Prognostic utility of blood inflammation biomarkers before and after treatment on the survival of patients with locally advanced non-small cell lung cancer undergoing stereotactic body radiotherapy.

BACKGROUND AND OBJECTIVE: The neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) were significant and succinct indicators of systemic inflammation. We assessed the influence of stereotactic body radiotherapy (SBRT) on NLR and PLR in patients with locally advanced non-small cell lung cancer (LA-NSCLC). METHODS: We reviewed the medical data of patients with LA-NSCLC who underwent SBRT between 1 January 2013 and 31 December 2018. NLR and PLR values recorded at pre- and post-SBRT were examined. We assessed the correlation between pre/post-SBRT NLR and PLR and survival outcomes. The decision tree evaluation was conducted using Chi-square automatic detection. RESULTS: In total, 213 patients were included in the study with a median follow-up duration of 40.00 (ranging from 5.28 to 100.70) months. Upon dichotomization by a median, we identified that post-SBRT NLR > 5.5 and post-SBRT PLR > 382.0 were negatively associated with shorter overall survival (OS). In the multivariate assessment, post-SBRT PLR > 382.0 was the only factor. Based on post-SBRT PLR, tumor locations, and tumor stage, we categorized patients into low, medium, or high-risk groups. CONCLUSIONS: Post-SBRT PLR > 382.0 correlated with survival in patients undergoing SBRT. The decision tree model might play a role in future risk stratification to guide the clinical practice of individualized SBRT for LA-NSCLC.

Correlation between morphological parameters and dosimetric parameters of the heart and spinal cord in the intermediate- and advanced-stage esophageal cancer.

BACKGROUND: Radiation therapy plays a pivotal role as the primary adjuvant treatment for esophageal cancer (EPC), emphasizing the critical importance of carefully balancing radiation doses to the target area and organs at risk in the radiotherapeutic management of esophageal cancer. AIMS: This study aimed to explore the correlation between morphological parameters and dosimetric parameters of the heart and spinal cord in intermediate- and advanced-stage esophagus cancer to provide a reference for clinical treatment. METHODS AND RESULTS: A total of 105 patients with intermediate- and advanced-stage EPC, who received treatment in our hospital from 2019 to 2021, were included. The morphological parameters were calculated by imaging. Intensity-modulated radiation therapy plan was executed at Raystation4.7. The PTV-G stood for the externally expanded planning target volume (PTV) of the gross tumor volume (GTV) and PTV-C for the externally expanded volume of the clinical target volume (CTV). The prescription dose of PTV-G and PTV-C was set as 60Gy/30F and 54Gy/30F, respectively. The linear regression model was used to analyze the correlation between morphologic parameters of EPC and dosimetric parameters of the heart and spinal cord. In 105 cases, the total lung length was correlated with the spinal cord maximum dose (D2 ). The heart mean doses (Dmean ) and heart V40 (the relative volume that receives 40 Gy or more) was correlated with PTV-G volume, PTV-G length; In middle- and upper-segment EPC cases, only the total lung volume was correlated with the spinal cord Dmean , spinal cord D2 , heart Dmean , and heart V40 ; In middle-stage EPC cases, the heart Dmean was correlated with the PTV-G volume, PTV-G length. The total lung length was correlated with the spinal cord D2 ; In middle- and lower-segment EPC, only the PTV-G volume and PTV-G length were correlated with the heart Dmean . All the aforementioned values were statistically significant. CONCLUSIONS: Combined with the unsegmented tumor and different locations, the organ at risk dose was comprehensively considered.

Discovery of novel oridonin sulfamide derivatives as potent NLRP3 inhibitors by a visible-light photocatalysis-enabled peripheral editing.

The progress of organicsyntheticmethod can promote late-stage lead compound modification and novel active compound discovery. Molecular editing technology in the field of organic synthesis, including peripheral and skeletal editing, facilitates rapid access to molecular diversity of a lead compound. Peripheral editing of CH bond activation is gradually used in lead optimization to afford novel active scaffolds and chemical space exploitation. To develop oridonin derivatives with high anti-inflammatory potency, novel oridonin sulfamides had been designed and synthesized by a scaffoldhopping strategy based on a visible-light photocatalysis peripheral editing. All novel compounds revealed measurable inhibition of IL-1ß and low cytotoxicity in THP-1 cells. The docking study indicated that the best active compound ZM640 was accommodated in thebinding site of NLRP3 with two hydrogen bond interaction. These preliminary results confirm that α, ß-unsaturated carbonyl of oridonin is not essential for NLRP3 inhibitory effect. This new oridonin scaffold has its potential to be further developed as a promising class of NLRP3 inhibitors.

