor thrombus.

Owing to the high objective response rate of atezolizumab plus bevacizumab (Atez/Bev) for hepatocellular carcinoma (HCC), the concept of sequential conversion to local treatment has recently become mainstream. The conversion concept is mainly applied to Barcelona Clinic for Liver Cancer (BCLC) stage B cases, and radiotherapy is rarely considered as a conversion local treatment. We herein report three patients who were treated with the novel concept of "sequential particle radiotherapy," consisting of Atez/Bev therapy followed by particle radiotherapy (PRT) for HCC with advanced portal vein tumor thrombus (Vp3/4 PVTT). All patients achieved partial response radiologically and were switched to PRT. All patients were recurrence free at 1 year after the introduction of Atez/Bev therapy without any additional treatment. This upcoming combination strategy includes the advocacy of sequential concepts for BCLC stage C cases and the introduction of PRT as a local treatment after Atez/Bev.

Efficacy and toxicity of bimodal radiotherapy in WHO grade 2 meningiomas following subtotal resection with carbon ion boost: Prospective phase 2 MARCIE trial.

BACKGROUND: Novel radiotherapeutic modalities using carbon ions provide an increased relative biological effectiveness (RBE) compared to photons, delivering a higher biological dose while reducing radiation exposure for adjacent organs. This prospective phase 2 trial investigated bimodal radiotherapy using photons with carbon-ion (C12)-boost in patients with WHO grade 2 meningiomas following subtotal resection (Simpson grade 4 or 5). METHODS: A total of 33 patients were enrolled from July 2012 until July 2020. The study treatment comprised a C12-boost (18 Gy [RBE] in 6 fractions) applied to the macroscopic tumor in combination with photon radiotherapy (50 Gy in 25 fractions). The primary endpoint was the 3-year progression-free survival (PFS), and the secondary endpoints included overall survival, safety and treatment toxicities. RESULTS: With a median follow-up of 42 months, the 3-year estimates of PFS, local PFS and overall survival were 80.3%, 86.7%, and 89.8%, respectively. Radiation-induced contrast enhancement (RICE) was encountered in 45%, particularly in patients with periventricularly located meningiomas. Patients exhibiting RICE were mostly either asymptomatic (40%) or presented immediate neurological and radiological improvement (47%) after the administration of corticosteroids or bevacizumab in case of radiation necrosis (3/33). Treatment-associated complications occurred in 1 patient with radiation necrosis who died due to postoperative complications after resection of radiation necrosis. The study was prematurely terminated after recruiting 33 of the planned 40 patients. CONCLUSIONS: Our study demonstrates a bimodal approach utilizing photons with C12-boost may achieve a superior local PFS to conventional photon RT, but must be balanced against the potential risks of toxicities.

Analysis of the cost-effectiveness of proton beam therapy for unresectable pancreatic cancer in Japan.

BACKGROUND: Proton beam therapy (PBT) has recently been included in Japan's social health insurance benefits package. This study aimed to determine the cost-effectiveness of PBT for unresectable, locally advanced pancreatic cancer (LAPC) as a replacement for conventional photon radiotherapy (RT). METHODS: We estimated the incremental cost-effectiveness ratio (ICER) of PBT as a replacement for three-dimensional conformal RT (3DCRT), a conventional photon RT, using clinical evidence in the literature and expense complemented by expert opinions. We used a decision tree and an economic and Markov model to illustrate the disease courses followed by LAPC patients. Effectiveness was estimated as quality-adjusted life years (QALY) using utility weights for the health state. Social insurance fees were calculated as the costs. The stability of the ICER against the assumptions made was appraised using sensitivity analyses. RESULTS: The effectiveness of PBT and 3DCRT was 1.67610615 and 0.97181271 QALY, respectively. The ICER was estimated to be ¥5,376,915 (US$46,756) per QALY. According to the suggested threshold for anti-cancer therapy from the Japanese authority of ¥7,500,000 (US$65,217) per QALY gain, such a replacement would be considered cost-effective. The one-way and probabilistic sensitivity analyses demonstrated stability of the base-case ICER. CONCLUSION: PBT, as a replacement for conventional photon radiotherapy, is cost-effective and justifiable as an efficient use of finite healthcare resources. Making it a standard treatment option and available to every patient in Japan is socially acceptable from the perspective of health economics.

Evaluation of proton and carbon ion beam models in TReatment Planning for Particles 4D (TRiP4D) referring to a commercial treatment planning system.

