Role of CD56-expressing immature biliary epithelial cells in biliary atresia

AIM: To analyze the clinical and pathological parameters and expression of the neural cell adhesion molecule(CD56) in patients with biliary atresia(BA).METHODS: Established clinical laboratory markers of hepatic function, including enzyme activity, protein synthesis, and bilirubin metabolism, were evaluated in patients with BA and compared with those in patients with choledochal cysts and neonatal hepatitis. Pathological changes in tissue morphology and fibrosis were examined by histological and tissue collagen staining. Immunohistochemical staining for the biliary epithelial cell markers CD56 and CK19 together with the Notch signaling related molecules Notch1 and Notch2 was performed in the context of alterations in the structure of intrahepatic biliary ducts.RESULTS: Differences in some clinical laboratoryparameters among the three diseases examined were observed, but they did not correlate with the pathological classification of fibrosis in BA. Immunohistochemical staining showed the presence of CD56-positive immature bile ducts in most patients(74.5%) with BA but not in patients with choledochal cysts or neonatal hepatitis. The number of CD56-expressing cells correlated with disease severity, with more positive cells present in the later stages of liver damage(81.8% vs 18.2%). Furthermore, bile plugs were mainly found in CD56-positive immature biliary ducts. Notch signaling was a key regulatory pathway in biliary duct formation and played a role in tissue fibrosis. Notch1 was co-expressed in CD56-positive cells, whereas Notch2 was found exclusively in blood vessels in the portal area of patients with BA. CONCLUSION: The maturation of biliary epithelial cells and the expression of Notch may play a role in the pathogenesis of BA.

Pathologic response after preoperative therapy predicts prognosis of Chinese colorectal cancer patients with liver metastases

Background: Pathologic response is evaluated according to the extent of tumor regression and is used to estimate the efficacy of preoperative treatment. Several studies have reported the association between the pathologic response and clinical outcomes of colorecal cancer patients with liver metastases who underwent hepatectomy.However, to date, no data from Chinese patients have been reported. In this study, we aimed to evaluate the association between the pathologic response to pre-hepatectomy chemotherapy and prognosis in a cohort of Chinese patients.Patients and methods: In this retrospective study, we analyzed the data of 380 liver metastases in 159 patients.The pathologic response was evaluated according to the tumor regression grade(TRG).The prognostic role of pathologic response in recurrence-free survival(RFS) and overall survival(OS) was assessed using Kaplan-Meier curves with the log-rank test and multivariate Cox models. Factors that had potential influence on pathologic response were also analyzed using multivariate logistic regression and Kruskal-Wallis/Mann-Whitney U tests.Results: Patients whose tumors achieved pathologic response after preoperative chemotherapy had significant longer RFS and OS than patients whose tumor had no pathologic response to chemotherapy(median RFS: 9.9 vs.6.5 months, P = 0.009; median OS: 40.7 vs. 28.1 months, P = 0.040). Multivariate logistic regression and Kruskal-Wallis/Mann-Whitney U tests showed that metastases with small diameter, metastases from the left-side primary tumors,and metastases from patients receiving long-duration chemotherapy had higher pathologic response rates than their control metastases(all P < 0.05). A decrease in the serum carcinoembryonic antigen(CEA) level after preoperative chemotherapy predicted an increased pathologic response rate(P < 0.05). Although the application of targeted therapy did not significantly influence TRG scores of all cases of metastases, the addition of cetuximab to chemotherapy resulted in a higher pathologic response rate when combined with irinotecan-based regimens rather than with oxaliplatin-based regimens.Conclusions: We found that the evaluation of pathologic response may predict the prognosis of Chinese colorectal cancer patients with liver metastases after preoperative chemotherapy. Small tumor diameter, long-duration chemotherapy, left primary tumor, and decreased serum CEA level after chemotherapy are associated with increased pathologic response rates.

