Objective The aim of this study was to explore the clinical application value and safety of immunotherapy combined with molecular targeted drugs in the treatment of advanced hepatocellular carcinoma(HCC).Methods According to the inclusion criteria,33 patients with advanced HCC who received immunotherapy combined with molecular targeted drug therapy were included.The clinical data such as blood biochemical indexes,tumor stage,tumor imaging characteristics and previous treatment strategies of patients before medication were recorded,following up the imaging reexamination results of patients and adverse reactions during medication until the end of follow-up and loss of follow-up or the patient death.The primary endpoints were Objective response rate(ORR)and safety,and the secondary endpoint were progression-free survival(PFS)and overall survival(OS).The Kaplan-Meier method was used to analyze the clinical curative effect of patients taking medication.Results As of the last follow-up,a total of 33 patients with advanced HCC had received the combination therapy of immune drugs and molecular targeted drugs,the ORR and the disease control rate(DCR)were 24.2% and 66.7%,respectively.The median progression-free survival(mPFS)and median overall survival(mOS)were 10.9 months and 11.8 months,respectively.Treatment-related grade 1-2 adverse events and their incidences were nausea and vomiting in 2 cases(6.1%),hand-foot skin reaction in 2 cases(6.1%),reactive cutaneous capillary endothelial proliferation in 2 cases(6.1%),and fatigue in 1 case(3.0%),1 case of stomach pain(3.0%),1 case of proteinuria(3.0%),9 cases of abdominal pain(27.3%),1 case of fever(3.0%),1 case of flatulence(3.0%),hypoalbuminemia 1 case(3.0%),5 cases(15.2%)with hyperbilirubinemia,4 cases with ALT elevation(12.1%),and 10 cases with AST elevation(30.3%).Treatment-related grade 3 or higher adverse reactions and their incidences were nausea and vomiting in 1 case(3.0%),abdominal pain in 1 case(3.0%),and AST elevation in 1 case(3.0%).No treatment-related deaths were observed,and adverse events were all effectively managed.Conclusion The combined use of immune drugs and molecular targeted drugs in the treatment of advanced HCC has a high DCR and a low incidence of adverse events.It can be used as a first-line treatment option for patients with advanced HCC and is worthy of further exploration.

Objective This study aimed to screen for cancer-testis antigens with immune function in differentially expressed genes between gastric cancer tissues and normal tissues, and to explore the effect of such antigens on survival and prognosis of gastric cancer.Methods The TCGA database was used to screen the genes with significant differences in the expression between gastric cancer tumor tissues and normal tissues.At the same time, the cancer-testis antigens that had been confirmed in the literature and induced immune responses were screened in the CTdatabase.The cancer-testis antigens with the function of inducing immune response were screened from the differentially expressed genes, and the survival analysis was carried out in combination with the clinical information of patients, and the prognosis-related cancer-testis antigens were further analyzed by CIBERSORT for immune infiltration.Results A total of 5514 differentially expressed genes were screened out through the TCGA database.There were 94 cancer-testis antigens with the function of inducing immune response in the CTdatabase.Comparing with the differential expressed genes of gastric cancer, a total of 33 differentially expressed cancer-testis antigens with the function of inducing immune response were obtained.Among them, 27 cancer-testis antigens were highly expressed in gastric cancer tumor tissues, including ARMC3, CDCA1, CEP55, CSAG2, CT45A1, CTAG2, CTCFL, CXorf61(KK-LC-1), DDX53, IGF2BP3, MAGEA1, MAGEA10, MAGEA12, MAGEA3, MAGEA4, MAGEA6, MAGEC1, MAGEC2, KIF2C, MPHOSPH1, PLAC1, PRAME, SAGE1, SEMG1, SPAG17, SSX1, TTK, and had been confirmed in the literature to have the ability to induce immune responses.The expressions of BAGE2, CCDC110, SPAG4, SPAG8, IGSF11 and MAGEB2 in tumor tissues were lower than those in normal tissues.Furthermore, the survival analysis found that the high expressions of CEP55, MAGEA10, MAGEA12, MAGEA3, MAGEC1, and PLAC1 was significantly associated with the shorter survival of patients with gastric cancer, and was positively correlated with the infiltration ratio of M1 macrophages with anti-tumor ability in the tumor immune microenvironment.The multivariate analysis by the Cox regression model showed that the expression of CEP55 was significantly associated with shorter survival of patients.Conclusion In this study, the cancer-testis antigens with the function of inducing immune response were screened from the highly expressed genes in gastric cancer tissues, which provided a basis for the search targets of gastric cancer immunotherapy.

