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Objective: To explore the predictive value of nomogram (Nomogram) prediction model based on clinicopathological features and dynamic contrast-enhanced magnetic resonance imaging (MRI) parameters for microsatellite instability in colorectal cancer (CRC). Methods: 335 CRC patients underwent dynamic contrast-enhanced MRI before operation, who were divided into microsatellite stable group (n=243) and microsatellite unstable group (n=92) according to the test results. The influencing factors of microsatellite insta- bility in CRC patients were analyzed by univariate and multivariate Logistic regression analysis. Nomogram prediction model of microsatellite instability in CRC patients was constructed. The predictive efficacy of the Nomogram prediction model for microsatellite instability in CRC patients were evaluated by receiver operating characteristic (ROC) curve. Results: The volume transfer constant (Ktrans), rate constant (Kep) and area under the initial enhancement curve (iAUC) in microsatellite instability group were lower than those in microsatellite stability group, the proportion of moderate/low differentiation, cancer nodules and lymph node metastasis in microsatellite instability group were higher than those in microsatellite stability group (P<0.05). Elevated Ktrans, Kep, and iAUC were protective factors for microsatellite instability in CRC patients, moderate/low differentiation, cancer nodules, and lymph node metastasis were risk factors for microsatellite instability in CRC patients (P<0.05). The prediction curve of the Nomogram prediction model was in good agreement with the ideal curve, ROC curve analysis showed that, the area under the curve (AUC) of the model for predicting microsatellite instability in CRC patients was 0.938. Conclusion: The increase of Ktrans, Kep and iAUC are all protective factor for microsatellite instability in CRC patients, moderate/low differentiation, cancer nodules and lymph node metastasis are risk factors for microsatellite instability in CRC patients, the Nomogram prediction model based on the above influencing factors has a high predictive value for microsatellite instability in CRC patients. [ABSTRACT FROM AUTHOR]

Objective To analyze their molecular characteristics of microsatellite instability (MSI) by sequencing colorectal cancer patients in Sichuan region. Methods Next generation sequencing (NGS) was used to test 14 239 colon cancer patients from 2017 to 2022 in the Third People's Hospital of Chengdu for single nucleotide variation (SNV), insertion-deletion (InDel), copy number variation (CNV), fusion, MSI, tumor mutational burden (TMB), and Epstein-Barr virus (EBV). The clinical and molecular characteristics of highly microsatellite unstable (MSI-H) patients (MSI-H group, n=1 018) and microsatellite stable (MSS) patients (MSS group, n=13 221) were compared. Results The incidence rate of MSI in colorectal cancer was 7.15%, and detection rate of MSI varied in terms of age at diagnosis, tumour location and sample type. TMB was significantly higher in patients with MSI-H than in patients with microsatellite stable (MSS) (92.8 mutations/Mb vs 12.7 mutations/Mb, P＜0.05). EBV positivity in patients with colorectal cancer was 0.43%, but no patient with positive EBV was found in MSI-H. ERBB2, PIK3CA and BRAF all had significantly higher mutation frequencies in the MSI-H group, however, the positive rates of APC (51.26% vs 70.76%, χ2=168.823, P

The occurrence and development of gastric cancer (GC) is determined by many factors. In recent years, the development of molecular biology has provided new ideas for the diagnosis and treatment of GC. Microsatellite instability (MSI) GC is a special type of GC caused by the body 's DNA mismatch repair (MMR) gene defect. Studies of the clinical characteristics, molecular mechanisms and prognosis of MSI GC found specific clinicopathological features and better prognosis in MSI GC compared with ordinary types of GC. However, there are still some controversies in the study of MSI gastric cancer at home and abroad. This article aims to review the concept of MSI, the relationship between MSI and clinicopathological features of gastric cancer, and the treatment progress of MSI gastric cancer.

Objective To investigate the expression and significance of secretory carrier membrane protein 2 (SCAMP2) in colorectal cancer (CRC). Methods Paraffin tissue samples and clinicopathological data were collected from 309 patients with primary CRC who were treated in The Affiliated Hospital of Qingdao University from January 2014 to August 2016, and immunohistochemistry was used to measure the expression level of SCAMP2 in CRC tissue and adjacent tissue. Results SCAMP2 showed a low expression level in CRC tissue and a high expression level in adjacent tissue, and there was a significant difference in the expression level of SCAMP2 between CRC tissue and adjacent tissue (t=5.042,P