Immune profiling of pancreatic cancer for radiotherapy with immunotherapy and targeted therapy: Biomarker analysis of a randomized phase 2 trial.

PURPOSE: Immunotherapy alone offered limited survival benefits in pancreatic cancer, while the role of immunotherapy-centric combined therapy remains controversial. Therefore, it is required to develop biomarkers to precisely deliver immunotherapy-based multimodality for pancreatic cancer. METHODS: This is a secondary analysis of an open label, randomized, phase 2 trial, whereas patients with locally recurrent pancreatic cancer after surgery were enrolled. Eligible patients with mutant KRAS and positive immunohistochemical staining of PD-L1 were randomly assigned to receive stereotactic body radiation therapy (SBRT) plus pembrolizumab and trametinib (SBRT + K + M) or SBRT and gemcitabine (SBRT + G). Meanwhile, patients were classified into PD-L1+/tumor infiltrating lymphocytes [TIL(s)]- and PD-L1+/TIL + group for each arm. RESULTS: A total of 170 patients were enrolled and randomly assigned to receive SBRT + K + M (n = 85) or SBRT + G (n = 85). The improved outcomes have been reported in patients with SBRT + K + M in the previous study. In this secondary analysis, the median overall survival (OS) was 17.2 months (95% CI 14.6-19.8 months) in patients with PD-L1+/TIL + and 12.7 months (95% CI 10.8-14.6 months) in patients with PD-L1+/TIL- (HR 0.62, 95% CI 0.39-0.97, p = 0.036) receiving SBRT + K + M. In SBRT + G group, the median OS was 13.1 months (95% CI 10.9-15.3 months) in patients with PD-L1+/TIL- and 12.7 months (95% CI 9.2-16.2 months) in patients with PD-L1+/TIL+ (HR 0.97, 95% CI 0.62-1.52, p = 0.896). Grade 3 or 4 adverse events were found in 16 patients (30.8%) and 10 patients (30.3%) with PD-L1+/TIL- and PD-L1+/TIL + in SBRT + K + M group respectively; whereas 9 (16.7%) and 8 patients (25.8%) with PD-L1+/TIL- and PD-L1+/TIL + in SBRT + G group. CONCLUSION: PD-L1, TILs and mutant KRAS may be a biomarker to guide clinical practice of radiotherapy and immunotherapy-based regimens in pancreatic cancer if further combined with MEK inhibitors as targeted therapy.

MUC1 attenuates neutrophilic airway inflammation in asthma by reducing NLRP3 inflammasome-mediated pyroptosis through the inhibition of the TLR4/MyD88/NF-κB pathway.

BACKGROUND: Neutrophilic airway inflammation is a challenge in asthma management and is associated with poor patient prognosis. Mucin 1 (MUC1), which contains a cytoplasmic tail (MUC1-CT), has been found to mediate glucocorticoid sensitivity in asthma; however, its role in modulating neutrophilic airway inflammation in asthma remains unknown. METHODS: Human-induced sputum cells were collected from healthy participants (n = 12), patients with mild-to-moderate asthma (n = 34), and those with severe asthma (n = 18). In vitro human lung bronchial 1 epithelial cell line (BEAS-2B) was transfected with small interfering RNA against MUC1 (MUC1-siRNA) and then stimulated by lipopolysaccharide (LPS), where some cells were pretreated with a TLR4 inhibitor (TAK-242). In vivo mouse model of asthmatic neutrophil airway inflammation was induced by ovalbumin (OVA)/LPS. Some groups were intraperitoneally injected with MUC1-CT inhibitor (GO-203) and/or TAK-242 . RESULTS: The mRNA expression of MUC1 was downregulated in the induced sputum of patients with asthma and correlated with asthmatic neutrophilic airway inflammation. The mRNA expressions of TLR4, MyD88, nucleotide-binding oligomerization domain-like pyrin domain-containing protein 3 (NLRP3), caspase-1, interleukin (IL)-18, and IL-1ß in induced sputum cells of patients with asthma were upregulated and related to the mRNA expression of MUC1. LPS activated the TLR4 pathway and NLRP3-mediated pyroptosis in BEAS-2B cells in vitro, which were significantly aggravated after MUC1-siRNA transfection. Furthermore, MUCl-CT interacted with TLR4, and the interaction between TLR4 and MyD88 was significantly increased after MUCl-siRNA transfection. Moreover, TAK-242 ameliorated TLR4/MyD88/nuclear factor kappa B (NF-κB) pathway activation, NLRP3 inflammasome-mediated pyroptosis, and neutrophilic inflammation exacerbated by MUC1 downregulation. GO-203 exacerbated TLR4/MyD88/NF-κB pathway activation in vivo, and NLRP3 inflammasome-mediated pyroptosis reduced in a mouse model of asthmatic neutrophil airway inflammation induced by OVA/LPS; these pathological changes were partially alleviated after TAK-242 application. CONCLUSION: This study revealed that MUC1 downregulation plays an important role in asthmatic neutrophilic airway inflammation. MUC1-CT reduces NLRP3 inflammasome-mediated pyroptosis by inhibiting the activation of the TLR4/MyD88/NF-κB pathway, thereby attenuating neutrophil airway inflammation in patients with asthma.

