Publications by authors named "Jiade Lu"

121 Publications

Mixed Photon and Carbon-Ion Beam Radiotherapy in the Management of Non-Metastatic Nasopharyngeal Carcinoma.

Front Oncol 2021 23;11:653050. Epub 2021 Jul 23.

Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Shanghai, China.

Background: Carbon-ion radiotherapy (CIRT) may further increase the therapeutic ratio for patients with newly diagnosed nasopharyngeal carcinoma (NPC). The purpose of the current study is to examine the effectiveness and toxicity profile of photon-based intensity-modulated radiotherapy (IMRT) plus CIRT boost in a relatively large cohort of NPC patients.

Methods: In the current study, non-metastatic NPC patients treated with IMRT plus CIRT boost at Shanghai Proton and Heavy Ion Center between June, 2015 and June, 2018 were included. Overall survival (OS), progression-free survival (PFS), local control, regional control, and distant control were calculated with Kaplan-Meier method. Acute and late toxicities were graded using CTCAE 4.03.

Results: A total of 69 patients were included in the analysis. Among those, 74% of the patients had locoregionally advanced (stage III/IV) disease, and 92.8% had cervical lymphadenopathy. With a median follow-up of 31.9 months, the 3-year OS, PFS, local control, regional control, and distant control rates were 94.9, 85.2, 96.9, 98.4, and 89.7%, respectively. Mixed treatment of IMRT with CIRT boost was well tolerated. Severe acute toxicities induced by radiation therapy were observed in only two patients (dermatitis). No severe radiation-induced late toxicity was observed at the time of analysis. Univariable analysis showed N2/3 disease was correlated with an inferior distant control ( = 0.040).

Conclusion: Mixed treatment of IMRT plus CIRT boost provides an excellent disease control and a favorable toxicity profile for patients with non-metastatic NPC. Further follow-up is necessary to evaluate the long-term survivals and toxicities more accurately.
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http://dx.doi.org/10.3389/fonc.2021.653050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8343069PMC
July 2021

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

J Neuroinflammation 2021 Jul 26;18(1):165. Epub 2021 Jul 26.

Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, 201321, China.

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.
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http://dx.doi.org/10.1186/s12974-021-02213-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8311950PMC
July 2021

A Systematic Review of Proton Therapy for the Management of Nasopharyngeal Cancer.

Int J Part Ther 2021 25;8(1):119-130. Epub 2021 Jun 25.

Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Purpose: With improved technology, more patients with nasopharyngeal cancer (NPC) are receiving definitive treatment with proton therapy, which allows greater sparing of dose to normal tissues without compromising efficacy. As there is no randomized data, the purpose of this study was to systematically review the available literature on proton therapy in this setting, focusing on the toxicity endpoints.

Materials And Methods: A systematic search using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines was conducted in 5 databases: PubMed, Embase, SCOPUS, Web of Science, and the Cochrane Central Register of Controlled Trials. A total of 491 studies were found on the topic of NPC and proton therapy. Following independent study selection by 2 investigators, 9 studies were found to have sufficient focus and relevance to be incorporated into the systematic review.

Results: All 9 studies were retrospective and examined only NPC patients except for one that also included paranasal sinus cancer. One study was a reirradiation study. Four studies used 3D or double scatter technique, while all others used intensity-modulated proton therapy. Oncologic outcomes were similar to intensity-modulated radiation therapy (IMRT) rates, with 2-year local and regional progression-free survival (LRFS) ranging from 84% to 100%, 2-year progression-free survival (PFS) ranging from 75% to 88.9%, and 2-year overall survival (OS) ranging from 88% to 95% in the up-front setting. Four comparison studies with IMRT found significantly lower feeding tube rates (20% versus 65%,  = .015; and 14% versus 85%,  < .001) with proton therapy as well as lower mucositis (G2 46% versus 70%,  = .019; and G3 11% versus 76%,  = .0002). All other acute and late effects were largely improved with proton therapy but not statistically significant.

Conclusions: NPC patients receiving proton therapy maintain good outcomes with improved toxicity profile, likely due to sparing of dose to normal structures. Prospective studies are ongoing to better quantify the magnitude.
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http://dx.doi.org/10.14338/IJPT-20-00082.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270076PMC
June 2021

Definitive carbon ion radiotherapy for tracheobronchial adenoid cystic carcinoma: a preliminary report.

BMC Cancer 2021 Jun 26;21(1):734. Epub 2021 Jun 26.

Shanghai Key Laboratory of Radiation Oncology, Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, 201321, China.

Background: Tracheobronchial adenoid cystic carcinoma (TACC) is a rare tumour. About one-third of patients miss their chance of surgery or complete resection as it is mostly detected in the advanced stage; hence, photon radiotherapy (RT) is used. However, the outcomes of photon RT remain unsatisfactory. Carbon ion radiotherapy (CIRT) is thought to improve the therapeutic gain ratio; however, the outcomes of CIRT in TACC are unclear. Therefore, we aimed to assess the effects and toxicities of CIRT in patients with TACC.

Methods: The inclusion criteria were as follows: 1) age 18-80 years; 2) Eastern Cooperative Oncology Group Performance Status 0-2; 3) histologically confirmed TACC; 4) stage III-IV disease; 5) visible primary tumour; and 6) no previous RT history. The planned prescription doses of CIRT were 66-72.6 GyE/22-23 fractions. The rates of overall survival (OS), local control (LC), and progression-free survival (PFS) were calculated using the Kaplan-Meier method. Treatment-induced toxicities and tumour response were scored according to the Common Terminology Criteria for Adverse Events and Response Evaluation Criteria in Solid Tumors, respectively.

Results: Eighteen patients with a median age of 48 (range 30-73) years were enrolled. The median follow-up time was 20.7 (range 5.8-44.1) months. The overall response rate was 88.2%. Five patients developed lung metastasis after 12.2-41.0 months and one of them experienced local recurrence at 31.9 months after CIRT. The rates of 2-year OS, LC, and PFS were 100, 100, and 61.4%, respectively. Except for one patient who experienced grade 4 tracheal stenosis, which was relieved after stent implantation, no other ≥3 grade toxicities were observed.

Conclusions: CIRT might be safe and effective in the management of TACC based on a short observation period. Further studies with more cases and longer observation are warranted.
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http://dx.doi.org/10.1186/s12885-021-08493-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236132PMC
June 2021

Association of IDH mutation and 1p19q co-deletion with tumor immune microenvironment in lower-grade glioma.

