Distal margin distance in radical resection of locally advanced rectal cancer after neoadjuvant therapy

Colorectal cancer has a high incidence and mortality rate in China, with the majority of cases being middle and low rectal cancer. Surgical intervention is currently the main treatment modality for locally advanced rectal cancer, with the common goal of improving oncological outcomes while preserving function. The controversy regarding the circumferential resection margin distance in rectal cancer surgery has been resolved. With the promotion of neoadjuvant therapy concepts and advancements in technology, treatment strategies have become more diverse.Following tumor downstaging, there is an increasing trend towards extending the safe distance of distal rectal margin. This provides more opportunities for patients with low rectal cancer to preserve their anal function.However, there is currently no consensus on the specific distance of distal resection margin.

Genetic mutations associated with sensitivity to neoadjuvant chemotherapy in metastatic colon cancer:A case report and review of literature

BACKGROUND Colorectal liver metastases(CLM)occur in 15%-30%of patients with colorectal cancer(CRC).Advancements in next generation sequencing(NGS)can provide more precise prognoses for cancer patients and help guide clinical treatment.However,the genetic variants that predict high sensitivity to neoadjuvant chemotherapy remain unclear,especially in patients with CLM.The aim of this study was to identify the relevant genetic variants in a single CLM patient and to summarize the current evidence on mutations and single nucleotide polymorphisms(SNPs)that objectively predict sensitivity to neoadjuvant chemotherapy.CASE SUMMARY A 76-year-old male patient,who was diagnosed as stage IV colon cancer with liver metastases,was found to have APC/TP53/KRAS mutations.He showed a good therapeutic response to 12 courses of oxaliplatin regimens combined with Bevacizumab.Genetic analysis of the patient identified 5 genes with 7 detected SNPs that may be related to a better response to chemotherapy drugs.In addition,a critical literature review was performed based on a standardized appraisal form after selecting the articles.Ultimately,21 eligible studies were appraised to assess the association between gene mutations and good prognosis.Mutations in KRAS,TP53,SMAD4,and APC were identified as being associated with a poor response to chemotherapy drugs,whereas mutations of CREBBP and POLD1 were associated with longer overall survival.CONCLUSION NGS can identify precise predictors of response to neoadjuvant chemotherapy,leading to improved outcomes for CRC patients.

Landscape of cell heterogeneity and evolutionary trajectory in ulcerative colitis-associated colon cancer revealed by single-cell RNA sequencing

Objective:The goal of this study was to get preliminary insight on the intra-tumor heterogeneity in colitisassociated cancer(CAC)and to reveal a potential evolutionary trajectory from ulcerative colitis(UC)to CAC at the single-cell level.Methods:Fresh samples of tumor tissues and adjacent UC tissues from a CAC patient with pT3N1M0 stage cancer were examined by single-cell RNA sequencing(scRNA-seq).Data from The Cancer Genome Atlas(TCGA)and The Human Protein Atlas were used to confirm the different expression levels in normal and tumor tissues and to determine their relationships with patient prognosis.Results:Ultimately,4,777 single-cell transcriptomes(1,220 genes per cell)were examined,of which 2,250(47%)and 2,527(53%)originated from tumor and adjacent UC tissues,respectively.We defined the composition of cancer-associated stromal cells and identified six cell clusters,including myeloid,T and B cells,fibroblasts,endothelial and epithelial cells.Notable pathways and transcription factors involved in these cell clusters were analyzed and described.Moreover,the precise cellular composition and developmental trajectory from UC to UCassociated colon cancer were graphed,and it was predicted that CD74,CLCA1,and DPEP1 played a potential role in disease progression.Conclusions:scRNA-seq technology revealed intra-tumor cell heterogeneity in UC-associated colon cancer,and might provide a promising direction to identify novel potential therapeutic targets in the evolution from UC to CAC.

