Nanoscale Metal-Organic Frameworks-Mediated Degradation of Mutant p53 Proteins and Activation of cGAS-STING Pathway for Enhanced Cancer Immunotherapy.

Activating cGAS-STING pathway has great potential to achieve effective antitumor immunotherapy. However, mutant p53 (mutp53), a commonly observed genetic alteration in over 50% of human cancer, will impede the therapeutic performance of the cGAS-STING pathway. Herein, multifunctional ZIF-8@MnO2 nanoparticles are constructed to degrade mutp53 and facilitate the cGAS-STING pathway. The synthesized ZIF-8@MnO2 can release Zn2+ and Mn2+ in cancer cells to induce oxidative stress and cytoplasmic leakage of fragmented mitochondrial double-stranded DNAs (dsDNAs). Importantly, the released Zn2+ induces variable degradation of multifarious p53 mutants through proteasome ubiquitination, which can alleviate the inhibitory effects of mutp53 on the cGAS-STING pathway. In addition, the released Mn2+ further increases the sensitivity of cGAS to dsDNAs as immunostimulatory signals. Both in vitro and in vivo results demonstrate that ZIF-8@MnO2 effectively promotes the cGAS-STING pathway and synergizes with PD-L1 checkpoint blockades, leading to remarkable regression of local tumors as well as distant metastases of breast cancer. This study proposes an inorganic metal ion-based nanoplatform to enhance the cGAS-STING-mediated antitumor immunotherapy, especially to those tumors with mutp53 expression.

Ultrasound-Driven Non-Metallic Fenton-Active Center Construction for Extensive Chemodynamic Therapy.

Chemodynamic therapy (CDT) is an emerging tumor microenvironment-responsive cancer therapeutic strategy based on Fenton/Fenton-like reactions. However, the effectiveness of CDT is subject to the slow kinetic rate and non-homogeneous distribution of H2 O2 . In this study, a conceptual non-metallic "Fenton-active" center construction strategy is proposed to enhance CDT efficiency using Bi0.44 Ba0.06 Na0.5 TiO2.97 (BNBT-6) nanocrystals. The separated charge carriers under a piezoelectric-induced electric field synchronize the oxidation of H2 O and reduction of H2 O2 , which consequently increases hydroxyl radical (·OH) yield even under low H2 O2 levels. Moreover, acceptor doping induces electron-rich oxygen vacancies to facilitate the dissociation of H2 O2 and H2 O and further promote ·OH generation. In vitro and in vivo experiments demonstrate that BNBT-6 induces extensive intracellular oxidative stress and enhances cell-killing efficiency by activating necroptosis in addition to the conventional apoptotic pathway. This study proposes a novel design approach for nanomaterials used in CDT and presents a new treatment strategy for apoptosis-resistant tumors.

Superficial vessel-based near infrared-assisted patient position recognition and real-time monitoring system (VIPS) for radiotherapy: A proof-of-concept study.

BACKGROUND: The accuracy and precision of patient position in radiotherapy process have dramatic impacts on the tumor local control and therapy-related side effects, and there exist demands to explore effective positioning solutions, particularly in the era with great progress in imaging recognition and matching. PURPOSE: Superficial vessel-based near infrared-assisted patient position recognition and real-time monitoring system (VIPS) was proposed to develop an automated, operator-independent and skin marker-free imaging system to improve patient setup and intrafractional motion monitoring. METHODS: VIPS includes two components, the imaging module and the image alignment software. Using a simulated blood vessel model, multiple NIR sources with various wavelength and bolus (pseudo-skin) were evaluated in terms of imaging quality to determine the optimal light source and the upper limit of superficial fatty tissue thickness. Then the performance of VIPS with reference to either CBCT or laser setup system was conducted using 3D phantom and clinical cases enrolled into the registered clinical trial. The position displacement from VIPS and laser system was compared, as well as the systematic and random errors of VIPS setup procedure. RESULTS: The NIR light source with the combined wavelengths of 760 nm + 940 nm (S760+940 nm ) provided the best performance among multiple tested light sources. The bolus (superficial fatty layer) thickness over 5 mm could dramatically compromise the NIR detection of vessels beneath. In the phantom study, the translational positional displacements according to VIPS guidance were within the submillimeter level with reference to CBCT, indicative of high setup accuracy. The clinical trial showed the prototype VIPS could effectively detect and control position displacement of patients in translational and rotational directions within an acceptable range, which was non-inferior to conventional laser/skin marker system. CONCLUSION: This proof-of-concept study validated the feasibility and reliability of VIPS in guiding radiotherapy setup. However, limitations and technical challenges should be resolved prior to further clinical evaluation, including isocenter alignment, potential NIR image distortion and the impact of the superficial tissues on the recognition of vessels.

Regulating electron transportation by tungsten oxide nanocapacitors for enhanced radiation therapy.