PURPOSE: To investigate the accuracy of the treatment planning system (TPS) TRiP4D in reproducing doses computed by the clinically used TPS SyngoRT. METHODS: Proton and carbon ion beam models in TRiP4D were converted from SyngoRT. Cubic plans with different depths in a water-tank phantom (WP) and previously treated and experimentally verified patient plans from SyngoRT were recalculated in TRiP4D. The target mean dose deviation (ΔDmean,T) and global gamma index (2%-2 mm for the absorbed dose and 3%-3mm for the RBE-weighted dose with 10% threshold) were evaluated. RESULTS: The carbon and proton absorbed dose gamma passing rates (γ-PRs) were ≥99.93% and ΔDmean,T smaller than -0.22%. On average, the RBE-weighted dose Dmean,T was -1.26% lower for TRiP4D than SyngoRT for cubic plans. In TRiP4D, the faster analytical 'low dose approximation' (Krämer, 2006) was used, while SyngoRT used a stochastic implementation (Krämer, 2000). The average ΔDmean, T could be reduced to -0.59% when applying the same biological effect calculation algorithm. However, the dose recalculation time increased by a factor of 79-477. ΔDmean,T variation up to -2.27% and -2.79% was observed for carbon absorbed and RBE-weighted doses in patient plans. The γ-PRs were ≥93.92% and ≥91.83% for patient plans, except for one proton beam with a range shifter (γ-PR of 64.19%). CONCLUSION: The absorbed dose between TRiP4D and SyngoRT were identical for both proton and carbon ion plans in the WP. Compared to SyngoRT, TRiP4D underestimated the target RBE-weighted dose; however more efficient in RBE-weighted dose calculation. Large variation for proton beam with range shifter was observed. TRiP4D will be used to evaluate doses delivered to moving targets. Uncertainties inherent to the 4D-dose reconstruction calculation are expected to be significantly larger than the dose errors reported here. For this reason, the residual differences between TRiP4D and SyngoRT observed in this study are considered acceptable. The study was approved by the Institutional Research Board of Shanghai Proton and Heavy Ion Center (approval number SPHIC-MP-2020-04, RS).

Daily Head and Neck Treatment Assessment for Optimal Proton Therapy Planning Robustness.

Robust optimization in proton therapy ensures adequate target coverage; however, validation of fractional plan quality and setup uncertainty in patients has not been performed. We aimed to assess plan robustness on delivered head and neck proton plans classified into two categories: (1) primary only (PO) and (2) primary and neck nodal (PNN) coverage. Registration at the machine was utilized for daily CBCT to generate a synthetic CT. The dose for the clinical target volume (CTV) and organs at risk (OAR) was compared to the expected robustness bands using 3.5% range uncertainty and 3 mm vs. 5 mm setup uncertainty. The fractional deviation was defined as D95% and V100% outside of uncertainty constraints. About 203 daily fractions from 6 patients were included for analysis. The percentage of fractions that exceeded robustness calculations was greater in 3 mm as compared to 5 mm setup uncertainty for both CTV and OAR volumes. PO plans had clinically insignificant average fractional deviation, less than 1%, in delivered D95% and V100%. In comparison, PNN plans had up to 2.2% average fractional deviation in delivered V100% using 3 mm robustness. Given the need to balance dose accuracy with OAR sparing, we recommend the utilization of 3 mm setup uncertainty as an acceptable simulation of the dose delivered.

An international approach to estimating the indications and number of eligible patients for carbon ion radiation therapy (CIRT) in Australia.

BACKGROUND AND PURPOSE: To establish the treatment indications and potential patient numbers for carbon ion radiation therapy (CIRT) at the proposed national carbon ion (and proton) therapy facility in the Westmead precinct, New South Wales (NSW), Australia. METHODS: An expert panel was convened, including representatives of four operational and two proposed international carbon ion facilities, as well as NSW-based CIRT stakeholders. They met virtually to consider CIRT available evidence and experience. Information regarding Japanese CIRT was provided pre- and post- the virtual meeting. Published information for South Korea was included in discussions. RESULTS: There was jurisdictional variation in the tumours treated by CIRT due to differing incidences of some tumours, referral patterns, differences in decisions regarding which tumours to prioritise, CIRT resources available and funding arrangements. The greatest level of consensus was reached that CIRT in Australia can be justified currently for patients with adenoid cystic carcinomas and mucosal melanomas of the head and neck, hepatocellular cancer and liver metastases, base of skull meningiomas, chordomas and chondrosarcomas. Almost 1400 Australian patients annually meet the consensus-derived indications now. CONCLUSION: A conservative estimate is that 1% of cancer patients in Australia (or 2% of patients recommended for radiation therapy) may preferentially benefit from CIRT for initial therapy of radiation resistant tumours, or to boost persistently active disease after other therapies, or for re-irradiation of recurrent disease. On this basis, one national carbon ion facility with up to four treatment rooms is justified for Australian patients.