A Predictive Model to Evaluate Pathologic Complete Response in Rectal Adenocarcinoma.

Introduction: Neoadjuvant chemo-radiotherapy (nCRT) before surgery was a standard treatment strategy for locally advanced rectal cancer (LARC). The aim of this study was to assess the relationship between the predictive factors and pathological complete response (pCR) in rectal cancer patients, especially in ultra-low ones. Method: A total of 402 patients were involved in this retrospective study. The logistic regression analyses were used to compare the different subgroups in univariate analysis. Multivariate analysis was performed to determine the independent predictive factors of pCR by using a logistic regression model. Results: A total of 402 patients received preoperative CRT. In all patients, multivariate analysis revealed that circumferential tumor extent rate (CER) (≤ 2/3cycle vs >2/3 cycle, P < .001, OR = 4.834, 95% CI: 2.309-10.121), carcinoembryonic antigen (CEA) level (both ≤ 5 vs pre > 5 and post ≤ 5 vs both > 5, P = .033, OR = 1.537, 95% CI: 1.035-2.281), and interval time between the end of CRT and surgery (P = .031, OR = 2.412, 95% CI: 1.086-5.358) were predictive factors for pCR. The area under the curve (AUC) of the predictive model was 0.709 (95% CI: 0.649-0.769), which was significantly higher than the CER (0.646, 95% CI: 0.584-0.709), interval time (0.563, 95% CI: 0.495-0.631) and CEA level (0.586, 95% CI: 0.518-0.655). In ultra-low rectal patients, multivariate logistic regression analysis revealed that CER (≤ 2/3 cycle vs > 2/3 cycle, P = .003, OR = 7.203, 95% CI: 1.934-26.823) and mismatch repair (MMR) status (pMMR vs dMMR, P = .016, OR = 0.173, 95% CI: 0.041-0.720) were predictive factors for pCR. The AUC of the predictive model was 0.653 (95% CI: 0.474-0.832). Conclusion: New predictive models were varied by the histologic types and MMR statuses to evaluate the trend of tumor response to nCRT in all RC cases and ultra-low RC patients, which may be used to individualize stratify for selected LARC patients.

Efficacy and toxicity of stereotactic body radiotherapy for un-resectable stage III non-small cell lung cancer patients unfit for concurrent chemoradiation therapy: a retrospective study.

