OBJECTIVE To study the toxicokinetics and tissue distribution characteristics of alpha-amanitin in rats.METHODS The tail venous blood was collected from SD rats before and 5,10,20,30 and 45 min,1,1.5,2.5,4 and 8 h after intraperitoneal injection of alpha-amanitin(1.5 mg·kg-1),and the concentration of alpha-amanitin in blood was determined by liquid chromatography-mass spectrometry(LC-MS/MS).DAS 2.0 software was used to analyze and plot the drug-time curve with toxicokinetic parame-ters.Based on the toxicokinetics results,18 SD rats were randomly divided into three groups.The rats were sacrificed,and left ventricular arterial(LVA)blood and 9 types of tissue samples involving the heart,liver,spleen,lung,kidney,whole brain,small intestine,stomach wall and testis were collected 15 min,40 min and 2.5 h after dosing,and the concentrations of alpha-amanitin were measured by LC-MS/MS to obtain the tissue distribution results of alpha-amanitin in SD rats.RESULTS Toxicokinetics studies revealed that the peak blood concentration(Cmax)was(633±121)μg·L-1,the elimination half-life(T1/2)was(0.72±0.37)h,and the peak time(Tmax)was(0.52±0.16)h.The total clearance rate(CLz)was(1.62±0.26)L·h·kg-1,the area under the curve(AUC0-t)was(946±183)μg·h·L-1,and the mean reten-tion time(MRT0-t)was(1.18±0.17)h.The apparent volume of distribution(Vz)was(1.65±0.86)L·kg-1.The results of tissue distribution study showed that alpha-amanitin was widely distributed in SD rats with the highest concentration in the kidney,followed by the lung,small intestines,stomach wall,LVA blood and liver,but was low in the heart,spleen,testicles and other tissues,and very low in the brain.Alpha-amanitin was absorbed and eliminated quickly,peaked at 40 min in each tissue,and the concen-tration was minimized after 2.5 h.CONCLUSION The absorption and elimination of alpha-amanitin by intraperitoneal injection are rapid in SD rats,and the blood concentration reaches the peak about 31 min after administration,but can not be detected 4 h later.Alpha-amanitin is mainly distributed in the kidney,followed by the tissues and metabolic organs with rich blood flow,such as the lung,small intestines,stomach wall,LVA blood and liver.The content of alpha-amanitin is low in the heart,spleen,testicles and other tissues,and very low in the brain.It is speculated that it may have toxic targeting effect on the kidney and low blood-brain barrier permeability.

Objective:This retrospective, single-center study aimed to evaluate the efficacy and safety of programmed death-1 (PD-1) inhibitors, either as monotherapy or in combination with chemotherapy, in the management of relapse/refractory classical Hodgkin's lymphoma (R/R cHL) .Methods:A total of 35 patients with R/R cHL who received treatment at the Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College from September 2016 to December 2020 were enrolled in this study. Among them, 17 patients received PD-1 inhibitor monotherapy (PD-1 inhibitor group), while 18 patients received a combination of PD-1 inhibitor and chemotherapy (PD-1 inhibitor + chemotherapy group). Clinical data and follow-up information were retrospectively analyzed, and survival analysis was conducted using the Kaplan-Meier method and Cox proportional hazards model.Results:The median age of the 35 patients with R/R cHL was 29 years (range: 11-61 years), with 54.3% being male. According to the Ann Arbor staging system, 62.9% of patients presented with advanced (stage Ⅲ/Ⅳ) disease, and 48.6% had extranodal involvement. Before PD-1 inhibitor therapy, the median number of prior lines of therapy was 2 (range: 1-3). Objective responses were observed in 28 patients, including 22 complete response (CR) cases, resulting in an overall response rate (ORR) of 80.0% and a CR rate of 62.9%. Specifically, the ORR and CR rates were 64.7% and 58.8%, respectively, in the PD-1 inhibitor group and 94.4% and 66.7%, respectively, in the PD-1 inhibitor + chemotherapy group. Among the 18 patients who underwent sequential autologous hematopoietic stem cell transplantation (auto-HSCT) [13 CR and five partial response (PR) cases], eight patients received PD-1 inhibitor therapy after auto-HSCT as consolidation therapy. All patients maintained a CR status after transplantation, and they exhibited significantly improved progression-free survival (PFS) rates compared with those who did not undergo sequential auto-HSCT (4-year PFS rates: 100% vs 53.5% ; P=0.041). The incidence of immune-related adverse events was 29%, with only one patient experiencing grade≥3 adverse reactions, which indicated a favorable safety profile for the treatment approach. Conclusions:PD-1 inhibitor monotherapy demonstrates notable efficacy and sustained response in patients with R/R cHL. PD-1 inhibitors combined with chemotherapy significantly improve response rates. Additionally, for salvage therapy-sensitive patients, consolidation treatment with PD-1 inhibitors after auto-HSCT exhibits the potential for prolonging PFS.