In the process of radiation therapy (RT), the cytotoxic effects of excited electrons generated from water radiolysis tend to be underestimated due to multiple biochemical factors, particularly the recombination between electrons and hydroxyl radicals (·OH). To take better advantage of radiolytic electrons, we constructed WO3 nanocapacitors that reversibly charge and discharge electrons to regulate electron transportation and utilization. During radiolysis, WO3 nanocapacitors could contain the generated electrons that block electron-·OH recombination and contribute to the yield of ·OH at a high level. These contained electrons could be discharged from WO3 nanocapacitors after radiolysis, resulting in the consumption of cytosolic NAD+ and impairment of NAD+-dependent DNA repair. Overall, this strategy of nanocapacitor-based radiosensitization improves the radiotherapeutic effects by increasing the utilization of radiolytic electrons and ·OH, warranting further validation in multiple tumour models and preclinical experiments.

Dose escalation based on 18F-FDG PET/CT response in definitive chemoradiotherapy of locally advanced esophageal squamous cell carcinoma: a phase III, open-label, randomized, controlled trial (ESO-Shanghai 12).

INTRODUCTION: Definitive chemoradiotherapy has established the standard non-surgical treatment for locally advanced esophageal cancer. The standard dose of 50-50.4 Gy has been established decades ago and been confirmed in modern trials. The theorical advantage of better local control and technical advances for less toxicity have encouraged clinicians for dose escalation investigation. 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) have the potential to tailor therapy for esophageal patients not showing response to CRT and pioneers the PET-based dose escalation. METHODS AND ANALYSIS: The ESO-Shanghai 12 trial is a prospective multicenter randomized phase 3 study in which patients are randomized to either 61.2 Gy or 50.4 Gy of radiation dose by PET response. Both groups undergo concurrent chemoradiotherapy with paclitaxel/cisplatin regimen for 2 cycles followed by consolidation chemotherapy for 2 cycles. Patients with histologically confirmed ESCC [T1N1-3M0, T2-4NxM0, TxNxM1 (Supraclavicular lymph node metastasis only), (AJCC Cancer Staging Manual, 8th Edition)] and without any prior treatment of chemotherapy, radiotherapy or surgery against esophageal cancer will be eligible. The primary endpoints included overall survival in PET/CT non-responders (SUVmax > 4.0) and overall survival in total population. Patients will be stratified by standardized uptake volume, gross tumor volume and tumor location. The enrollment could be ended, when the number of PET/CT non-responder reached 132 and the total population reached 646 for randomization. ETHICS AND DISSEMINATION: This trial has been approved by the Fudan University Shanghai Cancer Center Institutional Review Board. Trial results will be disseminated via peer reviewed scientific journals and conference presentations. Trial registration The trial was initiated in 2018 and is currently recruiting patients. Trial registration number NCT03790553.

Dosimetric Study of Deep Learning-Guided ITV Prediction in Cone-beam CT for Lung Stereotactic Body Radiotherapy.

Purpose: The purpose of this study was to evaluate the accuracy of a lung stereotactic body radiotherapy (SBRT) treatment plan with the target of a newly predicted internal target volume (ITVpredict) and the feasibility of its clinical application. ITVpredict was automatically generated by our in-house deep learning model according to the cone-beam CT (CBCT) image database. Method: A retrospective study of 45 patients who underwent SBRT was involved, and Mask R-CNN based algorithm model helped to predict the internal target volume (ITV) using the CBCT image database. The geometric accuracy of ITVpredict was verified by the Dice Similarity Coefficient (DSC), 3D Motion Range (R3D), Relative Volume Index (RVI), and Hausdorff Distance (HD). The PTVpredict was generated by ITVpredict, which was registered and then projected on free-breath CT (FBCT) images. The PTVFBCT was margined from the GTV on FBCT images gross tumor volume on free-breath CT (GTVFBCT). Treatment plans with the target of Predict planning target volume on CBCT images (PTVpredict) and planning target volume on free-breath CT (PTVFBCT) were respectively re-established, and the dosimetric parameters included the ratio of the volume of patients receiving at least the prescribed dose to the volume of PTV (R100%), the ratio of the volume of patients receiving at least 50% of the prescribed dose to the volume of PTV in the Radiation Therapy Oncology Group (RTOG) 0813 Trial (R50%), Gradient Index (GI), and the maximum dose 2 cm from the PTV (D2cm), which were evaluated via Plan4DCT, plan which based on PTVpredict (Planpredict), and plan which based on PTVFBCT (PlanFBCT). Result: The geometric results showed that there existed a good correlation between ITVpredict and ITV on the 4-dimensional CT [ITV4DCT; DSC= 0.83 ±0.18]. However, the average volume of ITVpredict was 10% less than that of ITV4DCT (p = 0.333). No significant difference in dose coverage was found in V100% for the ITV with 99.98 ± 0.04% in the ITV4DCT vs. 97.56 ± 4.71% in the ITVpredict (p = 0.162). Dosimetry parameters of PTV, including R100%, R50%, GI and D2cm showed no statistically significant difference between each plan (p > 0.05). Conclusion: Dosimetric parameters of Planpredict are clinically comparable to those of the original Plan4DCT. This study confirmed that the treatment plan based on ITVpredict produced by our model could automatically meet clinical requirements. Thus, for patients undergoing lung SBRT, the model has great potential for using CBCT images for ITV contouring which can be used in treatment planning.