Mol Ther Oncolytics 2021 Jun 29;21:288-302. Epub 2021 Apr 29.

Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai 201321, China.

Although the successful clinical trials of immunotherapy show promising strategies for many cancers, its application in glioma has lagged in comparison with the progress seen in other cancers. Both isocitrate dehydrogenase (IDH) mutations and 1p/19q codeletions are critical molecular alterations affecting therapeutic response in lower-grade glioma (LGG). The systematic and comprehensive characterization of the immunological phenotypes with different molecular subtypes is key to improving our understanding and application of immunotherapies in LGG. Here, we collected the RNA-sequencing, somatic mutation, and clinical data from 1,052 patients from The Cancer Genome Atlas and Chinese Glioma Genome Atlas and stratified patients into three genetic subgroups: IDH mutations with 1p/19q codeletions (IDH mut-codel), IDH mutations without 1p/19q codeletions (IDH mut-noncodel), and IDH wild-type. Our evaluations revealed that IDH mutations and 1p/19q codeletions were associated with distinct immunological tumor microenvironments in LGG. In addition, immune cell infiltration, the expression of immune checkpoint and human leukocyte antigen (HLA) gene, and the activity of immune signaling pathways shared gradual increase from IDH mut-codel to IDH wild-type. We further constructed and validated an immune-related prognostic signature that presented high value in predicting the overall survival time in LGG. In conclusion, our study may provide valuable information for immunotherapy strategies in LGG patients.
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http://dx.doi.org/10.1016/j.omto.2021.04.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167204PMC
June 2021

The Role of Notch, Hedgehog, and Wnt Signaling Pathways in the Resistance of Tumors to Anticancer Therapies.

Front Cell Dev Biol 2021 22;9:650772. Epub 2021 Apr 22.

R&D Dept, Shanghai Proton and Heavy Ion Center (SPHIC), Shanghai, China.

Resistance to therapy is the major hurdle in the current cancer management. Cancer cells often rewire their cellular process to alternate mechanisms to resist the deleterious effect mounted by different therapeutic approaches. The major signaling pathways involved in the developmental process, such as Notch, Hedgehog, and Wnt, play a vital role in development, tumorigenesis, and also in the resistance to the various anticancer therapies. Understanding how cancer utilizes these developmental pathways in acquiring the resistance to the multi-therapeutic approach cancer can give rise to a new insight of the anti-therapy resistance mechanisms, which can be explored for the development of a novel therapeutic approach. We present a brief overview of Notch, Hedgehog, and Wnt signaling pathways in cancer and its role in providing resistance to various cancer treatment modalities such as chemotherapy, radiotherapy, molecular targeted therapy, and immunotherapy. Understanding the importance of these molecular networks will provide a rational basis for novel and safer combined anticancer therapeutic approaches for the improvement of cancer treatment by overcoming drug resistance.
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http://dx.doi.org/10.3389/fcell.2021.650772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100510PMC
April 2021

Pretreatment F-FDG uptake heterogeneity can predict treatment outcome of carbon ion radiotherapy in patients with locally recurrent nasopharyngeal carcinoma.

Ann Nucl Med 2021 Jul 28;35(7):834-842. Epub 2021 Apr 28.

Department of Nuclear Medicine, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, 201315, China.

Objective: Our study was to investigate the value of pretreatment F-FDG uptake heterogeneity to predict the prognosis of patients with locally recurrent nasopharyngeal carcinoma (LRNPC) treated by carbon ion radiotherapy (CIRT).

Methods: Twenty-nine LRNPC patients who underwent whole-body F-FDG PET/CT scanning before CIRT were enrolled. Heterogeneity index (HI)-based F-FDG uptake, and the PET/CT traditional parameters, including SUVmax, MTV, and TLG were assessed. Receiver operator characteristics (ROC) determined the best cutoff value, and local recurrence-free survival (LRFS) and progression-free survival (PFS) were evaluated by the Kaplan-Meier method and log-rank test. And the predictive ability was evaluated by the ROC curve. Cox analyses were performed on LRFS and PFS.

Results: In this study, univariate analysis showed that HI was a significant predictor of LRNPC treated by CIRT. HI could be used to predict LRFS and PFS. Patients with HI (≥ 0.81) had a significantly worse prognosis of LRFS (12.25 vs. NR, p = 0.008), and of PFS (10.58 vs. NR, p = 0.014). The AUC and its sensitivity and sensitivity and specificity were 0.75, 84.21% and 70.00% for LRFS and 0.82, 80.95% and 75.00% for PFS, respectively. Multivariate analysis showed that HI was an independent predictor for the LFRS of LRNPC with CIRT.

Conclusion: F-FDG uptake heterogeneity may be useful for predicting the prognosis of patients with LRNPC treated by CIRT.
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http://dx.doi.org/10.1007/s12149-021-01621-8DOI Listing
July 2021

Carbon ion triggered immunogenic necroptosis of nasopharyngeal carcinoma cells involving necroptotic inhibitor BCL-x.

J Cancer 2021 1;12(5):1520-1530. Epub 2021 Jan 1.

Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, China.

To explore the potential and mechanisms of necroptosis, a form of immunogenic cell death, induced by carbon ion as compared to photon beams in established photon resistant- (PR-) and sensitive nasopharyngeal carcinoma (NPC) cells. MLKL is considered a central executor of necroptosis and phosphorylation of MLKL (p-MLKL) was a critical event of necroptosis. The clonogenic survival and DNA microarray demonstrated that after repeated photon irradiation, radiosensitive NPC cells became apoptosis-resistant but could be effectively inhibited by carbon ion irradiation. The relative biologic effectiveness (RBE) at D10 and D37 were 2.15 and 2.78 for PR-NPC cells. Carbon ion induced delayed DNA damage repair, cell cycle arrest, cytogenetic damage, morphological change and cell necrosis, indicating the possibility of necroptosis in both PR- and sensitive NPC cell types. The lower expression of necroptotic inhibitors (caspase-8 and Bcl-x) and higher level of MLKL in PR-NPC cells showed it was relatively more predisposed to necroptosis compared to the sensitive cells. Subsequent experiments demonstrated the significant upregulation of p-MLKL in the PR-NPC cells treated by carbon ion (4 Gy) compared with photon irradiation at both physical (4 Gy) and RBE (10 Gy) doses (P≤0.0001). Moreover, carbon ion induced a robust (up to 28 folds) p-MLKL in the PR-NPC cells as well as sensitive cells (up to 6-fold) coupled with a lower level of BCL-x expression and increased GM-CSF implicated in resculputure of immune system. These results suggested that carbon ion could induce necroptosis of NPC cells, especially in PR-NPC cells, and its mechanisms involve BCL-x.
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http://dx.doi.org/10.7150/jca.46316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847655PMC
January 2021

Biological Guided Carbon-Ion Microporous Radiation to Tumor Hypoxia Area Triggers Robust Abscopal Effects as Open Field Radiation.