PhaseⅡstudy of oxaliplatin combined with S-1 and leucovorin(SOL)for Chinese patients with metastatic colorectal cancer

Background:Fluoropyrimidine and oxaliplatin are widely used for patients with colorectal cancer.This phase II study was conducted to evaluate the efficacy and safety of the combination of S-1,oxaliplatin,and leucovorin(SOL) in the treatment of Chinese patients with metastatic colorectal cancer(mCRC).Methods:Eligible patients with untreated mCRC from four hospitals in China received intravenous oxaliplatin(85 mg/m2) on day 1,oral S-1 twice daily(80-120 mg per day) on day 1-7,and leucovorin twice daily(50 mg per day)simultaneously with S-1,every 2 weeks.Results and discussion:Forty patients were enrolled in our study.In total,296 cycles of SOL were administered.The overall response rate was 50.0%.At a median follow-up of 27 months,progression-free survival and overall surviva were 7.0 months(95%confidence interval[CI]6.0-10.6 months) and 22.2 months(95%CI 15.1-29.3 months),respectively.The most common grade 3/4 non-hematological adverse events were diarrhea(n = 8,20.0%),nausea(n = 3,7.5%),and vomiting(n = 3,7.5%).The most common grade 3/4 hematological toxicities were thrombocytopenia(n = 3,7.5%),neutropenia(n = 1,2.5%),and abnormal alanine transaminase/aspartate transaminase levels(n = 1,2.5%).There was one treatment-related death.Conclusions:The data indicate that the SOL regimen is effective and moderately tolerated in Chinese patients with mCRC.Trial registration:Clinical trial

Activation of autophagy in photoreceptor necroptosis after experimental retinal detachment

AIM:To investigate whether photoreceptor necroptosis induced by z-VAD-FMK(pan caspase inhibitor) was involved the activation of autophagy and whether Necrostatin-1, a specific necroptosis inhibitor, could inhibit this induction of autophagy after experimental retinal detachment.METHODS:Experimental retinal detachment models were created in Sprague-Dawley rats by subretinal injection of sodium hyaluronate and subretinal injections of z-VAD-FMK, vehicle or z-VAD-FMK plus Necrostatin-1.Three days after retinal detachment, morphologic changes were observed by transmission electron microscopy. In other animals, retinas were subjected to immunoprecipitation and Western Blotting, then probed with anti-RIP1, phosphoserine, LC-3II or caspase 8antibody.RESULTS:It was proved by immunoprecipitation and western blotting, that photoreceptor necroptosis was mediated by caspase-8 inhibition and receptor interacting protein kinase(RIP1) phosphorylation activation. Transmission electron microscope and western blotting results indicated that photoreceptornecroptosis was involved the LC-3II and autophagosomes induction. We also discovered Necrostatin-1 could inhibit RIP1 phosphorylation and LC-3II induction.CONCLUSION:These data firstly indicate photoreceptor necroptosis is associated with the activation of autophagy. Necrostatin-1 protects photoreceptors from necroptosis and autophagy by down-regulation of RIP1 phosphorylation and LC-3II.

Prevalence of and risk factors for diabetic macular edema in a northeastern Chinese population

AIM:To estimate the prevalence of diabetic macular edema(DME) and clinically significant macular edema(CSME),and to assess their risk factors in a population with type 2 diabetic mellitus(T2DM) located in northeast China.METHODS:Patients were included from the Fushun Diabetic Retinopathy Cohort Study(FS-DIRECT),a community-based study conducted in northeast China.The presence of DME and CSME was determined by the Early Treatment Diabetic Retinopathy Study(ETDRS) retinopathy scale of fundus photographs.The age-standardized prevalence of DME and CSME was estimated.The association between DME/CSME and risk factors was analyzed in a multivariate Logistical analysis.RESULTS:A total of 292(15.4%) and 166(8.8%) patients were diagnosed as DME and CSME,yielding the age and sex standardized prevalence of 13.5%(95%CI:11.9%-15.0%),and 7.1%(95%CI:5.9%-8.3%),respectively.Female patients had a higher prevalence of DME compared to their male counterparts(15.7% vs 10.4%,P=0.03).Multivariable Logistic regression analysis showed that younger age,insulin use,proteinuria,longer duration of diabetes,and higher glycosylated hemoglobin A1c,were associated with the prevalence of DME and CSME.Patients with higher fasting plasma glucose,systolic blood pressure,and blood urea nitrogen were also found to be associated with DME.CONCLUSION:Early fundus screening in diabetic patients is invaluable and given the relatively high prevalence of DME and CSME in this study cohort,those with a high risk of sight threatening maculopathy would invariably benefit from earlier detection.