Biomarkers for immune checkpoint inhibitors in colorectal cancer:recent advances and future perspectives

Colorectal cancer(CRC)has become a major threat to human health.Recent years,improvements have been seen in the treatment of advanced CRC with immune checkpoint inhibitors(ICIs).Nonetheless,sensitivity to ICIs notably varies among patients,thus greatly limiting clinical applications of ICIs in CRC.Hence,the identification of biomarkers that can accurately distinguish between ICI-sensitive and drug-resistant patients is of utmost importance.Such biomarkers are essential for selecting appropriate treatment regimens and achieving precision therapy(Figure 1).The biomarkers discussed below provide insights into the advancements made in this field(Table 1).

Tumor-associated macrophages regulate gastric cancer cell invasion and metastasis through TGFβ2/NF-κB/Kindlin-2 axis

Objective: Recent studies have shown that tumor-associated macrophages(TAMs) play an important role in cancer invasion and metastasis. Our previous studies have reported that TAMs promote the invasion and metastasis of gastric cancer(GC) cells through the Kindlin-2 pathway. However, the mechanism needs to be clarified.Methods: THP-1 monocytes were induced by PMA/interleukin(IL)-4/IL-13 to establish an efficient TAM model in vitro and M2 macrophages were isolated via flow cytometry. A dual luciferase reporter system and chromatin immunoprecipitation(Ch IP) assay were used to investigate the mechanism of transforming growth factor β2(TGFβ2) regulating Kindlin-2 expression. Immunohistochemistry was used to study the relationships among TAM infiltration in human GC tissues, Kindlin-2 protein expression, clinicopathological parameters and prognosis in human GC tissues. A nude mouse oncogenesis model was used to verify the invasion and metastasis mechanisms in vivo.Results: We found that Kindlin-2 expression was upregulated at both m RNA and protein levels in GC cells cocultured with TAMs, associated with higher invasion rate. Kindlin-2 knockdown reduced the invasion rate of GC cells under coculture condition. TGFβ2 secreted by TAMs regulated the expression of Kindlin-2 through the transcription factor NF-кB. TAMs thus participated in the progression of GC through the TGFβ2/NF-κB/Kindlin-2 axis. Kindlin-2 expression and TAM infiltration were significantly positively correlated with TNM stage, and patients with high Kindlin-2 expression had significantly poorer overall survival than patients with low Kindlin-2 expression. Furthermore, Kindlin-2 promoted the invasion of GC cells in vivo.Conclusions: This study elucidates the mechanism of TAMs participating in GC cell invasion and metastasis through the TGFβ2/NF-κB/Kindlin-2 axis, providing a possibility for new treatment options and approaches.

Cancer Ig G, a potential prognostic marker, promotes colorectal cancer progression

Objective: Currently, no satisfactory targets for colorectal cancer or markers for immunotherapy and diagnosis and prognosis are available. Immunoglobulin G(Ig G) is widely expressed in many cancers, and it promotes cancer progression. This study explored the role of cancer-derived Ig G(CIg G) in colorectal cancer.Methods: First, using a monoclonal antibody to CIg G, we examined the expression levels of CIg G in colorectal cancer cell lines by western blot and immunofluorescence analyses and in tissue specimens by immunohistochemistry. Second, the variable region gene was amplified by nested polymerase chain reaction(PCR), and PCR products were sequenced and analyzed. Third, we investigated the effect of CIg G on colorectal cancer cells by cell proliferation, wound healing, migration and invasion assays, and colony formation assay. Fourth, we performed in vivo tumorigenicity experiments to explore the effect of CIg G on tumorigenicity. Finally, we used RNA-seq analysis and co-immunoprecipitation experiments to further clarify possible mechanisms of CIg G.Results: We found that CIg G is widely expressed in colorectal cancer cells, and the overexpression of CIg G indicates significantly poor colorectal cancer prognosis. Furthermore, CIg G knockdown significantly inhibits the proliferation, migration and invasion ability of cells, and tumor growth in vivo. RNA-seq analysis indicated that CIg G knockdown results primarily in changes in expression of apical junction and epithelial-mesenchymal transition-related genes. CIg G may be involved in colorectal cancer invasion and metastasis through interacting with E-cadherin.Conclusions: CIg G is a potential human oncogene in colorectal cancer and that it has potential for application as a novel target in targeted therapy and a marker for prognostic evaluation.