Front Oncol 2020 19;10:597702. Epub 2020 Nov 19.

Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Shanghai, China.

Recently, a growing number of studies focus on partial tumor irradiation to induce the stronger non-target effects. However, the value of partial volume carbon ion radiotherapy (CIRT) targeting hypoxic region of a tumor under imaging guidance as well as its effect of inducing radiation induced abscopal effects (RIAEs) have not been well investigated. Herein, we developed a technique of carbon ion microporous radiation (CI-MPR), guided by F-FMISO PET/computerized tomography (CT), for partial volume radiation targeting the hypoxia area of a tumor and investigated its capability of inducing abscopal effects. Tumor-bearing mice were inoculated subcutaneously with breast cancer 4T1 cells into the flanks of both hind legs of mouse. Mice were assigned to three groups: group I: control group with no treatment; group II: carbon ion open field radiation (CI-OFR group) targeting the entire tumor; group III: partial volume carbon ion microporous radiation (CI-MPR group) targeting the hypoxia region. The tumors on the left hind legs of mice were irradiated with single fraction of 20 Gy of CIRT. Mice treated with CI-MPR or CI-OFR showed that significant growth delay on both the irradiated and unirradiated of tumor as compared to the control groups. Tumor regression of left tumor irradiated with CI-OFR was more prominent as compared to the tumor treated with CI-MPR, while the regression of the unirradiated tumor in both CI-MPR and CI-OFR group was similar. Biological-guided CIRT using the newly developed microporous technique targeting tumor hypoxia region could induce robust abscopal effects similar to CIRT covering the entire tumor.
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http://dx.doi.org/10.3389/fonc.2020.597702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713593PMC
November 2020

RBE-weighted dose conversions for patients with recurrent nasopharyngeal carcinoma receiving carbon-ion radiotherapy from the local effect model to the microdosimetric kinetic model.

Radiat Oncol 2020 Dec 10;15(1):277. Epub 2020 Dec 10.

Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, China.

Background: We sought to establish a conversion curve to convert the RBE-weighted doses calculated by local effect model I (LEM) (LEM RBE-weighted doses) in patients with locally recurrent nasopharyngeal carcinoma (rNPC) to the RBE-weighted doses calculated by microdosimetric kinetic model (MKM) (MKM RBE-weighted doses). We also converted the LEM dose constraints (RBE-weighted dose constraints in LEM plans) for the brain stem, spinal cord, and optic nerve based on this curve.

Methods: Data from 20 patients with rNPC receiving carbon-ion radiotherapy (CIRT) in our hospital were collected. LEM in Raystation (V8A, Raystation, Sweden) was used to generate treatment plans. The clinical target volume CTV1 (GTV + 5 mm) was given 3 Gy (RBE) per fraction. Ninety-nine percent of target volumes should be covered by 95% of the prescriptions; the maximum doses of the brainstem and spinal cord were < 45 Gy (RBE) and < 30 Gy (RBE), respectively. The doses covering 20% volumes of optical nerves/chiasms D20 were < 30 Gy (RBE). Then physical doses of the LEM plans were recalculated by using MKM in Raystation to generate MKM plans. A series of conversion factors (i.e., the ratio of LEM RBE-weighted dose to MKM RBE-weighted dose) was then obtained by using an isovolumetric dose method. The LEM plan prescriptions (LEM prescription) and dose constraints of the organs at risk (OARs) (OAR constraints) were converted to the corresponding MKM prescriptions and dose constraints using this conversion curve.

Results: For the CTV1 fractional RBE-weighted dose prescription of 3.00 Gy (RBE) and CTV2 of 2.70 Gy (RBE) in LEM plans, the conversion factors (LEM RBE-weighted dose/MKM RBE-weighted dose) were 1.37 (CI 95% 1.35-1.39) and 1.46 (1.41-1.51), respectively. The average conversion factors from 1.37 (CI 95% 1.33-1.41) to 3.09 (2.94-3.24) corresponded to the LEM fractionated doses from 2.86 Gy (RBE) to 0.24 Gy (RBE), including the doses constraining upon OARs. LEM RBE-weighted doses of 30 Gy (RBE) and 45 Gy (RBE) in 21 fractions were converted to MKM RBE-weighted doses of 16.64 Gy (RBE) and 30.72 Gy (RBE) in 16 fractions.

Conclusions: This conversion curve could be used to convert LEM RBE-weighted doses to MKM RBE-weighted doses for patients with rNPC receiving CIRT, providing dose references for re-irradiation therapy.
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http://dx.doi.org/10.1186/s13014-020-01723-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731771PMC
December 2020

A Comparison Study of Machine Learning (Random Survival Forest) and Classic Statistic (Cox Proportional Hazards) for Predicting Progression in High-Grade Glioma after Proton and Carbon Ion Radiotherapy.

Front Oncol 2020 30;10:551420. Epub 2020 Oct 30.

Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, China.

Background: Machine learning (ML) algorithms are increasingly explored in glioma prognostication. Random survival forest (RSF) is a common ML approach in analyzing time-to-event survival data. However, it is controversial which method between RSF and traditional cornerstone method Cox proportional hazards (CPH) is better fitted. The purpose of this study was to compare RSF and CPH in predicting tumor progression of high-grade glioma (HGG) after particle beam radiotherapy (PBRT).

Methods: The study enrolled 82 consecutive HGG patients who were treated with PBRT at Shanghai Proton and Heavy Ion Center between 6/2015 and 11/2019. The entire cohort was split into the training and testing set in an 80/20 ratio. Ten variables from patient-related, tumor-related and treatment-related information were utilized for developing CPH and RSF for predicting progression-free survival (PFS). The model performance was compared in concordance index (C-index) for discrimination (accuracy), brier score (BS) for calibration (precision) and variable importance for interpretability.

