Long-term outcomes after particle radiation therapy in patients with nasopharyngeal adenoid cystic carcinoma.

BACKGROUND: Nasopharyngeal adenoid cystic carcinoma (NACC) is a relatively rare salivary gland tumor that is generally associated with poor outcomes. High-dose radiotherapy is a key treatment for patients with NACC. This study reported the long-term efficacy and safety of particle beam radiation therapy (PBRT) for NACC. METHODS AND MATERIALS: Twenty-six patients with nonmetastatic NACC who received definitive PBRT alone were included in this retrospective study. The majority of patients (92.3%) had locally advanced disease. Twenty-five (96.15%) patients received intensity-modulated proton radiotherapy (IMPT) followed by a carbon ion radiotherapy (CIRT) boost, and one patient received CIRT alone. Overall survival (OS), local control (LC), regional control (RC), and distant metastasis control (DMC) rates were calculated via the Kaplan-Meier method. RESULTS: The median follow-up time was 46.95 months for the entire cohort. Seven patients experienced local recurrence, and one patient experience neck lymph node recurrence. The 3- and 4-year OS, LC, RC, and DMC rates were 100% and 91.7%, 92.3% and 84.6%, 95.8% and 87.8%, and 90.2% and 71.3%, respectively. A total of 91.3% of the patients achieved complete remission of gross tumors at 1 year after PBRT. Severe acute toxicity was observed in only two patients. A grade 4 decrease in visual acuity was observed in one patient with orbital apex invasion. No late grade 3 or 5 toxicity was observed. CONCLUSION: Definitive PBRT provided a satisfactory 4-year OS for patients with locally advanced NACC. The toxicity was acceptable and mild. Further follow-up is necessary to confirm the efficacy and safety of definitive PBRT for patients with NACC.

Carbon ion radiotherapy combined with immunotherapy: synergistic anti-tumor efficacy and preliminary investigation of ferroptosis.

Carbon ion radiotherapy (CIRT) may yield satisfactory clinical outcomes for patients who are resistant to radiotherapy. However, the therapeutic impact of carbon ions is still limited in certain recurring or refractory tumors. Therefore, we aimed to evaluate the synergistic anti-tumor effects of immune checkpoint inhibitors (ICIs) in combination with CIRT. We then explored the involvement of ferroptosis in a preliminary investigation. A tumor-bearing mouse model was established, and mice were inoculated subcutaneously with B16-OVA cells into the flanks of both hind legs. Mice were assigned to four groups to receive CIRT, ICIs, or combined treatment. Thereafter, we conducted transcriptome sequencing (RNA-seq), bioinformatics analysis, and various immune-related experiments on the available tumor tissues to investigate differences in the synergistic anticancer effects and potential mechanisms across the groups. The combination therapies significantly improved the survival of mice and inhibited tumor growth, both at local and distant sites. Based on bioinformatics and RNA-seq data, immune-related pathways and genes, immune cell infiltration, and the production of cytokines and chemokines were the most enhanced in the combined treatment group compared to other groups. Finally, we identified a potential role for ferroptosis in the development of local anti-tumor synergy during CIRT combination treatment. In conclusion, this study showed that CIRT and ICIs can enhance the anti-tumor immune effects. We also proposed that ferroptosis may induce anti-tumor effects in CIRT combination therapy, offering a unique perspective on its ability to enhance immunotherapy responses.

Proton radiotherapy in the treatment of IDH-mutant diffuse gliomas: an early experience from shanghai proton and heavy ion center.