Objective To analyze the relationships of T-box transcription factor 19 (TBX19) expression levels in pan-cancer tissues with patients' prognosis and the tumor immune microenvironment (immune cell infiltration, immune checkpoint genes, tumor mutation burden, and microsatellite instability) based on database data. Methods TBX19 expression levels in the pan-cancer tissues and corresponding normal tissues were obtained from The Cancer Genome Atlas (TCGA) database, and the TBX19 expression levels were compared in the pan-cancer tissues of patients with different WHO grades and TNM stages. Using Cox regression to analyze the relationship between TBX19 expression levels and the prognosis of tumor patients. The correlation between TBX19 expression levels and the abundance of immune cell infiltration was analyzed by Pearson method based on data from the Tumor Immune Estimation Resource (TIMER2). Correlations of TBX19 expression levels with immune scores, tumor mutation burden and microsatellite instability were analyzed by Pearson method using TCGA database in the Sanger Box website. Based on the Clinical Biosense House database data, the correlations between TBX19 expression levels and immune checkpoint genes were analyzed by the Spearman method. Re⁃ sults TBX19 was highly expressed in bladder urothelial carcinoma, cholangiocarcinoma, colon adenocarcinoma (CO‑AD), colorectal carcinoma (COADREAD), esophageal carcinoma, head and neck squamous cell carcinoma, renal clear cell carcinoma, renal papillary cell carcinoma, pan-kidney cohort, hepatocellular carcinoma (LIHC), lung adenocarcinoma, lung squamous cell carcinoma, pheochromocytoma and paraganglioma, rectum adenocarcinoma, gastric carcinoma, and stomach and esophageal carcinoma tissues (all P<0. 05), and was low expressed in breast invasive carcinoma, kidney chromophobe cell tumor, prostate adenocarcinoma, and endometrial carcinoma tissues (all P<0. 05). There were statistically significant differences in the TBX19 expression in COAD and COADREAD cancer tissues with different WHO grades as well as different TNM stages (all P<0. 05). Compared the tissues with low TBX19 expression, those with high TBX19 expression in LIHC cancer tissues had shorter overall survival, disease-specific survival, disease-free interval, and progression-free interval (all P<0. 05). In the COAD, KIRC, LIHC and other cancer tissues, TBX19 expression was closely associated with immune cell infiltration, immune checkpoint genes, tumor mutation burden, and microsatellite instability (all P<0. 05). Conclusions TBX19 expression levels in the pan-cancer tissues are predominantly elevated, and those with high TBX19 expression have poorer prognosis. High TBX19 expression in cancer tissues is associated with the tumor immune microenvironment, including elevated levels of immune infiltration, increased tumor mutation burden, and increased microsatellite instability in diverse tumors. [ABSTRACT FROM AUTHOR]

Background and purpose: Lynch syndrome associated endometrial carcinoma has unique clinicopathological features and treatment methods. The detection of mismatch repair (MMR) protein expression by immunohistochemical (IHC) staining in patients with newly diagnosed endometrial cancer can effectively screen patients with Lynch syndrome associated cancer. This study investigated the expression of mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2) in endometrioid adenocarcinoma and its relationship with clinicopathological features. Methods: A total of 515 cases of endometrioid adenocarcinoma were collected from Shengjing Hospital of China Medical University from January 2018 to August 2020.The patients were 28 to 81 (57.73 ± 8.41) years old. IHC method was used to detect the protein expressions of MLH1, MSH2, MSH6 and PMS2 in cancer tissues. Polymerase chain reaction (PCR) was used to detect the gene methylation of MLH1 protein expression deficient specimens, and the relationship between MMR protein expression deletion and clinicopathological features of endometrioid adenocarcinoma was analyzed. As long as there was a loss of MMR protein expression, it was judged as deficient mismatch repair (dMMR). If all MMR proteins were positive, it was judged as proficient mismatch repair (pMMR). Results: MMR protein was absent in 138 (26.8%) of 515 cases of endometrioid adenocarcinoma. The deletion rates of MLH1, PMS2, MSH2 and MSH6 proteins were 16.3% (84/515), 19.0% (98/515), 5.4% (28/515) and 8.0% (41/515), respectively. The loss of MMR protein expression was mainly the combined loss of MLH1 and PMS2 expressions (60.9%, 84/138), and the second was the combined deletion of MSH2 and MSH6 expressions (18.8%, 26/138). There were 2 cases of combined deletion of MSH2, MSH6 and PMS2 expressions (1.4%, 2/138). The single deletion rates of PMS2, MSH2 and MSH6 proteins were 8.0% (11/138), 1.4% (2/138) and 10.1% (14/138), respectively. MLH1 protein expression deletion was detected in 27 samples, and the results showed that the methylation positive rate was 85.2% (23/27). The loss of MMR protein expression in 515 cases of endometrioid adenocarcinoma was correlated with the age of onset, the International Federation of Gynecology and Obstetrics (FIGO) stage, the degree of histological differentiation, depth of invasion, vascular metastasis, nerve invasion, lymph node metastasis, abnormal expression of p53, tumor infiltrating lymphocytes and tumor with peritumoral lymphocyte infiltration. MMR protein status was not correlated with lower uterine segment involvement. Compared with pMMR patients, the onset age of dMMR was younger, and FIGO stage was mostly stage Ⅲ-Ⅳ. The histological differentiation degree was mostly low, most tumors had no myometrial infiltration, and most tumors had vascular metastasis, nerve invasion and lymph node metastasis. The lymphocyte infiltration in the tumor with dMMR was increased, and the tumor with peritumoral lymphocyte was more significant. Most patients with MSH6 protein deficiency had no abnormal expression of p53. Conclusion: Compared with pMMR patients, dMMR patients in Northeast China has unique clinicopathological characteristics. Detecting the expression of MMR protein by immunohistochemical staining and detection of the gene methylation of MLH1 expression deficient specimens can preliminarily screen patients with Lynch syndrome, which has certain guiding significance for immunotherapy of tumor patients.

