1.Oncogenic β-catenin-driven liver cancer is susceptible to methotrexate-mediated disruption of nucleotide synthesis
Fangming LIU ; Yuting WU ; Baohui ZHANG ; Shuhui YANG ; Kezhuo SHANG ; Jie LI ; Pengju ZHANG ; Weiwei DENG ; Linlin CHEN ; Liang ZHENG ; Xiaochen GAI ; Hongbing ZHANG
Chinese Medical Journal 2024;137(2):181-189
Background::Liver cancer is largely resistant to chemotherapy. This study aimed to identify the effective chemotherapeutics for β-catenin-activated liver cancer which is caused by gain-of-function mutation of catenin beta 1 ( CTNNB1), the most frequently altered proto-oncogene in hepatic neoplasms. Methods::Constitutive β-catenin-activated mouse embryonic fibroblasts (MEFs) were established by deleting exon 3 ( β-cateninΔ(ex3)/+ ), the most common mutation site in CTNNB1 gene. A screening of 12 widely used chemotherapy drugs was conducted for the ones that selectively inhibited β-cateninΔ(ex3)/+ but not for wild-type MEFs. Untargeted metabolomics was carried out to examine the alterations of metabolites in nucleotide synthesis. The efficacy and selectivity of methotrexate (MTX) on β-catenin-activated human liver cancer cells were determined in vitro. Immuno-deficient nude mice subcutaneously inoculated with β-catenin wild-type or mutant liver cancer cells and hepatitis B virus ( HBV); β-cateninlox(ex3)/+ mice were used, respectively, to evaluate the efficacy of MTX in the treatment of β-catenin mutant liver cancer. Results::MTX was identified and validated as a preferential agent against the proliferation and tumor formation of β-catenin-activated cells. Boosted nucleotide synthesis was the major metabolic aberration in β-catenin-active cells, and this alteration was also the target of MTX. Moreover, MTX abrogated hepatocarcinogenesis of HBV; β-cateninlox(ex3)/+ mice, which stimulated concurrent Ctnnb1-activated mutation and HBV infection in liver cancer. Conclusion::MTX is a promising chemotherapeutic agent for β-catenin hyperactive liver cancer. Since repurposing MTX has the advantages of lower risk, shorter timelines, and less investment in drug discovery and development, a clinical trial is warranted to test its efficacy in the treatment of β-catenin mutant liver cancer.
2.Study on the Expression of Tissue STAT3 and Serum STAT3 mRNA,IL-12p40 and IL-13R α 2 Levels in Children with Congenital Intestinal Atresia and Their Correlation with Prognosis
Yanqing DONG ; Huizhong NIU ; Pengju ZHANG ; Hui REN ; Pan CHEN ; Zhiguang ZHANG ; Bobo NIU
Journal of Modern Laboratory Medicine 2024;39(5):35-40,46
Objective To investigate the expression of tissue signal transducer and activator of transcription 3(STAT3)and serum STAT3 mRNA,IL-12p40 and IL-13R α 2 levels in children with congenital intestinal atresia and their correlation with prognosis.Methods From January 2020 to January 2023,100 cases of intestinal atresia lesion tissues,normal intestinal tissues and preoperative serum samples were collected from children with congenital intestinal atresia who underwent treatment in Hebei Children's Hospital.According to the Grosfeld typing criteria,these children were categorized into 39 cases of type Ⅰ,22 cases of type Ⅱ,30 cases of type Ⅲ and 9 cases of type Ⅳ.Based on the recovery situation at 6 months after surgery,these children were separated into a good prognosis group(n=78)and a poor prognosis group(n=22).Serum samples from 93 cases of healthy children undergoing medical examinations during the same period were regarded as control samples.Immunohistochemistry was applied to detect the positive expression and localization of STAT3 in tissues.Western blot was applied to detect the expression of STAT3 protein in tissues,and quantitative polymerase chain reaction(qPCR)was applied to detect the expression level of STAT3 mRNA in serum.Pearson correlation was applied to analyze the correlation between serum STAT3 and inflammatory factor levels in children with congenital intestinal atresia.Logistic regression was used to analyze the factors affecting the prognosis of children with congenital intestinal atresia.Receiver operating characteristic(ROC)curve was applied to analyze the predictive efficacy of serum STAT3 level on the prognosis of children with congenital intestinal atresia.Results Immunohistochemical