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.

Insights into genetic diversity and phenotypic variations in domestic geese through comprehensive population and pan-genome analysis.

BACKGROUND: Domestic goose breeds are descended from either the Swan goose (Anser cygnoides) or the Greylag goose (Anser anser), exhibiting variations in body size, reproductive performance, egg production, feather color, and other phenotypic traits. Constructing a pan-genome facilitates a thorough identification of genetic variations, thereby deepening our comprehension of the molecular mechanisms underlying genetic diversity and phenotypic variability. RESULTS: To comprehensively facilitate population genomic and pan-genomic analyses in geese, we embarked on the task of 659 geese whole genome resequencing data and compiling a database of 155 RNA-seq samples. By constructing the pan-genome for geese, we generated non-reference contigs totaling 612 Mb, unveiling a collection of 2,813 novel genes and pinpointing 15,567 core genes, 1,324 softcore genes, 2,734 shell genes, and 878 cloud genes in goose genomes. Furthermore, we detected an 81.97 Mb genomic region showing signs of genome selection, encompassing the TGFBR2 gene correlated with variations in body weight among geese. Genome-wide association studies utilizing single nucleotide polymorphisms (SNPs) and presence-absence variation revealed significant genomic associations with various goose meat quality, reproductive, and body composition traits. For instance, a gene encoding the SVEP1 protein was linked to carcass oblique length, and a distinct gene-CDS haplotype of the SVEP1 gene exhibited an association with carcass oblique length. Notably, the pan-genome analysis revealed enrichment of variable genes in the "hair follicle maturation" Gene Ontology term, potentially linked to the selection of feather-related traits in geese. A gene presence-absence variation analysis suggested a reduced frequency of genes associated with "regulation of heart contraction" in domesticated geese compared to their wild counterparts. Our study provided novel insights into gene expression features and functions by integrating gene expression patterns across multiple organs and tissues in geese and analyzing population variation. CONCLUSION: This accomplishment originates from the discernment of a multitude of selection signals and candidate genes associated with a wide array of traits, thereby markedly enhancing our understanding of the processes underlying domestication and breeding in geese. Moreover, assembling the pan-genome for geese has yielded a comprehensive apprehension of the goose genome, establishing it as an indispensable asset poised to offer innovative viewpoints and make substantial contributions to future geese breeding initiatives.

Identification of SNPs Associated with Goose Meat Quality Traits Using a Genome-Wide Association Study Approach.

(1) Background: Goose meat is highly valued for its economic significance and vast market potential due to its desirable qualities, including a rich nutritional profile, tender texture, relatively low-fat content, and high levels of beneficial unsaturated fatty acids. However, there is an urgent need to improve goose breeding by identifying molecular markers associated with meat quality. (2) Methods: We evaluated meat quality traits, such as meat color, shear force (SF), cooking loss rate (CLR), and crude fat content (CFC), in a population of 215 male Sichuan white geese at 70 days of age. A GWAS was performed to identify potential molecular markers associated with goose meat quality. Furthermore, the selected SNPs linked to meat quality traits were genotyped using the MALDI-TOP MS method. (3) Results: A dataset of 2601.19 Gb of WGS data was obtained from 215 individuals, with an average sequencing depth of 10.89×. The GWAS revealed the identification of 43 potentially significant SNP markers associated with meat quality traits in the Sichuan white goose population. Additionally, 28 genes were identified as important candidate genes for meat quality. The gene enrichment analysis indicated a substantial enrichment of genes within a 1Mb vicinity of SNPs in both the protein digestion and absorption pathway and the Glycerolipid metabolism pathway. (4) Conclusion: This study provides valuable insights into the genetic and molecular mechanisms underlying goose meat quality traits, offering crucial references for molecular breeding in this field.

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.

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).

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.

Poorly differentiated cluster grade-a vital predictor for lymph node metastasis and oncological outcomes in patients with T1 colorectal cancer: a retrospective study.