Background and purpose: Microsatellite instability (MSI) and mismatch repair (MMR) defects have attracted much attention recently as one of the important biomarkers for pan-tumor immunotherapy such as colorectal cancer (CRC). Conventional methods for MSI detection with polymerase chain reaction (PCR) often require non-tumor controls as well as a long turnaround time. The IdyllaTM system as a fully automated quantitative PCR unit with a turnaround time of only 2.5 h should be proved for its reliability among Chinese CRC patients before application. Methods: Formalin-fixed paraffin-embedded (FFPE) tissue samples were collected from 87 CRC patients in Fudan University Shanghai Cancer Center from March 2017 to March 2019 and were subjected to detect MMR protein expression and MSI using immunochemistry (IHC), conventional PCR (Promega MSI analysis) and the IdyllaTM MSI system, respectively. Results: Of the 87 CRC patients enrolled, 56 cases were identified to be deficient MMR (dMMR)/MSI-high (MSI-H) and 31 to be proficient MMR (pMMR)/microsatellite stable (MSS) by both IHC and Promega MSI analysis. However, 4 cases with dMMR/MSI-H were determined to be MSS and one case with pMMR/MSS to be MSI-H using IdyllaTM MSI system, yielding a sensitivity of 92.9% (52/56), specificity of 96.8% (30/31) and an overall concordance of 94.3% (82/87). Then, the above five discordant cases were re-examined using IdyllaTM with resection tissues, as a result, four cases with ≥20% tumor contents changed to be consistent with IHC/Promega MSI assay, however, there was still one inconsistent case with only 5% tumor content. Subsequently, the case was reconfirmed using IdyllaTM with enriched tumor tissue by macrodissection, as expected, the result was demonstrated to be MSI-H, consistent with Promega MSI analysis and IHC. Furthermore, repeatability of the IdyllaTM MSI assay was proved to be reliable in 5 cases with various tumor contents (20%-60%). Conclusion: The IdyllaTM MSI system provides a fast, reliable and fully automated solution to MSI detection in Chinese CRC patients with high sensitivity, specificity and reproducibility, especially for CRC with more than 20% tumor contents.

In recent years, the incidence of endometrial cancer (EC) has been on the rise, and the traditional pathological tissue typing cannot accurately guide the individual treatment and evaluate the prognosis of patients. The molecular typing of EC based on molecular biology technology came into being. This molecular typing has an important guiding role in postoperative chemoradiotherapy, immunotherapy and targeted therapy for EC patients. The microsatellite instability (MSI) type of EC is one of the molecular types of The Cancer Genome Atlas (TCGA). MSI type of EC has unique clinical and pathological features. In addition, it is different from other types of EC in terms of treatment and prognosis. Molecular classification has been integrated into the Guideline from European Society of Gynaecological Oncology. Recent studies have shown that the patients with MSI type of EC do not get more benefit from chemotherapy, but they can get benefits from immunotherapy. The immune therapy combined with anti-angiogenesis drugs therapy has been recommended for those patients. However, there are still some controversy on the pathological characteristics, prognosis and therapy of MSI type of EC. Several therapy protocols of the combined drugs are still under study. It is true that the individualized treatment according to the molecular classification of EC will be the research focus. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether the immunohistochemical results of two markers PMS2 and MSH6 (2-MMR) could replace the four markers MLH1, PMS2, MSH2 and MSH6 (4-MMR) to detect mismatch repair deficient (dMMR) cancers. Methods: A retrospective analysis was conducted with summary of immunohistochemical data from 7 867 cases of gastric cancer, colorectal cancer, endometrial cancer, and other diseases in the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China, from March 2018 to March 2023. The consistency of 2-MMR and 4-MMR results was examined. Microsatellite instability (MSI) and next-generation sequencing (NGS) were performed in patients with specific phenotypes. Results: The Cohen κ values of 2-MMR and 4-MMR in gastric cancer, colorectal cancer, endometrial cancer and other diseases were 0.88, 0.99, 0.88 and 1.00, respectively. The overall consistency, sensitivity and specificity were 0.97, 99.6%, and 100.0%, respectively. Both 2-MMR and 4-MMR could detect the difference between various clinicopathological features. 24 (0.3%) of the 7 867 patients were found to have a special phenotype of MMR, and 6 of them were selected for MSI and NGS molecular testing. MSI analysis showed MSI-H in all cases, while NGS found that 5 of them had MMR-related gene mutations and 1 had POLE p.S297F mutation. Conclusions: Compared with 4-MMR, 2-MMR has high consistency, specificity and sensitivity. The cases with special phenotype only account for extremely low proportion. Therefore, 4-MMR may be replaced with 2-MMR in dMMR screening.