The role of particle radiotherapy in the treatment of skull base tumors.

The skull base is an anatomically and functionally critical area surrounded by vital structures such as the brainstem, the spinal cord, blood vessels, and cranial nerves. Due to this complexity, management of skull base tumors requires a multidisciplinary approach involving a team of specialists such as neurosurgeons, otorhinolaryngologists, radiation oncologists, endocrinologists, and medical oncologists. In the case of pediatric patients, cancer management should be performed by a team of pediatric-trained specialists. Radiation therapy may be used alone or in combination with surgery to treat skull base tumors. There are two main types of radiation therapy: photon therapy and particle therapy. Particle radiotherapy uses charged particles (protons or carbon ions) that, due to their peculiar physical properties, permit precise targeting of the tumor with minimal healthy tissue exposure. These characteristics allow for minimizing the potential long-term effects of radiation exposure in terms of neurocognitive impairments, preserving quality of life, and reducing the risk of radio-induced cancer. For these reasons, in children, adolescents, and young adults, proton therapy should be an elective option when available. In radioresistant tumors such as chordomas and sarcomas and previously irradiated recurrent tumors, particle therapy permits the delivery of high biologically effective doses with low, or however acceptable, toxicity. Carbon ion therapy has peculiar and favorable radiobiological characteristics to overcome radioresistance features. In low-grade tumors, proton therapy should be considered in challenging cases due to tumor volume and involvement of critical neural structures. However, particle radiotherapy is still relatively new, and more research is needed to fully understand its effects. Additionally, the availability of particle therapy is limited as it requires specialized equipment and expertise. The purpose of this manuscript is to review the available literature regarding the role of particle radiotherapy in the treatment of skull base tumors.

Comparison of local ablative therapies, including radiofrequency ablation, microwave ablation, stereotactic ablative radiotherapy, and particle radiotherapy, for inoperable hepatocellular carcinoma: a systematic review and meta-analysis.

Surgical intervention is the first-line treatment in well-selected hepatocellular carcinoma (HCC) patients. However, only a few patients are suitable to receive radical surgery. We conducted a systematic review and meta-analysis to evaluate local control among four local ablative therapies in inoperable HCC patients, including radiofrequency ablation therapy (RFA), microwave ablation therapy (MWA), stereotactic ablative radiotherapy (SABR), and particle radiotherapy. The primary outcome was the local control rate and the secondary were regional and distant progression rates, overall survival rate, and adverse events. We included twenty-six studies from PubMed, EMBASE, and Cochrane Library databases. MWA (p < 0.001) and particle radiotherapy (p < 0.001) showed better performance of local control compared to RFA, while SABR (p = 0.276) showed a non-significant trend. However, SABR (p = 0.002) and particle radiotherapy (p < 0.001) showed better performance than RFA in HCCs of ≥ 30 mm in size. MWA showed a similar result to RFA while SABR and particle radiotherapy showed a lower survival rate in the 2-, 3-, and 4-year overall survival rates. Our results indicate that MWA, SABR and particle radiotherapy were safe and no inferior to RFA in local control rate. Besides, the local control rates of SABR and particle radiotherapy are better than RFA in HCC of ≥ 30 mm in size. As a result, we suggested that MWA, SABR and particle radiotherapy to be effective alternatives to RFA for inoperable HCC. Moreover, the tumor size should be taken into consideration for optimal treatment selection between local ablative therapies.

Radiation induced lymphopenia - a possible critical factor in current oncological treatment.