BACKGROUND: T1 colorectal cancers have a low lymph node metastasis rate and good prognosis. Thus, endoscopic resection is an attractive choice. This study aimed to describe the value of poorly differentiated cluster grade in identifying endoscopically curable T1 colorectal cancers. METHODS: We included 183 T1 colorectal cancer patients who underwent curative resection. Univariate and multivariate logistic regressions were used to identify lymph node metastasis predictors. The Akaike information criterion was used to determine whether poorly differentiated cluster grade was the best predictor. Backward regression was used to screen the variables. Survival analyses were conducted to determine the prognostic predictive power of poorly differentiated cluster grade. Correlations among predictors and concordance between our pathologists were also investigated. RESULTS: Poorly differentiated cluster grade was an independent predictor for lymph node metastasis (adjusted odds ratio [OR]G 3 = 0.001; 95% confidence interval [95% CI]G 3 = < 0.001, 0.139) in T1 colorectal cancer patients; moreover, it had the best predictive value (AIC = 61.626) among all indicators. It was also screened for inclusion in the predictive model. Accordingly, a high poorly differentiated cluster grade independently indicated shorter overall survival (hazard ratio [HR]G 2 = 4.315; 95% CIG 2 = 1.506, 12.568; HRG 3 = 5.049; 95% CIG 3 = 1.326, 19.222) and disease-free survival (HRG 3 = 6.621; 95% CIG 3 = 1.472, 29.786). CONCLUSIONS: Poorly differentiated cluster grade is a vital reference to manage T1 colorectal cancer. It could serve as an indicator to screen endoscopically curable T1 colorectal cancers.

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.

Psychosocial Adaptation Among Inflammatory Bowel Disease Patients and Associated Factors: A Cross-Sectional Study.

Purpose: Patients with inflammatory bowel disease (IBD) suffer from physical symptoms and psychosocial issues. This generates risks of psychosocial maladjustment that is closely linked with self-care ability and health-related quality of life. The study aimed to explore psychosocial adaptation of IBD patients in China and the influencing factors from individual and family levels. Patients and Methods: Using a cross-sectional design, 191 Chinese patients with IBD were recruited from October 2020 to September 2021. General information questionnaire, general family functioning scale, resilience scale for IBD, and psychosocial adaptation questionnaire for IBD were used for investigation. Multivariate linear regression was used to identify predictive factors of psychosocial adaptation. Results: IBD patients reported a moderate level of psychosocial adaptation. Regression analysis showed that personal resilience especially the three dimensions (i.e., positive illness perception, disease management, and support from fellow IBD patients), general family functioning, and disease conditions (i.e., extra-intestinal manifestations and current disease status) were the main contributing factors of psychosocial adaptation, explaining 49.3% of the total variance. Conclusion: The findings suggest that healthcare providers could focus on improving patients' illness perception about IBD and strengthening their disease management abilities, together with optimizing patients' family functioning to enhance their psychosocial adaptation level.

Safety and Efficacy Study of Neoadjuvant Radiohormonal Therapy for Oligometastatic Prostate Cancer: Protocol of an Open-Label, Dose-Escalation, Single-Centre Phase I/II Clinical Trial.

BACKGROUND: The optimal treatment for oligometastatic prostate cancer (OMPC) is still on its way. Accumulating evidence has proven the safety and feasibility of radical prostatectomy and local or metastasis-directed radiotherapy for oligometastatic patients. The aim of this trial is to demonstrate the safety and feasibility outcomes of metastasis-directed neoadjuvant radiotherapy (naRT) and neoadjuvant androgen deprivation therapy (naADT) followed by robotic-assisted radical prostatectomy (RARP) for treating OMPC. METHODS: The present study will be conducted as a prospective, open-label, dose-escalation, phase I/II clinical trial. The patients with oligometastatic PCa will receive 1 month of naADT, followed by metastasis-directed radiation and abdominal or pelvic radiotherapy. Then, radical prostatectomy will be performed at intervals of 4-8 weeks after radiotherapy, and ADT will be continued for 2 years. The primary endpoints of the study are safety profiles, assessed by the Common Terminology Criteria for Adverse Events (CTCAE) 5.0 grading scale, and perioperativemorbidities, assessed by the Clavien-Dindo classification system. The secondary endpoints include positive surgical margin (pSM), biochemical recurrence-free survival (bPFS), radiological progression-free survival (RPFS), postoperative continence, and quality of life (QoL) parameters. DISCUSSION: The optimal treatment for OMPC is still on its way, prompting investigation for novel multimodality treatment protocol for this patient population. Traditionally, radical prostatectomy has been recommended as one of the standard therapies for localized prostate cancer, but indications have expanded over the years as recommended by NCCN and EAU guidelines. RP has been carried out in some centres for OMPC patients, but its value has been inconclusive, showing elevated complication risks and limited survival benefit. Neoadjuvant radiotherapy has been proven safe and effective in colorectal cancer, breast cancer and other various types of malignant tumors, showing potential advantages in terms of reducing metastatic stem-cell activity, providing clinical downstaging, and reducing potential intraoperative risks. Existing trials have shown that naRT is well tolerated for high-risk and locally-advanced prostate cancer. In this study, we hope to further determine the optimal irradiation dose and patient tolerance for genitourinary, gastrointestinal and systemic toxicities with the design of 3+3 dose escalation; also, final pathology can be obtained following RP to further determine treatment response and follow-up treatment plans. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1900025743. http://www.chictr.org.cn/showprojen.aspx?proj=43065.

