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This study evaluates the feasibility of the pencil beam scanning technique of carbon ion radiotherapy (CIRT) in the setting of hepatocellular carcinoma (HCC) and establishes the maximum tolerated dose (MTD) calculated by the Local Effect Model version I (LEM-I) with a dose escalation plan. The escalated relative biological effectiveness-weighted dose levels included 55, 60, 65, and 70 Gy in 10 fractions. Active motion management techniques were employed, and several measures were applied to mitigate the interplay effect induced by a moving target. CIRT was planned with the LEM-I-based treatment planning system and delivered by raster scanning. Offline PET/CT imaging was used to verify the beam range. Offline adaptive replanning was performed whenever required. Twenty-three patients with a median tumor size of 4.3 cm (range, 1.7-8.5 cm) were enrolled in the present study. The median follow-up time was 56.1 months (range, 5.7-74.4 months). No dose limiting toxicity was observed until 70 Gy, and MTD had not been reached. No patients experienced radiation-induced liver disease within 6 months after the completion of CIRT. The overall survival rates at 1, 3, and 5 years were 91.3%, 81.9%, and 67.1% after CIRT, respectively. The local progression-free survival and progression-free survival rates at 1, 3 and 5 years were 100%, 94.4%, and 94.4% and 73.6%, 59.2%, and 37.0%, respectively. The raster scanning technique could be used to treat HCC. However, caution should be exercised to mitigate the interplay effect. CIRT up to 70 Gy in 10 fractions over 2 weeks was safe and effective for HCC.

Purpose To estimate the Lyman Kutcher Burman (LKB) and multivariate NTCP models predicting the AUT of prostate cancer treated with CIRT. Materials and methods A cohort of 154 prostate adenocarcinoma patients were retrospectively analyzed. The AUT levels were graded according to CTCAE 4.03. Based on dosimetric parameters and/or clinical factors, a set of variables with best-fit values determined in the two models was validated by the area under the receiver operating characteristic curve (AUC) and used to correlate the predicted and observed NTCP rates for both levels and related endpoints. Result 59 (38.3%) patients experienced AUT. For LKB model, the equivalent uniform doses (EUDs) were calculated to be 62.0 GyE (following V61.5 > 1.7%) and 61.2 GyE (following maximum dose > 63.0 GyE) with predicted NTCP rates of 37.0% (AUC: 0.71) and 15.6% (AUC: 0.65) for AUT G1&2 and G2 of bladder. While for the multivariate model, the predicted NTCP rates was 37.1% (AUC: 0.70) and 20.2% (AUC: 0.64) for AUT G1&2 and G2, associated with V61 and V65, respectively. Nocturia was associated with bladder volume and maximum dose for G1&2, with patient’s age and maximum bladder dose for G2. Other predictable endpoints were associated with V≥61. The predicted NTCPs agree with the observed complication rates for bladder and its wall. Conclusions The LKB model successfully predicted the NTCP rates of both AUT levels and urgency urination. The multivariate model predicted well on both levels and nocturia. Decreasing high bladder dose volume may reduce the incidence of AUT.

Purpose Radiotherapy is one of the main local treatment modalities for prostate cancer, while immunosuppressive effect induced by radiotherapy is an important factor of radiation resistance and treatment failure. Carbon ion radiotherapy (CIRT) is a novel radiotherapy technique and the immunomodulatory effect of CIRT provides the possibility of overcoming radioresistance and improving efficacy. The aim of this study was to assess the immune response evoked by CIRT in localized prostate cancer patients. Methods Thirty-two patients were treated by CIRT combined with or without hormone therapy and peripheral blood samples were collected before and after CIRT. Investigation of peripheral immune cell frequency, proliferation, and cytokine expression was conducted by flow cytometry, real-time quantitative PCR and ELISA. Results There were no significant differences in the frequencies of CD3 + , CD4 + , CD8 + T cells and NK cells after CIRT. CD4/CD8 ratio increased whereas B cells decreased. All lymphocyte subsets except regulatory T cells (Tregs) displayed increased proliferation and T cells exhibited increased functionality after CIRT, characterized by modestly increased cytokine secretion of TNF. Moreover, higher frequencies of Tregs were shown. Neither monocytic myeloid-derived suppressor cells (MDSCs) nor early MDSCs changed after CIRT. TGF-β1 gene expression decreased while IL-6 showed a non-significant trend towards a decrease. Both IL-10 gene expression and plasma TGF‐β1 level were unchanged. Conclusion CIRT demonstrates the potential to elicit immune activation in localized prostate cancer patients, based on sparing lymphocytes, increased lymphocyte proliferation, enhanced T-cell functionality, together with limited induction of immunosuppressive cells and reduced expression of immunosuppressive cytokines.