BACKGROUND: The effect of ionizing radiation on the immune system during the treatment of malignant tumors has long remained a point of great interest. This issue is currently gaining importance, especially in connection with the advancing development and availability of immunotherapeutic treatment. During cancer treatment, radiotherapy has the ability to influence the immunogenicity of the tumor by increasing the expression of certain tumor-specific antigens. These antigens can be processed by the immune system, stimulating the transformation of naïve lymphocytes into tumor-specific lymphocytes. However, at the same time, the lymphocyte population is extremely sensitive to even low doses of ionizing radiation, and radiotherapy often induces severe lymphopenia. Severe lymphopenia is a negative prognostic factor for numerous cancer dia-gnoses and negatively impacts the effectiveness of immunotherapeutic treatment. AIM: In this article, we summarize the possible influence of radiotherapy on the immune system, with a particular emphasis on the impact of radiation on circulating immune cells and the subsequent consequences of this influence on the development of cancer. CONCLUSION: Lymphopenia is an important factor influencing the results of oncological treatment, with a com-mon occurrence during radiotherapy. Strategies to reduce the risk of lymphopenia consist of accelerating treatment regimens, reducing target volumes, shortening the beam-on time of irradiators, optimizing radiotherapy for new critical organs, using particle radiotherapy, and other procedures that reduce the integral dose of radiation.

Inoperable or incompletely resected craniofacial osteosarcoma treated by particle radiotherapy.

Background: To report survival of craniofacial osteosarcoma patients treated by particle radiotherapy. Methods: Between January 2010 and December 2021, 51 patients with primary (N = 35) or recurrent (N = 16) inoperable or incompletely resected craniofacial osteosarcoma were treated. In most cases, intracranial infiltration (59%) and macroscopic tumor on MRI/CT (75%) were present. Thirteen had a secondary osteosarcoma (25%). Treatment concepts included combined ion beam radiotherapy (CIBRT, N = 18), protons only (N = 3), carbon ions only (N = 12), IMRT with a carbon ion boost (N = 5), and carbon ion re-irradiation (N = 13). Eighty percent (N = 41) received additionally chemotherapy, most frequently EURAMOS-1 (47%) or EURO-B.O.S.S. (18%). Results: The median age was 38, and all patients finished treatment predominantly as outpatients (N = 44). Information on overall survival was available for N = 49 patients. The median follow-up of the survivors was 55 months. For the whole cohort 1-, 2-, 3-, and 5-year overall survival (OS) was 82.8%, 60.4%, 55.2%, and 51.7%, respectively. Those treated by CIBRT (N = 17) demonstrated a superior OS with 92.9% after 1 and 2 years and 83.6% after 3 and 5 years. The median clinical target volume (CTV) was 192.7 and 95.2 cc for the primary and boost plan, respectively. CIBRT, primary diagnosis, age ≤40a, and no macroscopic residual tumor were associated with improved survival in univariate analysis (p = 0.006, p = 0.004, p = 0.002, p = 0.026, respectively), while any foregoing resection compared to biopsy was not identified as a prognostic factor. CIBRT and no macroscopic residual tumor were confirmed as independent predictors of OS on multivariate analysis (HR = 0.107, 95% CI = [0.014, 0.797], p = 0.029 and HR = 0.130, 95% CI = [0.023, 0.724], p = 0.020, respectively). No acute toxicity > grade III was observed. Conclusion: CIBRT shows promising results for patients with inoperable or incompletely resected craniofacial osteosarcoma.

National Effort to Re-Establish Heavy Ion Cancer Therapy in the United States.

In this review, we attempt to make a case for the establishment of a limited number of heavy ion cancer research and treatment facilities in the United States. Based on the basic physics and biology research, conducted largely in Japan and Germany, and early phase clinical trials involving a relatively small number of patients, we believe that heavy ions have a considerably greater potential to enhance the therapeutic ratio for many cancer types compared to conventional X-ray and proton radiotherapy. Moreover, with ongoing technological developments and with research in physical, biological, immunological, and clinical aspects, it is quite plausible that cost effectiveness of radiotherapy with heavier ions can be substantially improved.

DNA Damage Clustering after Ionizing Radiation and Consequences in the Processing of Chromatin Breaks.