Comparison of 3 Paclitaxel-Based Chemoradiotherapy Regimens for Patients With Locally Advanced Esophageal Squamous Cell Cancer: A Randomized Clinical Trial.

Importance: Multiple paclitaxel-based regimens are widely used in chemoradiation therapy against esophageal cancer, including regimens combining paclitaxel with fluorouracil, cisplatin, and carboplatin. However, which among these 3 regimens provides the best prognosis with minimum adverse events is still unknown. Objective: To compare the efficacy and adverse events of fluorouracil, cisplatin, and carboplatin in definitive chemoradiotherapy in patients with esophageal squamous cell carcinoma (ESCC). Design, Setting, and Participants: This randomized clinical trial of patients with ESCC was conducted in 11 treatment centers in China. Eligible patients were aged 18 to 75 years and had histologically confirmed ESCC stages IIa to IVa with no prior treatment, Eastern Cooperative Oncology Group performance status of 2 or lower, and adequate organ functions. The study was conducted between July 2015 and February 2018, and the cutoff date for data analysis was August 31, 2020. Interventions: Patients with locally advanced ESCC were randomly assigned (1:1:1) to groups combining paclitaxel treatment with fluorouracil, cisplatin, or carboplatin. Patients in the cisplatin group were treated with 2 cycles of concurrent chemoradiotherapy followed by 2 cycles of consolidation chemotherapy with monthly paclitaxel plus cisplatin. For the fluorouracil group, patients were administered 6 cycles of weekly paclitaxel plus fluorouracil in concurrent chemoradiotherapy followed by 2 cycles of monthly paclitaxel plus fluorouracil in consolidation chemotherapy. Patients in the carboplatin group were treated with 6 cycles of weekly paclitaxel plus carboplatin in concurrent chemoradiotherapy followed by 2 cycles of monthly paclitaxel plus carboplatin in consolidation chemotherapy. All patients received radiotherapy of 61.2 Gy delivered in 34 fractions. Main Outcomes and Measures: The primary end point was overall survival (OS). The secondary end points were progression-free survival and adverse events. Results: Overall, 321 patients (median [IQR] age, 64 years [59-69 years]; 248 [77.3%] men) with ESCC from 11 centers were randomized into fluorouracil, cisplatin, or carboplatin groups between July 2015 and February 2018. Over a median (IQR) follow-up time of surviving patients of 46.0 months (36.6-53.0 months), the 3-year OS rates were 57.2% in the fluorouracil group, 60.1% in the cisplatin group, and 56.5% in the carboplatin group, respectively (fluorouracil vs cisplatin: HR, 1.06; 95% CI, 0.71-1.60; P = .77; fluorouracil vs carboplatin: HR, 0.94; 95% CI, 0.63-1.40; P = .77). The cisplatin group had significantly higher incidences of acute grade 3 or 4 neutropenia (69 events [60.8%] vs 19 [17.8%] for fluorouracil and 37 [34.6%] carboplatin; P < .001), thrombocytopenia (14 events [13.1%] vs 4 [3.7%] for fluorouracil and 5 [4.7%] for carboplatin; P = .01), anemia (50 events above grade 2 [46.7%] vs 25 [23.4%] for fluorouracil and 37 [34.6%] for carboplatin; P = .35), fatigue (11 events [10.3%] vs 2 [1.9%] for fluorouracil and 1 [0.9%] carboplatin; P = .007), and vomiting (17 events above grade 2 [15.9%] vs 3 [2.8%] for fluorouracil and 5 [4.7%] for carboplatin; P < .001) than the other 2 groups. Conclusions and Relevance: In this randomized clinical trial, paclitaxel plus fluorouracil did not show OS superiority over paclitaxel plus cisplatin or paclitaxel plus carboplatin regimens in definitive chemoradiation in patients with locally advanced ESCC. Higher rates of hematologic and gastrointestinal toxic effects were reported in the cisplatin group compared with those in the fluorouracil or carboplatin groups. Trial Registration: ClinicalTrials.gov Identifier: NCT02459457.

Deep Learning-Based Internal Target Volume (ITV) Prediction Using Cone-Beam CT Images in Lung Stereotactic Body Radiotherapy.