Objective To determine the maximum tolerated dose (MTD) of proton and carbon ion radiation therapy (PCRT) for locally advanced pancreatic cancer (LAPC). Methods A single-institution, phase I dose escalation study was performed. The proton dose of 50.4 GyE in 28 fractions was delivered to clinical target volume, and carbon ion as a boost dose to gross tumor volume escalated from 12 GyE to 18 GyE with 3 GyE per fraction in 3 dose levels. The dose limiting toxicity (DLT) was defined as any treatment-related grade (G)3 or higher of non-hematological toxicity. The MTD was exceeded if ≥2 patients in a dose level developed DLT. Results From May 2015 to July 2016, ten patients were enrolled, 3 in dose level 1, 4 in dose level 2, and 3 in dose level 3. With a median follow-up of 17.4 months, no patient developed a DLT, and the acute G1-2 of gastrointestinal (GI) and hepatic toxicity occurred in 40% of patients, and G1 of GI late toxicity, in 30%. The median overall survival was 17.3 months. Conclusion Higher than 50.4 GyE could be given by PCRT with slight toxicity and good tolerance for LAPC, and the tumor control and survival had been improved, but not significantly. Better outcome may be achieved using carbon ion radiation therapy with higher biological equivalent dose.

Background: To skip brachytherapy from external radiation and brachytherapy for cervical carcinomas, a combined proton and carbon ion radiotherapy (PCRT) was used. This retrospective study reported the toxicity and short-term outcome. Methods: 16 cervical SCC patients were consecutively treated with PCRT in our center from August 2016 to July 2019. The acute and late toxicities, overall survival (OS), local control rate (LC), progression-free survival (PFS) and distant metastasis-free survival (DMFS) were analyzed.Results: For 16 cervical SCC, the prescribed dose for tumor was 76 Gy to 85.6 Gy (relative biologic efficacy (RBE)). With a median follow-up of 34.3 (range, 20.7-56.8) months, all of the acute toxicity were grade1-2 with 12.5% of hepatic toxicity, 75% of hematological toxicity and 18.8% of gastroenteric toxicity. No acute urinary toxicity occurred. No severe late toxicity was observed during the follow-up period. At the last follow-up visit, 11 patients were alive, 4 patients died and 1 lost for follow-up; 3 patients had local recurrences and 6 patients had distant metastases. OS, LC, PFS, and DMFS at 1-year, 2-year and 3-year were 100%, 100% and 77.9%; 86.7%, 86.7% and 78.0%; 75.0%, 68.8% and 61.9%; and 87.5%, 81.3% and 75.0%, respectively. Conclusions: PCRT was feasible to deliver high dose to cervical SCC, and the outcome was quite good. We thought that brachytherapy had the potential to be skipped when PCRT was used and long term results need to be further investigated.Trial registration: This was a retrospective analysis and it was retrospectively registered. The registration number was NCT05141825 and the date of registration was November 30th, 2021.