results showed that STAT3 positive expression was mainly localized in the cytoplasm and nucleus.The positive expression rate in congenital intestinal atresia tissue(86%)was higher than that in normal intestinal tissue(18%),and the difference was significant(x2=92.628,P<0.05).Western blot results showed that the relative expression level of STAT3 in congenital intestinal atresia tissue(1.59±0.21)was higher than that in normal intestinal tissue(0.81±0.12),and the difference was significant(t=30.567,P<0.05).The results of qPCR showed that serum STAT3(2.13±0.56),IL-12p40(0.89±0.13 ng/ml),and IL-13R α 2 levels(6.42±1.86ng/ml)in the congenital intestinal atresia group were higher than those in the control groups(1.06±0.11,0.37±0.08ng/ml,1.35±0.41ng/ml),and the differences were significant(t=18.101,33.170,25.708,all P<0.05).The levels of STAT3 and IL-12p40,IL-13R α 2 were gradually increased with the increase of the children's subtypes,and the differences were significant(F=52.666,160.300,25.82,all P<0.05).Pearson correlation analysis showed a positive correlation between serum STAT3,IL-12p40,and IL-13R α 2 levels in children with congenital intestinal atresia(r=0.496,0.564,all P<0.001).The expression level of serum STAT3 in poor prognosis group(3.01±0.75)was higher than that in good prognosis group(1.88±0.51),and the differences was statistically significant(t=8.212,P<0.05).Logistic regression showed that STAT3,IL-12p40,IL-13R α 2,and low birth quality were all independent risk factors for poor prognosis in children with congenital intestinal atresia(all P<0.05).The ROC curve showed that the area under the curve(AUC)for evaluating the prognosis of children with congenital intestinal atresia by serum STAT3 expression was 0.916,with a sensitivity of 81.82%and a specificity of 88.46%,respectively.When the serum STAT3 mRNA level was higher than 2.47,children with congenital intestinal atresia had a higher probability of poor prognosis.Conclusion The expression of STAT3 is increased in the tissues and serum of children with congenital intestinal atresia.Serum STAT3 may have a predictive value for the prognosis of affected children.
3.The investigation on body composition in patients with active ulcerative colitis and its correlation with clinical outcome
Wei WEI ; Pengguang YAN ; Kang YU ; Mengmeng ZHANG ; Pengju LIU ; Chunwei LI ; Peipei CHEN
Chinese Journal of Clinical Nutrition 2024;32(5):261-269
Objective:To evaluate the body composition of ulcerative colitis (UC) patients by bioelectrical impedance analysis (BIA) and explore the correlation between body composition indices and disease activity, laboratory indices, and readmission.Methods:Patients with active UC hospitalized in the Department of Gastroenterology of Peking Union Medical College Hospital were enrolled continuously, and age and sex ratio-matched healthy volunteers were recruited through recruitment posters. Body composition was measured via BIA. Appendicular skeletal muscle index (ASMI) and trunk skeletal muscle index (TSMI) were calculated and adjusted for height (m 2). Muscle function was evaluated via handgrip strength. Moreover, patients were followed up after discharge and the readmissions due to recurrence or aggravation of UC were recorded. Results:This study enrolled 62 UC patients and 38 healthy volunteers. TSMI decreased significantly ( P<0.001) while ASMI showed no significant difference in male patients compared with healthy controls. ASMI ( P<0.001) and TSMI ( P=0.002) in female patients were significantly lower than those in healthy controls. Compared with patients with normal TSMI, a larger proportion of patients with low TSMI tended to show severe disease activity ( P=0.075), while no such trend was observed in patients with low ASMI. Handgrip strength and phase angle were significantly positively correlated with ALB in UC patients ( P<0.05). The proportion of patients with readmission was significantly higher in the low phase angle group than that in the normal phase angle group (58.3% vs. 22.0%, P=0.040). Conclusions:There were abnormal body composition and gender differences in UC patients. TSMI correlated better with clinical characteristics than ASMI in UC patients. Low phase angle might be predictive for readmission in UC patients.