Objective: To analyze the clinical significance of molecular classification and hereditary phenotype in endometrial carcinoma (EC) based on high throughput sequencing (NGS). Methods: 97 EC samples were collected retrospectively from December 2019 to October 2022 in China-Japan Friendship Hospital. NGS technique was used to analyze the molecular classification, POLE hypermutation, microsatellite high Instability/mismatch repair dysfunction (MSI-H/MMRd), P53 protein abnormality (P53 abn), and non-specific molecular profile (NSMP). Lynch syndrome related genes and BRCA1/2 genes were detected by NGS and their genetic characteristics were analyzed. Results: Of the 97 EC cases, 77 were endometrial adenocarcinoma and 20 were other pathological subtypes. The proportions of the four molecular subtypes were 9.3% (9/97) POLE hypermutation, 16.5% (16/97) MSI-H, 17.5% (17/97) P53 abn and 56.7% (55/97) NSMP, respectively. There were significant differences in age, histological type, lymph node metastasis, pathological stage and other parameters among the four molecular types ( P ＜0.05). 8.2% (8/97) were multiple molecular typing and four multiple molecular typings detected, including POLEmut-MSI-H, POLEmut-P53abn, MSI-H-P53abn, P53abn-P53abn, which accounted for 1.0% (1/97), 3.1% (3/97), 1.0% (1/97) and 3.1% (3/97), respectively. The consistent rate of MSI-H and MMR protein expression was 92.9% ( Kappa =0.818, P ＜0.001). The coincidence rate between TP53 gene sequencing and P53 protein expression was 88.9% ( Kappa =0.661, P ＜0.001). In MSI-H type, 25.0% (4/16) were diagnosed as Lynch syndrome, and 75.0% (12/16) were diagnosed as Lynch like syndrome. 7.2% (7/97) BRCA2 somatic variation was detected, while BRCA1/2 germline variation was not detected in 97 cases. Conclusions: EC molecular classification has feasibility and clinical value. High throughput sequencing can detect low frequency mutations of TP53 gene, suggesting that it can provide more accurate molecular information and more accurate molecular typing effect. It is suggested to further detect Lynch syndrome related genes in patients with MSI-H, so as to carry out genetic management for patients and their families and achieve better therapeutic effect.

BackgroundThe role of microsatellite instability in the progression of endometrial cancer, a common cancer in women, has obtained increasing attentions in recent years. However, there are few studies regarding the association of microsatellite instability with clinicopathologic features and prognosis in patients with endometrial cancer.ObjectiveTo investigate the microsatellite instability and its clinical significance in patients with endometrial carcinoma.MethodsA total of 248 endometrial cancer patients who underwent surgery in Shiyan People's Hospital Affiliated to Hubei University of Medicine from January 2015 to December 2020 were selected. Their cancer tissue specimens were collected to detect the expression of MLH1, MSH2, MSH6 and PMS2 by immunohistochemistry. Relations of microsatellite instability with clinicopathologic features and prognosis were analyzed.ResultsThe rates of lost expression of MLH1, MSH2, MSH6 and PMS2 were 32.6% (78/239) , 22.2% (53/239) , 2.9% (7/239) and 65.7% (157/239) , respectively, in patients with endometrioid adenocarcinoma. For those with endometrial squamous cell carcinoma, the rates of lost expression of MLH1, MSH2, MSH6 and PMS2 were 5/5, 3/5, 5/5 and 4/5, respectively. And rates of lost expression of MLH1, MSH2, MSH6 and PMS2 were 4/4, 2/4, 3/4, and 2/4, respectively, in those with endometrial clear cell carcinoma. The rates of lost expression of MLH1, MSH2, MSH6 and PMS2 varied significantly by the pathological pattern of endometrial carcinoma (P0.05) . There were no significant differences of Kaplan-Meier curves for overall survival and disease-free survival in endometrial cancer patients with MSI-H, MSI-L and MSS (P>0.05) . Cox proportional hazards regression analysis results showed that the expression of mismatch repair protein was not the independent influencing factor for disease-free survival (P>0.05) , but for overall survival (P

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Copyright of China Oncology is the property of Editorial Board of China Oncology and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objective To investigate the effect of microsatellite status on peripheral blood lymphocyte subsets in patients with colorectal cancer (CRC) . Methods 825patients with CRC treated in the hospital from January 2019to December 2020were selected and divided into microsatellite highly unstable (MSI-H) group (90cases) and microsatellite stable/microsatellite low unstable (MSS/MSI-L) group (735cases) according to microsatellite status. The clinicopathological features and the level of peripheral blood lymphocyte subsets were compared between the two groups. Results There were significant differences between the two groups in age, sex, tumor location, tumor pathological type, degree of tumor differentiation, tumor TNM stage and the number of lymph nodes (P<0. 05), but there were no significant differences in the levels of carbohydrate antigen 19-9and carcinoembryonic antigen (P>0. 05) . There were significant differences in the levels of CD3+T, CD4+T and CD8+T cells in peripheral blood between the two groups (P<0. 05) . There were no significant differences in the values of CD4+/CD8+and the levels of natural killer cells and natural killer T cells (P>0. 05) . Conclusion The preoperative level of T lymphocyte subsets in peripheral blood of CRC patients with MSI-H is higher than that of MSS/MSI-L patients. The level of T lymphocyte subsets in peripheral blood can be used as a prognostic index of CRC patients with MSI-H. [ABSTRACT FROM AUTHOR]