Background Due to the physical dose distribution characteristic of “Bragg peak” and the biological effect as a kind of high linear energy transfer ray, heavy ion therapy has advantages over conventional photon therapy in both efficacy and safety. Based on the evidence that prostate cancer lesions before treatment are the most common sites of tumor residual or recurrence after treatment, simultaneous integrated boost radiation therapy for prostate cancer has been proven to have the advantage of improving efficacy without increasing toxicities. Methods This study is a prospective phase II randomized controlled clinical trial evaluating the efficacy and safety of functional imaging-guided carbon ion irradiation with simultaneous integrated boost for localized prostate cancer. One hundred and forty patients with localized prostate cancer will be randomized into carbon ion radiotherapy group and simultaneous integrated boost carbon ion radiotherapy group at a 1:1 ratio. The primary endpoint is to compare the incidence of treatment-related grade 2 and higher acute toxicities between the two groups according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03. Secondary endpoints are late toxicities, biochemical relapse-free survival, overall survival, progression-free survival, and quality of life. Discussion This study adopts functional imaging-guided simultaneous integrated boost of carbon ion radiotherapy for localized prostate cancer, aiming to evaluate the differences in the severity and incidence of acute toxicities in patients with localized prostate cancer treated with carbon ion radiotherapy and simultaneous integrated boost carbon ion radiotherapy, in order to optimize the carbon ion treatment strategy for localized prostate cancer. Trial registration ClinicalTrials.gov NCT05010343. Retrospectively registered on 18 August 2021

Purpose: The purpose of this study was to prospectively analyze the safety and feasibility of spot scanning carbon ion radiotherapy (CIRT) for patients with localized prostate cancer.Methods: 118 localized prostate cancer patients treated with spot scanning CIRT at Shanghai Proton and Heavy Ion Center (SPHIC) were enrolled in this dose escalated study. The dose was gradually increased from 59.2GyE to 65.6GyE in 16 fractions. The primary endpoint was the acute and late toxicities. Secondary endpoints were biochemical relapse free survival (bRFS), distant metastasis free survival (DMFS), prostate cancer-specific survival (PCSS), and overall survival (OS).Results: The median follow-up time was 30.2 months (4.8-62.7 months). Acute grade 1 and 2 genitourinary (GU) toxicities were 15.3% and 18.6%, while acute grade 1 and 2 gastrointestinal (GI) toxicities were 2.5% and 0%, respectively. Late grade 1 and 2 GU toxicities were 4.2% and 1.7%, respectively. No late GI toxicity were observed. There were no cases of severe acute or late toxicity (≥grade 3). The significant association was not found between the factors and the acute GU toxicities except for CTV volume (p=0.031) on multivariate analysis. The 2-year bRFS, DMFS, PCSS, OS were 100%, 100%, 100% and 98.8%, respectively.Conclusion: The 2 years’ outcomes are encouraging, providing additional and useful information on the feasibility and safety of spot scanning CIRT for prostate cancer. Long term follow-up and prospective multi-institutional data are warranted to reinforce the role of CIRT in the management of localized prostate cancer.Trial registration: Clinicaltrial, NCT02739659. Registered 15 April 2016

Background: Carbon ion radiotherapy (CIRT) is a novel and powerful tool for prostate cancer (PCa). However, the underlying mechanism for individualized treatment response after CIRT was not clear, and there was still no effective indicator to timely demonstrate the treatment response. Metabolic reprogramming is one of the main hallmarks of malignancy. Metabolic status might have a high relationship with the radiosensitivity and the individualized radiation response. The significant changes of metabolites profiles were detected after radiotherapy in the serum sample of different malignancies. But there was limited data regarding CIRT induced metabolic changes in prostate cancer. Our aim was to preliminary investigate the carbon-ion induced metabolic reprogramming in PCa patients and the individualized response of PCa patients to carbon ion. Methods: Urine samples collected from 15 pathology confirmed PCa patients before and after CIRT were enrolled into this analysis. High-throughput UPLC-MS/MS system was used for metabolites detection. XCMS online, MetDNA and MSDIAL were used for peak detection and identification of metabolites. Statistical analysis and metabolic pathway analysis were performed on Metaboanalyst.Results: A total of 1701 metabolites were monitored by high-throughput UPLC-MS/MS and 217 metabolites were identified. The PCA scores plot revealed clear discrimination of the patient’s urine metabolites profiles before (pre-CIRT) and after (pre-CIRT) CIRT treatment. 35 metabolites significantly altered after CIRT, and these metabolites mainly were amino acid. Pathway enrichment analysis further identified these metabolites could be enriched in 8 pathways (FDR2), while arginine biosynthesis and histidine metabolism pathways were the most significant. In addition, the HCA shows that after CIRT, the patients can be clustered into two groups according to the metabolites profiles. The discriminatory metabolites after CIRT in patients urine mainly enriched in the pathway of arginine biosynthesis and phenylalanine, tyrosine, and tryptophan biosynthesis. Conclusion: Metabolic reprogramming and metabolic inhibition seems one of the most important mechanisms of CIRT to cure PCa. Urine metabolites also showed their potentials to timely identify the individualized response of PCa patients to CIRT.