A new handheld fundus camera combined with visual artificial intelligence facilitates diabetic retinopathy screening

AIM: To explore the performance in diabetic retinopathy(DR) screening of artificial intelligence(AI) system by evaluating the image quality of a handheld Optomed Aurora fundus camera in comparison to traditional tabletop fundus cameras and the diagnostic accuracy of DR of the two modalities. METHODS: Overall, 630 eyes were included from three centers and screened by a handheld camera(Aurora, Optomed, Oulu, Finland) and a table-top camera. Image quality was graded by three masked and experienced ophthalmologists. The diagnostic accuracy of the handheld camera and AI system was evaluated in assessing DR lesions and referable DR.RESULTS: Under nonmydriasis status, the handheld fundus camera had better image quality in centration, clarity, and visible range(1.47, 1.48, and 1.40) than conventional tabletop cameras(1.30, 1.28, and 1.18;P<0.001). Detection of retinal hemorrhage, hard exudation,and macular edema were comparable between the two modalities, in principle, with the area under the curve of the handheld fundus camera slightly lower. The sensitivity and specificity for the detection of referable DR with the handheld camera were 82.1%(95%CI: 72.1%-92.2%) and 97.4%(95%CI: 95.4%-99.5%), respectively. The performance of AI detection of DR using the Phoebus Algorithm was satisfactory;however, Phoebus showed a high sensitivity(88.2%, 95%CI: 79.4%-97.1%) and low specificity(40.7%, 95%CI: 34.1%-47.2%) when detecting referable DR.CONCLUSION: The handheld Aurora fundus camera combined with autonomous AI system is well-suited in DR screening without mydriasis because of its high sensitivity of DR detection as well as its image quality, but its specificity needs to be improved with better modeling of the data. Use of this new system is safe and effective in the detection of referable DR in real world practice.

阿瑞匹坦用于预防女性胃肠道肿瘤患者化疗所致恶心呕吐的疗效研究

背景与目的 预防化疗所致恶心呕吐在肿瘤治疗的全程管理中是十分重要的一环。本研究评价了在高危女性胃肠道肿瘤患者中,在帕洛诺司琼、地塞米松基础上联用阿瑞匹坦能否进一步预防或减轻FOLFIRI方案(氟尿嘧啶、亚叶酸和伊立替康)或FOLFOX方案(氟尿嘧啶、亚叶酸和奥沙利铂)化疗所致恶心呕吐的发生率和严重程度。方法 本研究为随机、双盲、安慰剂对照、Ⅲ期临床研究。纳入患者为年龄≤50岁的年轻女性,既往饮酒较少或无饮酒史,确诊为胃肠道肿瘤且正在接受FOLFOX或FOLFIRI方案化疗。2015年8月4日至2020年3月31日期间共有248例女性患者入组,按1∶1比率随机分配至干预组和对照组。采用意向性分析评价患者的基线特征和疗效。分析日期为2020年10月30日。患者随机分配至阿瑞匹坦组(阿瑞匹坦:化疗第1天125 mg,化疗开始前60 min口服;第2、3天80 mg,每天早上口服;帕洛诺司琼0.25 mg静脉注射;地塞米松:化疗第1天6 mg,化疗开始前30 min口服)或安慰剂组(安慰剂:化疗第1天125 mg,化疗开始前60 min口服;第2、3天80 mg,每天早上口服;帕洛诺司琼0.25 mg静脉注射;地塞米松:化疗第1天12 mg,化疗开始前30 min口服)。主要研究终点为完全缓解(complete response,CR)率,定义为第1周期化疗后全程(overall phase)无呕吐发作或未使用解救性治疗药物的患者的比例。其他疗效指标,如无恶心、无呕吐的患者比例等,作为次要研究终点和探索性研究终点。结果 共有来自中国4个临床研究中心的248例患者入组,其中243例[阿瑞匹坦组125(51.4%)例、对照组118(48.5%)例]患者可进行疗效和安全性分析。所有患者的平均[mean(SD)]年龄为40.1(7.3)岁。阿瑞匹坦组的CR率显著高于对照组,包括全程[107(87.0%)vs. 80(66.7%),P<0.001]、急性期[114(92.7%)vs. 91(75.8%),P=0.001]和延迟期[109(88.6%)vs. 84 (70.0%),P=0.001]。两组不良事件的发生率[100(80.0%)vs. 96(81.3%),P=0.79]相似,未观察到与阿瑞匹坦治疗相关的3或4级不良事件。多因素分析显示阿瑞匹坦的应用是唯一与全程CR相关的独立因素。结论 在较年轻的、少量饮酒或无饮酒史的胃肠道肿瘤的女性患者中,帕洛诺司琼和地塞米松基础上联用阿瑞匹坦可增强FOLFOX或FOLFIRI方案化疗时的止吐疗效,耐受性良好。

