Background:The incidence of inflammatory bowel disease(IBD)is increasing recently. However,the pathogenesis has not been fully clarified. Aims:To investigate the expressions and significance of interleukin-22( IL-22),matrix metalloproteinase-9(MMP-9)and macrophage migration inhibitory factor(MIF)in peripheral blood of patients with IBD. Methods:A total of 80 patients with IBD admitted from May 2011 to Nov. 2014 at the First Affiliated Hospital of Soochow University were enrolled,in which 43 cases were Crohn’s disease(CD),37 cases were ulcerative colitis(UC). Forty healthy subjects were served as normal controls. Peripheral levels of IL-22,MMP-9 and MIF were detected by ELISA. Multivariate Logistic regression model was used to analyze IL-22,MMP-9 and MIF in active CD and UC and ROC curve was used to evaluate the diagnostic performance of these markers for screening of active CD and UC. Results:Compared with normal control group,peripheral levels of IL-22,MMP-9 and MIF increased significantly in CD and UC groups(P <0. 05),while no significant difference was found between CD and UC groups(P > 0. 05). Peripheral levels of IL-22, MMP-9 and MIF in active CD and UC were significantly higher than those in remission stage(P < 0. 05). For screening of active IBD,the area under ROC curve(AUC)of combined detection of IL-22 and MMP-9(0. 853 for CD,0. 867 for UC) was superior to that of IL-22,MMP-9 or MIF only(0. 747,0. 770 and 0. 699 for CD,0. 774,0. 815 and 0. 761 for UC). Conclusions:Peripheral levels of IL-22,MMP-9 and MIF increase markedly in IBD patients,which are correlated closely with the activity of IBD. Combined detection of IL-22 and MMP-9 might greatly increase the accuracy for screening of active IBD.

Objective· To evaluate the safety of neoadjuvant therapy which was constituted by docetaxel based systemic chemotherapy and maximal androgen blockage for patients with locally advanced prostate cancer and to summarize the related adverse events and clinical managements.Methods· From June 2015 to February 2017,the clinical data of 55 patients undergoing neoadjuvant chemotherapy combined with complete androgen deprivation were retrospectively reviewed.The patients were given docetaxel and prednisone as DP regimen every 3 weeks and LHRH analogues with bicalutamide as maximal androgen deprivation for a total of 4 cycles.All treatment-related adverse events were observed and then recorded.Results· Two cases with liver function impairment after 2 cycles of treatment were withdrawn from the study.No severe allergic reactions occurred during neoadjuvant therapy.The most common adverse events were hematologic toxicity,while 23.6％ of patients had grade Ⅲ-Ⅳ neutropenia,and about 12.7％ had anemia.Due to a relatively short course of treatment,the skin or mucous damage,peripheral neurotoxicity and fluid retention were rare.However,hot flash,male breast development as well as erectile dysfunction were very frequently observed due to maximal androgen deprivation.The majority of these adverse events were relieved by symptomatic and supportive treatment.Conclusion · After strict selection,4 cycles of neoadjuvant chemotherapy combined with total androgen blockade could be well tolerated by the patients with high-risk locally advanced prostate cancer.Even though the adverse events were controllable,they still need to be closely monitored during treatment in order to reduce the incidence.In addition,the very low testosterone level associated endocrinal metabolic disorders caused by complete androgen deprivation were also of great concern.