Recurrent ormetastatic gynecologic tumors are usually resistant to conventional cancertherapies.Immunotherapy such as PD-1/PD-L1 blocking antibodies has revolutionized the treatment strategy, and even achieved unprecedentedly long durations of response in advanced malignancies including gynecologic tumors. Nevertheless, immunotherapy has met a bottleneck that the majority of patients do not have a good response to PD-1/PD-L1 blocking antibodies due to primary or acquired drug resistance, and the mechanisms are currently poorly understood. Currently, several hot issues are emphasized in clinical practice. First, the benefits of PD-1/PD-L1 blocking antibodies in the overall population are still very low. Therefore, it is a new trend that combination therapies with other agents are administrated to improve the antitumor efficacy. Second, the most widely investigated predictive biomarkers for immunotherapy are sufficiently validated for clinical use. There is an urgent need to identify biomarkers that upfront predict whether a patient is likely to respond to immunotherapy. Third, both hyperprogression and pseudo-hyperprogression pose challenges for immunotherapy, therefore it is important to assess how and when to evaluate the treatment efficacy. At the same time, how to evaluate and manage immune-related adverse events is an urgent focus of future research as well. [ABSTRACT FROM AUTHOR]

Familial adenomatous polyposis and Lynch syndrome represent two different molecular pathways of colorectal carcinogenesis that are commonly considered mutually exclusive: chromosomal instability and microsatellite instability. Here, we report a rare case of familial adenomatous polyposis in an adult male with Lynch-like syndrome. A 46-year-old male patient was found to have hundreds of adenomatous polyps throughout the whole intestine, and irregular masses in rectum, sigmoid and transverse colon. Genetic test showed that the patient carried pathogenic germline APC (c.423-1G>A) variant and two variants of uncertain significance in MLH1 (p.R725H) and PTCH1 (p.S438N), combined with tumor characteristics of somatic AKT1/PIK3CA/KRAS co-mutations, microsatellite instability and high tumor mutation burden. The patient underwent laparoscopic total colectomy with abdominoperineal resection and end ileostomy, then received 4 cycles adjuvant chemotherapy of oxaliplatin with capecitabine. This patient was followed up to April 2024 and performed well without abnormalities in serum cancer biomarkers and radiological examinations.

Women with Lynch syndrome have a life-long risk of endometrial cancer and ovarian cancer. Endometrial cancer or ovarian cancer can be the first malignant tumor or the second primary malignant tumor in patients with Lynch syndrome. The main type of endometrial cancer associated with Lynch syndrome is endometrioid adenocarcinoma. In recent years, there have been few screening studies on endometrial cancer and ovarian cancer related to Lynch syndrome, mainly through outpatient endometrial biopsy, microsatellite high instability (MSI-H) status or MMR protein mutation and genetic testing to identify precancerous lesions and early cancers. In terms of prevention, oral contraceptives and preventive surgery removing the uterus and ovaries are used. Women with Lynch syndrome have a 40%～60% lifetime risk of endometrial cancer, and a 4%～24% lifetime risk of ovarian cancer. Therefore, it is of great significance for women with Lynch syndrome to have early screening and prevention of endometrial cancer and ovarian cancer. [ABSTRACT FROM AUTHOR]

Objective: To analyze the lympho-vascular space invasion (LVSI) in different molecular subtypes of the cancer genome atlas (TCGA) molecular subtypes of endometrial cancer (EC) and to evaluate the prognostic value of LVSI in EC patients with different molecular subtypes. Methods: A total of 258 patients diagnosed EC undergoing surgery in Peking University People's Hospital from January 2016 to June 2022 were analyzed retrospectively. Among 258 patients, 14 cases were classified as POLE-ultramutated subtype, 43 as high-microsatellite instability (MSI-H) subtype, 155 as copy-number low (CNL) subtype, and 46 as copy-number high (CNH) subtype. Fifty-four patients were positive for LVSI, while 203 tested negative. Results: (1) The incidence of LVSI was found to be highest in the CNH subtype (32.6%,15/46), followed by the MSI-H subtype (27.9%, 12/43), the CNL subtype (16.9%, 26/154), and the POLE-ultramutated subtype (1/14), with statistically significant differences ( χ 2 =7.79, P =0.044). (2) Staging and deep myometrial invasion were higher in the LVSI positive group than those in the LVSI negative group (all P <0.05), except for the POLE-ultramutated subtype. The grade, lymph node metastasis, and the expression of nuclear antigen associated with cell proliferation (Ki-67) were significantly higher in LVSI positive patients than those in LVSI negative EC patients with both MSI-H and CNL subtypes (all P <0.05). In CNL subtypes patients, LVSI was also associated with age, histology subtype,and progesterone receptor (PR; all P <0.05). (3) Of the 257 EC patients, 25 cases recurred during the follow-up period, with a recurrence rate of 9.7% (25/257); among them, the recurrence rate of LVSI positive patients was 22.2% (12/54), which was significantly higher than those with LVSI negative (6.4%, 13/203; χ 2 =12.15, P <0.001). During the follow-up period, none of the 14 patients with POLE-ultramutated had recurrence; among CNL patients, the recurrence rate was 19.2% (5/26) in LVSI positive patients, which was significantly higher than that in LVSI negative ones (5.5%, 7/128; χ 2 =3.94, P =0.047); where as no difference were found in both MSI-H [recurrence rates in LVSI positive and negative patients were 2/12 and 9.7% (3/31), respectively] and CNH subtype [recurrence rates between LVSI positive and negative patients were 5/15 and 9.7% (3/31), respectively] EC patients (both P >0.05). After log-rank test, the 3-year recurrence free survival (RFS) rate were significantly lower in LVSI positive patients from CNL subtype and CNH subtype than those in LVSI negative patients (CNL: 80.8% vs 94.5%; CNH: 66.7% vs 90.3%; both P <0.05). (4) Lymph node metastasis ( HR =6.93, 95% CI : 1.15-41.65; P =0.034) had a significant effect on the 3-year RFS rate of EC patients with MSI-H subtype. Multivariate analysis revealed that PR expression ( HR =0.04, 95% CI : 0.01-0.14; P <0.001) was significantly associated with the 3-year RFS rate of CNL subtype patients. Conclusions: LVSI has the highest positivity rate in CNH subtype, followed by MSI-H subtype, CNL subtype, and the lowest positivity rate in POLE-ultramutated subtype. LVSI is significantly associated with poor prognosis in CNL subtype patients and may affect the prognosis of CNH subtype patients. However, LVSI is not an independent risk factor for recurrence across all four TCGA molecular subtypes.