BACKGROUND: In this study, we evaluated the efficacy and toxicity of stereotactic body radiotherapy (SBRT) as replacement strategy of conventionally fractionated radiation therapy in stage III non-small cell lung cancer (NSCLC) patients unfit for concurrent chemoradiation therapy (CRT). METHODS: We analyzed the clinical outcomes in patients with unresectable stage III NSCLC who received SBRT from January 1, 2013 to December 31, 2018. Both induction and consolidation chemotherapy were allowed. The survival rates and toxicities were calculated using the Kaplan-Meier method, and potential risk factors were investigated by multivariate Cox regression. RESULTS: A total of 213 consecutive patients who had received SBRT were enrolled. The median overall survival (OS) and progression-free survival (PFS) were 36.5 months and 16.1 months respectively. The estimated 1-, 2- and 3-year OS rates were 90.6%, 73.7% and 52.0%, respectively and the corresponding PFS rates were 69.5%, 25.4% and 15.0%, respectively. Treatment failures were largely (n = 151, 70.9%) distant metastases, with low rates of local (n = 74, 34.74%) and regional (n = 76, 35.68%) recurrences. In 13.1% patients (n = 28), ≥ grade (G) 3 toxicities were identified, including radiation pneumonia (n = 20, 9.4%) and bronchopulmonary hemorrhage (n = 8, 3.8%). None of the patients suffered from ≥ G 3 late toxic effects. Compared with patients with peripheral tumors, patients with central tumors had lower median OS (P<0.001) and the biological effective dose (BED) was not a predictor for OS. CONCLUSIONS: SBRT combined with chemotherapy for stage III NSCLC produced favorable treatment outcomes with acceptable toxicity. For patients with central tumors, an appropriate BED reduction can be considered. Further studies are warranted. TRIAL REGISTRATION: Retrospectively registered.

Programmed Cell Death in Asthma: Apoptosis, Autophagy, Pyroptosis, Ferroptosis, and Necroptosis.

Bronchial asthma is a complex heterogeneous airway disease, which has emerged as a global health issue. A comprehensive understanding of the different molecular mechanisms of bronchial asthma may be an efficient means to improve its clinical efficacy in the future. Increasing research evidence indicates that some types of programmed cell death (PCD), including apoptosis, autophagy, pyroptosis, ferroptosis, and necroptosis, contributed to asthma pathogenesis, and may become new targets for future asthma treatment. This review briefly discusses the molecular mechanism and signaling pathway of these forms of PCD focuses on summarizing their roles in the pathogenesis and treatment strategies of asthma and offers some efficient means to improve clinical efficacy of therapeutics for asthma in the near future.

Using optimal controlled singlet spin order to accurately target molecular signal in MRI and MRS.

Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) have made great successes in clinical diagnosis, medical research, and neurological science. MRI provides high resolution anatomical images of tissues/organs, and MRS provides information of the functional molecules related to a specific tissue/organ. However, it is difficult for classic MRI/MRS to selectively image/probe a specific metabolite molecule other than the water or fat in tissues/organs. This greatly limits their applications on the study of the molecular mechanism(s) of metabolism and disease. Herein, we report a series of molecularly targeted MRI/MRS methods to target specific molecules. The optimal control method was used to efficiently prepare the singlet spin orders of varied multi-spin systems and in turn greatly expand the choice of the targeted molecules in the molecularly targeted MRI/MRS. Several molecules, such as N-acetyl-L-aspartic acid (NAA), dopamine (DA), and a tripeptide (alanine-glycine-glycine, AGG), have been used as targeted molecules for molecularly targeted MRI and MRS. We show in vivo NAA-targeted 1H MRS spectrum of a human brain. The high-resolution signal of NAA suggests a promising way to study important issues in molecular biology at the molecular level, e.g., measuring the local pH value of tissue in vivo, demonstrating the high potential of such methods in medicine.

Two-institution results of Stereotactic Body Radiation Therapy (SBRT) for treating adrenal gland metastases from liver cancer.

OBJECTIVE: Stereotactic Body Radiation Therapy (SBRT) has been found beneficial for adrenal gland metastases (AGMs) with a high local control rate and low toxicity. The role of SBRT for AGMs in patients with liver cancer has not been well-discussed before. We, therefore, report our two-institution experience to further elaborate on the feasibility and effectiveness of SBRT in the treatment of AGMs from liver cancer. METHODS: A total of 23 liver cancer patients (19 males, 4 females) with 24 AGMs treated by SBRT from July 2006 to April 2021 were retrospectively included in this study. Toxicity was assessed based on clinical adverse events using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The effectiveness was assessed based on local control (LC), progression-free survival (PFS), and overall survival (OS), which were calculated using the Kaplan-Meier method. Univariate analyses were compared by log-rank test. The relevant covariates were evaluated using Cox proportional hazards models. RESULTS: The median dose was 40 Gy in 5 fractions, with the corresponding median biological effective dose (BED10, α/ß = 10 Gy) of 72 Gy. The median overall follow-up time was 15.4 months (range: 4.2-70.6 months). The complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) rates were 25.0%, 20.8%, 33.3%, and 20.8%, respectively. All 6 patients with AGMs accompanying symptoms had varying degrees of alleviation after SBRT. The 0.5-, 1-year and 2-year LC rates were 87.5%, 77.8%, and 77.8%, respectively. The 0.5-, 1-year and 2-year OS rates were 95.5%, 66.8%, and 41.1%, respectively. The treatments were all tolerated with only one patient reporting a grade-3 hepatic injury. The univariate analysis concluded that only gross tumor volume (GTV) < 34.5 ml (p = 0.039) was associated with a favorable LC rate. After multivariate analysis, favorable predictors correlated with OS were GTV < 34.5 ml (p = 0.043), systemic therapy (p = 0.017), and without additional organ metastasis after SBRT (p = 0.009). CONCLUSION: Our results suggest that SBRT is a safe and effective technique to treat AGM from liver cancer, especially for small GTV (< 34.5ml). Moreover, the small metastatic lesion volume, fewer metastatic lesions, and intervention of systemic therapy are more likely to improve OS.