Results: The CPH model demonstrated a better performance in terms of integrated C-index (62.9%) and BS (0.159) compared to RSF model (C-index = 61.1%, BS = 0.174). In the context of variable importance, CPH model indicated that age (P = 0.024), WHO grade (P = 0.020), IDH gene (P = 0.019), and MGMT promoter status (P = 0.040) were significantly correlated with PFS in the univariate analysis; multivariate analysis showed that age (P = 0.041), surgical completeness (P = 0.084), IDH gene (P = 0.057), and MGMT promoter (P = 0.092) had a significant or trend toward the relation with PFS. RSF showed that merely IDH and age were of positive importance for predicting PFS. A final nomogram was developed to predict tumor progression at the individual level based on CPH model.

Conclusions: In a relatively small dataset with HGG patients treated with PBRT, CPH outperformed RSF for predicting tumor progression. A comprehensive criterion with accuracy, precision, and interpretability is recommended in evaluating ML prognostication approaches for clinical deployment.
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http://dx.doi.org/10.3389/fonc.2020.551420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662123PMC
October 2020

Volumetric parameters derived from FLT-PET performed at completion of treatment predict efficacy of Carbon-ion Radiotherapy in patients with locally recurrent Nasopharyngeal Carcinoma.

J Cancer 2020 17;11(23):7073-7080. Epub 2020 Oct 17.

Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Shanghai 201321, China.

The purpose of this study was to investigate the role of 3'-deoxy-3'-[F]fluorothymidine (FLT)-PET for predicting the outcome of patients with locally recurrent nasopharyngeal carcinoma (LR-NPC) treated by carbon-ion radiotherapy (CIRT). Patients received FLT-PET/CT scan one-week prior to or after completion of CIRT were enrolled in the study. All patients were from prospective trials or treated using a standardized protocol. Time-dependent receiver operator characteristics (ROC) were used to determine the optimal cutoff values for FLT-PET parameters. Univariable and multivariable analyses of local progression-free survival (LPFS) were performed using Cox regression, to examine the prognostic value of FLT-PET parameters, including SUV, metabolic tumor volume (MTV) and total lesion thymidine (TLT). A total of 41 patients were enrolled. Elevated MTV and TLT were significantly associated with worse LPFS, in both univariable and multivariable analyses. ROC analysis revealed that both an MTV value higher than 8.6 and a TLT value higher than 14.9 were predictive of increased risk of developing local recurrence, the adjusted HRs were 5.59 (=0.009) and 7.76 (=0.002), respectively. In conclusion, FLT-PET was found to be a promising prognostic tool for LR-NPC patients and might play a role in the treatment guidance.
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http://dx.doi.org/10.7150/jca.46490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591998PMC
October 2020

Particle Beam Radiation Therapy for Adenoid Cystic Carcinoma of the Nasal Cavity and Paranasal Sinuses.

Front Oncol 2020 30;10:572493. Epub 2020 Sep 30.

Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Shanghai, China.

Sinonasal adenoid cystic carcinoma (SNACC) presents a challenge to oncologists due to its complex anatomy and poor prognosis. Although radiation therapy, either definitive or adjuvant to surgery, is an important part of the multidisciplinary management of SNACC, photon-based radiotherapy yielded suboptimal local control. The purpose of this study was to report the clinical results of a large patient cohort treated with particle beam radiation therapy. Patients with SNACC that received proton beam therapy (PBT), carbon-ion radiotherapy (CIRT) or a combination of CIRT and PBT between May 2015 and May 2019 were included in the analysis. Three patients were treated with PBT, 17 with CIRT and 18 received PBT and a CIRT boost. Overall survival (OS), progression-free survival (PFS), local control (LC), regional control (RC), and distant metastasis-free (DMF) rates were calculated using the Kaplan-Meier method. Toxicities were reported using the CTCAE (version 4.03). A total of 38 patients were included in this analysis. Of these patients, 12 had recurrent disease, including 10 whose previous photon-based RT had failed. The most common primary tumor site was the maxillary sinus. Thirty-six patients (94.7%) suffered from locally advanced disease (T3-4). After a median follow-up of 27.2 months, the 3-year OS, PFS, LC, RC, and DMF rates were 96.7, 80.6, 90.0, 100, and 88.7%, respectively. No acute toxicities of grade 3 or above were observed. Two patients experienced grade 3 xerostomia or vision decreased, and one patient died of hemorrhage. PBT, CIRT or a combination of CIRT and PBT appeared to be a promising treatment option for SNACC and produced satisfactory local control and toxicity profile. Longer follow-up is needed to verify the long-term benefit of particle-beam radiation therapy (PBRT) for patients with SNACC.
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http://dx.doi.org/10.3389/fonc.2020.572493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556111PMC
September 2020

The Technical and Clinical Implementation of LATTICE Radiation Therapy (LRT).

Radiat Res 2020 Dec;194(6):737-746

Department of Radiation Oncology Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York.

The concept of spatially fractionated radiation therapy (SFRT) was conceived over 100 years ago, first in the form of GRID, which has been applied to clinical practice since its early inception and continued to the present even with markedly improved instrumentation in radiation therapy. LATTICE radiation therapy (LRT) was introduced in 2010 as a conceptual 3D extension of GRID therapy with several uniquely different features. Since 2014, when the first patient was treated, over 150 patients with bulky tumors worldwide have received LRT. Through a brief review of the basic principles and the analysis of the collective clinical experience, a set of technical recommendations and guidelines are proposed for the clinical implementation of LRT. It is to be recognized that the current clinical practice of SFRT (GRID or LRT) is still largely based on the heuristic principles. With advancements in basic biological research and the anticipated clinical trials to systemically assess the efficacy and risk, progressively robust optimizations of the technical parameters are essential for the broader application of SFRT in clinical practice.
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http://dx.doi.org/10.1667/RADE-20-00066.1DOI Listing
December 2020

Particle Beam Radiation Therapy for Skull Base Sarcomas.

Front Oncol 2020 16;10:1368. Epub 2020 Sep 16.

Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Shanghai, China.

