Application of immune checkpoint inhibitors and microsatellite instability in gastric cancer

In this editorial we comment on the article by Li published in the recent issue of the World Journal of Gastroenterology.We focus specifically on the application of immune checkpoint inhibitors(ICIs)and microsatellite instability(MSI)in gastric cancer(GC).The four pillars of GC management have long been considered,including surgery,chemotherapy,radiotherapy and targeted therapy.However,immunotherapy has recently emerged as a“fifth pillar”,and its use is rapidly expanding.There are four principal strategies for tumor immunotherapy:ICIs,tumor vaccines,adoptive immunotherapy and nonspecific immunomodulators.Of them,ICIs are the most advanced and widespread type of cancer immunotherapy for GC.Recent breakthrough results for ICIs have paved the way to a new era of cancer immunotherapy.In particular,inhibition of the PD-1/PD-L1 axis with ICIs,including nivolumab and pembrolizumab,has emerged as a novel treatment strategy for advanced GC.Unfortunately,these therapies are sometimes associated with often subtle,potentially fatal immune-related adverse events(irAEs),including dermatitis,diarrhea,colitis,endocrinopathy,hepatotoxicity,neuropathy and pneumonitis.We must be aware of these irAEs and improve the detection of these processes to prevent inappropriate discharges,emergency department revisits,and downstream complications.Recent studies have revealed that MSI-high or mismatch-repair-deficient tumors,regardless of their primary site,have a promising response to ICIs.So,it is important to detect MSI before applying ICIs for treatment of GC.

Clinicopathologic significance of HER-2/neu protein expression and gene amplification in gastric carcinoma

AIM:To study the HER-2/neu protein expression and gene amplification in gastric carcinoma and their relation.METHODS:One hundred and forty-five formalin-fixed and paraffin-embedded tumor tissue samples from Chinese gastric carcinoma patients were studied with immunohistochemistry(IHC)and fluorescence in situ hybridization(FISH)methods.Clinicopathologic data about all patients were collected.RESULTS:The levels of HER-2 3+,HER-2 2+and HER21+were measurable in 6.9%,8.3%and 17.2%of the samples,respectively.No HER-2 was stained in 67.6% of the samples.FISH showed that HER-2 gene was amplified in 18 samples,10 HER-2 3+samples,5 HER-2 2+samples,and 3 HER-2 1+samples with IHC staining.HER-2 status was not correlated with the sex and age of patients,and tumor size,location or differentiation,but with the depth of invasion,TNM stage,lymph node and distant metastasis as well as histopathological classification of gastric cancer(P<0.05).CONCLUSION:All samples with IHC as HER-2 expression should be analyzed with FISH.Detection of HER-2 gene amplification can assess the malignant biological behaviors and prognosis of gastric cancer.

Disease-specific mi R-34a as diagnostic marker of nonalcoholic steatohepatitis in a Chinese population

AIM To assess disease-specific circulating micro RNAs(mi RNAs) in non-alcoholic steatohepatitis(NASH) patients.METHODS A total of 111 biopsy-proven non-alcoholic fatty liver disease(NAFLD) or chronic hepatitis B(CHB) patients and healthy controls from China's Mainland were enrolled to measure their serum levels of mi R-122,-125 b,-146 b,-16,-21,-192,-27 b and-34 a. The correlations between serum mi RNAs and histological features of NAFLD were determined. The diagnostic value of mi RNA in NASH and significant fibrosis was analyzed and compared with that of cytokeratin-18(CK-18), fibrosis-4(FIB-4), and aspartate aminotransferase to platelet ratio index(APRI), respectively.RESULTS Circulating mi R-122,-16,-192 and-34 a showed differential expression levels between NAFLD and CHB patients, and mi R-34 a had an approximately 2-fold increase in NAFLD samples compared with that of CHB samples(P < 0.01). Serum mi R-122,-192 and-34a levels were correlated with steatosis(R = 0.302, 0.323 and 0.470, respectively, P < 0.05) and inflammatory activity(R = 0.445, 0.447 and 0.517, respectively, P < 0.01); only serum mi R-16 levels were associated with fibrosis(R = 0.350, P < 0.05) in patients with NAFLD. The diagnostic value of mi R-34 a for NASH(area under the receiver operating characteristic, 0.811, 95%CI: 0.670-0.953) was superior to that of alanine aminotransferase, CK-18, FIB-4 and APRI in NAFLD, but mi R-16 showed a limited performance in the diagnosis of significant fibrosis in NASH.CONCLUSION Circulating mi R-34 a may serve as a disease-specific noninvasive biomarker for the diagnosis of NASH.