Discovery of Novel 3,11-Bispeptide Ester Arenobufagin Derivatives with Potential in Vivo Antitumor Activity and Reduced Cardiotoxicity.

Arenobufagin, one of the bufadienolides isolated from traditional Chinese medicine Chan'su, exhibits potent antitumor activity. However, serious toxicity and small therapeutic window limits its drug development. In the present study, to our knowledge, novel 3,11-bispeptide ester arenobufagin derivatives have been firstly designed and synthesized on the base of our previous discovery of active 3-monopeptide ester derivative. The in vitro antiproliferative activity evaluation revealed that the moiety at C3 and C11 hydroxy had an important influence on cytotoxic activity and selectivity. Compound ZM350 notably inhibited tumor growth by 58.8 % at a dose 10 mg/kg in an A549 nude mice xenograft model. Therefore, compound ZM350 also presented a concentration-dependent apoptosis induction and low inhibitory effect against both hERG potassium channel and Cav1.2 calcium channel. Our study suggests that novel 3,11-bispeptide ester derivatives will be a potential benefit to further antitumor agent development of arenobufagin.

Distinguishing glutamate and glutamine in in vivo 1 H MRS based on nuclear spin singlet order filtering.

PURPOSE: The signals of glutamate (Glu) and glutamine (Gln) are often significantly overlapped in routine 1 H-MR spectra of human brain in vivo. Selectively probing the signals of Glu and Gln in vivo is very important for the study of the metabolisms in which Glu and Gln are involved. METHODS: The Glu-/Gln- targeted pulse sequences are developed to selectively probe the signals of Glu and Gln. The core part of the Glu-/Gln- targeted pulse sequences lies on the preparation of the nuclear spin singlet orders (SSOs) of the five-spin systems of Glu and Gln. The optimal control method is used to prepare the SSOs of Glu and Gln with high efficiency. RESULTS: The Glu-/Gln- targeted pulse sequences have been applied on phantoms to selectively probe the signals of Glu and Gln. Moreover, in the in vivo experiments, the signals of Glu and Gln in human brains of healthy subjects have been successfully probed separately. CONCLUSION: The developed Glu-/Gln- targeted pulse sequences can be used to distinguish the 1 H-MR signals of Glu and Gln in human brains in vivo. The optimal control method provides an effective way to prepare the SSO of a specific spin system with high efficiency and in turn selectively probe the signals of a targeted molecule.

Neoadjuvant radiohormonal therapy for oligo-metastatic prostate cancer: safety and efficacy outcomes from an open-label, dose-escalation, single-center, phase I/II clinical trial.

To evaluate the safety and efficacy of neoadjuvant radiohormonal therapy for oligometastatic prostate cancer (OMPC), we conducted a 3 + 3 dose escalation, prospective, phase I/II, single-arm clinical trial (CHiCTR1900025743), in which long-term neoadjuvant androgen deprivation was adopted 1 month before radiotherapy, comprising intensity modulated radiotherapy to the pelvis, and stereotactic body radiation therapy to all extra-pelvic bone metastases for 4-7 weeks, at 39.6, 45, 50.4, and 54 Gy. Robotic-assisted radical prostatectomy was performed after 5-14 weeks. The primary outcome was treatment-related toxicities and adverse events; secondary outcomes were radiological treatment response, positive surgical margin (pSM), postoperative prostate-specific antigen (PSA), pathological down-grading and tumor regression grade, and survival parameters. Twelve patients were recruited from March 2019 to February 2020, aging 66.2 years in average (range, 52-80). Median baseline PSA was 62.0 ng/mL. All underwent RARP successfully without open conversions. Ten patients recorded pathological tumor down-staging (83.3%), and 5 (41.7%) with cN1 recorded negative regional lymph nodes on final pathology. 66.7% (8/12) recorded tumor regression grading (TRG) -I and 25% (3/12) recorded TRG-II. Median follow-up was 16.5 months. Mean radiological progression-free survival (RPFS) was 21.3 months, with 2-year RPFS of 83.3%. In all, neoadjuvant radiohormonal therapy is well tolerated for oligometastatic prostate cancer.