4.Clinical efficacy of radical resection for lung metastasis from colorectal cancer and prognostic factors analysis
Pengju CHEN ; Tingting SUN ; Yunfeng YAO ; Yifan PENG ; Jun ZHAO ; Aiwen WU
Chinese Journal of Digestive Surgery 2021;20(3):301-305
Objective:To explore the clinical efficacy of radical resection for lung metastasis from colorectal cancer and the prognostic factors.Methods:The retrospective cohort study was conducted. The clinicopathological data of 63 colorectal cancer patients with lung metastasis who were admitted to Peking University Cancer Hospital from January 2004 to December 2015 were collected. There were 35 males and 28 females, aged (57±12)years. Patients underwent radical resection for primary lesion and lung metastasis from colorectal cancer. Observation indicators: (1) diagnosis and treatment; (2) follow-up and survival; (3) prognostic factors analysis. Follow-up was conducte by outpatient examination and telephone interview to detect the survival of patients after operation up to December 2018. Measurement data with normal distribution were represented as Mean±SD, and measurement data with skewed distribution were represented as M (range). Count data were described as absolute numbers or percentages. The Kaplan-Meier method was used to calculate survival rates and draw survival curves. Log-rank test was used for univariate analysis and COX proportional hazard model was used for multivariate analysis. Results:(1) Diagnosis and treatment: of 63 patients with lung metastasis from colorectal cancer, 6 had synchronous lung metastasis and 57 had metachronous lung metastasis. Eighteen cases of suspected lung metastasis were initially detected by chest X-ray, and further confirmed by computed tomography (CT). Forty-five cases of suspected lung metastasis were initially detected by chest CT. All the 63 patients underwent radical resection for primary and metastatic lesions. Two of 22 cases undergoing mediastinal lymph nodes dissection were detected one positive lymph node, respectively. All patients recovered well after operation, without severe complications. There were 57 of 63 patients receiving more than 6 months of postoperative adjuvant chemotherapy and targeted therapy based on fluorouracils. (2) Follow-up and survival: 63 patients were followed up for 8-143 months, with a median follow-up time of 58 months. During the follow-up, 19 of 63 patients died, 24 patients had secondary recurrence with a 5-year recurrence rate of 38.1%(24/63) and a recurrence interval of 18 months(range, 3-58 months). Of 24 patients with secondary recurrence, 19 had lung metastasis, 3 had brain metastasis, 2 had bone metastasis, 2 had liver metastasis; some patients had multiple metastases. Of 24 patients with secondary recurrence, 5 underwent reoperation and 19 underwent chemotherapy and radiochemotherapy. The 5-year overall survival rate of 63 patients was 62.7%. (3) Prognostic factors analysis: results of univariate analysis showed that location of primary lesion, the number of lung metastases and carcinoembryonic antigen (CEA) level before resection of lung metastasis were related factors for prognosis of patients with lung metastasis from colorectal cancer ( χ2=4.162, 7.175, 6.725, P<0.05). Results of multivariate analysis showed that the number of lung metastases and CEA level before resection of lung metastasis were independent influencing factors for prognosis of patients with lung metastasis from colorectal cancer ( hazard ratio=2.725, 2.778, 95% confidence interval as 1.051-7.064, 1.072-7.021, P<0.05). Conclusions:Radical resection for lung metastasis from colorectal cancer is safe and feasible. The number of lung metastases and CEA level before resection for lung metastasis are independent influencing factors for prognosis of patients with lung metastasis from colorectal cancer.
5. Prognostic Nomogram model for the efficacy of endoscopic treatment in gastric varices caused by liver cirrhosis
Xiaoqing ZENG ; Yuzhen ZENG ; Ji ZHOU ; Jie CHEN ; Tiancheng LUO ; Wen ZHANG ; Pengju XU ; Jianjun LUO ; Zhiping YAN ; Shiyao CHEN
Chinese Journal of Digestion 2020;40(1):23-29
Objective:
To predict the efficacy of endoscopic tissue adhesives in the treatment of gastric varices in patients with liver cirrhosis by Nomogram model.