PURPOSE: According to the presence or absence of isocitrate dehydrogenase (IDH) mutation, the 2021 WHO classification system bisected diffuse gliomas into IDH-mutant tumors and IDH-wildtype tumors. This study was aimed to evaluate the outcomes of proton radiotherapy treating IDH-mutant diffuse gliomas. PATIENTS AND METHODS: Between May 2015 and May 2022, a total of 52 consecutive patients with IDH-mutant diffuse gliomas were treated at Shanghai Proton and Heavy Ion Center. Tumor histologies were 33 cases of astrocytoma and 19 cases of oligodendroglioma. Tumor classified by WHO grade 2, 3 and 4 were 22, 25, and 5 cases, respectively. All 22 patients with WHO grade 2 tumors and one patient with brain stem WHO grade 4 tumor were irradiated with 54GyE. The other 29 patients with WHO grade 3 and 4 tumors were irradiated with 60GyE. Temozolomide was recommended to all patients, and was eventually conducted in 50 patients. RESULTS: The median follow-up time was 21.7 months. The 12/24-month progression-free survival (PFS) and overall survival (OS) rates for the entire cohort were 97.6%/78.4% and 100%/91.0% group. Examined by both univariate and multivariate analysis, WHO grade of tumor were of the most significant impact for both PFS and OS. No severe acute toxicity (grade 3 or above) was found. In terms of late toxicity, grade 3 radio-necrosis was developed in one case of oligodendroglioma, WHO grade 3. CONCLUSION: Proton radiotherapy produced a favorable outcome with acceptable adverse-effects in patients with IDH-mutant diffuse gliomas.

Particle beam radiotherapy in the treatment of WHO grade 2 and 3 meningiomas: an early experience from Shanghai Proton and Heavy Ion Center.

PURPOSE: To investigate the efficacy and safety of particle beam radiotherapy (PBRT) in the management of patients with WHO grade 2 and 3 meningiomas. METHODS: Thirty-six consecutive and non-selected patients with WHO grade 2 (n = 28) and grade 3 (n = 8) meningiomas were treated at the Shanghai Proton and Heavy Ion Center, from May 2015 to March 2022. The median age of the cohort at PBRT was 48 years. There were 25 and 11 patients treated with PBRT in the setting of newly diagnosed diseases and progressive/recurrent diseases, respectively. PBRT was utilized as re-irradiation in 5 patients. Proton radiotherapy (PRT) and carbon-ion radiotherapy (CIRT), with a median dose of 60 Gy-Equivalent (GyE), were provided to 30 and 6 patients, respectively. RESULTS: With a median follow-up of 23.3 months, the local control rates were 92.0%, 82.0%, and 82.0% at 1, 2, and 3 years for the entire cohort, respectively. Patients with WHO grade 2 meningiomas (100%, 94.1%, 94,1% at 1,2,3 years) had a much better local control than those with WHO grade 3 meningiomas (50%, 25%, 25% at 1,2,3 years; P < 0.001). Three patients, all with WHO grade 3 meningiomas, had deceased at the time of this analysis. Multivariate analyses revealed that WHO grade (grade 2 vs. 3) (p = 0.016) was a significant prognosticator for local control. No severe toxicities (G3 or above) were observed. CONCLUSIONS: Treatment-induced efficacy and toxicities to PBRT in WHO grade 2 and 3 meningiomas were both highly acceptable. Longer follow-up is needed to evaluate the long-term outcome in terms of disease control, survival, as well as potential late effects.

VMP1, a novel prognostic biomarker, contributes to glioma development by regulating autophagy.

BACKGROUND: Malignant glioma, especially glioblastoma, is a highly aggressive disease with a dismal prognosis. Vacuole membrane protein 1 (VMP1) is a critical autophagy-associated protein with roles in oncogenesis and tumor progression. However, the contribution of VMP1 to glioma development as well as its prognostic value has not been established. METHODS: The expression of VMP1 and clinicopathologic data for 1996 glioma samples were collected from authoritative public databases to explore its prognostic value. Lentiviral CRISPR-Cas9 gene editing system was performed to deplete VMP1 expression. Apoptosis assays, cell cycle assays, colony formation assays, and EdU incorporation analysis were conducted to validate the biological function of VMP1. Transmission electron microscopy was used to determine the role of VMP1 in regulating autophagy. RESULTS: VMP1 overexpression was associated with advanced disease and had a poor prognosis in patients with glioma. The depletion of VMP1 by CRISPR-Cas9 gene editing significantly inhibited cell proliferation, increased cell death, and induced cell cycle arrest. Mechanistically, VMP1 knockout blocked autophagic flux and thus sensitized glioma cells to radiotherapy and chemotherapy. Moreover, a nomogram model showed that VMP1 expression has high prognostic value for determining survival in glioma. CONCLUSIONS: Our results provide insights into the pathological and biological functions of VMP1, including its roles in promoting tumor growth and progression, and support its value as a new diagnostic and prognostic biomarker for glioma.