Purpose:This study aims to develop a deep learning (DL)-based (Mask R-CNN) method to predict the internal target volume (ITV) in cone beam computed tomography (CBCT) images for lung stereotactic body radiotherapy (SBRT) patients and to evaluate the prediction accuracy of the model using 4DCT as ground truth. Methods and Materials: This study enrolled 78 phantom cases and 156 patient cases who received SBRT treatment. We used a novel DL model (Mask R-CNN) to identify and delineate lung tumor ITV in CBCT images. The results of the DL-based method were compared quantitatively with the ground truth (4DCT) using 4 metrics, including Dice Similarity Coefficient (DSC), Relative Volume Index (RVI), 3D Motion Range (R3D), and Hausdorff Surface Distance (HD). Paired t-tests were used to determine the differences between the DL-based method and manual contouring. Results: The DSC value for 4DCTMIP versus CBCT is 0.86 ± 0.16 and for 4DCTAVG versus CBCT is 0.83 ± 0.18, indicating a high similarity of tumor delineation in CBCT and 4DCT. The mean Accuracy Precision (mAP), R3D, RVI, and HD values for phantom evaluation are 0.94 ± 0.04, 1.37 ± 0.36, 0.79 ± 0.02, and 6.79 ± 0.68, respectively. For patient evaluation, the mAP, R3D, RVI, and HD achieved averaged values of 0.74 ± 0.23, 2.39 ± 1.59, 1.27 ± 0.47, and 17.00 ± 19.89, respectively. These results showed a good correlation between predicted ITV and manually contoured ITV. The phantom p-value for RVI, R3D, and HD are 0.75, 0.08, 0.86, and patient p-value are 0.53, 0.07, 0.28, respectively. These p-values for phantom and patient showed no significant difference between the predicted ITV and physician's manual contouring. Conclusion:The current improved method (Mask R-CNN) yielded a good similarity between predicted ITV in CBCT and the manual contouring in 4DCT, thus indicating great potential for using CBCT for patient ITV contouring.

The relationship between the degree of brain edema regression and changes in cognitive function in patients with recurrent glioma treated with bevacizumab and temozolomide.

BACKGROUND: This retrospective study aims to assess the impacts on cognitive status and quality of life in recurrent high-grade glioma patients treated with temozolomide (TMZ), either alone or in combination with bevacizumab (BEV), and explore the relationship between the brain edema regression, BEV use, and cognitive status. METHODS: A total of 125 patients with recurrent high-grade glioma were enrolled in this study, of which 65 patients were treated with BEV (5-10 mg/kg IV every 2 weeks) plus TMZ (200 mg/m2 every 28 days, d1-5), and 60 patients were treated with TMZ (200 mg/m2 every 28 days, d1-5) alone. The treatment response was evaluated using the Response Assessment in Neuro-Oncology (RANO) criteria. Tumor-associated edema was evaluated with T2WI magnetic resonance imaging (MRI) and quantitative T2 mapping sequence, and an Edema Regression Index was designed to quantify volumetric changes in edema imaging after every treatment cycle. Cognitive intelligence state and quality of life were evaluated using the Mini-Mental State Examination (MMSE) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30). RESULTS: Radiologically, the partial response rate was 78.5% in the BEV + TMZ group and 38.3% in the TMZ group. After the first cycle of treatment, the mean score of the MMSE was 21.1±2.0 and 24.1±1.4 (P<0.001) in the TMZ group and the BEV + TMZ group, respectively. In the functioning domains of the QLQ-C30, scales of physical functioning, emotional functioning and cognitive functioning were 43.0±7.0 vs. 61.7±12.5 (P<0.001), 44.5±8.8 vs. 63.4±6.9 (P<0.001) and 42.4±8.8 vs. 63.7±12.0 (P<0.001) in the TMZ group and the BEV + TMZ group, respectively. In the BEV + TMZ group, a correlation between the Edema Regression Index and improvement in cognitive status and quality of life was observed. Patients with Edema Regression Index scores higher than 50% gained a 25.6% increase in the mean MMSE score from 19.9±1.6 to 25.0±1.1 (P<0.001). In the BEV + TMZ group, physical functioning, emotional functioning, and cognitive functioning increased by 76.8%, 53.1%, and 81.5%, respectively, while scores of nausea/vomiting decreased by 40.3% to 32.1. Patients with no evident edema observed in the pre-BEV MRI scans were given a prolonged four-cycle course of BEV. No significant improvement was observed in the MMSE score and the QLQ score with additional cycles of BEV. CONCLUSIONS: A close relationship was observed between Edema Regression Index and a change in cognitive function in patients treated with BEV and TMZ. Compared with TMZ alone, the combination of TMZ and BEV could improve the cognitive function and quality of life of patients with recurrent high-grade gliomas. The Edema Regression Index could be used as a surrogate imaging biomarker to predict patients who may or may not gain cognitive benefit from the combination therapy of TMZ and BEV, which warrants further prospective clinical studies for validation.

Cardiac Dose Control and Optimization Strategy for Left Breast Cancer Radiotherapy With Non-Uniform VMAT Technology.