Temporal Change in Treatment Patterns of Metastatic Colorectal Cancer and Its Association with Patient Survival:A Retrospective Cohort Study Based on an Intelligent Big-Data Platform

There is a lack of high-quality,large-scale,real-world evidence from patients with metastatic colorectal cancer(mCRC),especially in China.It remains unclear whether efforts to improve the quality of care for mCRC would improve patient survival outcomes in real-world practice.On the basis of an intelligent bigdata platform,we established a large-scale retrospective cohort of mCRC patients.We investigated the temporal changes in the systemic and local treatment(resection,ablation,or radiation to liver,lung,or extrahepatic and/or extrapulmonary metastases)patterns of mCRC,and whether these changes were associated with improved overall survival(OS)over time.Between July 2012 and December 2018,3403 eligible patients were included in this research.The median OS was 42.8 months(95%confidence interval(CI),40.7–46.6)for the entire cohort,25.6 months(95%CI,24.7–26.9)for those treated with systemic therapy only,and not reached(95%CI,78.6 months–not reached)for those receiving local therapy.The utility rate of local therapy increased continuously from 37.9%in 2012–2014 to 46.9%in 2017–2018.A dramatic increase in the utility rate of either cetuximab or bevacizumab was observed since 2017(39.9%,43.2%,and 60.3%in 2012–2014,2015–2016,and 2017–2018,respectively).Compared with 2012–2014,the OS of the entire population significantly improved in 2015–2016(hazard ratio(HR)=0.87(95%CI,0.78–0.99);P=0.034),but not for patients receiving systemic therapy only(HR=0.99(95%CI,0.86–1.14);P=0.889),whereas an improved OS was found in 2015–2018 for both the entire population(HR=0.75(95%CI,0.70–0.81);P<0.001)and for patients receiving systemic therapy only(HR=0.83(95%CI,0.77–0.91);P<0.001).In summary,the quality of care for mCRC,as indicated by the utility rate of targeted and local therapies,has been continuously improving over time in this study cohort,which is associated with continuously improving survival outcomes for these patients.

The Chinese Society of Clinical Oncology (CSCO): Clinical guidelines for the diagnosis and treatment of gastric cancer, 2023

The 2023 update of the Chinese Society of Clinical Oncology(CSCO)Clini-cal Guidelines for Gastric Cancer focuses on standardizing cancer diagnosis and treatment in China,reflecting the latest advancements in evidence-based medicine,healthcare resource availability,and precision medicine.These updates address the differences in epidemiological characteristics,clinicopatho-logical features,tumor biology,treatment patterns,and drug selections between Eastern and Western gastric cancer patients.Key revisions include a structured template for imaging diagnosis reports,updated standards for molecular marker testing in pathological diagnosis,and an elevated recommendation for neoadju-vant chemotherapy in stage III gastric cancer.For advanced metastatic gastric cancer,the guidelines introduce new recommendations for immunotherapy,anti-angiogenic therapy and targeted drugs,along with updated management strategies for human epidermal growth factor receptor 2(HER2)-positive and deficient DNA mismatch repair(dMMR)/microsatellite instability-high(MSI-H)patients.Additionally,the guidelines offer detailed screening recommendations for hereditary gastric cancer and an appendix listing drug treatment regimens for various stages of gastric cancer.The 2023 CSCO Clinical Guidelines for Gastric Cancer updates are based on both Chinese and international clinical research and expert consensus to enhance their applicability and relevance in clinical practice,particularly in the heterogeneous healthcare landscape of China,while maintaining a commitment to scientific rigor,impartiality,and timely revisions.