Objective:To conduct a quantitative and qualitative analysis of the issues found in quality management, establish a risk-based whole-process quality management model, and improve the quality of clinical trials.Methods:Based on the risk-based quality management theory, the issues found in the quality control of drug clinical trials in Beijing Cancer Hospital in 2020 were structured and classified by severity (mild to moderate to severe) and 10 categories, and the risk matrix was graded by a semi-quantitative method. Targeted quality control strategies for different levels of risk were carried out according to visual analysis of the informative quality analysis platform. Chi-square tests of the severity of quality control issues in our hospital in 2020 and 2021 and non-parametric tests of the number of issues per capita in each category were used to evaluate the effectiveness of the management model.Results:A risk matrix was established according to the severity and frequency of the issues found in the quality control in 2020. The issues with severe risks were categorized as protocol compliance and serious adverse events, and categories with moderate risks included informed consent, biological sample related, original records, and investigator folders. After using visual analysis and adopting the risk-based quality control strategy, the proportion of severe issues found in quality control in our hospital in 2021 was 0.92%, lower than that of 1.39% in 2020, and the difference was statistically significant. The average number of issues detected per capita in each category for each trial in 2021 was lower than that in 2020 with a statistical difference, indicating that the management model was effective.Conclusions:Using information technology to adopt risk-based quality management is helpful to improve the quality of hospital clinical trials.

Objective:To observe the inhibitory effect of berberine (BBR) on the apoptosis of human retinal vascular endothelial cells (hREC) under high glucose environment.Methods:hREC was divided into blank control group (NC group), high glucose group (HG group), BBR treatment group (BN group), and BBR+high glucose treatment group (BH group). The cells of each group were cultured in Dulbecco's modified eagle medium; 5.5 and 30.0 mmol/L glucose were added to the medium of the NC group and HG group, respectively; 5.0 mmol/L glucose and 5.0 mmol/L BBR was added to the BN group; 30.0 mmol/L glucose and 5.0 mmol/L BBR was added to the medium of the BH group. Flow cytometry was used to observe the apoptosis rate of each group. Western blotting was used to detect the relative expression levels of B-cell lymphoma-2 (Bcl-2), Bcl-2 related X protein (Bax), and Cytochrome C (Cyt-C) and cysteine aspastic acid-specific protease 3 (Caspase-3) proteins in each group of cells. The difference between the two groups was tested by t test, and the difference among multiple groups was analyzed by one-way analysis of variance. Results:The results of flow cytometry showed that compared with the NC group, the apoptosis rate of the HG group significantly increased, and the difference was statistically significant ( P<0.01); compared with the HG group, the apoptosis rate of the BH group significantly reduced, the difference was statistical significance ( P<0.05). Western blot test results showed that, compared with the NC group, the relative expression of Bax and Caspase-3 protein in the HG group increased, and the relative expression of Bcl-2 protein decreased. The difference was statistically significant ( P<0.01). Compared with the HG group, the relative expression of Bax, Cyt-C, and Caspase-3 protein in BH group cells decreased, and the relative expression of Bcl-2 protein increased, and the difference was statistically significant ( P<0.01). Conclusion:BBR can inhibit hREC apoptosis by affecting the expression of apoptotic protein under high glucose environment.

