Organoids are in vitro-cultured three-dimensional (3D) miniature structures derived from human pluripotent stem cells or adult stem cells from healthy individuals or patients. Compared to traditional two-dimensional (2D) cell lines or animal models, organoids are regarded as more promising high-fidelity models, possessing unique advantages in terms of disease modeling, drug development, the establishment of living biobanks, and the exploration of personalized treatment. Over recent years, the rapid development of organoid technology has brought new hopes for innovating preclinical experimental tumor models and promoting clinical personalized diagnosis and treatment. This review is intended to introduce the development status and latest progress of organoids in the field of radiotherapy for tumors, explore the advantages and limitations of organoid models for cancer, and prospect for its application in the field of radiotherapy.

Pancreatic cancer,as a common malignant tumor of the digestive system,has a very low survival rate.In recent years,pancreatic cancer has made great progress in diagnostic methods,radiation therapy techniques,and systemic chemotherapy,but its therapeutic effect has not been considerably improved.As a new type of tumor research platform,organoids have made research progress in many fields.Constructing pancreatic cancer organoids is of great research value to guide the individualized treatment of pancreatic cancer.This article reviews the research and clinical application prospect of organoid model in radiotherapy of pancreatic cancer.

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.
Male ; Humans ; Prostatic Neoplasms/radiotherapy* ; Prostate-Specific Antigen/therapeutic use* ; Neoadjuvant Therapy ; Androgen Antagonists/therapeutic use* ; Prospective Studies

Objective:To compare dose distributions of hypofractionated radiotherapy for pancreatic cancer between IMPT and VMAT.Methods:Ten pancreatic cancer cases were included in this retrospective study. Photon (Edge) and proton (Proteus?PLUS) plans were designed by Eclipse and RayStation TPS, respectively. All plans were transferred to MIM system for extraction of parameters, which included Dmin, Dmean and Dmax of PTV, conformity index (CI), new conformity index (nCI), homogeneity index (HI), gradient index (GI), coverage, Dmax and dose-volume of the organs at risk (OARs). Results:There was no significant difference in CI between the two groups. The higher PTV Dmin, Dmean, Dmax, D98%, D2%, HI, coverage and the better GI, D2 cmwere found in VMAT ( t/ Z=-4.63-5.32, P<0.05). The lower 10%_PD was found in IMPT ( t=-7.47, P<0.05). Regarding the OARs, Dmax of the intestine, stomach, and duodenum and Dmean of the left kidney were similar between two groups without significant difference ( P>0.05). The D5 cm 3 of the intestine, D10 cm 3 of the stomach, D5 cm 3 and D10 cm 3 of the duodenum, D2/3 of the left kidney, Dmean and D2/3 of the right kidney were lower in IMPT than those in VMAT ( t/ Z=-8.12--2.60, P<0.05). However, the Dmax and D0.35 cm 3 of the spinal cord were higher in IMPT than those in VMAT ( t=7.30, 6.77, P<0.05). Conclusions:Both of hypofractionated radiotherapy plans of pancreatic cancer designed by VMAT and IMPT could meet clinical needs. No significant difference was found in Dmax of the adjacent gastrointestinal tracts between the two groups. While IMPT had the advantage over VMAT in the case of lower dose-volumes of the gastrointestinal tracts. Nevertheless, less protections of the OARs in front of the tumor volume could be provided by IMPT compared with VMAT.