Methods:
From August 2014 to September 2017, 158 patients with liver cirrhosis caused esophagogastric variceal bleeding and received endoscopic tissue adhesives treatment at Zhongshan Hospital, Fudan University were collected. All patients were followed for 12 months. The primary outcome was rebleeding. The factors of rebleeding after endoscopic treatment of esophagogastric varices were analyzed. Nomogram prognostic model was developed and compared with Child-Pugh grading, computed tomography angiography (CTA) and hepatic venous pressure gradient (HVPG) in prognostic accuracy in rebleeding after endoscopic treatment in liver cirrhosis caused esophagogastric varices. Univariate and multivaricate Cox regression analysis, Kaplan-Meier curve and log-rank test were performed for statistical analysis.
Results:
During the follow-up, rebleading occurred in 18 cases (11.4%), 37 cases (23.4%) and 49 cases (31.0%) at 2, 6, and 12 months after endoscopic treatment. The results of univariate Cox regression analysis showed the risk factors of rebleeding after endoscopic treatment of gastric varices included gender, alcoholic liver cirrhosis, diabetes mellitus, Child-Pugh grade (Grade A vs. B or C), extraluminal vessels on CTA (presence vs. absence) HVPG (<16 mmHg vs. ≥16 mmHg, 1 mmHg = 0.133 kPa), extensive portal embolism, esophageal varices, type 2 gastric varices, injection points of tissue adhesive (≤3 points vs. > 3 points), injection volume of tissue adhesive (≤ 3 mL vs. > 3 mL) (hazard ratio (
6.Total neoadjuvant therapy followed by watch and wait approach or organ preservation for MRI stratified low-risk rectal cancer: early result from a prospective, single arm trial
Lin WANG ; Yiming ZHAO ; Tingting SUN ; Yuanlian XU ; Shijie LI ; Xiaoyan ZHANG ; Yong CAI ; Yongheng LI ; Zhongwu LI ; Pengju CHEN ; Yifan PENG ; Weihu WANG ; Aiwen WU
Chinese Journal of Gastrointestinal Surgery 2020;23(3):258-265
Objective:To explore the safety and efficacy of watch and wait strategy and organ preservation surgery after total neoadjuvant treatment for MRI stratified low-risk rectal cancer.Methods:A prospective single arm phase Ⅱ trial developed at Department of Gastrointestinal Cancer, Peking University Cancer Hospital & Institute was preliminarily analyzed. Subjects were enrolled from August 2016 to January 2019. Low-risk rectal cancer with following MRI features were recruited: mid-low tumor, mrT2-3b, MRF (-), EMVI (-), CRM (-), differentiation grade 1-3. Patients received intensity-modulated radiotherapy (IMRT) 50.6 Gy/22f with concurrent capecitabine and 4 cycles of consolidation CAPEOX. Patients with cCR/near-cCR confirmed by physical examination, rectal MRI, endoscopy, and serum CEA were recommended for watch & wait approach or local excision (LE). The main study outcomes were 2-year organ preservation rate (OPR) and sphincter preservation rate (SPR).Results:Thirty-eight patients were eligible for analysis, including 24 males and 14 females with median age of 56 years; 9 cases of mrT2 (23.7%), 14 cases of mrT3a (36.8%) and 15 cases of mrT3b (39.5%); 5 cases of well differentiated adenocarcinoma (13.2%), 32 cases of moderately differentiated adenocarcinoma (84.2%) and 1 case of mucinous adenocarcinoma (2.6%). Carcinoemobryonic antigen (CEA) was elevated before treatment in 1 case. One case (2.6%) of grade 3 radiation dermatitis occurred during IMRT; 18 cases (47.4%) occurred grade 3 to 4 adverse events during consolidation chemotherapy. After total neoadjuvant treatment, the cCR and near-cCR rates were 42.1% (16/38) and 23.7% (9/38), respectively, while non-cCR rate was 34.2% (13/38). Twenty patients (20/38, 52.6%) of cCR or near-cCR underwent watch & wait approach, with a local regrowth rate of 20% (4/20). Four patients received LE, including one salvage LE. Thirteen patients (4 were ypCR) received radical resection, including 10 cases of initial low anterior resections (LAR), 1 cases of initial abdominal perineal resection (APR) and 2 cases of salvage LAR, four patients refused operation. The median follow-up time was 23.5 (8.5-38.3) months. At the last interview of follow-up, the OPR and SPR were 52.6% (20/38) and 84.2% (32/38), respectively. Only one patient developed lung metastasis and no local recurrence occurred after radical resection or LE.Conclusion:Total neoadjuvant treatment for low-risk rectal cancer achieves high cCR/near-cCR rate, with increased probability of receiving watch and wait approach and organ preservation in this subgroup.