Objective:To investigate the clinical features, diagnosis, and treatment of the central nervous system (CNS) toxicity caused by bortezomib.Methods:This study reports five new cases of CNS toxicity caused by bortezomib to elucidate its characteristics along with a review of the literature.Results:CNS toxicity caused by bortezomib presents in three clinical forms: syndrome of inappropriate antidiuresis (SIAD) , posterior reversible encephalopathy syndrome (PRES) , and central fever, which is the most common clinical manifestation. Four of our five patients developed central fever after the administration of bortezomib, manifested as persistent high fever, anhidrosis, and absence of infective foci; the symptom could be improved by discontinuance of bortezomib. Of these patients, three concurrently presented with refractory hyponatremia and one was clearly diagnosed with SIAD. The bortezomib could have caused damages to the hypothalamus and induced both central fever and SIAD. In addition, one patient was diagnosed with PRES due to disturbance of consciousness and epilepsy after taking bortezomib. After discontinuation of bortezomib, the symptoms disappeared and did not recur. We also found that thrombocytopenia may be related to the severity of the CNS toxicity of bortezomib.Conclusion:Cases of CNS toxicity of bortezomib are extremely rare and present as SIAD, PRES and central fever. Early detection and treatment of bortezomib are very important to prevent irreversible neurological complications.

Objective:To investigate the efficacy of fludarabine and cyclophosphamide combined with rituximab (FCR) in previously untreated patients with chronic lymphocytic leukemia (CLL) .Methods:The clinical data of 43 enrolled patients from May 2004 to December 2017 were analyzed the efficacy and survival results.Results:A total of 43 patients with 31 males and 12 females, and the median age was 58 years old (range 36 to72) before treatment. There were 8 patients with symptom B. The median number of peripheral blood lymphocyte was 26 (3-550) ×10 9/L. IGHV unmutated was detected in 62.1% (18/29) patients, P53 deletion in 14% (6/43) patients, RB1 deletion in 18.6% (8/43) patients, Trisomy 12 in 25.6% (11/33) patients, ATM deletion in 16.7% (7/42) patients, respectively. The median number of treatment courses administered was 4 (range 2-6) . Twenty patients obtained CR (46.5%) , 18 patients obtained PR, 4 patients were SD, 1 patient was PD. The overall response rate (ORR) was 88.37%. Seven patients obtained MRD negative. After the median follow-up time of 51 (6-167) months, median PFS was 67 (29-105) months, median OS was not reach, 5-year PFS was (62.1±8.6) %, 10-year PFS was (31±14.3) %, 5-year OS was (70.5±8.3) %, and 10-year OS was (51.3±13.8) %. Less than 4 courses predicted adverse OS ( P<0.05) . P53 deletion and less than 4 courses were associated with poor PFS ( P<0.001) , and the prognostic value still remained after multivariate analysis[ HR=7.65 (95% CI 1.74-33.60) , P=0.007; HR=3.75 (95% CI 1.19-11.80) , P=0.025]. Eighteen patients (41.9%) appeared grade 2-3 infection after chemotherapy, and 19 patients (44.2%) appeared grade 3-4 hematological adverse reactions. One patient (2.3%) was developed tumor lysis syndrome. All adverse reactions were controlled or recovered spontaneously. Conclusion:Previously untreated CLL patients treated with FCR had a high response rate and good survival rate, which is an important treatment choice for fit patients.