Objective To investigate the efficacy and safety of docetaxel chemotherapy combined with androgen-deprivation therapy (ADT) for patients with metastatic hormone-sensitive prostate cancer.Methods One hundred and ninety-two cases of metastatic hormone-sensitive prostate cancer in Renji Hospital between January 2015 and July 2016 were analyzed retrospectively.Patients' age was 39 to 90,the median age was 71 years.The median prostate-specific antigen (PSA) at diagnosis was 90.6ng/ml (4.1-2 556.0 ng/ml).One hundred and eighty were with bone metastasis and 12 were with distant lymphatic metastasis.Sixty-one of them received docetaxel chemotherapy plus ADT for 3 weeks,131 received hormonal treatment alone.The median age of combination therapy group was 67 years (39-80 years),that of single treatment group was 75 years (50-93 years) (P ＜ 0.001).The median PSA baseline of the two groups were 91.6 ng/ml (35.5-157.5ng/ml) and 89.1 ng/ml (59.6-191.0 ng/ml) (P =0.324).Gleason score of combination therapy group showed that 3 cases (4.9％) was 6,23 cases (37.7％) 7,35 cases (57.4％) ≥8.That of single treatment group showed that 17 cases (13.0％) 6,51 cases (38.9％) 7,63 cases (48.1％) ≥8.There was no statistic difference between the two groups (P =0.122).But there was statistic difference in the rate of T3 or T4 clinical stage in primary lesion,that of combination therapy group was 50.7％ (37/61) and 34.4％ (21/61),and that of single treatment group was 60.3％ (79/131) and 21.4％ (28/131) (P =0.011).Imaging showed local lymph node metastasis in the two groups (80.3％ vs.67.9％,P =0.005).As to physical condition,the combination therapy group showed a lower ECOG score than the single treatment group (P ＜ 0.001).All the patients' survival condition,PSA response rate and adverse events were analyzed.Results One hundred and ninety-two patients were regularly followedup.The median follow-up time was 23.3 (14.4-33.4) months.Median progression free survival time of combination therapy group and single treatment group were respectively 24.4 (7.5-31.3) months vs.17.5(3.0-30.7) months (P ＜ 0.001).There were 1 and 16 cases died in the two groups due to disease progression.During the treatment,the rate of PSA level less than 0.2 ng/ml was 29.5％ (18/61) vs.13.7％ (18/131) in combination therapy group and single treatment group.Regarding the tolerance of combination therapy group,the incidence rate of grade 3-4 neutropenia was 27.9％ (17/61).Skin and mucous membrane damaged in 24.6％ (15/61) patients,transaminase rised in 13.1％ (8/61) patients,and peripheral nerve toxicity occurred in 9.8％ (6/61) patients.There was no significant difference between the 2 groups in relevant events caused by ADT,gynecomastia (14.8％ vs.16.3％) and erectile dysfunction (100％ vs.100％).Most of them could be relieved by symptomatic treatment.Conclusions For metastatic hormone-sensitive prostate cancer,docetaxel combined with hormonal treatment showed longer progression free survival than ADT alone with adverse reactions acceptable.

Objective:To investigate the clinical efficacy of neoadjuvant chemo-hormonal therapy(NCHT)followed by radical prostatectomy(RP) plus extended pelvic lymphadenectomy for very-high-risk locally advanced prostate cancer.Methods:The data of 327 cases of very-high-risk locally advanced prostate cancer treated in Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine, The Second Hospital of Tianjin Medical University, and The Third Affiliated Hospital of Sun Yat-sen University from December 2014 to July 2019 were retrospectively analyzed. Patients were divided into two groups according to treatment regimens: the RP group (direct RP + extended pelvic lymphadenectomy 4-6 weeks after the biopsy of prostate) and the NCHT group (4-6 cycles of NCHT prior to RP). There were 171 cases in RP group and 156 cases in NCHT group, respectively. In the RP group, the median age was 67 (ranging 44-83)years. The median PSA at diagnosis was 27.24 (ranging 4.55-207.00) ng/ml. Patients’numbers of clinical T 2, T 3a, T 3b, T 4 stage were 13, 85, 57, 16, respectively, and clinical N 1, N 0 stage were 33 and 138, respectively. Patients’numbers