Purpose: A novel in-house technology "Non-Uniform VMAT (NU-VMAT)" was developed for automated cardiac dose reduction and treatment planning optimization in the left breast radiotherapy. Methods: The NU-VMAT model based on IGM (gantry MLC Movement coefficient index) was established to optimize the volumetric modulated arc therapy (VMAT) MLC movement and modulation intensity in certain gantry angles. The ESAPI embedded in Eclipse® was employed to connect TPS and the optimization program via I/O relevant DICOM RT files. The adjuvant whole-breast radiotherapy of 14 patients with left breast cancer was replanned using our NU-VMAT technology in comparison with VMAT and IMRT technology. Dosimetric parameters including D1%, D99%, and Dmean of PTV, V5, V10, and V20 of ipisilateral lung, V5, D20, D30, and Dmean of heart, monitor units (MUs), and delivery time derived from IMRT, VMAT, and NU-VMAT plans were evaluated for plan quality and delivery efficiency. The quality assurance (QA) was conducted using both point-dose and planar-dose measurements for all treatment plans. Results: The IGM-NU-VMAT curves with plan optimization (range from 50% to 147%) were converged more significantly than IGM-VMAT curves (range from 0% to 297%). The dose distribution requirements of the target and normal tissues could be met using IMRT, VMAT, or NU-VMAT; the lowest Dmean was achieved in NU-VMAT plans (5.38 ± 0.46 Gy vs 5.63 ± 0.61 Gy in IMRT and 7.95 ± 0.52 Gy in VMAT plans). Statistically significant differences were found in terms of delivery time and MU when comparing IMRT with VMAT and NU-VMAT plans (P < .05). In comparison with IMRT plans, the MU and delivery time in NU-VMAT plans dramatically decreased by 69.8% and 28.4%, respectively. Moreover, NU-VMAT plans showed a high gamma passing rate (96.5% ± 1.11) in plane dose verification and minimal dose difference (2.4% ± 0.19) in point absolute dose verification. Conclusion: Our non-uniform VMAT facilitated the treatment strategy optimization for left breast cancer radiotherapy with dosimetric advantage in cardiac dose reduction and delivery efficiency in comparison with the conventional VMAT and IMRT.

ZIF-Based Nanoparticles Combine X-Ray-Induced Nitrosative Stress with Autophagy Management for Hypoxic Prostate Cancer Therapy.

Although reactive oxygen species (ROS)-mediated tumor treatments are predominant in clinical applications, ROS-induced protective autophagy promotes cell survival, especially in hypoxic tumors. Herein, X-ray triggered nitrite (NO2- ) is used for hypoxic prostate cancer therapy by inhibiting autophagy and inducing nitrosative stress based on an electrophilic zeolitic imidazole framework (ZIF-82-PVP). After internalization of pH-responsive ZIF-82-PVP nanoparticles, electrophilic ligands and Zn2+ are delivered into cancer cells. Electrophilic ligands can not only consume GSH under hypoxia but also capture low-energy electrons derived from X-rays to generate NO2- , which inhibits autophagy and further elevates lethal nitrosative stress levels. In addition, dissociated Zn2+ specifically limits the migration and invasion of prostate cancer cells through ion interference. In vitro and in vivo results indicate that ZIF-82-PVP nanoparticles under X-ray irradiation can effectively promote the apoptosis of hypoxic prostate cancer cells. Overall, this nitrosative stress-mediated tumor therapy strategy provides a novel approach targeting hypoxic tumors.

Adoption of Biologically Effective Dose of the Non-Target Lung Volume to Predict Symptomatic Radiation Pneumonitis After Stereotactic Body Radiation Therapy With Variable Fractionations for Lung Cancer.

Background: This study aims to establish lung biologically effective dose (BED)-based uniform dosimetric constraints for minimizing the risk of symptomatic radiation pneumonitis (SRP) from stereotactic body radiation therapy (SBRT) using variable fractionations in patients with lung tumors. Materials and Methods: A total of 102 patients with primary or oligometastatic lung tumors treated with SBRT in our institution were enrolled into this study. The associations between the clinical and dosimetric parameters and the incidences of SRP were analyzed using univariate and multivariate Cox regression hazard models. The receiver operating characteristic (ROC) curve was generated to evaluate the predictive performance of lung BED on the SRP risk compared with the physical dose. Results: SRP occurred in 11 patients (10.8%). In univariate analysis, the mean lung dose (p = 0.002), V5 (p = 0.005), V20 (p < 0.001), and the percentage of non-target normal lung volume receiving more than a BED of 5-170 Gy (VBED5-170, p < 0.05) were associated with SRP. Multivariate logistic regression analysis showed that there existed a significant statistical correlation between SRP and VBED70 (p < 0.001), which performed better than V5 or V20 on the ROC curves, resulting in an optimal cut-off value of lung VBED70 of 2.22%. Conclusions: This retrospective study indicated that non-target lung BED may better predict SRP from patients with SBRT-treated lung cancer. Limiting the lung VBED70 below 2.22% may be favorable to reduce the incidence of SRP, which warranted further prospective validation.