Short-Term Outcomes and Clinical Efficacy of Stereotactic Body Radiation Therapy (SBRT) for Oligometastases of Prostate Cancer in China.

Objective: To assess the efficacy and safety of stereotactic body radiation therapy (SBRT) in managing oligometastases of prostate cancer. Moreover, it is the largest-to-date study in China to report the safety and efficacy of SBRT by CyberKnife for oligometastases of prostate cancer. Methods: In this retrospective study, 75 patients with 108 oligometastases were treated by SBRT from May 2012 to February 2021. Among these patients, 43 patients were treated with the intention to control all known metastatic lesions and 32 were treated for palliative care. Patients received regular follow-up evaluations every 3 months. Efficacy was assessed based on local control (LC) rates, biochemical progression-free survival (bPFS), progression-free survival (PFS), and overall survival (OS). Safety was assessed based on clinical adverse events. Results: Median follow-up time was 23.2 months (1.2-106.9 months). The complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) rates were 63.0%, 10.2%, 21.3% and 5.6%, respectively. The 6-month, 1-, and 2-year LC rates were 100%, 97.5%, and 96.0% respectively while the 6-month, 1-, and 2-year bPFS rates were 74.6%, 53.3%, and 47.9%, respectively. Additionally, 6-month, 1-, and 2-year PFS rates were 77.5%, 50.8%, and 47.2%, respectively. The 6-month, 1-, and 2-year OS rates were 97.0%, 88.8%, and 87.0%, respectively. For the 15 metastatic castration-resistant prostate cancer (mCRPC) patients with 23 lesions, the 2-year LC rates were 93.8%, while for 60 metastatic hormone-sensitive prostate cancer (mHSPC) patients with 85 lesions, the 2-year LC rates were 96.7%. No predictors of LC were found after univariate analysis. In those not on androgen deprivation therapy (ADT; n = 27), the 2-year freedom from ADT was 44.0%. All of the 24 patients with oligmetastase-induced complications experienced varying degrees of alleviation after SBRT. The treatment was well tolerated. No grade 3 or higher toxicity was observed. Conclusion: SBRT is a safe and effective treatment modality in the management of oligometastases of mHSPC and mCRPC with high LC rates and acceptable toxicity. SBRT could provide a treatment choice for mCRPC, as well as an alternative to delay the start of ADT for mHSPC.

Neutrophil extracellular traps are associated with enhanced procoagulant activity in liver cirrhosis patients with portal vein thrombosis.

OBJECTIVE: Patients with liver cirrhosis (LC) commonly exhibit hypercoagulability and tend to develop thrombosis. Neutrophil extracellular traps (NETs) are associated with a variety of thrombotic conditions, but their possible value in portal vein thrombosis (PVT) is not known. We assessed whether NETs promote thrombosis and contribute to the procoagulant state in patients with LC. METHODS: The circulating levels of NETs markers (myeloperoxidase, neutrophil elastase, citrullinated histone H3) were measured in 72 patients (median age, 55 years; 48 [66.7%] men) with LC from September 2020 to February 2021. Then they were divided into two groups: patients with or without PVT. NETs procoagulant activity was assessed based on thrombin-antithrombin complex (TAT complex) and Factor X. The levels of plasma markers were determined by ELISA. RESULTS: There were 28 patients with PVT and 44 patients without PVT. The levels of NETs markers and hypercoagulability markers in the plasma of cirrhosis patients with PVT were significantly higher than those of cirrhosis patients without PVT (p < 0.05). Additionally, the levels of the NETs markers correlated with TAT complex and Factor X (Spearman correlation rho >0.73, p < 0.0001). CONCLUSIONS: Neutrophil extracellular traps seem to enhance procoagulant activity in LC patients with PVT; thus, they may be a practical predictor of PVT as well as a rapid and easy-to-use diagnostic and treatment guide for PVT in patients with cirrhosis.