Clinical outcomes of carbon-ion radiotherapy for patients with locoregionally recurrent nasopharyngeal carcinoma.

BACKGROUND: Reirradiation for locoregionally recurrent nasopharyngeal carcinoma (LR-NPC) after high-dose radiotherapy (RT) is challenging and usually is associated with poor survival and severe toxicities. Because of its physical and biological advantages over photon-beam RT, carbon-ion RT (CIRT) could be a potential treatment option for patients with LR-NPC. METHODS: Patients with LR-NPC who underwent salvage therapy using CIRT at the Shanghai Proton and Heavy Ion Center between May 2015 and June 2019 were analyzed. CIRT doses were 50 to 69 gray equivalent (GyE) (2.0-3.0 GyE per fraction). Overall survival (OS), local control, regional control, distant control, and acute and late toxicities were analyzed. Univariable and multivariable analyses of OS and local control were performed using the Cox regression model. RESULTS: Among the 206 patients included, 139 patients (67.5%) had recurrent American Joint Committee on Cancer stage III or stage IV disease. With a median follow-up of 22.8 months, the 2-year OS, local control, regional control, and distant control rates were 83.7%, 58.0%, 87.3%, and 94.7%, respectively. Multivariable analysis revealed that older age (P = .017) was predictive of worse OS, whereas a larger tumor volume (P = .049) and a lower biological equivalent dose (P = .029) were associated with inferior local control. No patient developed an acute toxicity of ≥grade 3 during CIRT. Severe (≥grade 3) late toxicities included temporal lobe necrosis (0.97%), cranial neuropathy (0.49%), hearing loss (1.46%), xerostomia (0.49%), and mucosal necrosis (16.02%) (toxicities were graded using the Radiation Therapy Oncology Group and European Organization for Research and Treatment of Cancer criteria). CONCLUSIONS: Salvage treatment using CIRT is efficacious for patients with LR-NPC and its toxicities are acceptable. CIRT may improve the survival and toxicity profiles substantially for patients with LR-NPC compared with the reported results after photon-based intensity-modulated RT.

Pharmacological Properties of the Type 1 Tyramine Receptor in the Diamondback Moth, Plutella xylostella.

Tyramine receptors (TARs) can be activated by tyramine (TA) or octopamine (OA) and have been shown to be related to physiological regulation (e.g., gustatory responsiveness, social organization, and learning behavior) in a range of insect species. A tyramine receptor gene in Plutella xylostella, Pxtar1, was cloned and stably expressed in the HEK-293 cell line. Pharmacological properties and expression profile of Pxtar1 were also analyzed. Tyramine could activate the PxTAR1 receptor, increasing the intracellular Ca2+ concentration ((Ca2+)i) at an EC50 of 13.1 nM and reducing forskolin (10 µM)-stimulated intracellular cAMP concentration ((cAMP)i) at an IC50 of 446 nM. DPMF (a metabolite of amitraz) and L(-)-carvone (an essential oil) were found to act as PxTAR1 receptor agonists. Conversely, yohimbine and mianserin had significant antagonistic effects on PxTAR1. In both larvae and adults, Pxtar1 had the highest expression in the head capsule and expression of Pxtar1 was higher in male than in female reproductive organs. This study reveals the temporal and spatial differences and pharmacological properties of Pxtar1 in P. xylostella and provides a strategy for screening insecticidal compounds that target PxTAR1.

Pharmacological characterization of a ß-adrenergic-like octopamine receptor in Plutella xylostella.

The ß-adrenergic-like octopamine receptor (OA2B2) belongs to the class of G-protein coupled receptors. It regulates important physiological functions in insects, thus is potentially a good target for insecticides. In this study, the putative open reading frame sequence of the Pxoa2b2 gene in Plutella xylostella was cloned. Orthologous sequence alignment, phylogenetic tree analysis, and protein sequence analysis all showed that the cloned receptor belongs to the OA2B2 protein family. PxOA2B2 was transiently expressed in HEK-293 cells. It was found that PxOA2B2 could be activated by both octopamine and tyramine, resulting in increased intracellular cyclic AMP (cAMP) levels, whereas dopamine and serotonin were not effective in eliciting cAMP production. Further studies with series of PxOA2B2 agonists and antagonists showed that all four tested agonists (e.g., naphazoline, clonidine, 2-phenylethylamine, and amitraz) could activate the PxOA2B2 receptor, and two of tested antagonists (e.g., phentolamine and mianserin) had significant antagonistic effects. However, antagonist of yohimbine had no effects. Quantitative real-time polymerase chain reaction analysis showed that Pxoa2b2 gene was expressed in all developmental stages of P. xylostella and that the highest expression occurred in male adults. Further analysis with fourth-instar P. xylostella larvae showed that the Pxoa2b2 gene was mainly expressed in Malpighian tubule, epidermal, and head tissues. This study provides both a pharmacological characterization and the gene expression patterns of the OA2B2 in P. xylostella, facilitating further research for insecticides using PxOA2B2 as a target.