Pancreas-sparing duodenectomy with regional lymph node dissection for early-stage ampullary carcinoma: A case control study using propensity scoring methods

AIM:To investigate the outcomes of pancreas-sparing duodenectomy(PSD)with regional lymph node dissection vs pancreaticoduodenectomy(PD).METHODS:Between August 2001 and June 2014,228 patients with early-stage ampullary carcinoma(Amp Ca)underwent surgical treatment(PD,n=159;PSD with regional lymph node dissection,n=69).The patients were divided into two groups:the PD group and the PSD group.Propensity scoring methods were used to select patients with similar disease statuses.A total of 138 matched cases,with 69 patients in each group,were included in the final analysis.RESULTS:The median operative time was shorter among the patients in the PSD group(435 min)compared with those in the PD group(481 min,P=0.048).The median blood loss in the PSD group was significantly less than that in the PD group.The median length of hospital stay was shorter for patients in the PSD group vs the PD group.The incidence of pancreatic fistula was higher among patients in the PD group vs the PSD group.The 1-,3-,and 5-year overall survival and disease-free survival rates for patients in the PSD group were 83%,70%,44%and 73%,61%,39%,respectively,and these values were not different than compared with those in the PD group(P=0.625).CONCLUSION:PSD with regional lymph node dissection presents an acceptable morbidity in addition to its advantages over PD.PSD may be a safe and feasible alternative to PD in the treatment of earlystage Amp Ca.

MLH1 promoter germline-methylation in selected probands of Chinese hereditary non-polyposis colorectal cancer families

AIM: To detect the MLH1 gene promoter germline- methylation in probands of Chinese hereditary non- polyposis colorectal cancer (HNPCC), and to evaluate the role of methylation in MLH1 gene promoter and molecular genetics in screening for HNPCC. METHODS: The promoter germline methylation of MLH1 gene was detected by methylation-specific PCR (MSP) in 18 probands from unrelated HNPCC families with high microsatellite-instability (MSI-H) phenotype but without germline mutations in MSH2, MLH1 and MSH6 genes. At the same time, 6 kindreds were col- lected with microsatellite-stability (MSS) phenotype but without germline mutations in MSH2, MLH1 and MSH6 genes as controls. The results of MSP were confirmed by clone sequencing. To ensure the reliability of the results, family H65 with nonsense germline mutation at c.2228C > A in MSH2 gene was used as the negative control and the cell line sw48 was used as the known positive control along with water as the blank control. Immunochemical staining of MLH1 protein was per- formed with Envision two-step method in those patients with aberrant methylation to judge whether the status of MLH1 gene methylation affects the expression of MLH1 protein. RESULTS: Five probands with MLH1 gene promoter methylation were detected in 18 Chinese HNPCC fami- lies with MSI-H phenotype but without germline muta- tions in MSH2, MLH1 and MSH6 genes. Two of the five probands from families H10 and H29 displayed exhaus- tive-methylation, fulfilling the Japanese criteria (JC) and the Amsterdam criteria (AC), respectively. The other 3 probands presented part-methylation fulfilling the AC. Of the 13 probands with unmethylation phenotype, 8 ful- filled the JC and the Bethesda guidelines (BG), 5 fulfilled the AC. The rate of aberrant methylation in MLH1 gene in the AC group (22.2%, 4/18) was higher than that in the JC/BG groups (5.6%, 1/18) in all HNPCC families with MSI-H phenotype but without germline mutations in MSH2, MLH1 and MSH6 genes. However, no proband with methylation in MLH1 gene was found in the families with MSS phenotype and without germline mutations in MSH2, MLH1 and MSH6 genes. No expression of MLH1 protein was found in tumor tissues from two patients with exhaustive-methylation phenotype, whereas posi- tive expression of MLH1 protein was observed in tumor tissues from patients with partial methylation phenotype (excluding family H42 without tumor tissue), indicating that exhaustive-methylation of MLH1 gene can cause defective expression of MLH1 protein. CONCLUSION: Methylation phenotype of MLH1 gene is correlated with microsatellite phenotype of MMR genes, especially with MSI-H. Exhaustive-methylation of MLH1 gene can silence the expression of MLH1 pro- tein. MLH1 promoter methylation analysis is a promis- ing tool for molecular genetics screening for HNPCC.

Three novel missense germline mutations in different exons of MSH6 gene in Chinese hereditary non-polyposis colorectal cancer families

AIM: To investigate the germline mutations of MSH6 gene in probands of Chinese hereditary non-polyposis colorectal cancer (HNPCC) families fulfilling different clinical criteria. METHODS: Germline mutations of MSH6 gene were detected by PCR-based DNA sequencing in 39 unrelated HNPCC probands fulfilling different clinical criteria in which MSH2 and MLH1 mutations were excluded. To further investigate the pathological effects of detected missense mutations, we analyzed the above related MSH6 exons using PCR-based sequencing in 137 healthy persons with no family history. The clinicopathological features were collected from the Archive Library of Cancer Hospital, Fudan University and analyzed. RESULTS: Four germline missense mutations distributed in the 4th, 6th and 9th exons were observed. Of them, three were not found in international HNPCC databases and did not occur in 137 healthy controls, indicating that they were novel missense mutations. The remaining mutation which is consistent with the case H14 at c.3488A>T of exon 6 of MSH6 gene was also found in the controls, the rate was approximately 3.65% (5/137) and the type of mutation was not found in the international HNPCC mutational and SNP databases, suggesting that this missense mutation was a new SNP unreported up to date. CONCLUSION: Three novel missense mutations and a new SNP observed in the probands of Chinese HNPCC families, may play an important role in the development of HNPCC.