of ISUP grade groups of 1, 2, 3, 4, 5 were 5, 35, 41, 51, 39, respectively. In the NCHT group, The median age was 67 years, ranging 46-78 years. The median PSA at diagnosis was 72.09(ranging 4.08-722.95)ng/ml. Patients’ numbers of clinical T 2, T 3a, T 3b, T 4 stage were 11, 47, 58, 40, respectively, and clinical N 1, N 0stage were 76 and 80, respectively. Patients’numbers of ISUP grade groups of 1, 2, 3, 4, 5 were 1, 11, 33, 43, 68, respectively. At baseline, the NCHT group showed higher PSA, higher ISUP grade, and more advanced clinical stage at diagnosis( P<0.05). The PSA, pathological down-staging rate, and positive surgical margin rate as well as the biochemical recurrence free survival(bRFS)were compared between the two groups. Results:After radical prostatectomy, compared with the RP group, the NCHT group had a higher proportion of patients achieving PSA<0.2 ng/ml at 6-week postoperative follow-up ( P<0.001), a higher pathologic tumor stage down-staging rate ( P<0.001), a higher ISUP down-grading rate ( P<0.001), and a lower positive surgical margins rate ( P<0.001). In addition, 10.9% of the NCHT group achieved pT 0 or minimal residual disease in postoperative pathology exams. Eighty-three patients (48.5%) in the RP group and 125 patients (80.1%) in the NCHT group achieved undetectable PSA after surgery and entered further analysis for bRFS, which showed NCHT group had significantly longer bRFS (19.46 months vs. 6.35 months). NCHT significantly reduced the risk for biochemical recurrence in locally advanced prostate cancer patients( HR=0.278, 95% CI 0.198-0.390, P<0.001). Such a reduce in risk for biochemical recurrence was seen in all subgroups( P<0.001). Conclusions:NCHT might improve surgical outcomes as well as bRFS in very-high-risk locally advanced prostate cancer patients.

Objective:To compare the efficacy and safety of radium-223 in the treatment of metastatic castration-resistant prostate cancer (mCRPC) patients with and without homologous recombination repair (HRR) gene mutation.Methods:The clinical data of 27 patients with mCRPC bone metastases who received radium-223 therapy from April 2021 to November 2022 in Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine were retrospectively analyzed. Among the 27 mCRPC patients, 18 patients carrying HRR gene mutations belonged to the HRD(+ ) group, and 9 patients without HRR gene mutation belonged to the HRD(-) group. The age of patients in HRD(+ ) group was 69.5 (63.8, 77.0) years old, alkaline phosphatase (ALP) was 243.0 (82.8, 301.3) U/L, prostate specific antigen (PSA) was 71.6 (7.3, 329.8) ng/ml, pain score was 3.0 (1.0, 5.0) points. Eastern Cooperative Oncology Group (ECOG) score ranged from 0 to 1 points in 7 cases, and 2 points in 11 cases. In the HRD(-) group, the median age was 72.0 (64.5, 76.5) years old, ALP was 88.0 (67.5, 260.6) U/L, PSA was 19.1 (1.1, 117.8) ng/ml, and pain score was 2.0 (0, 4.5) points. The ECOG score ranged from 0 to 1 in 4 cases, and 2 in 5 cases in the HRD(-) group. There was no significant difference in the above general data between the two groups ( P>0.05). All patients received radium-223 treatment every 4 weeks, no more than 6 times. The changes of ALP, PSA, pain score and hematological adverse reactions were compared between the two groups. Results:In the HRD(+ ) group, the median number of radium-223 treatment was 4.5 (3.0, 5.3) couses, 4 patients (22.2%) completed 6 courses, and 6 patients died of prostate cancer during follow-up. In the HRD(-) group, the median number of radium treatment was 4.0 (2.5, 6.0) couses, 3 patients (33.3%) completed 6 courses, and 1 patient died of prostate cancer during follow-up. There was no significant difference in the number of radium treatment courses between the two groups ( P=0.320). ALP in HRD(+ ) group was 101.8 (61.3, 147.0) U/L after radium-223 treatment, which was significantly lower than that before treatment ( P=0.002). ALP in HRD(-) group was 73.0 (64.0, 113.5) U/L after radium-223 treatment, and it was not significantly different from that before treatment ( P=0.327). The rate of ALP response (ALP