Pancreatic ductal adenocarcinoma(PDAC)is the most common type of pancreatic cancer,and the prognosis is extremely poor.Surgical resection is the only radical cure at present,but most patients have lost the chance of surgery when they seek medical adviee.As an emerging treatment,immunotherapy shows promising prospects in the treatment of various solid tumors and hematological malignancies.However,the low antigenicity and the immunosuppressive microenvironment of PDAC make its immunotherapy difficult.This article provides new ideas for the immunotherapy research of PDAC by reviewing the characteristics of the tumor microenvironment composition of PDAC and the current novel immunotherapy strategies.

B cells are an critical component of the tumor microenvironment.However,the impact of B cells on tumor progression and treatment response is still controversial,reflecting the heterogeneity of tumor infiltrating B cells(TIL-Bs)subsets.In fact,these TIL-Bs are polarized in different directions with the immune microenvironment in which they are located to obtain different phenotypes and functions,and at the same time reversely shape the composition and type of the microenvironment,eventually leading to completely different clinical outcomes.This article summarizes the composition characteristics and formation mechanism of TIL-Bs.Further,combined with clinical trials and preclinical studies,we try to explain the influence of TIL-Bs heterogeneity on the effect of tumor immunotherapy.Elucidating the composition,generation,and nature of associated immune networks of B cell subsets in tumors are of great importance for a comprehensive understanding of B cell responses in tumors and for the design of more effective cancer immunotherapies.

Src homology region 2-containing protein tyrosine phosphatase 2(SHP2)is the only cytoplasmic protein tyrosine phosphatase that has been confirmed to promote cancer.There are highly expressed in a variety of malignant tumors.SHP2 can promote tumor development and affect tumor prognosis by mediating RAS/ERK,PI3K/Akt,JAK/STAT and other signal pathways downstream of receptor tyrosine kinase(RTK).At the same time,SHP2 is involved in the regulation of immune checkpoint signaling pathways such as PD-1 / PD-L1,CTLA-4,BLTA and TIGIT,and plays an important role in regulating various immune cells in the tumor microenvironment.Targeting SHP2 can treat malignant tumors not only by inhibiting RTK downstream signaling pathways,but also by improving the immune microenvironment.Therefore,SHP2 has the function of dual treatment tumor by immunity and targeting,and it shows extremely high potential and value as a target for anti-tumor therapy.

Gut microbiota is the general term for microorganisms that live in the intestine.The microbiota is affected by many factors such as the host's diet and drugs.At the same time, the microbiota can also participate in the regulation of the host's immune status.At present, some studies have confirmed that the intestinal flora is related to the efficacy and adverse reactions of anti-tumor immunotherapy, and regulating the flora can improve the efficacy of immunotherapy, but the specific mechanism is still unclear.This article systematically reviews the current research progress and shortcomings of gut microbiota and tumor immunotherapy.

The small intestine is the longest section of the digestive tract,and it is the main place for food digestion,absorption and energy conversion.However,there are few reports on the small intestine tumors.Primary malignant tumors of the small intestine are rare in clinical practice.Due to the lack of typical clinical manifestations and effective treatment methods,the prognosis is extremely poor.The large surface area of the small intestine and the state of rapid epithelial renewal clearly contradict the low incidence of tumors.The scientific problem about the lower incidence of small tumors has become a century-old mystery that plagues the field of medical science.This review mainly analyzes the reasons for the rareness of small intestinal tumors from four aspects:the unique physiological barrier of the small intestine,gene regulatory system,commensal flora and mucosal immune system.Understanding the precise regulatory mechanism of the small intestine will provide new ideas for further studies of aging,gut microbiota,and cancer prevention and treatment.Based on previous studies and the latest research progress,this article reviews the epidemiological status of small intestine tumors,the possible reasons for the low incidence,and their implications for tumor prevention and treatment.