In recent years, immune checkpoint inhibitors (ICIs) have been widely used in malignant solid tumors with remarkable efficacy. However, in colorectal cancer (CRC), ICIs have shown significant therapeutic effects only in patients with highly microsatellite unstable/mismatch repair-deficient metastatic CRC and these patients are only a minority of all CRC patients. In contrast, the majority of patients, those with microsatellite stable (MSS)/mismatch repair-complete (pMMR)-type metastatic CRC, could hardly benefit from ICI monotherapies, and immune combination therapies have become the key to solveing this clinical challenge. This article introduces the common patterns and possible mechanisms of immune-combination therapies for MSS/pMMR-type CRC, the exploration and progress made in the application of immune-combination therapies, as well as the possible predictive markers of efficacy of immune therapies. The prospects and directions of ICIs in the treatment of MSS/pMMR-type CRC are also discussed.

The surgical treatment of colorectal cancer will be more and more accurate and minimally invasive under the guidance of precision medicine. At the same time, it will derive and evolve non-surgical paths, such as immune checkpoint inhibitors and immune targeted therapy for microsatellite instability high/mismatch repair deficient colorectal cancer, and wait and watch path after neoadjuvant treatment for low advanced rectal cancer. Laparoscopic minimally invasive surgery for colorectal cancer will be gradually iterated by robots, which is the only way to intelligent surgery.

Objective To explore the effect of Survivin 31G/C polymorphism on microsatellite instability (MSI), chem other apy sensitivity and clinical prognosis in patients with colorectal cancer (CRC) . Methods 158 CRC patients who had undergone Survivin 31G/C genotyping and used oxaliplatin as the main chemotherapy drug were selected as the research subjects. The genotyping results were 64 cases with CC genotype, 61 cases with GC genotype and 33 cases with GG genotype. Immunohistochemistry (IHC) was used to analyze the MSI status among patients with three different genotypes, and to follow up the patients' treatment effect and recurrence and metastasis. Results The MSI H phenotype of patients with GG genotype was significantly higher than that of CC and GC genotypes. Patients with CC genotype had a significantly lower sensitivity to chemotherapy than patients with GG geno type, had shorter survival time than GG genotype, and had a higher risk of recurrence or metastasis than patients with GG geno type. Conclusion The polymorphism of Survivin 31G/C may affect the MSI phenotype, chemotherapy senstivity and clinical prognosis of CRC,and its locus genotype analysis can be used as one of the methods to judge the prognosis of CRC patients. [ABSTRACT FROM AUTHOR]

Microsatellite instability (MSI) is caused by the loss of functions of DNA mismatch repair (MMR) proteins. This molecular's characteristics is recognized as an important genetic marker which has important clinical significance in the screening，classification， diagnosis， treatment and prognosis for colorectal cancer. This review will discuss MSI status and MSI-related colorectal cancer types (hereditary and sporadic tumors)，focusing on the update knowledge of the molecular techniques used for the determination of MMR and MSI status and the immunotherapy used for immune checkpoint inhibitors (ICPIs). [ABSTRACT FROM AUTHOR]

Neoadjuvant therapy for locally advanced colorectal cancer has made great progress in the past 20 years, but there are still limitations such as side effects, organ dysfunction and unsatisfactory control of metastasis. In recent years, with the improvement of surgical techniques and further development of molecular research, how to further improve local control, reduce distant metastasis, and even avoid surgery according to clinical remission to achieve organ preservation, is the current demand and research goal. With the advancement of molecular research, colorectal cancer has different treatment strategies based on microsatellite status. For patients with microsatellite instability locally advanced colorectal cancer, immune checkpoint inhibitor therapy significantly increased the pathologic complete response rate, reduced the incidence of adverse events and improved organ function compared with conventional chemoradiotherapy. For patients with microsatellite stable locally advanced colon cancer, neoadjuvant therapy is still in the exploratory stage. The standard of care is surgery combined with perioperative chemotherapy. For microsatellite stable locally advanced rectal cancer, the complete response rate is improved by enhancing neoadjuvant therapy, which helps to preserve organs. On the other hand, selective radiotherapy preserves organ function and improves quality of life. This article reviews the neoadjuvant treatment strategies for locally advanced colorectal cancer based on organ-sparing strategies.