Full-Process Radiosensitization Based on Nanoscale Metal-Organic Frameworks.

Full-process radiosensitization, that is, pre-increasing radiation sensitivity of cancer cells, magnifying •OH formation during ionizing irradiation, and intervention on the resultant DNA repair for final cells death, could enhance the overall radiotherapeutic effects, but has not yet been achieved. Herein, Hf-nMOFs with Fe3+ ions uniformly dispersed (Hf-BPY-Fe) were constructed to integratedly improve radiotherapeutic effects via a multifaceted mechanism. The in vitro experiments demonstrated that persistent reactive oxygen species stress from Hf-BPY-Fe-activated in situ Fenton reaction reassorted cell cycle distribution, consequently contributing to increased tumoral radiosensitivity to photon radiation. Upon irradiation during the course of radiation therapy, Hf4+ in Hf-BPY-Fe gave substantial amounts of high-energy electrons, which partially converted H2O to •OH and, meanwhile, relaxed to a low-energy state in nMOF pores, leading to an electron-rich environment. These aggregated electrons facilitated the reduction from Fe3+ to Fe2+ and further promoted the production of •OH in the Fenton process to attack DNA. The Hf-BPY-Fe postponed the DNA damage response process by interfering with certain proteins involved in the DNA repair signaling pathway. The in vivo experiments showed improved radiotherapeutic effects from integrated contributions from Fe3+-based Fenton reaction and Hf4+-induced X-ray energy conversion in tumors. This work provides a nMOFs-based full-process radiosensitizing approach for better radiotherapeutic efficacy.

Morphological classification of pre-invasive lesions and early-stage lung adenocarcinoma based on CT images.

OBJECTIVE: To retrospectively analyze the computed tomography (CT) features in patients with pre-invasive lesions and early-stage lung adenocarcinoma and to explore the correlation between tumor morphological changes and pathological diagnoses. MATERIALS AND METHODS: CT morphological characteristics in 2106 patients with pre-invasive (stage 0) and early-stage (stage I) lung adenocarcinoma were analyzed; lesions were confirmed by surgical pathology. Based on the morphological characteristics, the lesions were divided into eight types: I (cotton ball, ground-glass nodules), II (solid fill), III (granular), IV (dendriform), V (bubble-like lucencies), VI (alveolate or honeycomb), VII (scar-like), and VIII (notched or umbilication). The different distributions of eight morphological types in pathological types of the lesions and subtypes of invasive adenocarcinoma were analyzed by chi-squared or Fisher's exact test. Correlation between the percentage of ground-glass opacity in the lesions and pathology types were analyzed by two-tailed Pearson's test. RESULTS: A negative correlation was observed between the pathological types and proportion of ground-glass component in the lesions (p < 0.001 and r = - 0.583). Significant differences in morphological characteristics among various pathological types of pre-invasive lesions and early lung adenocarcinomas were observed (p < 0.05). Furthermore, among the different pathological subtypes of stage I invasive adenocarcinoma, the differences in their manifestation as morphological types I, II, III, and VI were statistically significant (p < 0.05). CONCLUSION: The eight types of morphological classification of pre-invasive lesions and early-stage (stage 0 or stage I) lung adenocarcinoma has different pathological bases, and morphological classification may be useful for the diagnosis and differential diagnosis of lung adenocarcinoma. KEY POINTS: • CT morphological classification of pre-invasive lesions and lung adenocarcinoma is intuitive. • CT morphological classification characterizes morphological changes of the entire lesion. • Different pathological types of lung adenocarcinoma have different morphological features.

CT characterization of different pathological types of subcentimeter pulmonary ground-glass nodular lesions.

OBJECTIVE: To explore the CT characteristics of small lung nodules and improve the diagnosis of pulmonary ground-glass nodules less than 10 mm in size. METHODS: We retrospectively analyzed CT images of 161 pulmonary nodules (less than 10 mm in size) with spiculation, lobulation, vacuoles, and pleural indentation and compared these images with pathological results or follow-up CT images. The relationships between the ground-glass nodules (GGNs) and blood vessels were observed. The GGN-vessel relationship was divided into four types, Type I (pass-by), Type II (pass-through), Type III (distorted/dilated), Type IV (complicated). The vessels traveling through a GGN were divided into three categories, category A (arteries), category B (veins), category C (arteries and veins). RESULTS: 161 GGNs were divided into three groups (benign group, pre-invasive group, and adenocarcinoma group) according to their pathological diagnosis. Significant differences in density of nodules were observed among the three different groups (p < 0.05). Significant differences in the shape (round/round-like or not) of the nodules were observed between the benign group and the pre-invasive group and between the pre-invasive group and the adenocarcinoma group (p < 0.05). No significant differences in the presence of vacuoles were observed between the benign group and the pre-invasive group or between the pre-invasive group and the adenocarcinoma group (p ＞0.05), but a significant difference was observed between the benign group and the adenocarcinoma group (p < 0.05). The differences in the vascularization of the lesions among the three groups were statistically significant (p < 0.05). No significant differences or correlations were observed between vascular categories and GGN groups (p > 0.05). CONCLUSION: For subcentimeter nodules, mixed GGNs with vacuoles, well-defined border, combined with Type III or Type IV GGN-vessel relationship may strongly suggest malignant. ADVANCES IN KNOWLEDGE: Previous studies mainly focused on CT diagnosis of pulmonary nodules (≤ 3 cm in diameter), but this study focused on ground-glass nodules less than 10 mm in diameter, which had not been fully studied. For subcentimeter nodules, mixed GGNs with vacuoles, well-defined border, especially the GGN-vessel relationship manifest as Type III (distorted/dilated) or Type IV (complicated) may strongly suggest malignant.