Effect of stereotactic body radiotherapy dose escalation plus pembrolizumab and trametinib versus stereotactic body radiotherapy dose escalation plus gemcitabine for locally recurrent pancreatic cancer after surgical resection on survival outcomes: A secondary analysis of an open-label, randomised, controlled, phase 2 trial.

Background: There are a lack of studies about whether radiation dose escalation synergizes with immunotherapy and targeted therapy in pancreatic cancer. In this study, we performed a secondary analysis to investigate whether a high radiation dose rather than a low dose plus pembrolizumab and trametinib provided improved survival compared with gemcitabine in post-operative locally recurrent pancreatic cancer. Methods: In this open-label, randomised, controlled, phase 2 trial, eligible patients with pancreatic ductal adenocarcinoma characterized by mutant KRAS and positive immunohistochemical staining of PD-L1 and documented post-operative local recurrence were randomly assigned using an interactive voice or web response system, without stratification, to receive stereotactic body radiation therapy (SBRT) with doses ranging from 35 to 40Gy in five fractions, pembrolizumab 200 mg every three weeks and oral trametinib 2 mg once daily (SBRT + K + M) or SBRT and gemcitabine (1000 mg/m2) on day 1 and 8 of each 21-day cycle (SBRT + G) until disease progression in our hospital in China. Those had radiotherapy, immunotherapy or targeted therapy were excluded. Patients and investigators were not masked to the assignment. In each arm, patients were stratified based on biologically effective dose (BED10; α/ß = 10) of 60-65Gy and BED10 ≥65Gy. The primary endpoint was overall survival (OS) and the secondary endpoint was progression-free survival (PFS). All patients received their assigned treatment and were included in the efficacy and safety analyses. This study is registered with ClinicalTrials.gov, NCT02704156. Findings: Between Oct 10, 2016, and Oct 28, 2017, 147 of 170 randomly assigned participants were eligible for inclusion in this analysis. In BED10 of 60-65Gy group, 34 and 29 patients had SBRT + G and SBRT + K + M, respectively. While there were 42 and 42 patients with SBRT + G and SBRT + K + M in BED10 ≥65Gy group. Patients in the SBRT + K + M group had longer OS compared with the SBRT + G group, but this did not reach statistical significance (median: 15.1 vs. 12.4 months, HR 0.67 [95%CI 0.43-1.04]; p = 0.071). For BED10 of 60-65Gy, OS was similar between patients in the SBRT + K + M and SBRT + G groups (median, 13.6 vs. 12.4 months; HR 0.69 [95% CI 0.41-1.16]; p = 0.16). For BED10 of ≥65Gy, PFS was prolonged with SBRT + K + M versus SBRT + G (median: 8.6 vs. 5.0 months, HR 0.48 [95% CI 0.31-0.77]; p = 0.0021). For BED10 of 60-65Gy, there was no significant difference in PFS between the two groups (PFS: median, 7.9 vs. 4.3 months; HR 0.69 [95% CI 0.42-1.15]; p = 0.16). In BED10 of 60-65Gy group, 7 (20.6%) and 8 patients (27.6%) with SBRT + G and SBRT + K + M had grade 3 or 4 adverse events (p = 0.52). In BED10 ≥65Gy group, 8 (19.0%) and 12 patients (28.6%) with SBRT + G and SBRT + K + M had grade 3 or 4 adverse events (p = 0.31). No treatment-related death occurred. Interpretation: Dose escalation of SBRT may improve PFS with pembrolizumab and trametnib versus gemcitabine for patients with post-operative locally recurrent pancreatic cancer. However, benefits of PFS did not translate into longer OS. This may be ascribed to small sample size and post-hoc analysis that was not powered to determine the significance. Therefore, synergy of high dose of SBRT with immunotherapy and targeted therapy required further investigations in phase 3 trials. Funding: Shanghai Shenkang Centre and Changhai Hospital.