7.Total neoadjuvant therapy followed by watch and wait approach or organ preservation for MRI stratified low-risk rectal cancer: early result from a prospective, single arm trial
Lin WANG ; Yiming ZHAO ; Tingting SUN ; Yuanlian XU ; Shijie LI ; Xiaoyan ZHANG ; Yong CAI ; Yongheng LI ; Zhongwu LI ; Pengju CHEN ; Yifan PENG ; Weihu WANG ; Aiwen WU
Chinese Journal of Gastrointestinal Surgery 2020;23(3):258-265
Objective:To explore the safety and efficacy of watch and wait strategy and organ preservation surgery after total neoadjuvant treatment for MRI stratified low-risk rectal cancer.Methods:A prospective single arm phase Ⅱ trial developed at Department of Gastrointestinal Cancer, Peking University Cancer Hospital & Institute was preliminarily analyzed. Subjects were enrolled from August 2016 to January 2019. Low-risk rectal cancer with following MRI features were recruited: mid-low tumor, mrT2-3b, MRF (-), EMVI (-), CRM (-), differentiation grade 1-3. Patients received intensity-modulated radiotherapy (IMRT) 50.6 Gy/22f with concurrent capecitabine and 4 cycles of consolidation CAPEOX. Patients with cCR/near-cCR confirmed by physical examination, rectal MRI, endoscopy, and serum CEA were recommended for watch & wait approach or local excision (LE). The main study outcomes were 2-year organ preservation rate (OPR) and sphincter preservation rate (SPR).Results:Thirty-eight patients were eligible for analysis, including 24 males and 14 females with median age of 56 years; 9 cases of mrT2 (23.7%), 14 cases of mrT3a (36.8%) and 15 cases of mrT3b (39.5%); 5 cases of well differentiated adenocarcinoma (13.2%), 32 cases of moderately differentiated adenocarcinoma (84.2%) and 1 case of mucinous adenocarcinoma (2.6%). Carcinoemobryonic antigen (CEA) was elevated before treatment in 1 case. One case (2.6%) of grade 3 radiation dermatitis occurred during IMRT; 18 cases (47.4%) occurred grade 3 to 4 adverse events during consolidation chemotherapy. After total neoadjuvant treatment, the cCR and near-cCR rates were 42.1% (16/38) and 23.7% (9/38), respectively, while non-cCR rate was 34.2% (13/38). Twenty patients (20/38, 52.6%) of cCR or near-cCR underwent watch & wait approach, with a local regrowth rate of 20% (4/20). Four patients received LE, including one salvage LE. Thirteen patients (4 were ypCR) received radical resection, including 10 cases of initial low anterior resections (LAR), 1 cases of initial abdominal perineal resection (APR) and 2 cases of salvage LAR, four patients refused operation. The median follow-up time was 23.5 (8.5-38.3) months. At the last interview of follow-up, the OPR and SPR were 52.6% (20/38) and 84.2% (32/38), respectively. Only one patient developed lung metastasis and no local recurrence occurred after radical resection or LE.Conclusion:Total neoadjuvant treatment for low-risk rectal cancer achieves high cCR/near-cCR rate, with increased probability of receiving watch and wait approach and organ preservation in this subgroup.
8. "Watch and wait" strategy after neoadjuvant therapy for rectal cancer: status survey of perceptions, attitudes and treatment selection in Chinese surgeons
Tingting SUN ; Lin WANG ; Yunfeng YAO ; Yifan PENG ; Jun ZHAO ; Tiancheng ZHAN ; Jiahua LENG ; Hongyi WANG ; Nan CHEN ; Pengju CHEN ; Yingjie LI ; Xiao ZHANG ; Xinzhi LIU ; Yue ZHANG ; Aiwen WU
Chinese Journal of Gastrointestinal Surgery 2019;22(6):550-559
Objective:
To understand the perceptions, attitudes and treatment selection of Chinese surgeons on the "watch and wait" strategy for rectal cancer patients after achieving a clinical complete response (cCR) following neoadjuvant chemoradiotherapy (nCRT).