A protocol for a randomized trial evaluating the role of carbon-ion radiation therapy plus camrelizumab for patients with locoregionally recurrent nasopharyngeal carcinoma.

PURPOSE: Management of locoregionally recurrent nasopharyngeal carcinoma (LR NPC) is difficult. Although carbon-ion radiation therapy (CIRT) could substantially improve the overall survival (OS) of those patients, around 40% of the patients may still develop local failure. Further improvement of the disease control is necessary. Immunotherapy, such as immune checkpoint inhibitors (ICIs) becomes a promising antitumor treatment. The role of ICIs was proved in head and neck cancers including recurrent/metastatic NPC. Preclinical studies indicated potential synergistic effects between radiation therapy and ICIs. Therefore, we conduct a randomized phase 2 trial to evaluate the efficacy and safety of camrelizumab, an anti-PD-1 monoclonal antibody, along with CIRT in patients with LR NPC. METHODS: Patients will be randomly assigned at 1:1 to receive either standard CIRT with 63 Gy (relatively biological effectiveness, [RBE]) in 21 fractions, or standard CIRT plus concurrent camrelizumab. Camrelizumab will be administered intravenously with a dose of 200 mg, every 2 week, for a maximum of 1 year. We estimate addition of camrelizumab will improve the 2-year progression-free survival (PFS) from 45% to 60%. A total of 146 patients (with a 5% lost to follow-up rate) is required to yield a type I error of 0.2, and a power of 0.8. RESULTS AND CONCLUSION: The results of the trial may shed insights on the combined therapy with ICIs and CIRT.

Tumor volume instead of recurrent T category predicts clinical outcome of patients with locally recurrent nasopharyngeal carcinoma salvaged by carbon ion radiation therapy.

BACKGROUND: Although carbon ion radiation therapy (CIRT) substantially improves the overall survival (OS) of patients with LR-NPC, approximately 40% of the patients may develop local recurrence. The purpose of study is to assess the value of tumor volume (TV) as a predictive tool to guide individualized CIRT. METHODS: Consecutive patients with LR-NPC treated using CIRT at Shanghai Proton and Heavy Ion Center between April 2015 and May 2019 were included. TV before CIRT was delineated and calculated. The generalized additive Cox model was used to examine the relationship between TV and OS and local progression-free survival (LPFS). A cutoff value of tumor volume was identified to best discriminate patients with different 2-year OS rates, using receiver operating characteristic (ROC) analysis. RESULTS: A total of 157 patients were enrolled. The median tumor volume was 22.49 (2.52-90.13) ml. In the univariable analyses, tumor volume was significantly associated with OS (p < 0.001) and LPFS (p = 0.01). The relationships with OS (p = 0.009) and LPFS (p = 0.020) remained significant in multivariable analyses. Using ROC analysis, a TV of 26.69 ml was identified to predict the 2-year OS rate. To facilitate potential clinical use, 25 ml was designated as the final cutoff value. The 2-year OS and LPFS rates were 88.6 % vs 62.3 %, and 54.7 % vs 35.5 %, for patients with a TV ≤ 25 ml and > 25 ml, respectively. CONCLUSION: Tumor volume could predict the OS and LPFS of patients. We propose that tumor volume should be considered in the risk stratification and CIRT-based treatment for patients with LR-NPC.

TRIB3 promotes malignancy of head and neck squamous cell carcinoma via inhibiting ferroptosis.