Purpose: The purpose of this study was to evaluate the outcomes of patients with extracranial chordoma or chondrosarcoma treated by carbon ion radiotherapy (CIRT). Patients and methods: Between May 2015 and April 2018, 21 consecutive patients with chordoma (n=16) or chondrosarcoma (n=5) treated by CIRT at Shanghai Proton and Heavy Ion Center (SPHIC) were enrolled. The local control (LC), progression free survival (PFS), and overall survival (OS) rates were estimated using the Kaplan-Meier method. Association between each of the candidate prognostic factors and the estimated LC, PFS or OS was tested using the log rank test. Results: The median gross tumor volume (GTV) was 512.7 ml (range, 142.6-2893.0 ml). The median prescription dose was 69 gray equivalent (GyE) (range, 57-80 GyE). After a median follow-up of 21.8 months (range, 7.2-39.2 months), the 1-year LC, PFS, and OS were 93.8%, 88.4%, and 100%, respectively, whereas the 2-year LC, PFS, and OS were 85.2%, 80.4%, and 100%, respectively. A univariate analysis revealed that age, metal implant status, treatment status, sex, dose, and GTV were not significant prognostic factors for LC, PFS or OS. No grade 2 or higher early and late toxicities were observed within the follow-up. Conclusion: The results of this retrospective study are encouraging. Patients with extracranial chordoma or chondrosarcoma treated by CIRT in our center achieved a favorable shot-term outcome, without developing severe acute or late adverse events. The long-term results deserve further investigation, even in a prospective randomized trial.

Background The study objective was to establish the local effect model (LEM) rectum constraints for 12-, 8-, and 4-fraction carbon-ion radiotherapy (CIRT) in patients with localized prostate carcinoma (PCA) using microdosimetric kinetic model (MKM)-defined and LEM-defined constraints for 16-fraction CIRT. Methods We analyzed 40 patients with PCA who received 16- or 12-fraction CIRT at our center. Linear-quadratic (LQ) and RBE-conversion models were employed to convert the constraints into various fractionations and biophysical models. Based on them, the MKM LQ strategy converted MKM rectum constraints for 16-fraction CIRT to 12-, 8-, and 4-fraction CIRT using the LQ model. Then, MKM constraints were converted to LEM using the RBE-conversion model. Meanwhile the LEM LQ strategy converted MKM rectum constraints for 16-fraction CIRT to LEM using the RBE-conversion model. Then, LEM constraints were converted from 16-fraction constraints to the rectum constraints for 12-, 8-, and 4-fraction CIRT using the LQ model. The LEM constraints for 16- and 12-fraction CIRT were evaluated using rectum doses and clinical follow-up. To adapt them for the MKM LQ strategy, CNAO LEM constraints were first converted to MKM constraints using the RBE-conversion model. Results The NIRS (i.e. DMKM|v, V-20%, 10%, 5%, and 0%) and CNAO rectum constraints (i.e. DLEM|v, V-10 cc, 5 cc, and 1 cc) were converted for 12-fraction CIRT using the MKM LQ strategy to LEM 37.60, 49.74, 55.27, and 58.01 Gy (RBE), and 45.97, 51.70, and 55.97 Gy (RBE), and using the LEM LQ strategy to 39.55, 53.08, 58.91, and 61.73 Gy (RBE), and 49.14, 55.30, and 59.69 Gy (RBE). We also established LEM constraints for 8- and 4-fraction CIRT. The 10-patient RBE-conversion model was comparable to 30-patient model. Eight patients who received 16-fraction CIRT exceeded the corresponding rectum constraints; the others were within the constraints. After a median follow-up of 10.8 months (7.1–20.8), No ≥ G1 late rectum toxicities were observed. Conclusions The LEM rectum constraints from the MKM LQ strategy were more conservative and might serve as the reference for hypofractionated CIRT. However, Long-term follow-up plus additional patients is necessary.