New insights into digestive tract tumors

Digestive tract tumors,ranging from esophageal to colorectal cancers(CRCs),pose a substantial challenge in oncology because of their high global incidence and mortality.1,2 The heterogeneity of these malignancies underscores the complexity of their etiology,which is influenced by a combination of genetic,epigenetic,and environmental factors.3 Unraveling the molecular complexities and clinical implications of these tumors is of growing importance,as they provide insights that can inform the development of more effective diagnostic,therapeutic,and preventative approaches.The Special Issue,titled“Basic research and clinical practice on gastrointestinal cancer”,aims to highlight the recent advances in molecular mechanisms and clinical research in the field of digestive tract oncology.We hope that by presenting these findings we can foster collaboration and dialog among experts in the field,ultimately leading to innovative perspectives on the diagnosis and treatment of these cancers.

Expressions of cyclin E, cyclin dependent kinase 2 and p57^(KIP2) in human gastric cancer

Objective To investigate the expressions of cyclin E, cyclin dependent kinase 2(CDK-2)and cyclin-dependent kinase inhibitor p57 KIP2 in human gastric cancer, and to evaluate the relationships between protein levels and clinicopathological parameters. Methods Western blot was used to measure the expressions of cyclin E, CDK-2 and p57 KIP2 proteins in the surgically resected gastric carcinoma, adjacent normal mucosa and metastatic lymph nodes from 36 patients. Results Cyclin E and CDK-2 protein levels were higher in gastric cancer tissues in comparison with normal tissues (P<0.05). Overexpression of cyclin E was correlated with lymph node involvement, poor histological grade and serosa invasion (P<0.05). Overexpression of CDK-2 was correlated with lymph nodes involvement (P<0.05). No statistically significant difference between cyclin E and CDK-2 expression was found when samples were stratified according to tumor size (P>0.05). Expression of cyclin E and CDK-2 showed a positive linear correlation (r=0.451, P=0.01). Protein levels of p57 KIP2 were lower in gastric cancer tissues than in the normal mucosa (P<0.05). Decreased expression of p57 KIP2 was correlated with lymph node involvement (P<0.05). No statistically significant difference in p57 KIP2 expression was found when sample were stratified according to tumor size, histological grade or serosa invasion (P>0.05). In metastatic lymph nodes, expression of cyclin E was increased and the expression of p57 KIP2 decreased. Conclusion Overexpressions of cyclin E, CDK-2 and downregulated expression of p57 KIP2 may play important roles in tumorigenesis and metastatic potential of gastric cancer.

Overexpression of N-cadherin is correlated with metastasis and worse survival in colorectal cancer patients

N-cadherin is related to the progression and metastases of several solid carcinomas.However,it was still unclear whether N-cadherin is overexpressed in colorectal malignant tumors that have stronger malignant tendency.In this study,we used immunohistochemistry to detect the expression patterns of N-cadherin in both the primary tumors and their normal mucosa tissues of 120patients with colorectal cancer.We revealed that N-cadherin was expressed in 78.3%(94/120)of colorectal tumor tissues and in only 9.2%(11/120)of paired distant normal mucosa tissues with a significant difference(P=0.000).The low,moderate,and high expression of N-cadherin protein was 42.5%,30.8%,and 26.7%,respectively.N-cadherin overexpression was associated with advanced TNM stage,lymph nodes metastasis and distant metastasis(P<0.05).Patients with N-cadherin overexpressed showed the obvious lower overall survival rate than those with moderate and low expression,and patients with low expression had a better survival rate than those with moderate and high expression(P<0.05).In conclusion,high N-cadherin expression may lead to tumor aggressiveness and metastatic potential in colorectal cancer,and may prove to be a possible prognostic factor.