Tribbles pseudokinase 3 (TRIB3) has been identified recently as a novel oncogene in several cancers. Still, further extensive research is imperative to elucidate its function and the molecular mechanisms underlying its involvement in the progression of head and neck squamous cell carcinoma (HNSCC). In our study, we found that TRIB3 silencing significantly promoted cell death by inducing ferroptosis. The interaction of TRIB3 with Transcription Factor 4 (TCF4) and ß-catenin created a heterotrimeric complex, which directly interacts with the ALOXE3 promoter, detrimentally impacting its activation. The consequential partial neutralization of ferroptosis induced by TRIB3 deficiency is observed through the implementation of ALOXE3 knockdown. Furthermore, the study demonstrated that the molecular inhibitor hesperidin, targeting TRIB3, not only reduced cell malignancy but also induced ferroptosis, thereby suppressing tumor growth. Overall, our findings unequivocally validate the proposition that TRIB3 deficiency precipitates the iron death mechanism, thereby indicating that the strategic targeting of TRIB3 could emerge as an innovative therapeutic strategy for HNSCC.

Exploring the Therapeutic Potential of Triptonide in Salivary Adenoid Cystic Carcinoma: A Comprehensive Approach Involving Network Pharmacology and Experimental Validation.

BACKGROUND: Salivary Adenoid Cystic Carcinoma (ACC) is characterized by a highly invasive and slow-growing pattern, and its etiology remains unidentified. Triptonide (TN) has demonstrated efficacy as a pharmacotherapeutic agent against ACC. Nonetheless, the specific targets and mechanism of molecular action underlying the effectiveness of TN in treating ACC have not been elucidated. OBJECTIVES: By integrating network pharmacology within laboratory experiments, this research delves into the prospective targets and molecular mechanisms associated with the application of TN in treating ACC. METHODS: Initially, pertinent targets associated with TN against ACC were acquired from public databases. Subsequently, a combination of network pharmacology and bioinformatics analysis was utilized to screen the top 10 hub targets and key signal pathways of TN-treating ACC. Finally, in vitro experiments involving various molecular assays were conducted to evaluate the biological phenotypes of cells following TN treatment, encompassing assessments of apoptosis levels, plate migration, and other parameters, thereby validating pivotal genes and pathways. RESULTS: A total of 23 pertinent targets for TN in relation to ACC were identified, with the top 10 hub genes being MAPK8, PTGS2, RELA, MAPK14, NR3C1, HDAC1, PPARG, NFKBIA, AR, and PGR. There was a significant correlation between the TNF signaling pathway and the treatment of ACC with TN. In vitro experiments demonstrated that TN treatment elevated RELA phosphorylation while concurrently reducing MAPK14 phosphorylation and inducing G2/M arrest. TN exhibited the ability to enhance the apoptosis rate through increased caspase-3 activity, elevated levels of Reactive Oxygen Species (ROS), mitochondrial dysfunction, and inhibition of cell migration. CONCLUSION: There is a potential therapeutic role for TN in the treatment of ACC through the activation of the TNF signaling pathway. Among the identified candidates, MAPK8, HDAC1, PTGS2, RELA, NR3C1, PPARG, NFKBIA, AR, and PGR emerge as the most pertinent therapeutic targets for TN in the context of ACC treatment.

Preliminary clinical outcomes of head and neck squamous cell carcinoma treated with particle beam radiation therapy.

PURPOSE: Further improvement in clinical outcomes is needed for patients with head and neck squamous cell carcinoma (HNSCC), as there is typically a poor prognosis at diagnosis. This study aimed to report the preliminary therapeutic outcomes and side effects in patients with HNSCC receiving particle beam radiotherapy (PBRT), owing to the physical and biological advantages of this approach. METHODS: We retrospectively analyzed 68 patients with newly diagnosed HNSCC who received PBRT at the Shanghai Proton and Heavy Ion Center (SPHIC) between August 2015 and December 2020. The Kaplan-Meier approach was used to determine overall survival (OS), disease-specific survival (DSS), progression-free survival (PFS), local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), and distant metastasis-free survival (DMFS). Common Terminology Criteria for Adverse Events (CTCAE) 4.03 was also used to grade acute and late toxicities. RESULTS: With a median follow-up time of 24.5 months (range, 3-65), the 3-year OS, DSS, PFS, LRFS, RRFS, and DMFS rates for the entire cohort were 79.0%, 84.7%, 67.9%, 83.5%, 83.3%, and 96.1%, respectively. Univariate and multivariate analyses showed that N category was a significant predictor of OS, PFS, and RRFS. In terms of acute toxicities, two patients demonstrated severe mucositis or dysphagia, and two patients also displayed a late toxicity of significant mucosal necrosis. CONCLUSION: These findings suggest that PBRT can provide patients with HNSCC with a promising therapeutic benefit and manageable toxicity. Prospective evaluation of clinical outcomes with PBRT for HNSCC is warranted, with an emphasis on clinical effectiveness as well as adverse effects and patient quality of life.