To compare the dosimetric difference between various modalities in the radiation treatment for renal retroperitoneal soft tissue sarcoma recurrence or metastasis (RRSTSRM) after radical nephrectomy, and assess the dosimetric advantage on protecting the organs at risk (OARs) in the carbon and proton radiotherapy for the patients with a single kidney. A total of 12 patients with RRSTSRM who underwent radical nephrectomy were enrolled in this study. Carbon, proton, and photon radiotherapy were implemented for treatment planning. The prescription dose was fulfilled by simultaneously integrated boosting technique, with giving the planning target volume-1 (PTV-1) 51Gy (RBE) and planning target volume-2 (PTV-2) 60 Gy (RBE). Doses in the patient���s spinal cord, stomach, duodenum, bowel, colon, and contralateral kidney were evaluated. The normal tissue complication probability (NTCP) of the duodenum, bowel, colon, and contralateral kidney was derived under Lyman-Kutcher-Burman (LKB) estimation. In the carbon plans, the percentage volume of 95% prescription dose (V95%) covering PTV-1 (PTV-2) was 95.93% �� 3.42% (95.61% �� 4.26%). No significant dosimetric difference on the target was obtained between the four radiation modalities (P > .05). The percentage volume of receiving 40 Gy (RBE) [V40Gy (RBE)] in the duodenum could be reduced from 12.94% �� 15.99% in the IMRT plans to 6.36% �� 8.79% (8.44% �� 12.35%) in the carbon (proton) plans (P < .05). The V40Gy (RBE) in the bowel could be reduced from 13.48% �� 13.12% in the IMRT plans to 7.04% �� 9.32% (7.34% �� 9.89%) in the carbon (proton) plans (P < .05). The mean value of NTCP for the duodenum was 0.43 �� 0.47 (0.45 �� 0.48) by using carbon (proton) radiation. The value was 0.05 (0.03) lower than the IMRT plans on average, with a reduction of 0.20 (0.13) for the patients with lesions P < .05). Compared to the conventional radiation techniques, particle radiotherapy of carbon and proton could significantly spare more OARs in the treatment for RRSTSRM after radical nephrectomy. Patients, especially those whose residuals are close to the duodenum would potentially benefit from the particle radiation therapy for RRSTSRM on the decrease in radiation-related side-effect.

We generated low-flux X-ray micro-planar beams (MPBs) using a laboratory-scale industrial X-ray generator (60 kV/20 mA) with custom-made collimators with three different peak/pitch widths (50/200 μm, 100/400 μm, 50/400 μm). To evaluate normal skin reactions, the thighs of C3H/HeN mice were exposed to 100 and 200 Gy MPBs in comparison with broad beams (20, 30, 40, 50, 60 Gy). Antitumor effects of MPBs were evaluated in C3H/HeN mice with subcutaneous tumors (SCCVII). After the tumors were irradiated with 100 and 200 Gy MPBs and 20 and 30 Gy broad beams, the tumor sizes were measured and survival analyses were performed. In addition, the tumors were excised and immunohistochemically examined to detect γ-H2AX, ki67 and CD34. It was shown that antitumor effects of 200 Gy MPBs at 50/200 μm and 100/400 μm were significantly greater than those of 20 Gy broad beams, and were comparable with 30 Gy broad beams. γ-H2AX-positive cells demonstrated clear stripe-patterns after MPB irradiation; the pattern gradually faded and intermixed over 24 h. The chronological changes in ki67 positivity did not differ between MPBs and broad beams, whereas the CD34-positive area decreased significantly more in MPBs than in broad beams. In addition, it was shown that skin injury after MPB irradiation was significantly milder when compared with broad-beam irradiation at equivalent doses for achieving the same tumor control effect. Bystander effect and tumor vessel injury may be the mechanism contributing to the efficacy of MPBs.