Comparison of paclitaxel in combination with cisplatin (TP), carboplatin (TC) or fluorouracil (TF) concurrent with radiotherapy for patients with local advanced oesophageal squamous cell carcinoma: a three-arm phase III randomized trial (ESO-Shanghai 2).

INTRODUCTION: Concurrent chemoradiation is the standard therapy for patients with local advanced oesophageal carcinoma unsuitable for surgery. Paclitaxel is an active agent against oesophageal cancer and it has been proved as a potent radiation sensitiser. There have been multiple studies evaluating paclitaxel-based chemoradiation in oesophageal cancer, of which the results are inspiring. However, which regimen, among cisplatin (TP), carboplatin (TC) or fluorouracil (TF) in combination with paclitaxel concurrent with radiotherapy, provides best prognosis with minimum adverse events is still unknown and very few studies focus on this field. The purpose of this study is to confirm the priority of TF to TP or TF to TC concurrent with radiotherapy in terms of overall survival and propose a feasible and effective plan for patients with local advanced oesophageal cancer. METHODS AND ANALYSIS: ESO-Shanghai 2 is a three-arm, multicenter, open-labelled, randomised phase III clinical trial. The study was initiated in July 2015 and the duration of inclusion is expected to be 4 years. The study compares two pairs of regimen: TF versus TP and TF versus TC concurrent with definitive radiotherapy for patients with oesophageal squamous cell carcinoma (OSCC). Patients with histologically confirmed OSCC (clinical stage II, III or IVa based on the sixth Union for International Cancer Control-tumour, node, metastasis classification) and without any prior treatment of chemotherapy, radiotherapy or surgery against oesophageal cancer will be eligible. A total of 321 patients will be randomised and allocated in a 1:1:1 ratio to the three treatment groups. Patients are stratified by lymph node status (N0, N1, M1a). The primary endpoint is overall survival and the secondary endpoint is progression-free survival and adverse events. ETHICS AND DISSEMINATION: This trial has been approved by the Fudan University Shanghai Cancer Centre Institutional Review Board. Trial results will be disseminated via peer reviewed scientific journals and conference presentations. TRIAL STATUS: The trial was initiated in July 2015 and is currently recruiting patients in all of the participating institutions above. TRIAL REGISTRATION NUMBER: NCT02459457.

Scintillator-Based Nanohybrids with Sacrificial Electron Prodrug for Enhanced X-ray-Induced Photodynamic Therapy.

X-ray-induced photodynamic therapy (X-PDT) has high depth of penetration and has considerable potential for applications in cancer therapy. Scintillators and heavy metals have been adopted to absorb X-rays and transmit the energy to photosensitizers. However, the low efficiency of converting X-rays to reactive oxygen species (ROS) presents a challenge for the use of X-PDT to cure cancer. In this study, a new method based on LiLuF4:Ce@SiO2@Ag3PO4@Pt(IV) nanoparticles (LAPNP) is presented that could be used to enhance the curative effects of X-PDT. To make full use of the fluorescence produced by nanoscintillators (LiLuF4:Ce), a cisplatin prodrug Pt(IV) was utilized as a sacrificial electron acceptor to increase the yield of hydroxyl radicals (·OH) by increasing the separation of electrons and holes in photosensitizers (Ag3PO4). Additionally, cisplatin is produced upon the acceptance of electrons by Pt(IV) and further enhances the damage caused by ·OH. Via two-step amplification, the potential of LAPNP to enhance the effects of X-PDT has been demonstrated.

Dual-Energy Computed Tomography-Based Iodine Quantitation for Response Evaluation of Lung Cancers to Chemoradiotherapy/Radiotherapy: A Comparison With Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography-Based Positron Emission Tomography/Computed Tomography Response Evaluation Criterion in Solid Tumors.