Stereotactic body radiotherapy plus pembrolizumab and trametinib versus stereotactic body radiotherapy plus gemcitabine for locally recurrent pancreatic cancer after surgical resection: an open-label, randomised, controlled, phase 2 trial.

BACKGROUND: There is paucity of investigations into immunotherapy or targeted therapy for postoperative locally recurrent pancreatic cancer. We aimed to assess the efficacy of stereotactic body radiotherapy (SBRT) plus pembrolizumab and trametinib in these patients. METHODS: In this open-label, randomised, controlled, phase 2 study, participants were recruited from Changhai Hospital affiliated to the Naval Medical University, Shanghai, China. Eligible patients were aged 18 years or older with histologically confirmed pancreatic ductal adenocarcinoma characterised by mutant KRAS and positive immunohistochemical staining of PD-L1, Eastern Cooperative Oncology Group performance status of 0 or 1, and documented local recurrence after surgery followed by chemotherapy (mFOLFIRINOX [ie, 5-fluorouracil, oxaliplatin, irinotecan, and folinic acid] or 5-fluorouracil). Eligible participants were randomly assigned (1:1) using an interactive voice or web response system, without stratification, to receive SBRT with doses ranging from 35-40 Gy in five fractions, intravenous pembrolizumab 200 mg once every 3 weeks, and oral trametinib 2 mg once daily or SBRT (same regimen) and intravenous gemcitabine (1000 mg/m2) on day 1 and 8 of a 21-day cycle for eight cycles until disease progression, death, unacceptable toxicity, or consent withdrawal. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in the as-treated population in all participants who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02704156, and is now complete. FINDINGS: Between Oct 10, 2016, and Oct 28, 2017, 198 patients were screened, of whom 170 patients were enrolled and randomly assigned to receive SBRT plus pembrolizumab and trametinib (n=85) or SBRT plus gemcitabine (n=85). As of the clinical cutoff date (Nov 30, 2020), median follow-up was 13·1 months (IQR 10·2-17·1). Median overall survival was 14·9 months (12·7-17·1) with SBRT plus pembrolizumab and trametinib and 12·8 months (95% CI 11·2-14·4) with SBRT plus gemcitabine (hazard ratio [HR] 0·69 [95% CI 0·51-0·95]; p=0·021). The most common grade 3 or 4 adverse effects were increased alanine aminotransferase or aspartate aminotransferase (ten [12%] of 85 in SBRT plus pembrolizumab and trametinib group vs six [7%] of 85 in SBRT plus gemcitabine group), increased blood bilirubin (four [5%] vs none), neutropenia (one [1%] vs nine [11%]), and thrombocytopenia (one [1%] vs four [5%]). Serious adverse events were reported by 19 (22%) participants in the SBRT plus pembrolizumab and trametinib group and 12 (14%) in the SBRT plus gemcitabine group. No treatment-related deaths occurred. INTERPRETATION: The combination of SBRT plus pembrolizumab and trametinib could be a novel treatment option for patients with locally recurrent pancreatic cancer after surgery. Phase 3 trials are needed to confirm our findings. FUNDING: Shanghai Shenkang Center and Changhai Hospital. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Five-year outcomes of stereotactic body radiation therapy (SBRT) for prostate cancer: the largest experience in China.