Objective:To compare the dose distribution among CyberKnife, Tomotherapy, Edge, Triology and γ-knife in stereotactic body radiation therapy (SBRT) for pancreatic cancer.Methods:Clinical data of 10 panreatic cancer patients receiving CyberKinife treatment were retrospectively analyzed. The treatment plans were designed by five apparatuses from five centers according to the uniform requirement. All plans were transferred to MIM system for the extraction of parameters, which mainly included D min, D mean and D max of PTV, conformity index (CI), new conformity index (nCI), homogeneity index (HI), gradient index (GI), coverage, D max and dose-volume of the stomach and bowel. Results:The best CI and nCI were obtained in Triology ( P<0.001), and the worst HI was found in γ-knife ( P<0.001). The best GI was found in CyberKnife, followed by γ-knife and Tomotherapy, and Edge showed the worst GI ( P<0.001). The highest D min of PTV was found in both Edge and Triology, while lower D min of PTV was found in CyberKnife and Tomotherapy ( P<0.001). Additionally, γ-knife provided the highest D mean and D max of PTV ( P<0.001). Regarding the organs at risk, the lowest D max and D 5cm 3 of the bowel ( P<0.001), D max of the stomach ( P=0.003), D max( P=0.001), D 5cm 3 ( P<0.001) and D 10cm 3 ( P=0.005) of the duodenum, D max( P<0.001) and D 0.35cm 3 ( P<0.001) of the spinal cord were found in CyberKnife. The highest D max of the bowel was found in γ-knife. Furthermore, the highest D 5cm 3 of the duodenum was demonstrated in Edge ( P<0.001) and Tomotherapy provided the highest D max( P<0.001) and D 0.35cm 3 of the spinal cord ( P<0.001). Conclusions:All five radiotherapy apparatuses can meet the requirement of SBRT for pancreatic cancer. More rapid dose fall-off could be obtained via CyberKnife and γ-knife. Triology and Edge provide better target conformity. CyberKnife can better protect the gastrointestinal tract.

Objective To evaluate the efficacy of stereotactic body radiation therapy (SBRT) on the survival of patients with early stage pancreatic cancer.Methods The clinical data of 103 T1-2N0M0 pancreatic cancer patients treated by CyberKnife SBRT at the Department of Radiation Oncology of Changhai Hospital from January 2012 to December 2016 was retrospectively analyzed.Kaplan-Meier method was used for survival analysis and Cox proportional hazards model was utilized to identify survival related factors.Results The median overall survival(OS) of T1-2N0M0 pancreatic cancer patients who had unresectable pancreatic cancer or refused surgery was 17.7 (16.1-19.3) months.1-year and 2-year OS rate were 86.3％ and 24.6％,respectively.The median progression free survival(PFS) was 13.0(10.7-15.3) months.1-year and 2-year PFS rate were 54.5％ and 6.3％,respectively.Patients with chemoradiation,BED10 ≥60 Gy and CA19-9 decrease ＞ 50％ after treatment had longer OS and PFS.Conclusions SBRT is a safe and effective treatment for patients with T1-2N0M0 pancreatic cancer.

Objective To identify the effect of stereotactic body radiation therapy (SBRT) on the survival of patients with recurrent pancreatic cancer after surgery.Methods The data of 104 patients with recurrent pancreatic cancer after surgery who underwent SBRT in the Department of Radiation Oncology of Changhai Hospital,Navy Medical University from February 2012 to December 2016 were retrospectively analyzed.The prescription doses ranged from 35-40 Gy/4-8 f.Survival analysis was performed using the Kaplan-Meier method,and relevant factors affecting patients' survival were screened by the Cox proportional hazards model.Results The median overall survival (OS) and progression free survival (PFS) was 12.5 (11.0-14.0) months and 7.3 (6.0-8.7) months,respectively,while the 1-year rate of OS and PFS was 55.8％ and 22.1％,respectively.Multivariate analysis indicated that tumor stage,biological effect dose (α/β =10,BED10),the decrease of CA19-9 level after treatment,and follow-up chemotherapy were all related factors affecting overall survival;tumor stage,BED10,the degree of pain relief and the decrease of CA19-9 level after treatment were related factors affecting PFS.Conclusions Patients suffering recurrent pancreatic cancer with early tumor stage,normal CA19-9 level and mild pain before treatment could be better treated by SBRT,BED10 ≥60 Gy and follow-up chemotherapy after radiotherapy can prolong the survival of patients.