decrease >10%) in HRD(+ ) group was significantly higher than that in HRD(-) group [83.3% (15/18) vs. 44.4% (4/9), P=0.037]. PSA was 105.9(5.2, 798.4) ng/ml in HRD (+ ) group after radium-223 treatment, and was 25.6(0.8, 1 031.0) ng/ml in HRD(-) group, and they were not significantly different from that before treatment ( P=0.145, P=0.386). There were no significant differences in the rate of PSA response (PSA decrease>10%) between HRD(+ ) group and HRD(-) group [38.9% (7/18) vs. 22.2% (2/9), P=0.386]. The median pain score of HRD(+ ) group was 3.0 (0, 4.0) points after treatment, which was significantly lower than that before treatment ( P=0.028). The pain score of HRD(-) group was 1.0(0, 3.0) points after treatment, and it was not significantly different from that before treatment ( P=0.129). There was no significant difference in pain relief rate between HRD(+ ) group and HRD(-) group [66.7% (12/18) vs. 44.4% (4/9), P=0.411]. The incidence of at least one hematological adverse event during radium-223 treatment in the HRD(+ ) group was higher than that in the HRD(-) group [77.8% (14/18) vs. 33.3% (3/9), P=0.039]. There was no significant difference in the incidence of grade 1-2 hematological adverse events between the two groups [72.2%(13/18) vs. 33.3%(3/9), P=0.097]. Only 1 patient in the HRD(+ ) group experienced grade 3 anemia during treatment which was recovered after blood transfusion. Conclusions:Compared to mCRPC patients without HRR gene mutation, patients with HRR gene mutations had better ALP response and bone pain relief after radium-223 treatment. The overall incidence of adverse events in the HRD(+ ) group is higher than that in HRD(-) group, and there was no significant difference in grade 1-2 hematological adverse events between the two goups. It is necessary to expand the sample size to further verify the conclusion.

A patient aged 68 years old presented urinary frequency, urgency, and gross hematuria for 1 month, with initial PSA of 72.72 ng/ml and alkaline phosphatase (ALP)of 114 U/L. Prostate biopsy pathology showed small cell neuroendocrine carcinoma of prostate. The patient was immediately administered 6 cycle of chemotherapy including etoposide and cisplatin combined with medical castration. The CDK4 gene was detected 1.99 times amplification by peripheral blood free DNA (cfDNA)gene analysis. The chemotherapy was followed by parbosini therapy. The number and density of bone metastases continued to decrease significantly by bone scan at 3 and 6 months after treatment, with a continuous decline of ALP and PSA. After 1 year of follow-up, pelvic MRI and bone systemic imaging indicated stable lesions, with PSA of 0.05 ng/ml and ALP of 59 U/L.

Objective To determine the influence of abiraterone acetate (AA) on neuroendocrine differentiation (NED) in metastatic castration-resistant prostate cancer (mCRPC) and the prognostic predicting value of the serum NED markers in mCRPC patients treated with AA.Methods We conducted an analysis in 115 chemotherapy-naive mCRPC patients who were treated with chemotherapy in Renji hospital from 2013 to 2017.The median age was 70,ranged from 65 to 76 years old.The median CgA,NSE and PSA levels were 101.1 ng/ml (78.5-150.0 ng/ml),13.4 ng/ml (10.5-17.6 ng/ml) and 38.8 ng/ml (11.2-123.2 ng/ml),respectively.Among them,48 cases were classified as the group without AA treatment.The other 67 cases were classified as group after AA failure.In group without AA treatment,the median CgA,NSE and PSA levels were 109.1 ng/ml(80-151.5 ng/ml);13.8 ng/ml(10.8-18.2 ng/ml) and 39.2 ng/ml (8.6-200 ng/ml),respectively.In group after AA failure,the median CgA,NSE and PSA levels were 105.4 ng/ml(78.8-175.5 ng/ml),13.8 ng/ml(10.8-17.6 ng/ml) and 39.0 ng/ml(8.4-219.8 ng/ml),respectively.In the group with serial evaluation of NED markers during AA treatment,the median serum CgA,NSE levels at baseline were 115.9 ng/ml(90.1-201.5 ng/ml),13.3 ng/ml (10.4-18.1 ng/ml),respectively.The endpoints were PSA PFS(progression-free survival) and radiographic PFS (rPFS).Results In 34 patients with serial evaluation,serum NED markers level in 19 patients