Neoadjuvant immunotherapy has achieved exciting efficacy with high clinical complete response (cCR) and pathologic complete response (pCR) rates and durable long-term effects. PD-1 checkpoint blockade-based immunotherapy has been highly successful in microsatellite instability high (MSI-H)/mismatch repair deficiency (dMMR) colorectal cancer and has been recommended as the first-line treatment for metastatic colorectal cancer by domestic and international guidelines. Several studies have shown that immunotherapy can be a potentially curable treatment for MSI-H rectal cancer and has even shown promise in organ preservation in colon cancer. In this study, we first clarified the feasibility of the watch-and-wait strategy after PD-1 checkpoint blockade treatment by indirect and direct evidence. Then from the assessment tools (including digital rectal examination, endoscopy, radiology, and lymph node assessment), the viable assessment methods of cCR for immunotherapy and related difficulties are proposed. Finally, the medication choices of immunotherapy, the treatment regimen, and the follow-up strategy are further discussed. We hope that neoadjuvant immunotherapy could be appropriately applied in MSI-H/dMMR colorectal cancer so that more patients can achieve organ preservation.

Objective To investigate the expressions of CD8, CD68, PD-1 and PD-L1 in microsatellite stability/instability (MSS/MSI) gastric cancer and the prognostic value of microsatellite stability. Methods Sixty consecutive primary gastric cancer samples were collected from March 2012 to August 2012. The clinical pathological and survival information was collected as well. Immunohistochemistry of MLH1, MSH2, MSH6, PMS2, CD8, CD68, PD-1 and PD-L1 was conducted for each sample. The survival prognosis was analyzed by log-rank test. Results There were 15 MSI gastric cancer samples (25.0%) with negative staining of MLH1, MSH2, MSH6 and PMS2. There was no significant difference in the expression of CD8, PD-1 or PD-L1 between MSS and MSI gastric cancer, but the CD68 positive macrophages infiltration was higher in MSS than in MSI gastric cancer (P=0.046). Type II (CD8-PD-L1-) was the major immune type (46.67%) in MSI gastric cancer, and the main immune type of MSS gastric cancer was type II (33.33%) and type IV (CD8+PD-L1- , 31.11%). The disease-free survival (P =0.036) and overall survival (P =0.041) in MSI gastric cancer was longer than in MSS. Conclusion MSI gastric cancer predicts a better prognosis although the tumor microenvironment shows a lower immune response. [ABSTRACT FROM AUTHOR]

Ｍｉｃｒｏｓａｔｅｌｌｉｔｅ ｉｎｓｔａｂｉｌｉｔｙ （ＭＳＩ） ｗｈｉｃｈ ｒｅｓｕｌｔｅｄ ｆｒｏｍ ｔｈｅ ｄｅｆｉｃｉｅｎｃｙ ｏｆ ＤＮＡ ｍｉｓｍａｔｃｈ ｒｅｐａｉｒ （ＭＭＲ）， ｉｓ ａｎ ｉｍｐｏｒｔａｎｔ ｃｌｉｎｉｃａｌ ｓｉｇｎｉｆｉｃａｎｃｅ ｉｎ ｔｈｅ ｒｅｌａｔｅｄ ｓｏｌｉｄ ｔｕｍｏｒｓ， ｓｕｃｈ ａｓ ｃｏｌｏｒｅｃｔａｌ ｃａｎｃｅｒ ａｎｄ ｅｎｄｏｍｅｔｒｉａｌ ｃａｎｃｅｒ． Ｔｈｅｒｅ ａｒｅ ｓｅｖｅｒａｌ ｍｅｔｈｏｄｓ ｔｏ ｄｅｔｅｃｔ ＭＳＩ ｓｔａｔｕｓ， ｉｎｃｌｕｄｉｎｇ ｉｍｍｕｎｏｈｉｓｔｏｃｈｅｍｉｓｔｒｙ ｆｏｒ ＭＭＲ ｐｒｏｔｅｉｎ， ｍｕｌｔｉｐｌｅｘ ｆｌｕｏｒｅｓｃｅｎｔ ｐｏｌｙｍｅｒａｓｅ ｃｈａｉｎ ｒｅａｃｔｉｏｎ （ ＰＣＲ） ｆｏｒ ｍｉｃｒｏｓａｔｅｌｌｉｔｅ ｓｉｔｅ ａｎｄ ＭＳＩ ａｌｇｏｒｉｔｈｍ ｂａｓｅｄ ｏｎ ｎｅｘｔ ｇｅｎｅｒａｔｉｏｎ ｓｅｑｕｅｎｃｉｎｇ （ＮＧＳ）． Ｔｈｅ ｃｏｎｓｅｎｓｕｓ ｅｌａｂｏｒａｔｅｓ ｔｈｅ ｄｅｆｉｎｉｔｉｏｎ ａｎｄ ｃｌｉｎｉｃａｌ ｓｉｇｎｉｆｉｃａｎｃｅ ｏｆ ＭＳＩ ａｓ ｗｅｌｌ ａｓ ｔｈｅ ａｄｖａｎｔａｇｅｓ ａｎｄ ｄｉｓａｄｖａｎｔａｇｅｓ ｏｆ ｔｈｅ ｔｈｒｅｅ ｄｅｔｅｃｔｉｏｎ ｍｅｔｈｏｄｓ． Ｔｈｒｏｕｇｈ ｔｈｉｓ ｅｘｐｅｒｔ ｃｏｎｓｅｎｓｕｓ， ｗｅ ｈｏｐｅ ｔｏ ｐｒｏｍｏｔｅ ｔｈｅ ｓｃｒｅｅｎｉｎｇ ｗｈｉｃｈ ｂａｓｅｄ ｏｎ ＭＳＩ ｓｔａｔｕｓ ｉｎ ｍａｌｉｇｎａｎｔ ｔｕｍｏｒｓ ａｎｄ ｉｍｐｒｏｖｅ ｔｈｅ ａｃｋｎｏｗｌｅｄｇｅ ｏｆ ｃｌｉｎｉｃｉａｎｓ ａｂｏｕｔ ｖａｒｉｏｕｓ ｔｅｓｔｉｎｇ ｍｅｔｈｏｄｓ． Ｔｈｅｒｅｂｙ， ｔｈｅｙ ｃｏｕｌｄ ｉｎｔｅｒｐｒｅｔ ｔｈｅ ｒｅｓｕｌｔｓ ｍｏｒｅ ａｃｃｕｒａｔｅｌｙ ａｎｄ ｐｒｏｖｉｄｅ ｂｅｔｔｅｒ ｃｌｉｎｉｃａｌ ｓｅｒｖｉｃｅｓ ｔｏ ｐａｔｉｅｎｔｓ． [ABSTRACT FROM AUTHOR]