Objective To comprehensively analyse the immunophenotype of primary pancreatic cancer,providing biological clues for treating pancreatic cancer.Methods The genome nap of 177 primary pancreatic cancer patients from the Cancer Genome Atlas (TCGA) database were enrolled.The overall immune infiltration score (IIS),T cell infiltration score (TIS) and antigen presenting machinery (APM) score were quantified for each specimen.By using unsupervised clustering,the patients were divided into immune-high group and immune-low group according to IIS,TIS,and APM scores.The differences on the inffiltration of immune cell subtype,expression of immune checkpoint and immunological function evaluation were compared between two groups.Results In the radiotherapy population,the survival rate of immune-high group was slightly higher than that of immune-low group with no statistical significance.The immune-high group had more infiltrated neutrophils (63.4％ vs 36.6％),eosinophils (75.5％ vs 24.5％),activated CD4 + memory T lymphocytes (80.7％ vs 19.3％),naive CD4 + T lymphocytes (81.2％ vs 18.8％) and naive B lymphocytes (59.5％ vs 40.5％) compared with immune low group;while the immune-low group had more activated NK cells (67.3％ vs 32.7％),regulatory T lymphocytes (68.9％ vs 31.1％),T follicular helper (67.7％ vs 32.3％),and activated mast cells (62.9％ vs 37.1％).Co-stimulatory molecules such as CD28,ICOS,CD40,CD40L,CD27,CD27L,4-1BB,OX40,GITR and co-inhibitory molecules including CTLA-4,PD-L2,PD-1,VISTA,LAG-3,TIGIT,Galectin-9,TIM-3,and IDO-1 were significantly higher expressed in the immune-low group (all P ＜ 0.05).The PC1 value of principal component analysis of chemokine expression levels and the cytolytic activity (CYT) in the immune-high group were significantly higher (all P ＜0.001).Conclusions Clustering on the three inmune quantification scores could be preliminarily used for immunophenotyping pancreatic cancer.The immune-high group may have synergistic effect with radiation therapy.Treatment with immune checkpoint inhibitor may be effective in immune-low group.