Meta-analysis of clinical efficacy and safety of kidney Tonifying therapy in the treatment of interstitial lung disease

Objective:To evaluate the efficacy and safety of kidney tonifying therapy in the treatment of Interstitial Lung Disease(ILD).Methods:We searched Wanfang Data,CNKI,CBM,VIP,Pub Med,EMBASE,Web of science and Cochrane Library for Randomized Controlled Trials(RCTs)of kidney tonifying therapy in the treatment of ILD.The retrieval time was from the establishment of the database to December 15,2020.Rev man 5.3 software was used to analyze and summarize the collected literature,and the methodological quality of the included studies was evaluated by the bias risk assessment scale of Cochrane Collaboration Network.Results:A total of 15 articles with 1045 patients were included.The results of meta-analysis showed that compared with the control group treated with conventional western medicine alone,kidney tonifying therapy or combined with conventional western medicine was beneficial to improve the clinical total effective rate[RR=1.33(95%CI 1.24-1.43),P<0.00001].At the same time,compared with the control group treated with routine western medicine,kidney tonifying therapy or combined with routine western medicine can improve cough and wheezing symptoms of patients[MD=-0.62(95%CI-0.78~-0.46),P<0.00001]and MD=-0.79(95%CI-0.18~-0.49),P<0.00001].However,there was no significant improvement in 6-minute walk test and lung function(DLCO%)(P>0.05);only one study reported 7 patients with adverse reactions,but after corresponding treatment,the symptoms were significantly relieved.The analysis of the characteristics of intervention measures in the treatment group showed that there were a total of 80 traditional Chinese medicines involved,of which Shu Dihuang appeared the most frequently,and the tonic drugs were used the most.The two meridians of the lung and kidney appear most frequently.Among the four qi and five flavors,warm and sweet medicines have the highest frequency.Conclusion:Adopting kidney-tonifying method or combined with conventional Western medicine treatment can improve the total clinical effectiveness of patients.Adopting kidney-tonifying method or combined with conventional Western medicine treatment to improve symptoms such as coughing and wheezing.No serious adverse reactions have been reported,and the safety is reliable.Due to the low quality of the included literature,the results of this study need to be verified by high-quality,large sample randomized controlled trials.

针刺临床研究方法学:进展与挑战

Acupuncture is one of the most widely used complementary and alternative medicines worldwide.In recent years,rapid progress has been made in clinical research on acupuncture.Clinical studies on acupuncture treatment for diseases such as chronic severe functional constipation,female stress urinary incontinence,migraine prophylaxis,chronic stable angina,and postprandial distress syndrome have been published in top journals including Annals of Internal Medicine,British Medical Journal,etc.These studies have further confirmed the effects of acupuncture and promoted the international development and influence of acupuncture.High-quality clinical research on acupuncture is inseparable from the scientific application of clinical research methodology.Although clinical research methodology has been well established,there still faces many challenges in evaluating the effects of acupuncture.

Placebo response of sham acupuncture in patients with primary dysmenorrhea:A meta-analysis

Background The placebo response of sham acupuncture in patients with primary dysmenorrhea is a substantial factor associated with analgesia.However,the magnitude of the placebo response is unclear.Objective This meta-analysis assessed the effects of sham acupuncture in patients with primary dysmenorrhea and the factors contributing to these effects.Search strategy PubMed,Embase,Web of Science,and Cochrane CENTRAL databases were searched from inception up to August 20,2022.Inclusion criteria Randomized controlled trials(RCTs)using sham acupuncture as a control for female patients of reproductive age with primary dysmenorrhea were included.Data extraction and analysis Pain intensity,retrospective symptom scale,and health-related quality of life were outcome measures used in these trials.Placebo response was defined as the change in the outcome of interest from baseline to endpoint.We used standardized mean difference(SMD)to estimate the effect size of the placebo response.Results Thirteen RCTs were included.The pooled placebo response size for pain intensity was the largest(SMD=−0.99;95%confidence interval[CI],−1.31 to−0.68),followed by the retrospective symptom scale(Total frequency rating score:SMD=−0.20;95%CI,−0.80 to−0.39.Average severity score:SMD=−0.35;95%CI,−0.90 to−0.20)and physical component of SF-36(SMD=0.27;95%CI,−0.17 to 0.72).Studies using blunt-tip needles,single-center trials,studies with a low risk of bias,studies in which patients had a longer disease course,studies in which clinicians had<5 years of experience,and trials conducted outside Asia were more likely to have a lower placebo response.Conclusion Strong placebo response and some relative factors were found in patients with primary dysmenorrhea.PROSPERO registration number:CRD42022304215.