Tumor-intrinsic YTHDF1 drives immune evasion and resistance to immune checkpoint inhibitors via promoting MHC-I degradation.

The recently described role of RNA methylation in regulating immune cell infiltration into tumors has attracted interest, given its potential impact on immunotherapy response. YTHDF1 is a versatile and powerful m6A reader, but the understanding of its impact on immune evasion is limited. Here, we reveal that tumor-intrinsic YTHDF1 drives immune evasion and immune checkpoint inhibitor (ICI) resistance. Additionally, YTHDF1 deficiency converts cold tumors into responsive hot tumors, which improves ICI efficacy. Mechanistically, YTHDF1 deficiency inhibits the translation of lysosomal genes and limits lysosomal proteolysis of the major histocompatibility complex class I (MHC-I) and antigens, ultimately restoring tumor immune surveillance. In addition, we design a system for exosome-mediated CRISPR/Cas9 delivery to target YTHDF1 in vivo, resulting in YTHDF1 depletion and antitumor activity. Our findings elucidate the role of tumor-intrinsic YTHDF1 in driving immune evasion and its underlying mechanism.

Identification of molecular subtypes based on inflammatory response in lower-grade glioma.

BACKGROUND: Inflammatory response is an important characteristic affecting prognosis and therapeutic response in lower-grade glioma (LGG). However, the molecular subtypes based on inflammatory response are still under exploitation. METHODS: The RNA sequencing, somatic mutation, and corresponding clinical data from 1205 LGG patients were obtained from the TCGA, CGGA, and Rembrandt cohorts. Consensus clustering was performed to identify molecular subtypes associated with inflammation. Prognosis, clinicopathologic features, immune cell infiltration, and somatic mutation profile were compared among these inflammation-associated subtypes. RESULTS: Our results demonstrate that LGG could be categorized into inflammation-, low, -mid, and -high subtypes with distinct clinicopathologic features, prognostic and tumor microenvironment. We established that this categorization was reproducible, as well as predictable. In general, inflammation-high subtype presents a dismal prognosis with the immunosuppressive microenvironment and high frequency of oncogene mutation. Inversely, inflammation-low subtype was associated with the most favorable clinical outcomes with the immunoreactive microenvironment among three subtypes. Moreover, we develop and validate an inflammation-related prognostic model, which shows strong power for prognosis assessment. CONCLUSION: In conclusion, we established a novel glioma classification based on the inflammation subtype. This classification had significant outcomes for estimating the prognosis, as well as the tumor microenvironment.

Development of a normal tissue complication probability (NTCP) model using an artificial neural network for radiation-induced necrosis after carbon ion re-irradiation in locally recurrent nasopharyngeal carcinoma.

Background: The aim of the present study was to build a normal tissue complication probability (NTCP) model using an artificial neural network (ANN) for radiation-induced necrosis after carbon ion re-irradiation in locally recurrent nasopharyngeal carcinoma (rNPC), and to determine the predictive parameters applied to the model. Methods: A total of 150 patients with rNPC treated at Shanghai Proton and Heavy Ion Center during 2015-2019 were selected to determine the dominant factors causing mucosal necrosis after carbon therapy. An ANN was built to study both dose-volume histogram (DVH) and clinical factors. Simple oversampling and data normalization were used in the training process. Ten-fold cross validation was conducted to prevent overfitting. Results: Of the DVH factors, the prediction accuracy ranged from 58.3-65.2%, whereas planning target volume (PTV) receiving dose more than 25 GyE (PTV.V25) yielded the best prediction accuracy. Of the clinical factors, baseline necrosis, sex, and biologically equivalent dose (BED) of initial treatment could increase the accuracy of PTV.V25 by 0.5%, 0.5%, and 1.5%, respectively. Conclusions: An ANN was built to predict radiation-induced necrosis after re-irradiation in rNPC. The best accuracy and area under receiver-operating characteristic (ROC) curve (AUC) were 66.7% and 0.689. The most predictive dosimetric and clinical parameters were PTV.V25 and BED of initial treatment.