OBJECTIVE: To determine the incidence of surgical site infection (SSI) after abdominal surgery and to further evaluate the related risk factors of SSI in China. METHODS: The multicenter cross-sectional study collected clinical data of all adult patients who underwent abdominal surgery from May 1, 2018 to May 31, 2018 in 30 domestic hospitals, including basic information, perioperative parameters, and incisional microbial culture results. The primary outcome was the incidence of SSI within postoperative 30 days. SSI was classified into superficial incision infection, deep incision infection, and organ/gap infection according to the US Centers for Disease Control and Prevention (CDC) criteria. The secondary outcome variables were ICU stay, postoperative hospital stay, total hospital stay, 30-day mortality and treatment costs. Multivariate logistic regression was used to analyze the risk factors of SSI. RESULTS: A total of 1666 patients were enrolled in the study, including 263 cases of East War Zone Hospital of PLA, 140 cases of Affiliated Hospital of Qingdao University, 108 cases of The First Affiliated Hospital of Nanchang University, 87 cases of Central War Zone Hospital of PLA, 77 cases of West China Hospital, 74 cases of Guangdong General Hospital, 71 cases of Chenzhou First People's Hospital, 71 cases of Zigong First People's Hospital, 64 cases of Zhangjiagang First People's Hospital, 56 cases of Nanyang City Central Hospital, 56 cases of Lanzhou General Hospital of Lanzhou Military Command, 56 cases of Shandong Provincial Hospital, 52 cases of Shangqiu First People's Hospital, 52 cases of People's Hospital of Xinjiang Uygur Autonomous Region, 48 cases of The Second Xiangya Hospital of Central South University, 48 cases of Chinese PLA General Hospital, 44 cases of Affiliated Hospital of Xuzhou Medical University, 38 cases of Hunan Province People's Hospital, 36 cases of Dongguan Kanghua Hospital, 30 cases of Shaoxing Central Hospital, 30 cases of Northern Jiangsu People's Hospital, 29 vases of The First Affiliated Hospital of Zhengzhou University, 27 cases of General Hospital of Tianjin Medical University, 22 cases of Zigong Fourth People's Hospital, 21 cases of The Second Hospital of University of South China, 18 cases of Tongji Hospital, 15 cases of Nanchong Central Hospital, 12 cases of The 901th Hospital of PLA, 11 cases of Hunan Cancer Hospital, 10 cases of Lanzhou University Second Hospital. There were 1019 males and 647 females with mean age of (56.5±15.3) years old. SSI occurred in 80 patients (4.8%) after operation, including 39 cases of superficial incision infection, 16 cases of deep incision infection, and 25 cases of organ/interstitial infection. Escherichia coli was the main pathogen of SSI, and the positive rate was 32.5% (26/80). Compared with patients without SSI, those with SSI had significantly higher ICU occupancy rate [38.8%(31/80) vs. 13.9%(220/1586), P<0.001], postoperative hospital stay (median 17 days vs. 7 days, P<0.001) and total hospital stay (median 22 days vs. 13 days, P<0.001), and significantly higher cost of treatment (median 75 000 yuan vs. 44 000 yuan, P<0.001). Multivariate analysis showed that male rise(OR=2.110, 95%CI:1.175-3.791, P=0.012), preoperative blood glucose level rise(OR=1.100, 95%CI: 1.012-1.197, P=0.026), operative time (OR=1.006, 95%CI:1.003-1.009, P<0.001) and surgical incision grade (clean-contaminated incision:OR=10.207, 95%CI:1.369-76.120, P=0.023; contaminated incision: OR=10.617, 95%CI:1.298-86.865, P=0.028; infection incision: OR=20.173, 95%CI:1.768-230.121, P=0.016) were risk factors for SSI; and laparoscopic surgery (OR=0.348, 95%CI:0.192-0.631, P=0.001) and mechanical bowel preparation(OR=0.441,95%CI:0.221-0.879, P=0.020) were protective factors for SSI. CONCLUSIONS The incidence of postoperative SSI in patients with abdominal surgery in China is 4.8%. SSI can significantly increase the medical burden of patients. Preoperative control of blood glucose and mechanical bowel preparation are important measures to prevent SSI.