Objective The aim of this study was to explore the effect of different molecular types of breast cancer with type 2diabetes.Methods The breast cancer patients with type 2 diabetes admitted to the Affiliated Cancer Hospital of Xinjiang Medical University from January 2000 to December 2019 were retrospectively analyzed as the diabetes group(335 cases),and the non-diabetic patients with breast cancer who visited at the same time were randomly selected as the non-diabetic group(181 cases),the clinicopathologic features of the two groups were compared.The patients were divided into the metformin group(169 cases)and non-metformin group(166 cases)according to whether the diabetic group took metformin orally or not.The Kaplan-Meier method was applied to compare the disease-free survival(DFS)and overall survival(OS)of breast cancer patients with different molecular types.Univariate and multivariate Cox regression models were used to analyze the correlation between clinicopathological features and prognosis.Results The patients in the diabetes group were older than those in the non-diabetes group,and the proportion of postmenopausal patients was higher(P＜0.001).Cox regression analysis showed that tumor size,lymph node metastasis and Ki67 were related to OS and DFS,and menopausal status was an independent factor affecting DFS.Survival analysis showed that the 1-year,3-year,5-year and 10-year disease-free survival and total survival rate were 91.5%,83.3%,81.1%,64.3% and 97%,88.9%,85.1%,72.1% in the non-metformin group,respectively.It was significantly lower than that of metformin group and non-diabetic group(P＜0.05).In 516 cases of breast cancer,299 cases of luminal type breast cancer,141 cases were HER2 positive breast cancer,and 76 cases were triple negative breast cancer.In luminal breast cancer,there was no significant difference in OS and DFS curves among the three groups(P＞0.05);In HER2 positive breast cancer,OS and DFS in the metformin group and non-diabetes group were higher than those the non-metformin group(P＜0.05);In triple-negative breast cancer,DFS in the metformin group was significantly better than in the non-metformin group(P＜0.05).Conclusion Metformin can significantly improve the prognosis of triple-negative,HER2 positive breast cancer patients with type 2 diabetes.

Objective The aim of this study was to explore the efficacy,safety difference and prognostic factors between first-line immune checkpoint inhibitor combined with standard chemotherapy and standard chemotherapy alone in patients with advanced esophageal squamous cell carcinoma(ESCC)in the real world.Methods The clinical data of 107 patients with locally advanced or metastatic ESCC who were treated in our hospital from January 2018 to December 2020 were retrospectively analyzed.According to their first-line treatment schemes,they were divided into the application of programmed cell death protein-1(PD-1)inhibitors combined standard chemotherapy group and the standard chemotherapy group alone.The progression free survival(PFS),Objective response rate(ORR),disease control rate(DCR)and the occurrence of treatment-related adverse events(TRAEs)were compared between of the two groups and influencing factors related to PFS in patients with advanced ESCC were analyzed.Results A total of 107 patients(56 in the combined treatment group and 51 in the chemotherapy group)were collected.After propensity score matching(PSM),31 patients in the combined treatment group and 31 patients in the chemotherapy group were obtained.There was no significant difference in ORR between the combined chemotherapy group and the chemotherapy alone group(38.7% vs. 19.4%,P＞0.05);the difference in DCR was not statistically significant(96.8% vs. 90.3%,P＞ 0.05);the difference in PFS was statistically significant(median PFS:11.87 months vs. 7.7 months,P=0.001).Cox regression analysis showed that use of PD-1 inhibitors and the location of lesions were independent influencing factors of PFS.The incidence of TRAEs in the combined chemotherapy group and chemotherapy alone group were 80.6% and 67.7%,respectively,and 5 cases(16.1%)in the combined chemotherapy group had immune-related adverse events(irAEs),and the above adverse reactions were tolerable or relieved after drug treatment,without affecting the use of chemotherapy drugs.Conclusion In the real world clinical practice,the efficacy of first-line immune checkpoint inhibitor combined with standard chemotherapy in patients with advanced ESCC is better than that of standard chemotherapy alone.No discontinuation due to immunotherapy-related adverse reactions was observed.The prognosis of patients with ESCC lesions located in the upper and middle segments is better than that of patients with ESCC lesions located in the lower segment.