Objective To investigated the influence of different combined treatment sequence of stereotactic body radiation therapy (SBRT) and chemotherapy (CT) on the survival of very elderly patients with locally advanced pancreatic cancer ( LAPC) .Methods The data of LAPC patients ≥60 years old treated by CyberKnife SBRT at Shanghai Changhai Hospital from January 2012 to December 2016 was retrospectively analyzed.According to treatment sequences , patients were divided into three groups:CT+SBRT group ( first chemotherapy and then SBRT ) , SBRT+CT group ( first SBRT and then chemotherapy ) and CT+SBRT+CT group ( first chemotherapy , then SBRT and finally chemotherapy ) .Patients were recommended to receive a 6-month chemotherapy .Intravenous administration of 1000 mg/m2 gemcitabine was initiated on day 1, 8, and 15 every 4 weeks or S-1 was orally given at a dose of 80 mg/m2 for 28 days followed by a 14-day rest , which repeated for 6 cycles.Radiotherapy parameters: the median total prescription dose was 36(30-45)Gy; the median per fraction dose was 7(5-9)Gy;the median number of fractions was 5(5-8) fractions;the median biological equivalent dose (BED10) were 61.92(48-85.5) Gy, respectively.The interval between SBRT and chemotherapy ranged from 2 to 3 weeks.Patients were followed every 3 months.The main outcome measures were overall survival ( OS) and median progression free survival ( PFS) .Second outcome measure was adverse events.Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE 4.0) was employed to evaluate adverse events , and RTOG/EORTC was used to assess the adverse events of radiotherapy .Overall survival (OS) and PFS were calculated by Kaplan-Meier method.Univariate and multivariate logistic regression model were used to analyze the independent risk factors .Results A total of 260 patients were enrolled in the study , including 28 patients treated with CT+SBRT, 163 patients undergoing SBRT +CT and 69 patients treated with CT+SBRT+CT.The median OS and PFS were 13.2(95％CI 12.8-13.6)months and 8.2(95％CI 7.7-8.7)months, respectively.OS in CT +SBRT, SBRT +CT and CT +SBRT +CT group was 12.2 (10.9-13.9),13.4 ( 12.9-13.9 ) and 13.1 ( 12.7-13.5 ) months, and the differences were not statistically significant(P=0.425).PFS in CT+SBRT, SBRT+CT and CT+SBRT+CT group was 6.4(5.9-6.9), 8.3(7.8-8.8) and 8.2(7.2-9.2)months, and the differences were statistically significant (P=0.008).In univariate analysis , ECOG, SIRI, the extent of decreased CA 19-9 after treatment and BED 10 were important factors of OS.In multivariate analysis, the CA19-9 response and BED10 were independent factors for OS . Multivariate analysis showed that the extent of decreased CA 19-9 after treatment and BED 10 were important factors of OS.In CT+SBRT group, patients had lower ECOG score (χ2 =115.325,P<0.001) and earlier clinical staging (χ2 =24.788, P<0.001 ).In SBRT +CT group, patients had advanced staging (χ2 =159.759,P<0.001) and lymph node metastasis(χ2 =40.925,P<0.001).Only 1 patient experienced grade 3 radiotherapy associated duodenitis .The adverse events of patients who were first treated by chemotherapy included grade 3 neutropenia in 4 patients and grade 3 gastrointestinal reaction in 5 patients.The adverse events of patients who were first treated by radiotherapy included grade 3 neutropenia or/and leucopenia in 18 patients and grade 3 abdominal pain, nausea or vomit in 16 patients.The adverse events of CT +SBRT+CT patients included grade 3 neutropenia or/and leucopenia in 4 patients and grade 3 abdominal pain or nausea in 5 patients.There was no grade ≥4 adverse events.Conclusions For very elderly patients with LAPC , the survival of patients who received pre-SBRT chemotherapy , post-SBRT chemotherapy and pre-and post-SBRT chemotherapy was comparable , but SBRT+CT group and CT +SBRT+CT group had longer PFS than CT +SBRT group.

Objective To explore the prognostic value of ADC tot of diffusion-weighted magnetic resonance imaging with multiple diffusion gradient factor ( b) values ( Mb DWI) in predicting overall survival (OS) of patients with locally advanced pancreatic cancer (LAPC) undergoing CyberKnife and sequential S-1. Methods Forty-one LAPC patients were enrolled (28 male and 13 female), who had routine pancreatic MRI and multiple b value DWI (Mb DWI, b value =0, 25, 50, 75, 100, 150, 200, 400, 600, 800 and 1000 s/mm2) scan (3.0 T) prior to radiotherapy.ADCtot value was calculated using single index model .Two independent radiologists on abdominal radiology manually drew the target area of interest and measured ADC tot at 1-month interval, and the interclass correlation coefficient (ICC) was calculated.The median ADCtot was used as a standard to divided the data into high value and low value .The survival was analyzed by Kaplan-Meier method and compared by log rank test .Cox proportional hazard model was employed to identify predictive factors for OS.Results The median ADCtot value by two independent radiologists was (1.54 ±0.27) ×10 -3 and(1.55 ±0.28) ×10 -3 mm2/s, respectively.The ICC was 0.994, and the consistency was good.Pre-treatment ADC tot value was the independent prognostic factor for the OS of patients who received CyberKnife and S-1 (HR: 1.083, 95％CI 1.083-12.554,P=0.0368), indicating that the mortality increased by 1.083 times as ADCtot increased by 1 unit.Similarly, CyberKnife combined with S-1 was also the independent prognostic factor for the OS (HR:0.329, 95％CI 0.142-0.765, P=0.0098), indicating that the mortality of patients treated by CyberKnife and S-1 was 0.329 times of that of patients who did not take S-1. Conclusions The pre-treatment ADC tot was an independent predictor for OS of LAPC patients treated by CyberKnife and sequential S-1, which had a certain prognostic value .