Comparison of the efficacy and toxicity of postoperative proton versus carbon ion radiotherapy for head and neck cancers.

Background: To compare the efficacy and toxicity of adjuvant proton beam vs. carbon-ion beam radiotherapy for head and neck cancers after radical resection and to explore the value of particle beam radiotherapy (PBRT) in postoperative radiotherapy for head and neck cancers. Methods: Data from 38 head and neck cancer patients who received adjuvant PBRT after complete surgical resection at the Shanghai Proton and Heavy Ion Center (SPHIC) between October 2015 and March 2019 were retrospectively analyzed. In total, 18 patients received adjuvant proton beam therapy (54-60 GyE/27-30 fractions) and 20 received adjuvant carbon-ion radiotherapy (CIRT) (54-60 GyE/18-20 fractions). Survival rates were calculated using Kaplan-Meier analysis. Toxicity was evaluated according to the Common Terminology Criteria for Adverse Effects (version 4.03). Results: With a median follow-up time of 21 (range, 3-45) months, the 2-year overall survival (OS), progression-free survival (PFS), local-regional recurrence-free survival (LRRFS) and distant metastasis-free survival (DMFS) rates were 93.3%, 87.4%, 94.1%, and 90.7%, respectively, for the entire cohort. The rates after proton beam therapy vs. CIRT were 94.1% vs. 91.7% (P=0.96), 88.1% vs. 86.2% (P=0.96), 94.4% vs. 93.3% (P=0.97), and 88.1% vs. 92.9% (P=0.57), respectively. Furthermore, 16 of the 18 (88.9%) patients developed acute grade I/II dermatitis (13 grade I; 3 grade II) after proton beam therapy, and only 7 of the 20 (35%) patients developed acute grade I dermatitis after CIRT (P=0.001). The incidence of acute grade I/II mucositis and xerostomia in proton and carbon ion cases were 45% vs. 55% (P=0.75) and 56% vs. 50% (P=0.87) respectively. Conclusions: Adjuvant proton beam therapy and CIRT after radical surgical resection for head and neck cancers provided satisfactory therapeutic effectiveness, but no significant difference was observed between the two radiotherapy technologies. However, adjuvant CIRT was associated with a more favorable acute toxicity profile as compared to proton beam therapy with significantly lower frequency and severity of acute dermatitis observed.

Carbon-ion radiotherapy boost with standard dose proton radiation for incomplete-resected high-grade glioma: a phase 1 study.

Background: To investigate the maximal tolerated dose (MTD) of a carbon-ion radiotherapy (CIRT) boost prior to standard dose proton radiotherapy (PRT) for newly diagnosed glioblastoma (GBM) and anaplastic astrocytoma (AA) patients with residual lesion after resection. Methods: In total, 18 patients with high-grade glioma (HGG) (16 with GBM and 2 with AA) were enrolled in a prospective 3×3 design phase 1 trial. We investigated four dose-levels of CIRT boost [9 (starting level), 12, 15, and 18 Gy relative biological effectiveness (RBE)] delivered in three equal fractions prior to the standard dose PRT (60 Gy RBE in 30 fractions). Concurrent temozolomide (TMZ) was not provided during the CIRT boost but was initiated on the first day of PRT. Acute and late toxicities were scored based on the Common Terminology Criteria for Adverse Events (CTCAE, v 4.03). Dose-limiting toxicities (DLTs) were defined as radiation-induced severe toxicities (≥ grade 3). Results: With a median follow-up of 17.9 months, no severe (≥ grade 3) acute or late toxicities were observed in patients treated with the first three dose levels (CIRT boost doses of 9, 12, 15 Gy RBE). Severe late toxicity (grade 3 radiation necrosis) was observed in the first patient treated with the 18 Gy RBE CIRT boost level. Therefore, this trial was terminated and the MTD of the induction CIRT boost was determined at 15 Gy RBE in 3 fractions. At the time of this analysis, both patients with AA were alive without disease progression. The progression-free survival (PFS) and overall survival (OS) for GBM at 12 months were 50.6% and 78.6%, respectively. Conclusions: Particle beam radiotherapy consisting of a CIRT boost of 15 Gy RBE (in 3 fractions) following standard dose PRT (60 Gy RBE in 30 fractions), and used in conjunction with TMZ, is safe and potentially effective for patients with HGG.