OBJECTIVE: To evaluate the efficacy and safety of SBRT for localized prostate cancer (PCa) with CyberKnife in China. Moreover, it is the largest-to-date pilot study to report 5-year outcomes of SBRT for localized PCa from China. METHODS: In this retrospective study, 133 PCa patients in our center were treated by SBRT with CyberKnife (Accuray Inc., Sunnyvale, USA) from October 2012 to July 2019. Follow-up was performed every 3 months for efficacy and toxicity evaluation. Biochemical progression-free survival (bPFS) and toxicities were assessed using the Phoenix definition and the Common Terminology Criteria for Adverse Events (CTCAE) v.5.0, respectively. Factors predictive of bPFS were identified with COX regression analysis. RESULTS: 133 patients (10 low-, 21 favorable intermediate-, 31 unfavorable intermediate-, 45 high-, and 26 very high risk cases on the basis of NCCN risk classification) with a median age of 76 years (range 54-87 years) received SBRT. The median dose was 36.25 Gy (range 34-37.5 Gy) in 5 fractions. Median follow-up time was 57.7 months (3.5-97.2 months). The overall 5-year bPFS rate was 83.6% for all patients. The 5-year bPFS rate of patients with low-, favorable intermediate-, unfavorable intermediate-, high-, and very high risk PCa was 87.5%, 95.2%, 90.5%, 86.3%, and 61.6%, respectively. Urinary symptoms were all alleviated after SBRT. All patients tolerated SBRT with 1 (0.8%) patient reporting grade-3 acute and 1 (0.8%) patient reporting grade-3 late genitourinary (GU) toxicity, respectively. There were no grade 4 toxicities. Gleason score (P < 0.001, HR = 7.483, 95%CI: 2.686-20.846) was the independent predictor of bPFS rate after multivariate analysis. CONCLUSION: SBRT is an efficient and safe treatment modality for localized PCa with high 5-year bPFS rates and acceptable toxicities.

Stereotactic body radiotherapy plus pembrolizumab and trametinib versus stereotactic body radiotherapy plus gemcitabine for locally recurrent pancreatic cancer after surgical resection: an open-label, randomised, controlled, phase 2 trial.

BACKGROUND: There is paucity of investigations into immunotherapy or targeted therapy for postoperative locally recurrent pancreatic cancer. We aimed to assess the efficacy of stereotactic body radiotherapy (SBRT) plus pembrolizumab and trametinib in these patients. METHODS: In this open-label, randomised, controlled, phase 2 study, participants were recruited from Changhai Hospital affiliated to Naval Medical University, Shanghai, China. Eligible patients were aged 18 years or older with histologically confirmed pancreatic ductal adenocarcinoma characterised by mutant KRAS and positive immunohistochemical staining of PD-L1, Eastern Cooperative Oncology Group performance status of 0 or 1, and documented local recurrence after surgery followed by chemotherapy (mFOLFIRINOX or 5-fluorouracil). Eligible participants were randomly assigned (1:1) using an interactive voice or web response system, without stratification, to receive SBRT with doses ranging from 35-40 Gy in five fractions, intravenous pembrolizumab 200 mg once every 3 weeks, and oral trametinib 2 mg once daily or SBRT (same regimen) and intravenous gemcitabine (1000 mg/m2) on day 1 and 8 of a 21-day cycle for eight cycles until disease progression, death, unacceptable toxicity, or consent withdrawal. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in the as-treated population in all participants who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02704156, and is now complete. FINDINGS: Between Oct 10, 2016, and Oct 28, 2017, 198 patients were screen, of whom 170 patients were enrolled and randomly assigned to receive SBRT plus pembrolizumab and trametinib (n=85) or SBRT plus gemcitabine (n=85). As of the clinical cutoff date (Nov 30, 2020), median follow-up was 23·3 months (IQR 20·5-27·4). Median overall survival was 24·9 months (23·3-26·5) with SBRT plus pembrolizumab and trametinib and 22·4 months (95% CI 21·2-23·6) with SBRT plus gemcitabine (hazard ratio [HR] 0·60 [95% CI 0·44-0·82]; p=0·0012). The most common grade 3 or 4 adverse effects were increased alanine aminotransferase or aspartate aminotransferase (ten [12%] of 85 in SBRT plus pembrolizumab and trametinib group vs six [7%] of 85 in SBRT plus gemcitabine group), increased blood bilirubin (four [5%] vs none), neutropenia (one [1%] vs nine [11%]), and thrombocytopenia (one [1%] vs four [5%]). Serious adverse events were reported by 19 (22%) participants in the SBRT plus pembrolizumab and trametinib group and 12 (14%) in the SBRT plus gemcitabine group. No treatment-related deaths occurred. INTERPRETATION: The combination of SBRT plus pembrolizumab and trametinib could be a novel treatment option for patients with locally recurrent pancreatic cancer after surgery. Phase 3 trials are needed to confirm our findings. FUNDING: Shanghai Shenkang Center and Changhai Hospital. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Stereotactic body radiation therapy with sequential S-1 for patients with locally advanced pancreatic cancer and poor performance status: An open-label, single-arm, phase 2 trial.