Dynamic single-cell mapping unveils Epstein-Barr virusimprinted T-cell exhaustion and on-treatment response

Epstein-Barr virus(EBV)-associated gastric cancer(GC)manifests an intriguing immunotherapy response.However,the cellular basis for EBV-imprinted tumour immunity and on-treatment response remains undefined.This study aimed to finely characterize the dynamic tumour immune contexture of human EBV(+)GC treated with immunochemotherapy by longitudinal scRNA-seg and paired scTCR/BCR-seq.EBV(+)GC exhibits an inflamed-immune phenotype with increased T-cell and B-cell infiltration.

The Chinese Society of Clinical Oncology(CSCO):clinical guidelines for the diagnosis and treatment of gastric cancer

China is one of the countries with the highest incidence of gastric cancer.There are differences in epidemiological characteristics,clinicopathological features,tumor biological characteristics,treatment patterns,and drug selection between gastric cancer patients from the Eastern and Western countries.Non-Chinese guidelines cannot specifically reflect the diagnosis and treatment characteristics for the Chinese gastric cancer patients.The Chinese Society of Clinical Oncology(CSCO)arranged for a panel of senior experts specializing in all sub-specialties of gastric cancer to compile,discuss,and revise the guidelines on the diagnosis and treatment of gastric cancer based on the findings of evidence-based medicine in China and abroad.By referring to the opinions of industry experts,taking into account of regional differences,giving full consideration to the accessibility of diagnosis and treatment resources,these experts have conducted experts’consensus judgement on relevant evidence and made various grades of recommendations for the clinical diagnosis and treatment of gastric cancer to reflect the value of cancer treatment and meeting health economic indexes.This guideline uses tables and is complemented by explanatory and descriptive notes covering the diagnosis,comprehensive treatment,and follow-up visits for gastric cancer.

The Chinese Society of Clinical Oncology(CSCO):Clinical guidelines for the diagnosis and treatment of gastric cancer,2021

There exist differences in the epidemiological characteristics,clinicopathological features,tumor biological characteristics,treatment patterns,and drug selections between gastric cancer patients from the Eastern and Western countries.The Chinese Society of Clinical Oncology(CSCO)has organized a panel of senior experts specializing in all sub-specialties of gastric cancer to compile a clinical guideline for the diagnosis and treatment of gastric cancer since 2016 and renews it annually.Taking into account regional differences,giving full consideration to the accessibility of diagnosis and treatment resources,these experts have conducted expert consensus judgment on relevant evidence and made various grades of recommendations for the clinical diagnosis and treatment of gastric cancer to reflect the value of cancer treatment and meeting health economic indexes in China.The 2021 CSCO Clinical Practice Guidelines for Gastric Cancer covers the diagnosis,treatment,follow-up,and screening of gastric cancer.Based on the 2020 version of the CSCO Chinese Gastric Cancer guidelines,this updated guideline integrates the results ofmajor clinical studies from China and overseas for the past year,focused on the inclusion of research data from the Chinese population for more personalized and clinically relevant recommendations.For the comprehensive treatment of non-metastatic gastric cancer,attentions were paid to neoadjuvant treatment.The value of perioperative chemotherapy is gradually becoming clearer and its recommendation level has been updated.For the comprehensive treatment of metastatic gastric cancer,recommendations for immunotherapy were included,and immune checkpoint inhibitors fromthird-line to the first-line of treatment for different patient groups with detailed notes are provided.

The efficacy and safety of modified FOLFIRINOX as first-line chemotherapy for Chinese patients with metastatic pancreatic cancer