Dosimetric and biological comparisons of single planning and double plannings for bilateral lung cancer SBRT planning based on the Cyber-Knife system.

Objective: The aim is to investigate the influence of single planning (Plan S) and double plannings (Plan D) on bilateral lung cancer stereotactic body radiation therapy planning from the perspective of dosimetry and biology respectively. Methods Cases with bilateral lung cancer patients who had undergone SBRT with the Cyber-Knife were enrolled, and a single planning and double plannings were designed in the Multiplan@4.2 treatment planning system equipped with the Cyber-Knife system. The single plan was to optimize the two target volumes in a separate plan, while the dual plan is to optimize two target volumes respectively in two separate plans, then perform dose superposition. Then based on the dosimetric results, the biological parameters were calculated. Thus the quality of SBRT plans for those bilateral lung cancer designed by the two methods were compared and evaluated according to the dosimetric and biological results. Results: The dose distribution of both planning target volumes and surrounding organs at risk in Plan S and Plan D could meet the clinical prescription requirements. The target conformity index and the new conformity index of PTV were closer to 1 in the Double plannings, and the dose gradient GI in the Plan D was smaller than Plan S. For organs at risks, the doses received by the Plan D were relatively small. In terms of biological models, for the equivalent uniform dose of normal lung tissue, heart and esophagus, the Plan D was 6.51% (P=0.045), 19.8% (P=0.022), 27.08% (P>0.05) lower than Plan S respectively. The results showed that the equivalent uniform dose of normal tissue in the Plan D was lower relative to Plan S. Conclusions: Dosimetric and biological results show that both the use of Plan D have an advantage of protecting normal tissues, and it was suggested that to design double plannings for bilateral lung cancer stereotactic body radiation therapy planning based on Cyber-Knife in the clinical practice.

Protocol of the integrated boost to the dominant intraprostatic nodule in stereotactic body radiation therapy for localized prostate cancer.

Aim: To explore the safety and efficacy of the integrated boost to the dominant intraprostatic nodule (DIN) based on 68Ga prostate-specific membrane antigen PET/MRI in stereotactic body radiation therapy (SBRT) for patients with localized prostate cancer. Methods: SBRT regimen is employed - namely, sequential integrated boost (SIB) to the DIN based on 68Ga prostate-specific membrane antigen PET/MRI. SIB prescription dose of 36.25 Gy in five fractions to fixed prophylactic tumoricidal region is delivered, followed by 7.25 Gy in one fraction added to the DIN every other day. The primary end point of the study will be toxicity assessed by the Common Terminology Criteria for Adverse Events 5.0 grading scale. Secondary end points include biochemical progression-free survival, local progression-free survival, distant metastasis-free survival and overall survival. Discussion: This trial is to prove the safety and efficacy of sequential integrated boost to the DIN in SBRT. Clinical Trial Registration: NCT04599699 (ClinicalTrials.gov).

Stratified treatment of localized cervical esophageal squamous cell carcinoma induced by neoadjuvant immunotherapy plus chemotherapy (SCENIC).