To report the clinical experience of carbon-ion and proton radiation therapy for skull base sarcomas. An analysis of the retrospective data registry from the Shanghai Proton and Heavy Ion Center for patients with skull base sarcomas was conducted. The 1-/2-year local relapse-free, distant metastasis-free, progression-free, and overall survival (LRFS, DMFS, PFS, OS) rates as well as associated prognostic indicators were analyzed. Radiotherapy-induced acute and late toxicities were summarized. Between 7/2014 and 5/2019, 62 patients with skull base sarcomas of various subtypes received carbon-ion radiation therapy (53), proton radiation therapy (5), or proton radiation therapy + carbon-ion boost (4). With a median follow-up of 20.4 (range 2.73-91.67) months, the 1-/2-year OS, LRFS, DMFS, and PFS rates were 91.2%/80.2%, 89.2%/80.2%, 86.0%/81.1%, and 75.8%/62.9%, respectively. Grade 3 mucositis and grade 4 hemorrhage were observed in 1 patient for each. Only grade 1 and grade 2 toxicities were observed except for the same patient with grade 4 acute toxicity died of severe hemorrhage (grade 5). Multivariate analyses revealed the lack of prior RT was an independent favorable prognostic factor for OS, PFS, and LRFS, age under 40 was associated with improved OS, early T-disease (T1/2) showed a significant association with better PFS. With few observed acute and late toxicities, particle beam radiation therapy provided effective tumor control and overall survival for patients with skull base sarcomas.
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http://dx.doi.org/10.3389/fonc.2020.01368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525010PMC
September 2020

Particle beam radiation therapy for sinonasal malignancies: Single institutional experience at the Shanghai Proton and Heavy Ion Center.

Cancer Med 2020 11 25;9(21):7914-7924. Epub 2020 Sep 25.

Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Shanghai, China.

Background: Sinonasal malignancies (SNM) include malignant neoplasms of various histologies that originate from the paranasal sinuses or nasal cavity. This study reported the safety and efficacy of particle-beam radiation therapy (PBRT) for the treatment of sinonasal malignancies.

Methods And Materials: One-hundred-and-eleven patients with nonmetastatic sinonasal malignancies received definitive (82.9%) or salvage (31.5%) PBRT. The majority (85.6%) of patients presented with T3/4 disease, and only 19 (17.1%) had R0 or R1 resection. Seventy (63.1%) patients received carbon-ion radiotherapy (CIRT), 37 received proton radiotherapy (PRT) followed by CIRT boost, and 4 received PRT alone. Prognostic factors were analyzed using Cox regression for univariate and multiple regression. Toxicities were reported using the Common Terminology Criteria for Adverse Events (version 4.03).

Results: The median follow-up was 20.2 months for the entire cohort. The 2-year local progression-free survival (LPFS), regional progression-free survival (RPFS), distant metastasis-free survival (DMFS), progression-free survival (PFS), and overall survival (OS) rates were 83%, 97.2%, 85.9%, 66%, and 82%, respectively. Re-irradiation and large GTV were the significant factors for OS. Melanoma and sarcoma patients had significantly higher distant metastatic rate, and poorer OS and PFS. Late toxicity occurred in 22 (19.8%) patients, but only 4 (3.6%) patients experienced grades 3-4 late toxicity.

Conclusions: Particle-beam radiation therapy results in excellent local-regional control with extremely low serve toxicities for patients with SNM. Sarcoma and melanoma were featured with a greater risk of death from distant dissemination. Patients who underwent re-irradiation had significantly worse OS. PBRT is feasible and safe in the management of SNM.
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http://dx.doi.org/10.1002/cam4.3393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643686PMC
November 2020

The Impacts of Different Types of Radiation on the CRT and PDL1 Expression in Tumor Cells Under Normoxia and Hypoxia.

Front Oncol 2020 19;10:1610. Epub 2020 Aug 19.

Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, China.

Introduction: Hypoxia is a hallmark of cancer that may contribute to an immunosuppressive microenvironment and promote radioresistance. High linear energy transfer (LET) radiation is considered to be able to overcome the negative effects of hypoxia. However, the anti-tumorigenic effects induced by low or high LET radiation have not been fully elucidated. This study aimed to compare the effects of different types of radiation on the immune response, particularly the impact on calreticulin (CRT), and programmed cell death ligand 1 (PDL1) expression.

Methods: Four human tumor cell lines were investigated in this study. Cells in normoxic and hypoxic groups were irradiated with 4Gy (physical dose) photon, proton, and carbon-ion radiation, respectively. The expression of CRT and PDL1 was detected 48 h after irradiation, and the median fluorescence intensities (MFIs) were compared by flow cytometry. Meanwhile, the radiosensitivity of tumor cells in each group was also compared by colony formation assays and flow cytometry.

Results: All types of radiation could significantly inhibit the colony formation of tumor cells under normoxia. However, the efficacy of photon and proton radiation was impaired under hypoxia. Carbon-ion radiation could still inhibit colony formation. The percentage of viable cells after irradiation was higher under hypoxia compared with those under normoxia. The CRT expression under normoxia was significantly increased after radiation. Carbon-ion radiation enhanced CRT expression compared to photon and proton radiation. Conversely, under hypoxia, the CRT expression level was significantly upregulated at baseline (0Gy). Radiation could not increase the expression further. PDL1 expression was also significantly increased by radiation under normoxia in all cell lines except the Ln18 cell line. Carbon-ion radiation induced the most significant increase. Under hypoxia, the PDL1 expression level was also upregulated at baseline and radiation could not increase expression further.

Conclusion: Tumor cells were resistant to photon and proton but sensitive to carbon-ion radiation under hypoxia. Carbon-ion radiation could induce the highest CRT and PDL1 expression under normoxia. However, under hypoxia, radiation could not further enhance the high baseline expression of CRT and PDL1.
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http://dx.doi.org/10.3389/fonc.2020.01610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466457PMC
August 2020

Intensity-modulated particle beam radiation therapy in the management of olfactory neuroblastoma.

Ann Transl Med 2020 Aug;8(15):926

Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Shanghai, China.

Background: To report the clinical experience and short-term efficacy in the management of olfactory neuroblastoma (ONB).