Background: Oxaliplatin, irinotecan, 5-fluorouracil, and l-leucovorin (FOLFIRINOX) has become one of the first-line treatment options for advanced pancreatic cancer (PC). However, the relatively high rate of grade 3 or 4 adverse events associated with the standard dosage of FOLFIRINOX limits its widespread use in clinical practice. In this study, we were to evaluate the efficacy and safety of a modified FOLFIRINOX regimen as a first-line chemotherapy for Chinese patients with metastatic PC. Methods: Patients with histologically confirmed primary metastatic pancreatic adenocarcinoma with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2 were recruited to receive the modified FOLFIRINOX regimen (intravenous infusion of oxaliplatin, 65 mg/m2;irinotecan, 150 mg/m2;l-leucovorin, 200 mg/ m2;and 5-fluorouracil, 2400 mg/m2, repeated every 2 weeks). The treatment was continued for 12 cycles unless the patient had progressive disease (PD), stable disease (SD) with symptom deterioration, unacceptable adverse events, or requested to terminate the treatment prematurely. The primary endpoint was objective response rate (ORR). Results: Sixty-five patients were enrolled from July 2012 to April 2017 in three institutions, and they all received at least one cycle of chemotherapy, with a median of 8 cycles (range 1-12 cycles). No complete response was observed. Twenty-one (32.3%) patients had partial responses, and 27 (41.5%) had SD. The ORR and disease control rate of the study cohort was 32.3% and 73.8%. The estimated median overall survival and progression-free survival were 11.60 (95% confidence interval [CI] 8.76-14.44) and 5.77 (95% CI 5.00-6.54) months. Major grade 3 or 4 adverse events included neutropenia (12.3%) and diarrhea (6.2%). No treatment-related death was observed. Conclusions: Modified FOLFIRINOX was well-tolerated and might be a promising option as first-line therapy for Chinese patients with metastatic PC.

In Situ Electron Backscatter Diff raction Analysis for Microstructure Evolution and Deformation Models of Mg–Ce Alloy During Uniaxial Loading

Previous studies showed that signifi cant increases in elongation in Mg–Ce alloys due to the Ce addition and the solute drag eff ect by Ce addition were ascribed to the non-basal dislocation slip activating and the texture altering. The microstructure evolution and deformation models of extruded Mg-0.5 wt%Ce alloy rods under uniaxial tension have been studied using in situ electron backscatter diff raction. The basal and non-basal slips were characterized by using slip line trace analysis. The results provide evidence for that pyramidal slip activated during deformation, besides basal slip and extension twinning, which contributes to the texture weakening and ductility increasing in Mg-0.5 wt%Ce alloy.

Elevated peripheral blood neutrophil-to-lymphocyte ratio is associated with an immunosuppressive tumour microenvironment and decreased benefit of PD-1 antibody in advanced gastric cancer

Background Due to its limited efficacy and potential toxicity,anti-PD-1 monoclonal antibody is not suitable for all advanced gastric cancer(AGC)patients and predictive biomarkers identifying patients who can benefit from it are urgently needed.This study aimed to evaluate the predictive and prognostic value of inflammatory markers in the context of the systemic inflammatory status and tumour microenvironment.Methods The study included 58 patients from a prospective study investigating the safety and efficacy of toripalimab in chemorefractory AGC patients.Patient characteristics,treatment outcomes,and haematological parameters were analysed.Immune-cell infiltration and gene expression in tumour tissue were examined using transcriptome sequencing.Results In this cohort,the median follow-up time was 4.5 months,the median progression-free survival was 1.9 months,and the median overall survival(OS)was 4.8 months.The objective response rate was 12.1%and th disease control rate(DCR)was 39.7%.Both the baseline blood neutrophil-to-lymphocyte ratio(bNLR)with a cut-point of 2.7 and the early elevated dynamic change of the bNLR(dNLR)with a cut-point of 1.5 were prognostic factors of survival.Patients in the high bNLR or dNLR group had remarkably poor DCR(25.8%vs 59.1%,P=0.023;15.8%vs 54.6%,P=0.008).In multivariate analysis,bNLR and tumour mutational burden were independent prognostic factors of OS.Tumour RNA-seq analysis revealed enriched neutrophil infiltration and a higher tumour NLR in the bNLR-high group.Corresponding tumour gene-expression profiles were associated with neutrophil recruitment and inflammatory cytokine aggregation.Conclusions Our study demonstrated the potential clinical utility of NLR as a biomarker for patient selection and clinical management in predicting the prognosis of AGC patients as well as response to anti-PD-1 therapy.In addition,high bNLR reflected the imbalance of tumour-tissue-infiltrating neutrophils and lymphocytes,and was associated with an immunosuppressive and pro-tumour microenvironment.