Charged-particle radiotherapy (CPRT) utilizing low and high linear energy transfer (low-/high-LET) ionizing radiation (IR) is a promising cancer treatment modality having unique physical energy deposition properties. CPRT enables focused delivery of a desired dose to the tumor, thus achieving a better tumor control and reduced normal tissue toxicity. It increases the overall radiation tolerance and the chances of survival for the patient. Further improvements in CPRT are expected from a better understanding of the mechanisms governing the biological effects of IR and their dependence on LET. There is increasing evidence that high-LET IR induces more complex and even clustered DNA double-strand breaks (DSBs) that are extremely consequential to cellular homeostasis, and which represent a considerable threat to genomic integrity. However, from the perspective of cancer management, the same DSB characteristics underpin the expected therapeutic benefit and are central to the rationale guiding current efforts for increased implementation of heavy ions (HI) in radiotherapy. Here, we review the specific cellular DNA damage responses (DDR) elicited by high-LET IR and compare them to those of low-LET IR. We emphasize differences in the forms of DSBs induced and their impact on DDR. Moreover, we analyze how the distinct initial forms of DSBs modulate the interplay between DSB repair pathways through the activation of DNA end resection. We postulate that at complex DSBs and DSB clusters, increased DNA end resection orchestrates an increased engagement of resection-dependent repair pathways. Furthermore, we summarize evidence that after exposure to high-LET IR, error-prone processes outcompete high fidelity homologous recombination (HR) through mechanisms that remain to be elucidated. Finally, we review the high-LET dependence of specific DDR-related post-translational modifications and the induction of apoptosis in cancer cells. We believe that in-depth characterization of the biological effects that are specific to high-LET IR will help to establish predictive and prognostic signatures for use in future individualized therapeutic strategies, and will enhance the prospects for the development of effective countermeasures for improved radiation protection during space travel.

Omentum flap as a spacer before carbon ion radiotherapy for gynecological recurrences. A technical note.

Re-irradiation of pelvic recurrent gynecological cancer is a challenge due to the proximity of high-radiation-sensitive organs, such as the bowel and the urinary tract. Hadrontherapy for re-irradiation emerges as a safe and effective treatment with a mild rate of morbidity of surrounding normal tissue. To improve the dose to the tumor, a prophylactic displacement of organs at risk is needed, and a multidisciplinary approach is recommended. In this technical note, we report a surgical technique of omentum spacer placement for patients enrolled for carbon ion radiotherapy as re-irradiation for recurrent gynecological tumors.

Human mesenchymal stromal cells maintain their stem cell traits after high-LET particle irradiation - Potential implications for particle radiotherapy and manned space missions.

The influence of high-linear energy transfer (LET) particle radiation on the functionalities of mesenchymal stromal cells (MSCs) is largely unknown. Here, we analyzed the effects of proton (1H), helium (4He), carbon (12C) and oxygen (16O) ions on human bone marrow-MSCs. Cell cycle distribution and apoptosis induction were examined by flow cytometry, and DNA damage was quantified using γH2AX immunofluorescence and Western blots. Relative biological effectiveness values of MSCs amounted to 1.0-1.1 for 1H, 1.7-2.3 for 4He, 2.9-3.4 for 12C and 2.6-3.3 for 16O. Particle radiation did not alter the MSCs' characteristic surface marker pattern, and MSCs maintained their multi-lineage differentiation capabilities. Apoptosis rates ranged low for all radiation modalities. At 24 h after irradiation, particle radiation-induced ATM and CHK2 phosphorylation as well as γH2AX foci numbers returned to baseline levels. The resistance of human MSCs to high-LET irradiation suggests that MSCs remain functional after exposure to moderate doses of particle radiation as seen in normal tissues after particle radiotherapy or during manned space flights. In the future, in vivo models focusing on long-term consequences of particle irradiation on the bone marrow niche and MSCs are needed.

Roles of skull base surgery and particle radiotherapy for orbital malignant tumors involving the skull base.

PURPOSE: To investigate the oncological outcomes of orbital malignant tumors invading the skull base. METHODS: A retrospective analysis was conducted on 16 patients with orbital malignant tumors invading the skull base. Eleven patients were treated with skull base surgery, four patients were treated with particle therapies, and one patient was treated with chemoradiotherapy (CRT) as initial treatment. RESULTS: The most frequent histological type was adenoid cystic carcinoma in seven patients, followed by squamous cell carcinoma in two patients. Local recurrence occurred in two of the six surgically treated patients who did not receive postoperative radiotherapy (RT) or CRT. One of them was successfully salvaged by RT, and the other died of disease. With a median follow-up of 24 months, the 2-year overall, local control, and disease-free survival rates of all patients were 82.5%, 87.5%, and 59%, respectively. CONCLUSIONS: Patients with positive surgical margins were at risk of local recurrence. Postoperative RT should be considered for all surgically treated patients.Level of Evidence: 4.

Robust Angle Selection in Particle Therapy.

The popularity of particle radiotherapy has grown exponentially over recent years owing to the marked advantage of the depth-dose curve and its unique biological property. However, particle therapy is sensitive to changes in anatomical structure, and the dose distribution may deteriorate. In particle therapy, robust beam angle selection plays a crucial role in mitigating inter- and intrafractional variation, including daily patient setup uncertainties and tumor motion. With the development of a rotating gantry, angle optimization has gained increasing attention. Currently, several studies use the variation in the water equivalent thickness to quantify anatomical changes during treatment. This method seems helpful in determining better beam angles and improving the robustness of planning. Therefore, this review will discuss and summarize the robust beam angles at different tumor sites in particle radiotherapy.