Methods:
A cross
9. Short-term outcomes and prognosis of palliative surgery for malignant bowel obstruction caused by peritoneal metastasis of colorectal cancer
Pengju CHEN ; Lin WANG ; Nan CHEN ; Xinyou LU ; Huaisong WANG ; Xun HE ; Zhi WANG ; Aiwen WU
Chinese Journal of Gastrointestinal Surgery 2019;22(11):1051-1057
Objective:
To explore the short-term efficacy and prognosis of palliative surgical treatment for malignant bowel obstruction (MBO) caused by peritoneal metastasis of colorectal cancer (mCRC).
Methods:
A retrospective cohort study was conducted. The inclusion criteria for patients were as follows: (1) primary colorectal cancer; (2) massive peritoneal metastasis; (3)obstructive site located below Treitz ligament by imaging; (4) obstruction refractory to conservative treatment; (5) estimated rese survival time more than 2 months; (6) patients and their families had strong willingness for operation; (7) surgical treatment included stoma/bypass and debulking surgery. In accordance with the above criteria, clinicopathological data of 46 patients undergoing palliative surgery at Peking University Gastrointestinal Cancer Center, Unit III from January 2016 to October 2018 were retrospectively collected. Postoperative symptomatic relief rate, morbidity of complication within 30 days, complication classification (Clavien-Dindo classification), mortality and survival after operation were analyzed. Kaplan-Meier method was used to evaluate survival and Cox regression analysis was used to identify prognostic factors.
Results:
Among 46 patients, 30 were male and 16 were female with median age of 63 (19-87) years; 23 patients received stoma/bypass surgery (stoma/bypass group), and 23 cases received tumor debulking surgery (debulking group). The overall symptom relief rate was 76.1% (35/46), while symptom relief rate in the debulking group was 91.3% (21/23), which was significantly higher than 60.9% (14/23) in the stoma/bypass group (χ2=4.301,
10.A clinical analysis of 19 patients with hepatic pseudolymphoma
Chenchen DAI ; Xiaodong ZHU ; Lingli CHEN ; Yang ZHOU ; Pengju XU ; Jianjun ZHOU
Chinese Journal of Hepatobiliary Surgery 2019;25(5):337-339
Objective To study the clinical features of hepatic pseudolymphoma.Methods A retrospective study was conducted on 19 patients with hepatic pseudolymphoma who were diagnosed and treated at Zhongshan Hospital in Shanghai from June 2013 to December 2017.Eighteen patients were females and one was a male.The mean age was (55±9) years,range 36 to 68 years.This study mainly analyzed the imaging features,treatment and postoperative results.Results All patients were diagnosed accidentally,and 78.9% patients did not exhibit any evidence of hepatic B viral infection.A monofocal lesion was found in 14 patients and multifocal lesions in 5 patients.Surgical treatment was performed in all the patients.The lesion size was (1.1±0.4) cm (range 0.5~2.4 cm).Ultrasound revealed hypo-or slightly hypo-echogenicity.On MRI,diffusion weighted imaging showed slight hyperintensity or hyperintensity,all lesions manifested as homogeneous and slightly hyperintensity on T2WI and hypointensity on T1WI.Dynamic enhancement pattern,wash in and wash out,degressive and persistent enhancement were observed in 16(55.2%),12(41.4%),and 1 (3.4%) patients,respectively.More than 70% of lesions were diagnosed as malignant tumors on preoperative imaging.During a follow-up of 6 ~ 44 months (median:19 months),no patient developed metastasis or recurrence.Conclusions Hepatic pseudolymphoma commonly occurred in women with a small sized lesion.Due to the lack of specific clinical manifestations and imaging findings,preoperative diagnosis was difficult.Surgical resection is still the most optimal treatment.The patients usually have favorable prognosis.

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