Methods: We performed a retrospective analysis of 12 ONB patients treated with particle beam radiation therapy (PBRT) between 12/2015 and 5/2019 at the Shanghai Proton and Heavy Ion Center. Four (33.3%) patients presented with Kadish B ONB, and 8 (66.7%) presented with Kadish C or D disease. Eleven patients received proton radiotherapy (PRT) followed by a carbon ion radiotherapy (CIRT) boost, one patient received CIRT only. The 2-year survival rates were calculated using the Kaplan-Meier method. Acute and late adverse events were summarized and scored according to the CTCAE (version 4.03).

Results: With a median follow-up of 17.5 (range, 2.53-49.9) months, all patients but 1 were alive. Eight patients were alive without evidence of disease, and 2 additional patients achieved partial response and remained alive with residual disease. One patient died of toxicity associated with salvage chemotherapy for distant metastasis and local failure. Another patient developed distant metastasis only and was alive at the time of the last follow-up. The 2-year OS, PFS, LRPFS, and DMFS rates were 83.3%, 75.8%, 87.5%, and 79.5%, respectively. No acute or late toxicities of ≥ grade 3 was observed.

Conclusions: Intensity modulated PBRT of ONB is well tolerated. While longer follow-up is needed, early outcomes suggested that PBRT is safe and effective for the treatment of ONB with minimal adverse events.
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http://dx.doi.org/10.21037/atm-19-4790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475427PMC
August 2020

Carbon ion radiation therapy for sinonasal malignancies: Promising results from 2282 cases from the real world.

Cancer Sci 2020 Dec 16;111(12):4465-4479. Epub 2020 Oct 16.

Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Shanghai, China.

The aim of this study is to compare the effectiveness of carbon ion radiation therapy (CIRT), proton radiation therapy (PRT), and photon-based intensity-modulated radiation therapy (IMRT) in the treatment of sinonasal malignancies. We identified studies through systematic review and divided them into three cohorts (CIRT group/PRT group/IMRT group). Primary outcomes of interest were overall survival (OS) and local control (LC). We pooled the outcomes with meta-analysis and compared the survival difference among groups using Chi (χ ) test. A representative sample of 2282 patients with sinonasal malignancies (911 in the CIRT group, 599 in the PRT group, and 772 in the IMRT group) from 44 observation studies (7 CIRT, 16 PRT, and 21 IMRT) was included. The pooled 3-year OS, LC, distant metastasis-free survival, and progression-free survival rates were 67.0%, 72.8%, 69.4%, and 52.8%, respectively. Through cross-group analysis, the OS was significantly higher after CIRT (75.1%, 95% CI: 67.1%-83.2%) than PRT (66.2%, 95% CI: 57.7%-74.6%; χ  = 13.374, P < .0001) or IMRT (63.8%, 95% CI: 55.3%-72.3%; χ  = 23.814, P < .0001). LC was significantly higher after CIRT (80.2%, 95% CI: 73.9%-86.5%) than PRT (72.9%, 95% CI: 63.7%-82.0%; χ  = 8.955, P = .003) or IMRT (67.8%, 95% CI: 59.4%-76.2%; χ  = 30.955, P < .0001). However, no significant difference between PRT and IMRT for OS and LC was observed. CIRT appeared to provide better OS and LC for patients with malignancies of nasal cavity and paranasal sinuses. A prospective randomized clinical trial is needed to confirm the superiority of CIRT in the treatment of sinonasal tumors.
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http://dx.doi.org/10.1111/cas.14650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734163PMC
December 2020

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

Cancer 2020 12 15;126(23):5173-5183. Epub 2020 Sep 15.

Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Shanghai, China.

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.
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http://dx.doi.org/10.1002/cncr.33197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693227PMC
December 2020

Intensity-Modulated Radiation Therapy for Esthesioneuroblastoma: 10-Year Experience of a Single Institute.

Front Oncol 2020 17;10:1158. Epub 2020 Jul 17.

Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.

To evaluate efficacy and safety of intensity-modulated radiotherapy (IMRT) in the management of esthesioneuroblastoma (ENB). A retrospectively analysis of 52 ENB patients treated with IMRT between 8/2008 and 8/2018 was performed. Thirteen of the 44 patients (29.5%) with newly diagnosed and 2 of the 8 patients with recurrent disease presented regional lymph node metastasis. The median dose of IMRT was 66 (range 52.5-75) Gy for all patients. Elective nodal irradiation (ENI) was provided to all excluding 6 patients in this cohort. With a median follow-up time of 32.5 (6~121) months, the 3-year overall survival (OS), progression-free survival (PFS), local progression-free survival (LPFS), regional progression-free survival (RPFS), and distant metastasis-free survival (DMFS) rates for the entire cohort were 89.7, 69.5, 89.7, 95.1, and 85.4%, respectively. Multivariate analysis revealed that N-classification (N- vs. N+) at presentation was the only significant prognosticators for PFS. No significant prognosticator was identified for other survival outcome. No severe (i.e., grade 3 or 4) IMRT-induced acute toxicity was observed. Severe late toxicities were infrequent (11.5%), which included dysosmia (3.8%), hearing loss (3.8%), radiation brain injury (1.9%), and temporal lobe necrosis (1.9%). Moreover, late ocular toxicity secondary to IMRT was not observed. IMRT produced acceptable 3-year outcomes in terms of OS (89.7%), LPFS (89.7%), and RPFS (95.1%) rates without substantial late adverse effects. Further investigations for a more effective systemic strategy for distant disease control as well as a precision radiation technique for further improvement in local control are needed.
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http://dx.doi.org/10.3389/fonc.2020.01158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7379860PMC
July 2020

Mesoporous Bi-Containing Radiosensitizer Loading with DOX to Repolarize Tumor-Associated Macrophages and Elicit Immunogenic Tumor Cell Death to Inhibit Tumor Progression.

ACS Appl Mater Interfaces 2020 Jul 1;12(28):31225-31234. Epub 2020 Jul 1.

Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Shanghai 201321, China.