PURPOSE: The optimal treatment for a particularly neglected group of patients with locally advanced pancreatic cancer (LAPC) and poor performance status, who are usually excluded from most clinical trials, is required. Therefore, we aim to investigate the efficacy and safety of stereotactic body radiation therapy (SBRT) with sequential S-1 for those patients. METHODS: Eligible patients had histologically and radiographically confirmed LAPC and ECOG performance status of 2 or more points determined by two independent physicians. Radiation doses ranged from 35-40 Gy/5f. S-1 was taken orally, twice daily, at a dose of 80 mg/m2 for 28 days, followed by a 14-day interval, which repeated for 6 cycles and was initiated one month after SBRT. The primary endpoint was 1-year overall survival (OS). The secondary endpoints were OS, progression free survival (PFS), treatment-related toxicity and quality of life. The study was registered at ClinicalTrials.gov: NCT02704143. RESULTS: Sixty-three patients were enrolled. At the time of data cut-off, all patients died. No patients were lost to follow-up. Median follow-up was 15.8 months (95%CI 12.9-18.7 months). One-year OS was noted in 46 of 63 patients (73.0%, 95%CI 67.4%-78.6%). The median OS and PFS was 14.4 (95%CI 13.2-15.6 months) and 10.1 months (95%CI 9.7-10.5 months) respectively. Eighteen patients (28.6%) had grade 3 toxicity. According to Quality of Life Questionnaire-Core 30, significant improvements of abdominal pain were found, and patients with poorer baseline global health status had greater improvement of health status and pain relief after treatment. CONCLUSIONS: SBRT with sequential S-1 shows promising efficacy and acceptable toxicity in poor performance status patients with LAPC.

Development and Validation of Multicenter Predictive Nomograms for Locally Advanced Pancreatic Cancer After Chemoradiotherapy.

OBJECTIVE: Due to common practice of hypofractionated radiotherapy in pancreatic cancer and heterogeneous chemotherapy regimens in previous studies, modified nomograms are required. Therefore, we aim to develop and validate prognostic nomograms for locally advanced pancreatic cancer (LAPC) after stereotactic body radiation therapy (SBRT) and chemotherapy. METHODS: The development cohort comprised 925 patients with LAPC receiving SBRT and gemcitabine-based chemotherapy in our center, while 297 patients from another two centers formed the validation cohort. Nomograms were created from COX models and internally validated by bootstrap. Model discriminations were evaluated by calibration plots and concordance index (C-index). A decision curve analysis (DCA) was performed to evaluate clinical benefits of nomograms. Additionally, recursive partitioning analysis (RPA) was used for stratifications of survival probability based on the total score of each patient calculated by nomograms. RESULTS: Weight loss, tumor diameter, radiation dose, CA19-9 kinetics after treatment and surgical resection were included in the nomogram for overall survival (OS), while the five factors plus performance status formed the nomogram for progression free survival (PFS). The corrected C-indexes for estimated 1-year and 2-year OS of the development cohort were 0.88 (95% CI: 0.85-0.91) and 0.86 (95% CI: 0.83-0.90). For those of the validation cohort, it was 0.88 (95% CI: 0.82-0.94) and 0.83 (95% CI: 0.74-0.91). Additionally, the corrected C-index for predicted 1-year PFS in the development and validation cohort was 0.83 (95% CI: 0.81-0.86) and 0.82 (95% CI: 0.78-0.87), respectively. The calibration plots showed good agreement of 1- and 2-year OS and 1-year PFS between the estimations and actual observations. Potential clinical benefits were demonstrated with DCA. Additionally, for 1- and 2-year OS and 1-year PFS, patients were stratified into four groups with different survival probability by RPA. CONCLUSION: The validated nomograms provided useful predictions of OS and PFS for LAPC with chemoradiotherapy.