OBJECTIVE: The objective of this study was to investigate the correlation between dual-energy computed tomography (DECT)-based iodine quantitation and fluorine-18 fluorodeoxyglucose (F-FDG) positron emission tomography (PET)/computed tomography (CT) imaging for response evaluation of lung cancers to treatment. METHODS: In this prospective study, a total of 32 pairs of DECT and F-FDG PET/CT imaging acquired consecutively from 13 patients with primary or metastatic lung cancers receiving either radiotherapy alone or chemoradiotherapy were analyzed. Imaging examinations were performed before, immediately, and no later than 6 months after treatment for response evaluation. Iodine-related parameters including the total iodine uptake (TIU) and vital volume (VIV) from DECT and metabolic metrics such as the standardized uptake value normalized to lean body mass (SULpeak), metabolic tumor volume (MTV), and the total lesion glycolysis (TLG) from F-FDG-PET/CT were generated and measured by semiautomatic approaches. Dual-energy CT and PET/CT metrics were calculated and followed up with comparison with response evaluation criteria in solid tumors (RECIST). RESULTS: Analysis of pretreatment imaging data revealed a strong correlation between DECT metrics (RECIST, TIU, and VIV) and F-FDG PET/CT metrics (MTV, TLG) with coefficients of R ranging from 0.86 to 0.90 (P < 0.01). With the delivery of treatment, all measured DECT and PET/CT metrics significantly decreased whereas the descending amplitude in RECIST was significantly smaller than that of the remaining parameters (P < 0.05). During follow-up examinations, both metrics followed a similar changing pattern. Overall, strong consistency was found between RECIST, TIU, VIV and SULpeak, MTV, TLG (R covers 0.78-0.96, P < 0.05). CONCLUSIONS: Semiautomatic iodine-related quantitation in DECT correlated well with metabolism-based measurements in F-FDG PET/CT, suggesting that DECT-based iodine quantitation might be a feasible substitute for assessment of lung cancer response to chemoradiotherapy/radiotherapy with comparison with F-FDG PET/CT.

[China National Lung Cancer Screening Guideline with Low-dose Computed 
Tomography (2018 version)].

BACKGROUND: Lung cancer is the leading cause of cancer-related death in China. The results from a randomized controlled trial using annual low-dose computed tomography (LDCT) in specific high-risk groups demonstrated a 20% reduction in lung cancer mortality. The aim of tihs study is to establish the China National lung cancer screening guidelines for clinical practice. METHODS: The China lung cancer early detection and treatment expert group (CLCEDTEG) established the China National Lung Cancer Screening Guideline with multidisciplinary representation including 4 thoracic surgeons, 4 thoracic radiologists, 2 medical oncologists, 2 pulmonologists, 2 pathologist, and 2 epidemiologist. Members have engaged in interdisciplinary collaborations regarding lung cancer screening and clinical care of patients with at risk for lung cancer. The expert group reviewed the literature, including screening trials in the United States and Europe and China, and discussed local best clinical practices in the China. A consensus-based guidelines, China National Lung Cancer Screening Guideline (CNLCSG), was recommended by CLCEDTEG appointed by the National Health and Family Planning Commission, based on results of the National Lung Screening Trial, systematic review of evidence related to LDCT screening, and protocol of lung cancer screening program conducted in rural China. RESULTS: Annual lung cancer screening with LDCT is recommended for high risk individuals aged 50-74 years who have at least a 20 pack-year smoking history and who currently smoke or have quit within the past five years. Individualized decision making should be conducted before LDCT screening. LDCT screening also represents an opportunity to educate patients as to the health risks of smoking; thus, education should be integrated into the screening process in order to assist smoking cessation. CONCLUSIONS: A lung cancer screening guideline is recommended for the high-risk population in China. Additional research , including LDCT combined with biomarkers, is needed to optimize the approach to low-dose CT screening in the future.

SnWO4-based nanohybrids with full energy transfer for largely enhanced photodynamic therapy and radiotherapy.

The "partial matching" between upconversion nanoparticle (UCNP) emission and absorption by photosensitizers (PSs) often leads to a theoretically reduced therapeutic efficiency in UC-based photodynamic therapy (PDT) strategies in which the chosen PSs have limited capabilities and are unable to utilize all the near-infrared-upconverted light. In this study, needle-like SnWO4 nanocrystals (SWs) with a broad UV-vis absorption region were synthesized to solve the problem. After covalent conjugation with UCNPs, all the UCNP-emitted light was effectively absorbed by SWs, triggering the type-I PDT process to activate ROS maxima. The unique nanostructure of the as-formed UCNP-SnWO4 nanohybrids (USWs) also enhanced the receiving light intensities of SW, which further boosted the antitumor efficacy. Meanwhile, the strong X-ray attenuation capacity of both tungsten and tin elements qualified the USWs as excellent radio-sensitizers for radiotherapy (RT) enhancement, which played a complementary role with PDT treatment because PDT-mediated induction arrested the cells in the G0-G1 cell cycle phase, and RT was more damaging toward cells in the G2/M phase. The remarkably enhanced UC-PDT/RT efficiency of USWs was next validated in vitro and in vivo, and the combined NIR light and ionizing irradiation treatment completely suppressed tumor growth, revealing its great potential as an efficient anticancer therapeutic agent against solid tumors.