Tumor-associated macrophages (TAMs) were a major component of tumor, which comprised up to 50% of tumor mass, and correlated with poor prognosis in more than 80% of cases. TAMs were resistant to radiotherapy and chemotherapy, and radiation could further activate TAMs to promote tumor progression. Herein, we explored a kind of Bi-based mesoporous upconversion nanophosphor (UCNP) loaded with doxorubicin (UCNP-DOX) to elicit immunogenic tumor cell death and repolarize TAMs to an antitumor M1-like type for strengthening the tumor-specific antitumor immune effects of X-ray radiotherapy. The repolarization effect of UCNP-DOX with X-ray was confirmed in THP-1 cell line, mouse model, and hydrothorax of a non-small-cell lung carcinoma patient. Moreover, the UCNP-DOX and X-ray radiation could elicit immunogenic tumor necrosis, presenting more tumor antigens for tumor-specific immune response. In a cell co-incubation system, activated macrophages could significantly inhibit cancer colony formation, migration, and invasion. After treatment, xenografted tumor in mice was also found to be significantly regressed and presented substantial CD8-positive T cells. This study opens the door to further enhance the abscopal effects and inhibit the metastasis in radiotherapy.
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http://dx.doi.org/10.1021/acsami.0c08074DOI Listing
July 2020

A machine learning framework with anatomical prior for online dose verification using positron emitters and PET in proton therapy.

Phys Med Biol 2020 09 14;65(18):185003. Epub 2020 Sep 14.

Department of Medical Physics, Wuhan University, Wuhan, 430072 People's Republic of China.

We developed a machine learning framework in order to establish the correlation between dose and activity distributions in proton therapy. A recurrent neural network was used to predict dose distribution in three dimensions based on the information of proton-induced positron emitters. Hounsfield Unit (HU) information from CT images and analytically derived stopping power (SP) information were incorporated as auxiliary inputs. Four different scenarios were investigated: Activity only, Activity + HU, Activity + SP and Activity + HU + SP. The performance was quantitatively studied in terms of mean absolute error (MAE) and mean relative error (MRE), under different signal-to-noise ratios (SNRs). In addition to the first dataset of mono-energetic beams, three additional datasets were validated to help evaluate the generalization capability of our proposed model: a dataset of a lower SNR, five reconstructed PET images, and a dataset of spread-out Bragg peaks. Good verification accuracy of dose verification in three dimensions is demonstrated. The inclusion of anatomical information improves both accuracy and generalization. For an activity profile with an SNR of 4 (the mono-energetic case), the framework is able to obtain an MRE of ∼ 0.99% over the whole range and a range uncertainty of ∼ 0.27 mm. The machine learning-based framework may emerge as a useful tool to allow for online dose verification and quality assurance in proton therapy.
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http://dx.doi.org/10.1088/1361-6560/ab9707DOI Listing
September 2020

Evaluating dosimetric constraints for carbon ion radiotherapy in the treatment of locally advanced pancreatic cancer.

Radiat Oncol 2020 May 7;15(1):101. Epub 2020 May 7.

Department of Medical Physics, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, 4365 Kangxin Road, Shanghai, 201318, China.

Objective: To identify a safe carbon ion radiotherapy (CIRT) regimen for patients with locally advanced pancreatic cancer (LAPC).

Methods: We generated treatment plans for 13 consecutive, unselected patients who were treated for LAPC with CIRT at our center using three dose and fractionation schedules: 4.6 GyRBE × 12, 4.0 GyRBE × 14, and 3.0 GyRBE × 17. We tested the ability to meet published dose constraints for the duodenum, stomach, and small bowel as a function of dose schedule and distance between the tumor and organs at risk.

Results: Using 4.6 GyRBE × 12 and 4.0 GyRBE × 14, critical (high-dose) constraints could only reliably be achieved when target volumes were not immediately adjacent to organs at risk. Critical constraints could be met in all cases using 3.0 GyRBE × 17. Low-dose constraints could not uniformly be achieved using any dose schedule.

Conclusion: While selected patients with LAPC may be treated safely with a CIRT regimen of 4.6 GyRBE × 12, our dosimetric analyses indicate that a more conservative schedule of 3.0 GyRBE × 17 may be required to safely treat a broader population of LAPC patients, including those with large tumors and tumors that approach gastrointestinal organs at risk. The result of this work was used to guide an ongoing clinical trial.
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http://dx.doi.org/10.1186/s13014-020-01515-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204055PMC
May 2020

Experience of a Radiation Oncology Center Operating During the COVID-19 Outbreak.

Authors:
Jiade J Lu

Adv Radiat Oncol 2020 Jul-Aug;5(4):548-549. Epub 2020 Apr 10.

Shanghai Proton and Heavy Ion Center, Shanghai, China.

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http://dx.doi.org/10.1016/j.adro.2020.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195375PMC
April 2020

Particle radiation therapy in the management of malignant glioma: Early experience at the Shanghai Proton and Heavy Ion Center.

Cancer 2020 06 13;126(12):2802-2810. Epub 2020 Mar 13.

Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, China.

Background: The objective of this study was to evaluate the outcomes of patients with high-grade glioma who received treatment with particle radiotherapy.

Methods: Between June 2015 and October 2018, 50 consecutive and nonselected patients with glioblastoma multiforme (n = 34) or anaplastic glioma (n = 16) were treated at the Shanghai Proton and Heavy Ion Center. Twenty-four patients received proton radiotherapy (at a dose of 60 gray-equivalents in 30 daily fractions), and 26 patients received proton radiotherapy plus a carbon-ion radiotherapy (CIRT) boost in various dose-escalating schemes. All patients received temozolomide because of their age or their O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. Progression-free survival (PFS) and overall survival (OS) rates, as well as treatment-induced toxicities, were analyzed.

Results: At a median follow-up of 14.3 months (range, 4.8-39.6 months), the 12-month and 18-month OS rates were 87.8% (95% CI, 77.6%-98.0%) and 72.8% (95% CI, 56.7%-88.9%), respectively, and the 12-month and 18-month PFS rates were 74.2% (95% CI, 60.9%-87.5%) and 59.8% (95% CI, 43.1%-76.5%), respectively. Univariate analyses revealed that age (>50 vs ≤50 years), World Health Organization grade (3 vs 4), and Karnofsky performance status (>80 vs ≤80) were significant prognosticators for OS, and IDH mutation and World Health Organization grade were significant for predicting PFS. Furthermore, MGMT promoter methylation, performance status, and age showed a trend toward predicting PFS. No significant predictive factors for PFS or OS were identified in multivariate analyses. Twenty-nine patients experienced grade 1 treatment-related acute adverse effects, and 11 developed grade 1 (n = 6) or grade 2 (n = 5) late adverse effect of radiation-induced brain necrosis. No grade 3, 4, or 5 toxicities were observed.