Background: Definitive chemoradiation is the preferred treatment for cervical esophageal carcinoma (CEC), per the National Comprehensive Cancer Network (NCCN) guidelines. However, in treatment failures, salvage surgery poses significant technical challenges. If non-responders could be identified, prior to chemoradiation, these patients may benefit from primary esophagectomy. Programmed cell death protein 1 (PD-1) inhibitor is widely used and recognized as an effective treatment method in various cancers including esophageal cancer. Therefore, we propose to screen for treatment response to neoadjuvant immunotherapy plus chemotherapy to select patients who are radiosensitive and potential candidates for laryngeal preservation. While non-responders are likely to be insensitive to chemoradiation would be offered radical esophagectomy. Methods: A total of 36 patients with histopathologically-confirmed locally advanced CEC have been enrolled in our study. All participants will receive 2 cycles of induction therapy, which was tislelizumab combined with paclitaxel and carboplatin. Patients will be classified into 3 groups according to their response to induction therapy: a remarkable response (RR) group, limited partial response (LPR) group, and poor response (POR) group. Stratified patients will receive the following follow-up treatments: those in the RR group will receive dCRT, and those in the LPR and POR groups will undergo radical surgery. Then, participants in the RR group will be administrated with tislelizumab alone for 1 year. The choice of postoperative treatment for patients in the LPR and POR groups will depend on the patient's condition, including chemotherapy, radiotherapy, immunotherapy, or follow-up. The primary endpoint of the study is the 2-year event-free survival (EFS). The secondary endpoints are disease-free survival (DFS), regression-free survival (RFS), objective response rate (ORR), and 5-year overall survival (OS). At the same time, we will assess the patient's quality of life (QoL). Conclusions: Screening CEC patients after immune-induction therapy combined with chemotherapy using different treatment strategies might lead to improvements in their QoL and OS time. No relevant double-endpoint studies have been reported until now. Our study is the first multicenter, prospective, exploratory study to seek the optimal treatment for locally advanced CEC patients. The results may offer high-level evidence for future CEC treatment. Trial Registration: Chictr.Org identifier: ChiCTR2200057732.

Stereotactic body radiotherapy (SBRT) versus androgen deprivation therapy (ADT) for oligometastatic prostate cancer: protocol for a prospective randomised control clinical trial.

INTRODUCTION: The systemic therapy, especially androgen deprivation therapy (ADT), is currently recommended for patients with oligometastatic prostate cancer (PCa). However, the results have not been satisfactory including adverse reactions and castration resistance. Therefore, it is necessary to explore more effective treatment to prolong biochemical progression-free survival (bPFS) and delay the start of hormonal therapy for treating oligometastatic PCa. Stereotactic body radiotherapy (SBRT) is an emerging treatment alternative for patients with oligometastases with high local control rates and minimal toxic effects. This prospective trial aims to demonstrate whether SBRT for the oligometastases of hormone-sensitive PCa can delay the start of ADT and prolong the time from inception of the study to castration-resistant prostate cancer (CRPC). METHODS AND ANALYSIS: Patients with ≤3 oligometastatic recurrences, diagnosed on Ga-68 prostate-specific membrane antigen PET/CT, will be randomised in a 1:1 ratio between arm A (ADT only) and arm B (SBRT for oligometastases only). SBRT is conducted by CyberKnife with prescription dose 30-50 Gy in 3-5 fractions. One of the primary endpoints is ADT-free survival of arm B, the other is the time from inception of the study to CRPC. The secondary endpoints include radiotherapy-related toxicity, ADT-related toxicity, bPFS, local PFS and overall survival. Toxicity will be assessed using the National Cancer Institute Common Toxicity Criteria V.5.0. ETHICS AND DISSEMINATION: This protocol was approved by the institutional review board of Shanghai Changhai Hospital (CHEC2020-101). This is a randomised control clinical trial comparing SBRT to ADT for men with oligometastatic PCa. The study will be performed in compliance with applicable local legislation and in accordance with the ethical principles developed by the World Medical Association in the Declaration of Helsinki 2013. Study results will be disseminated through conferences and peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov identifier:NCT04599686.

Biologically effective doses of 60-70Gy versus >70Gy of stereotactic body radiotherapy (SBRT) combined with chemotherapy in locally advanced pancreatic cancer: protocol of a single-centre, phase II clinical trial.

INTRODUCTION: There is a paucity of studies about whether dose escalation of stereotactic body radiation therapy (SBRT) prolongs survival compared with de-escalation for patients with locally advanced pancreatic cancer (LAPC). Therefore, the aim of the study is to compare the survival benefits of biologically effective dose (BED10, α/ß=10) of 60-70 Gy with those of BED10 >70 Gy. METHODS AND ANALYSIS: This study is a single-centre, phase II trial. Patients with LAPC are randomly allocated to receive SBRT with BED10 of 60-70 Gy or >70 Gy in 5-6 fractions combined with gemcitabine plus albumin-bound paclitaxel. The primary outcome is progression-free survival. The secondary outcomes are adverse events, local control and overall survival. ETHICS AND DISSEMINATION: The trial protocol has been approved by the Ethics committee of Shanghai Changhai Hospital. The ethics number is CHEC2020-100. Study results will be disseminated through peer-reviewed journals and released in related medical conferences. TRIAL REGISTRATION NUMBERS: NCT04603586.