Abdomen ; surgery ; Adult ; Aged ; China ; Cross-Sectional Studies ; Female ; General Surgery ; statistics & numerical data ; Humans ; Male ; Middle Aged ; Operative Time ; Postoperative Complications ; prevention & control ; Preoperative Period ; Retrospective Studies ; Risk Factors ; Surgical Wound Infection ; prevention & control

Objective: To study the anti-inflammatory effect and mechanism of Gutong plasters in acute inflammatory model of rats. Methods:Totally 60 SD rats were randomly divided into the blank group,the model group,Gutong plasters at low,medium and high dose groups(0.594,1.188 and 2.376 g/patch containing crude drug 0.48,0.96 and 1.92 g,respectively) and prednisone ace-tate group(0.005 4 g·kg-1). The acute inflammation model was prepared by injecting 5% formaldehyde into right side of foot plan-tar. And then,the anti-inflammatory effect was evaluated by measuring the foot plantar volume. Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of nitric oxide(NO),histamine(HIS) and 5-hydroxytryptamine(5-HT) in serum and inflam-matory tissue,the levels of prostaglandin E2(PGE2),tumor necrosis factor alpha(TNF-α),interleukin 1 beta(IL-1β) and interleu-kin 6 (IL-6) in inflammatory tissue were also determined. Pathological changes were observed through the pathological sections pre-pared by HE staining. Results:When compared with the model group,Gutong plasters could significantly inhibit the swelling of foot plantar in inflammatory rats(P<0.01). At the same time,Gutong plasters could significantly reduce the levels of NO,5-HT and HIS in serum and inflammatory tissue in different degrees(P<0.05 or P<0.01),significantly reduce the content of PGE2in inflammatory tissue (P<0.05 or P<0.01),increase the content of IL-6 in inflammatory tissue and improve the pathological changes of inflammato-ry tissues (the pathological score was significantly reduced). In partical indictor changes,Gutong plasters and prednisone acetate showed an equal effect.In addition,Gutong plasters didn't show significant dose-dependent manner in inhibiting foot swelling,affect-ing inflammatory mediators and improving pathological changes(P>0.05). Conclusion:Gutong plasters have better anti-inflammato-ry effect in the acute inflammation model induced by formaldehyde in rats. The anti-inflammatory effect may be associated with the de-crease of the levels of NO,5-HT and HIS in serum and inflammatory tissue,the decrease of the content of PGE2and the increase of the content of IL-6 in inflammatory tissue. In addition,the anti-inflammatory effect may be relevant to improving the local inflammatory tis-sue subcutaneous edema and inflammatory cell infiltration.

Objective: To evaluate the efficacy and long-term outcome of a combined protocol for multiple myeloma (MM) , including induction therapy, autologous hematopoietic stem cell transplantation (ASCT) and consolidation and maintenance therapy. Methods: Clinical records of 144 patients with MM from January 1, 2005 to February 1, 2016 were retrospectively analyzed. Results: The overall response rate (ORR) after ASCT was 100.0%, in which the complete remission (CR) was 64.1% and the best treatment response rate of superior to PR was 89.4%. During a median follow-up of 47 months, patients with an overall survival (OS) and progression free survival (PFS) was 120.9 and 56.9 months respectively. 5y-OS (73.7±4.7) %, 7y-OS (60.5±6.3) %; 3y-PFS (69.2±4.2) %, 5y-PFS (47.8±5.3) %. The median OS and PFS between the first line transplantation group and salvage transplantation group were 120.9 months vs 50.1 months and 60.2 months vs 16.7 months (all P=0.000). In 127 patients with R-ISS staging, the median survival of Ⅰ, Ⅱ, Ⅲ stage was 120.9 months (n=43) , 88.4 months (n=64) , 35.6 months (n=20) , respectively (P=0.000). For subgroup analysis of survival in early and late ASCT, the median OS of patients with R-ISS stage Ⅲ (35.6 months vs 15.8 months, P=0.031) and the median PFS of two groups (phase Ⅰ: 72.1 months vs 18.9 months, P=0.000; Ⅱ: 53.4 months vs 16.7 months, P=0.012; Ⅲ: 28.5 months vs 5.9 months, P=0.001) were different. Multivariate analysis showed that only R-ISS and the degree of remission before transplantation had impact on OS (HR=8.486, 95% CI 2.549-28.255, P=0.003) and PFS (HR=2.412, 95% CI 1.364-4.266, P=0.002) , respectively. Conclusion The combined protocol containing ASCT is effective for MM patients, improving remission rate and remission depth, prolonging PFS and OS. First line transplantation could significantly prolong the OS and PFS as compared with salvage transplantation. R-ISS and pre-transplantation remission depth are prognostic factors for survival.