Objective The aim of this study was to investigate the predictive effect of NLR, PLR and LDH on immune-related adverse events(irAEs)in advanced non-small cell lung cancer(NSCLC), and to analyze their correlation between them and survival outcomes.Methods Clinical data of 169 patients with advanced NSCLC who were treated with PD-1/PD-L1 inhibitor in Weifang People′s Hospital from January 1, 2017 to January 1, 2021 were retrospectively analyzed.These patients were divided into the irAEs group(n=61)and non-irAEs group(n=108).The clinical data of the two groups were compared.Receiver operating characteristic(ROC)curve was drawn to determine the threshold value of baseline peripheral blood parameters to predict the occurrence of irAEs.Multivariate logistic regression analysis was used to explore the relationship between peripheral blood markers and the incidence of irAEs.Cox regression model was used to analyze the influencing factors of progression-free survival(PFS)and overall survival(OS).Results The baseline peripheral blood NLR and PLR of patients in the irAEs group were lower than those in the non-irAEs group, and the LDH was higher than those in the non-irAEs group(P＜0.05).The best critical values of NLR, PLR and LDH before treatment for predicting the occurrence of irAEs were 3.18(AUC=0.80), 181.56(AUC=0.62), and 209.50(AUC=0.63), respectively.Multivariate logistic regression analysis showed that low NLR and high LDH were independent risk factors for the occurrence of irAEs(P＜0.05).The PFS and OS in low NLR, low PLR and low LDH groups were significantly better than those in the high NLR, high PLR and high LDH groups(P＜0.05).Cox regression model showed that high NLR, high PLR and high LDH were independent risk factors for PFS and OS.Conclusion NLR and LDH can predict the occurrence of irAEs in advanced NSCLC patients.High NLR, high PLR, and high LDH are associated with poor prognosis of immunotherapy for advanced NSCLC.

N6-methyladenosine(m6A)methylation is a dynamic reversible reaction under the co-regulation of methyltransferase,demethyltransferase,the m6A-specific protein-YT521-B homology(YTH)structure family,insulin-like growth factor 2(IGF2BPs)and heterogeneous nuclear ribonucleoproteins(HNRNPs).It is currently the most studied as RNA pre-transcriptional modifications.Basic and clinical studies have found that under the interaction between various modifying enzymes and tumor genes,m6A methylation modification not only affects the occurrence of tumors,but also regulates the proliferation and differentiation of cancer stem cells,thereby promoting the development and distant metastasis of malignant tumors.Therefore,further study of m6A methylation modification will help to clarify the pathogenesis of malignant tumors and further improve the treatment strategy of malignant tumors.

Endoscopic submucosal dissection(ESD)has been widely accepted as the first-line treatment for early esophageal cancer and precancerous lesions.However,large areas of esophageal lesions after ESD often cause severe esophageal stenosis,which greatly decreases the quality of life for patients.At present,there are many methods to prevent esophageal stricture after ESD,including drug prevention,mechanical expansion,tissue shielding,and regenerative medicine,which have achieved certain clinical effects.However,there are problems such as easy recurrence of strictures and complicated operation.A more effective treatment scheme for preventing stricture that is easy to be used in clinical practice needs further research.This article reviews the current research on the prevention of stenosis after ESD for early esophageal cancer.