One-third of patients with medulloblastoma die due to recurrence after various treatments including radiotherapy. Although it has been postulated that cancer stem-like cells are radio-resistant and play an important role in tumor recurrence, the "stemness" of medulloblastoma cells surviving irradiation has not yet been elucidated. Using a medulloblastoma cell line ONS-76, cells that survived gamma irradiation were investigated on their "stemness" in vitro. From 10 500 cells, 20 radio-resistant clones were selected after gamma ray irradiation (5 Gy × two fractions) using the replica micro-well technique. These 20 resistant clones were screened for CD133 positivity by flow cytometry followed by side population assay, tumor sphere formation assay and clonogenic survival assay. Results revealed CD133 fractions were significantly elevated in three clones, which also exhibited significantly increased levels of tumor sphere formation ability and side population fraction. Clonogenic survival assay demonstrated that their radio-resistance was significantly higher than the parental ONS-76. This may support the hypothesis that a small number of cancer stem-like cells (CSCs) are the main culprits in local recurrence after radiotherapy, and disruption of the resistance mechanism of these CSCs is a critical future issue in improving the outcome of patients with medulloblastoma.

Background. Refractoriness of glioblastoma multiforme (GBM) largely depends on its radioresistance. We investigated the radiosensitizing effects of celecoxib on GBM cell lines under both normoxic and hypoxic conditions. Methods. Two human GBM cell lines, U87MG and U251MG, and a mouse GBM cell line, GL261, were treated with celecoxib or g-irradiation either alone or in combination under normoxic and hypoxic conditions. Radiosensitizing effects were analyzed by clonogenic survival assays and cell growth assays and by assessing apoptosis and autophagy. Expression of apoptosis-, autophagy-, and endoplasmic reticulum (ER) stress– related genes was analyzed by immunoblotting. Results. Celecoxib significantly enhanced the radiosensitivity of GBM cells under both normoxic and hypoxic conditions. In addition, combined treatment with celecoxib and g-irradiation induced marked autophagy, particularly in hypoxic cells. The mechanism underlying the radiosensitizing effect of celecoxib was determined to be ER stress loading on GBM cells. Conclusion. Celecoxib enhances the radiosensitivity of GBM cells by a mechanism that is different from cyclooxygenase-2 inhibition. Our results indicate that celecoxib may be a promising radiosensitizing drug for clinical use in patients with GBM.

To clarify the properties of clinical high-energy protons by comparing with clinical high-energy X-rays.Human tumor cell lines, ONS76 and MOLT4, were irradiated with 200 MeV protons or 10 MV X-rays. In situ DNA double-strand breaks (DDSB) induction was evaluated by immunocytochemical staining of phosphorylated histone H2AX (γ-H2AX). Apoptosis was measured by flow-cytometry after staining with Annexin V. The relative biological effectiveness (RBE) was obtained by clonogenic survival assay.DDSB induction was significantly higher for protons than X-rays with average ratios of 1.28 (ONS76) and 1.59 (MOLT4) at 30 min after irradiation. However the differences became insignificant at 6 h. Also, apoptosis induction in MOLT4 cells was significantly higher for protons than X-rays with an average ratio of 2.13 at 12 h. However, the difference became insignificant at 20 h. RBE values of protons to X-rays at 10% survival were 1.06 ± 0.04 and 1.02 ± 0.15 for ONS76 and MOLT4, respectively.Cell inactivation may differ according to different timings and/or endpoints. Proton beams demonstrated higher cell inactivation than X-rays in the early phases. These data may facilitate the understanding of the biological properties of clinical proton beams.