Targeted Alpha-Particle Radiotherapy and Immune Checkpoint Inhibitors Induces Cooperative Inhibition on Tumor Growth of Malignant Melanoma.

Radiotherapy can facilitate the immune recognition of immunologically "cold" tumors and enhance the efficacy of anti-PD-1 and anti-CTLA-4 immune checkpoint inhibitors (ICIs) in melanoma. Systemic administration of receptor-targeted radionuclide therapy has the potential to selectively deliver radionuclides to multiple tumors throughout the body in metastatic settings. By triggering immunologic cell death and increasing the immune susceptibility of surviving tumor cells in these locations, targeted radionuclide therapies may overcome resistance to ICIs and render immunologically "cold" tumors throughout the body responsive to ICIs and immunologically "hot". Here, we show the anti-tumor cooperation of targeted α-particle radionuclide therapy (α-TRT) and ICIs in preclinical models of melanoma. Melanocortin 1 receptor (MC1R)-targeted radiopeptide [212Pb]VMT01 was employed to deliver α-radiation to melanoma tumors in mice. A single injection of 4.1 MBq [212Pb]VMT01 significantly slowed the tumor growth of B16-F10 melanoma and the combination of [212Pb]VMT01 and ICIs induced a cooperative anti-tumor effect leading to 43% complete tumor response with no sign of malignancy on autopsy. Animals with complete response developed anti-tumor immunity to reject further tumor inoculations. This therapeutic cooperation was completely abolished in RAG1 KO mice, which are deficient in T-cell maturation. In addition, the anti-tumor cooperation was compromised when fractionated [212Pb]VMT01 was used in the combination. We also demonstrated that [212Pb]VMT01 induced immunogenic cell death in tumor vaccination assays and in vitro exposure to [212Pb]VMT01 sensitized immunotolerant melanoma to ICIs treatment in vivo. Enhanced tumor infiltrating CD3+, CD4+, CD8+ lymphocytes were observed following injection of 1.4 MBq [212Pb]VMT01. Overall, we demonstrated anti-tumor cooperation between α-TRT and ICIs in melanoma that is mediated by tumor specific immunity.

Focused Ion Microbeam Irradiation Induces Clustering of DNA Double-Strand Breaks in Heterochromatin Visualized by Nanoscale-Resolution Electron Microscopy.

BACKGROUND: Charged-particle radiotherapy is an emerging treatment modality for radioresistant tumors. The enhanced effectiveness of high-energy particles (such as heavy ions) has been related to the spatial clustering of DNA lesions due to highly localized energy deposition. Here, DNA damage patterns induced by single and multiple carbon ions were analyzed in the nuclear chromatin environment by different high-resolution microscopy approaches. MATERIAL AND METHODS: Using the heavy-ion microbeam SNAKE, fibroblast monolayers were irradiated with defined numbers of carbon ions (1/10/100 ions per pulse, ipp) focused to micrometer-sized stripes or spots. Radiation-induced lesions were visualized as DNA damage foci (γH2AX, 53BP1) by conventional fluorescence and stimulated emission depletion (STED) microscopy. At micro- and nanoscale level, DNA double-strand breaks (DSBs) were visualized within their chromatin context by labeling the Ku heterodimer. Single and clustered pKu70-labeled DSBs were quantified in euchromatic and heterochromatic regions at 0.1 h, 5 h and 24 h post-IR by transmission electron microscopy (TEM). RESULTS: Increasing numbers of carbon ions per beam spot enhanced spatial clustering of DNA lesions and increased damage complexity with two or more DSBs in close proximity. This effect was detectable in euchromatin, but was much more pronounced in heterochromatin. Analyzing the dynamics of damage processing, our findings indicate that euchromatic DSBs were processed efficiently and repaired in a timely manner. In heterochromatin, by contrast, the number of clustered DSBs continuously increased further over the first hours following IR exposure, indicating the challenging task for the cell to process highly clustered DSBs appropriately. CONCLUSION: Increasing numbers of carbon ions applied to sub-nuclear chromatin regions enhanced the spatial clustering of DSBs and increased damage complexity, this being more pronounced in heterochromatic regions. Inefficient processing of clustered DSBs may explain the enhanced therapeutic efficacy of particle-based radiotherapy in cancer treatment.