Gastric cancer(GC)is a common malignant tumor of the digestive system,which is mainly treated by surgery.With the improvement of medical level,the survival rate of gastric cancer patients has improved compared with the past.Postoperative complications have also attracted people′s attention.Clinical practice has found that some patients with GC may develop cholecystolithiasis or cholecystitis after surgery,and some even require secondary surgery,which seriously affects the quality of patients′ life.At present,there is no unified consensus on the risk factors of cholecystolithiasis after GC surgery.The relatively clear factors include neural factors,the scope of gastrectomy,gastrointestinal hormones,gastrointestinal reconstruction and lymph node dissection.At present,there is no consensus on the prevention of cholecystolithiasis after GC surgery,especially whether preventive cholecystectomy is needed,which is also the focus of clinicians.This article reviews the risk factors of cholecystolithiasis after GC surgery and the latest preventive measures,hoping to help clinical work.

Type 2 innate lymphoid cells(ILC2s)are a kind of unique immune effectors’ cells,which play an important role in anti-infection,regulating inflammation and maintaining immune homeostasis.Recent studies have shown that ILC2s are also involved in the regulation of tumor immunity,and ILC2s have been found in the tumor microenvironment.However,the role of ILC2s in tumor immune response and immunotherapy has not been clarified.Studies have shown that ILC2s expression immune checkpoints,interleukin-33(IL-33)can activate ILC2s in the tumor microenvironment,and the inhibitory checkpoint receptor PD-1 of ILC2s expression,PD-1 blockers directly act on ILC2s,reduce the inherent PD-1 inhibition of ILC2s cells,finally increase the infiltration of CD8⁺ cytotoxic T lymphocytes(CTL)in tumor tissues,and enhances the tumor immune response.The activated tumor ILC2s can be used as the target of anti-PD-1 immunotherapy.This review will discuss the possible mechanisms of ILC2s involved in the regulation of tumor immunity and explore new targets of tumor immune checkpoint inhibitors.

Breast cancer is the malignant tumor with the highest incidence in the world,which seriously affects women′s health.As an important therapeutic target for breast cancer,human epidermal growth factor receptor 2(HER2)has improved the prognosis of these patients.In the past diagnosis and treatment process,breast cancer with low HER2 expression was classified as HER2 negative breast cancer.With the deepening research,it is found that breast cancer patients with HER2 low expression have some differences in clinicopathological and molecular biological characteristics,as well as survival prognosis,and are difficult to benefit from traditional anti-HER2 therapy.Several studies have explored the efficacy and safety of antibody-drug conjugates(ADCs)and other new drugs in breast cancer with low HER2 expression.This article will review the research progress of breast cancer with low HER2 expression.

Runt-related transcription factor 1(RUNX1),a member of the RUNX family,is one of the key regulatory proteins in vertebrates.RUNX1 is involved in embryonic development,haematopoiesis,angiogenesis,tumorigenesis and immune response.In the past decades,the research mainly focused on the mechanism of RUNX1 in acute leukaemia,and there were few reports on the role of RUNX1 in the pathological process of lung cancer.The latest research shows that RUNX1 is highly expressed in the mesenchymal and epithelial cells of the human development and postnatal lung,and is closely related to the occurrence and progression of lung cancer.This article reviews the research progress of RUNX1 in the occurrence and progress of lung cancer.

Stereotactic body radiotherapy(SBRT)is a breakthrough in radiotherapy in recent years.It has the advantages of high fractionated dose,high biological effect and less segmentation times,which can significantly improve the radiosensitivity of renal cell carcinoma.Molecular targeted therapy has greatly extended the progression-free survival and overall survival of some patients,but systemic drug resistance is inevitable in most cases.In recent years,the combination of SBRT and targeted drugs in the treatment of metastatic renal cell carcinoma has initially shown its effectiveness and safety,which may become a more effective treatment scheme.This article reviews the research progress in the treatment of metastatic renal cell carcinoma with SBRT combined with targeted drugs.