Gastrointestinal Stromal Tumors with KIT Mutation Coexisting with Wild-type Gastrointestinal Stromal Tumors in a Patient with Neurofibromatosis Type 1

To the Editor： Neurofibromatosis type 1 （NFI） is one of the most common autosomal dominant inherited disorders with a prevalence of approximately 1 in 3000 individuals, Gastrointestinal stromal tumors （GISTs） are the most common mesenchymal tumors of the gastrointestinal tract. Studies have suggested that NF 1 associated GISTs （NF 1-GISTs） manifest at younger ages than sporadic GISTs.

Examined lymph node numbers influence prognosis in rectal cancer treated with neoadjuvant therapy

Background:The number of lymph nodes examined(LNe)is often insufficient in patients with rectal cancer(RC)treated with neoadjuvant therapy;however,its prognostic value remains controversial.Thus,we retrospectively explored whether LNe had an influence on staging and prognosis and investigated whether there was a cut-off value for better prognosis in patients with RC treated with neoadjuvant therapy.Methods:Data were collected from seven prospective hospital databases in China from July 2002 to May 2018.Binary logistic regression models were used to predict lymph node metastasis.The cut-off value for LNe was determined using X-tile 3.6.1.Survival outcomes and risk factors were analyzed using the log-rank test and Cox regression model.Results:A total of 482 patients were included,of whom 459 had complete overall survival(OS)information.Using the percentile method,the total number of lymph nodes examined(TLNe)was 14-16(40th-60th percentile),and the proportion of patients with lymph node metastasis reached a maximum of 48.1%.Cox multivariate analysis showed that the odds ratio(OR)remained the highest when TLNe was 14-16(OR=3.379,P=0.003).The 3-year and 5-year OS were 85.4% and 77.8%,respectively.Negative lymph nodes examined(NLNe)of≤6 was an independent risk factor for 3-year and 5-year OS(3-year OS 71.1%vs.85.9%,P=0.004;5-year OS 66.3%vs.74.3%,P=0.035).Subgroup analysis for patients with ypN+showed that higher 3-year and 5-year OS were achieved when the TLNe was>10,78.8%vs.54.0%(P=0.005),and 60.8%vs.36.0%(P=0.012),respectively.Patients with ypN0M0 had a higher 5-year OS when the TLNe was>19(P=0.055).Conclusion:The TLNe and NLNe influenced the staging accuracy and demonstrated prognostic value in patients with RC treated with neoadjuvant therapy.

Durable response to olaparib in pancreatic duct adenocarcinoma with deleterious ARID1A mutation

To the Editor:Pancreatic cancer is one of the leading causes of cancer death worldwide.The significant symptoms prompting diagnosis often appear once the tumor invades surrounding tissues or metastasizes,resulting in the late diagnosis and the infeasibility of complete resection.For the patients at advanced stage,the shortage of efficient medication for systemic therapy further limited their survival time.Olaparib,a poly(ADP-ribose)polymerase(PARP)inhibitor(PARPi),possesses several documented mechanisms of action,including the inhibition of base excision repair as well as trapping of PARP.[1]These mechanisms inhibit the repair of single-stranded break(SSB)and therefore lead to the induction of doublestranded break(DSB).Tumors with severe defect in homologous recombination-DNA damage repair(HRDDR)are ineffective in repair of DSB,which is theoretically susceptible to PARPi therapy.ARID1A,a part of the large ATP-dependent chromatin remodeling complex SNF/SWI,is required for transcriptional activation of genes normally repressed by chromatin.Both truncating mutation and loss of copy number may lead to the shortage of functional ARID1A protein,causing HR-DRR deficiency that associates with the response to PARPi.Preclinical studies showed the loss of ARID1A may sensitize cancer cells to PARPi.[2]However,no relevant trial or case report of pancreatic ductal adenocarcinoma(PDAC)was published to date.Here we present the report of a PDAC patient with deleterious ARID1A mutation(p.Q1327*)who remained response to olaparib-based therapy for more than 13.0 months.