increased after the failure of AA treatment.Median serum CgA and NSE levels were 115.9 ng/ml(90.1-201.5 ng/ml)and 13.25 ng/ml (10.37-18.14 ng/ml) at baseline.Median serum CgA and NSE levels were 129.6ng/ml (75.5-230.5 ng/ml) and 14.7 ng/ml (11.8-19.1 ng/ml) after 6 months treatment,respectively.The median serum CgA and NSE levels were 130.4 ng/ml (95.7-205.7 ng/ml) and 15.2 ng/ml(12.4-18.7 ng/ml) at the time of failure of AA treatment,respectively.There was no significant difference of NED markers between baseline and failure of AA treatment (P =0.243).In logistic univariate analysis,AA treatment and its duration were not independent factors influencing NED(P =0.30;P =0.52).Compared with the NED markers elevation group in the first 6 months of AA treatment and baseline supranormal NED markers group,the NED markers decline group(PSA PFS(17.1 vs.10.4 months,P ＜ 0.001) and rPFS (17.0 vs.10.4 months,P =0.003)) and baseline normal NED markers group(PSA PFS(14.1 vs.9.5 months,P =0.001) and rPFS(16.4 vs.10.5 months,P ＜ 0.001)) has a longer median PSA PFS and rPFS respectively.In multivariate Cox analysis,baseline NED markers level and NED markers variation during the first 6 months of AA treatment remained significant predictors of rPFS(P ＜ 0.05),and PSA-PFS (P ＜ 0.05).Conclusions We found there was heterogeneity in changes of NED markers in different mCRPC patients during AA treatment,and AA might not significantly lead to progression of NED of mCRPC in general.Serial CgA and NSE evaluation might help clinicians guide clinical treatment of mCRPC patients.Serum NED markers elevation during the first 6 months of AA treatment and elevated baseline NED markers levels indicated poor prognosis in mCRPC treated with AA.

Fibrosis is one of the key factors that lead to the immune exclusion of solid tumors. Although degradation of fiber is a promising strategy, its application was still bottlenecked by the side effects of causing metastasis, resulting in the failure of immunotherapy. Here, we developed an antimetastatic polymer (HPA) for the delivery of chemo-drug and antifibrotic siPAI-1 to form the nano-permeator. Nano-permeator shrank after protonation and deeply penetrated into the tumor core to down-regulate the expression of PAI-1 for antifibrosis, and further promoted the sustained infiltration and activation of T cells for killing tumor cells. Moreover, metastasis after fiber elimination was prevented by multivalent CXCR4 antagonistic HPA to reduce the attraction of CXCL12 secreted by distant organs. The administration of stroma-alleviated immunotherapy increased the infiltration of CD8⁺ T cells to 52.5% in tumor tissues, inhibiting nearly 90% metastasis by HPA in distant organs. The nano-permeator reveals the mechanism and correlation between antifibrosis and antimetastasis and was believed to be the optimizing immunotherapy for solid fibrotic tumors.

The amygdala is an important hub for regulating emotions and is involved in the pathophysiology of many mental diseases, such as depression and anxiety. Meanwhile, the endocannabinoid system plays a crucial role in regulating emotions and mainly functions through the cannabinoid type-1 receptor (CB₁R), which is strongly expressed in the amygdala of non-human primates (NHPs). However, it remains largely unknown how the CB₁Rs in the amygdala of NHPs regulate mental diseases. Here, we investigated the role of CB₁R by knocking down the cannabinoid receptor 1 (CNR1) gene encoding CB₁R in the amygdala of adult marmosets through regional delivery of AAV-SaCas9-gRNA. We found that CB₁R knockdown in the amygdala induced anxiety-like behaviors, including disrupted night sleep, agitated psychomotor activity in new environments, and reduced social desire. Moreover, marmosets with CB₁R-knockdown had up-regulated plasma cortisol levels. These results indicate that the knockdown of CB₁Rs in the amygdala induces anxiety-like behaviors in marmosets, and this may be the mechanism underlying the regulation of anxiety by CB₁Rs in the amygdala of NHPs.
Animals ; Callithrix ; Receptors, Cannabinoid ; Anxiety ; Amygdala ; Cannabinoids ; Phenotype