Intensity-modulated proton and carbon-ion radiation therapy in the management of major salivary gland carcinomas.

Background: Primary major salivary gland carcinomas (SGCs) present with diverse histological types that are known to be largely radioresistant with a high tendency to develop distant metastasis (DM). Photon-based radiotherapy (RT) is limited in terms of its therapeutic effect and toxicities. In view of the physical and biological advantages of intensity-modulated proton and/or carbon-ion radiation therapy, we aimed to evaluate the short-term therapeutic effect and toxicities in patients with major SGCs treated with this form of radiation therapy. Methods: Between August 2015 and November 2019, a total of 55 consecutive and non-selected major SGC patients who received particle RT at the Shanghai Proton and Heavy Ion Center (SPHIC) were retrospectively analyzed. The 2-year overall survival (OS), progression-free survival (PFS), local-regional recurrence-free survival (LRRFS), and distant metastasis-free survival (DMFS) rates, as well as prognostic factors were analyzed. Additionally, acute and late toxicities were also analyzed. Results: With a median follow-up time of 24 (range, 6-57) months, the 2-year OS, PFS, LRRFS, and DMFS rates were 91.6%, 78.6%, 94.2%, and 83.9%, respectively. At the time of this analysis, four patients had developed local or regional recurrence, and seven additional patients had developed DM. Three patients had died due to disease progression, and another patient with recurrence experienced a late Grade 5 event (hemorrhage) at 9 months after re-irradiation with carbon ion and subsequently died. Otherwise, none of the patients had grade 3 or higher treatment-induced acute or late adverse effects except one who developed grade 3 acute mucositis. Conclusions: Overall, intensity-modulated proton and/or carbon-ion radiation therapy provided satisfactory therapeutic effectiveness in our major SGCs patients with a low incidence of acute and late toxicities.

The role of carbon-ion radiotherapy in the treatment of adenoid cystic carcinoma of the nasopharynx.

Background: Nasopharyngeal adenoid cystic carcinoma (NACC) is a distinct subgroup of adenoid cystic carcinoma (ACC) with limited surgical access but predilection of regional and distant metastasis. Although radiotherapy is an integral treatment for patients with NACC, photon-based radiotherapy yielded suboptimal local control. Because of its advantages in biology and physics properties, carbon-ion radiotherapy (CIRT) was attempted for the treatment of head and neck ACC; however, the use of CIRT specifically for NACC has not been investigated. Methods: Patients with NACC that received CIRT alone or a combination of CIRT and proton beam therapy (PBT) at the Shanghai Proton and Heavy Ion Center (SPHIC) between July 2016 and March 2019 were included in the analysis. Patients with newly diagnosed NACC received combined therapy of CIRT (as boost) and PBT, and those with recurrent disease received CIRT alone. Overall survival (OS), local progression-free survival (LPFS), regional progression-free survival (RPFS), and distant metastasis-free survival (DMFS) were calculated by Kaplan-Meier method. Results: A total of 22 patients were included in this analysis. Among those, 18 patients had newly diagnosed NACC (17 with locally advanced disease), and 4 had recurrent NACC including 2 failed previous irradiation. After a median follow-up of 30.9 months, the 2-year OS rate, PFS rate, LPFS rate, RPFS rate and DMFS rate were 100%, 84.8%, 94.4%, 100%, and 84.8%, respectively. Three patients experienced grade 3 mucositis or xerostomia. No late toxicity of grade ≥3 was observed. Conclusions: CIRT alone or in combination with PBT appeared to be a promising modality for the treatment of NACC and produced satisfactory local disease control and toxicity profile. Distant metastasis remained to be a substantial mode for treatment failure. Further follow-up is necessary to evaluate long-term survivals and late toxicity profile.