Conclusions: Particle radiotherapy produced 18-month OS and PFS rates of 72.8% and 59.8%, respectively, with acceptable adverse effects in patients with high-grade glioma. Particle radiotherapy at a dose ≥60 gray-equivalents appears to be safe and potentially effective.
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http://dx.doi.org/10.1002/cncr.32828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317504PMC
June 2020

Depletion of MLKL inhibits invasion of radioresistant nasopharyngeal carcinoma cells by suppressing epithelial-mesenchymal transition.

Ann Transl Med 2019 Dec;7(23):741

Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai 201321, China.

Background: To examine whether MLKL participated in the invasion of radiosensitive nasopharyngeal carcinoma (NPC) cell (CNE-2) and radioresistant NPC cell (CR) through regulating epithelial-mesenchymal transition (EMT).

Methods: siRNA and CRISPR/Cas9 technique were used to decrease MLKL expression in NPC cell (CNE-2 and CR). Trans-well assay was conducted to evaluate invasion. Gene expression profiling was performed using Human U133 2.0 plus arrays (Affymetrix). Kyoto Encyclopedia of Genes and Genomes (KEGG) was adopted to analyze gene expression profiling. Hub genes at a functional level were accessed by protein-to-protein network (PPI). Quantitative real-time PCR and Western blot were used to access EMT markers.

Results: Invasion of CR was about 3~fold change higher than that of CNE-2. Silencing MLKL by siRNA inhibited invasion of CR, not CNE-2. Further, depleting MLKL by CRISPR-Cas9 in CR (CR-MLKL KO) also inhibited its invasion. KEGG pathway analysis showed invasion-related pathways were altered, such as adherent junction, TGF-β signaling pathway. PPI demonstrated that compared with CNE-2, CR showed 9 elevated hub genes including and 1 downregulated hub gene . After MLKL depletion, 8 hub genes were downregulated () and 2 hub genes were upregulated (). Quantitative real-time PCR results showed that compared with CNE-2, CR displayed decreased epithelial markers significantly (E-Cadherin) and increased mesenchymal markers significantly (Vimentin, N-Cadherin, Zeb1), indicating irradiation-induced EMT. After depletion of MLKL in CR, the expression of E-Cadherin, Vimentin, N-Cadherin, Zeb1 was reversed to the level of CNE-2. Western blot confirmed the results from qRT-PCR.

Conclusions: Depletion of MLKL efficiently inhibits invasion of radioresistant NPC by suppressing EMT. MLKL may be an important target to suppress distant metastasis of NPC patients who relapsed after radiotherapy.
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http://dx.doi.org/10.21037/atm.2019.11.104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990020PMC
December 2019

Proton and carbon ion radiation therapy for locally advanced pancreatic cancer: A phase I dose escalation study.

Pancreatology 2020 Apr 20;20(3):470-476. Epub 2020 Jan 20.

Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Shanghai, China; Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, China. Electronic address:

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.
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http://dx.doi.org/10.1016/j.pan.2020.01.010DOI Listing
April 2020

Proton minibeams-a springboard for physics, biology and clinical creativity.

Br J Radiol 2020 Mar 24;93(1107):20190332. Epub 2020 Jan 24.

Department of Radiation Oncology, Mayo Clinic Florida, Jacksonville, FL, USA.

Proton minibeam therapy (PMBT) is a form of spatially fractionated radiotherapy wherein broad beam radiation is replaced with segmented minibeams-either parallel, planar minibeam arrays generated by a multislit collimator or scanned pencil beams that converge laterally at depth to create a uniform dose layer at the tumor. By doing so, the spatial pattern of entrance dose is considerably modified while still maintaining tumor dose and efficacy. Recent studies using computational modeling, phantom experiments, and preclinical models, and early clinical feasibility assessments suggest that unique physical and biological attributes of PMBT can be exploited for future clinical benefit. We outline some of the guiding principle of PMBT in this concise overview of this emerging area of preclinical and clinical research inquiry.
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http://dx.doi.org/10.1259/bjr.20190332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066973PMC
March 2020

Comparison of the effects of photon, proton and carbon-ion radiation on the ecto-calreticulin exposure in various tumor cell lines.

Ann Transl Med 2019 Oct;7(20):542

Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai 201321, China.

Background: Accumulating evidence suggested that radiotherapy can activate anti-tumor immune responses by triggering immunogenic cell death (ICD) of tumor cells. Calreticulin is regarded as one of the most important markers of ICD. The cell surface translocation of calreticulin (ecto-CRT) serves as an "eat me" signal for phagocytosis of dying cells, which plays a pivotal role in activating anti-tumor immunity. However, there is limited knowledge describing the effects of proton and carbon-ion radiation on ecto-CRT exposure. Hence, we investigated ecto-CRT exposure in multiple human carcinoma cell lines irradiated by proton and carbon-ion in comparison to photon.

Methods: This study examined four human cancer cell lines including A549 (lung adenocarcinoma), U251MG (glioma), Tca8113 (tongue squamous carcinoma), and CNE-2 (nasopharyngeal carcinoma). Cell lines were irradiated with photon, proton or carbon-ion at 0, 2, 4, 10 Gy (physical dose). The ecto-CRT exposure level was analyzed by flow cytometry at 12, 24, and 48 h post-irradiation. The median fluorescence intensity was calculated by FlowJo.

Results: All three types of radial beam increased ecto-CRT exposure of the 4 tumor cell lines in a time-dependent manner. Ecto-CRT exposure significantly elevated 1.5-2.4 times over 48 h post-irradiation compared with controls (P<0.05). Proton and photon increased ecto-CRT exposure with dose escalation. Photon and proton at 10 Gy increased the most ecto-CRT exposure (P<0.05), while carbon-ion increased most ecto-CRT exposure at 4 Gy rather than 10 or 2 Gy. When compared with iso-physical dose at 48 h post-irradiation, proton showed a similar effectiveness with photon. While carbon-ion has significantly stronger effects on increasing ecto-CRT than proton and photon at 2 and 4 Gy, but changed oppositely at 10 Gy (P<0.05).

Conclusions: All the three types of radiation can increase the ecto-CRT exposure in a time-dependent manner. Proton and photon radiation were equally effective in inducing ecto-CRT exposure, while carbon-ion revealed a different effectiveness in comparison to photon and proton.
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http://dx.doi.org/10.21037/atm.2019.09.128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861809PMC
October 2019
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