Gastrointestinal (GI) cancers are the most common tumors of the digestive system, and their high morbidity and cancer-related mortality dramatically threaten the health of the population. With the researching progress of immunotherapy, its use in the treatment of GI cancers in the perioperative and advanced stages is becoming more and more important. Currently, immunotherapy has become the standard first-line treatment for MSI-H late-stage colorectal cancer, while in the first-line treatment of late-stage gastric cancer, immunotherapy combined with chemotherapy and HER2-targeted drugs (in HER2-positive patients) has also achieved significant efficacy and long-term survival benefits. Advances in immunotherapy in the neoadjuvant and adjuvant treatment and in the second- and later-line treatment of late-stage GI cancers have demonstrated its promising therapeutic potential. However, there is still an urgent need for future studies to explore more immunotherapy combination strategies for patients with GI cancers, especially with MSS colorectal cancers.

Objective To investigate the expression of mismatch repair gene(MMR) protein and microsatellite instability(MSI) in the endometrial tissues of different pathological types and its related influence factors. Methods The expression of MMR proteins(MLH1, MSH2, MSH6, and PMS2) in the normal cycle endometria(normal group, n=50), atypical hyperplasia endometria(hyperplasia group, n=50) and endometrioid adenocarcinoma(adenocarcinoma group, n=100) was detected by immunohistochemistry. The negative expression of one or more MMR proteins was judged as MSI, and the differences of expression rates of MSI, MLH1, MSH2, MSH6 and PMS2 were compared, and the difference of expression rate of MSI and MLH1, MSH2, MSH6 and PMS2 protein was compared between the above groups. The endometrioid adenocarcinoma with MSI was identified as suspicious lynch syndrome(LS)-associated endometrial carcinoma, the endometrioid adenocarcinoma without MSI was diagnosed as sporadic carcinoma, and its clinical and pathological characteristics were analyzed. Results The negative expression rate of MLH1 and PMS2 was in the following order:adenocarcinoma group>hyperplasia group>normal group(all P<0.05). There was no significant difference in the negative expression rates of MSH2 and MSH6 in all groups(all P>0.05). For the incidence of MSI:adenocarcinoma group>hyperplasia group>normal group(all P<0.05). LS-related endometrial carcinoma was significantly different from sporadic carcinoma in terms of age, history of other malignant tumors(all P<0.05), but there was no significant difference in BMI, menarche age, FIGO stage, depth of invasion, degree of differentiation, or lymph node metastasis(all P>0.05). Conclusion During the development of endometrioid adenocarcinoma, the loss of MLH1 and PMS2 proteins may lead to MSI, and the occurrence of MSI is related to the younger age and the history of other malignant tumors. [ABSTRACT FROM AUTHOR]

Lynch syndrome(LS) is the most common hereditary colorectal cancer syndrome， an autosomal dominant inherited disease which is caused by mismatch repair system defect. Learning knowledge in the genetics and diagnosis of LS， and identifying at-risk patients and making a correct diagnosis are the keys to successful screening and surgical decision-making and chemoprevention which is important to decrease formation of and death from cancers. This article reviews recent developments in mainly the clinical features， genetics，current diagnostic standard and diagnosis， surveillance， management， treatment and other related syndromes of LS. [ABSTRACT FROM AUTHOR]

Objective: To investigate the impact of relative locations of multiple foci and microsatellite status of sporadic, synchronous, multiple, primary, colorectal carcinomas on clinicopathological features and prognosis. Methods: The clinicopathologic and prognostic data of 278 patients with sporadic, synchronous, multiple, primary, colorectal carcinomas who had been admitted to the Department of Colorectal Surgery at Zhejiang Cancer Hospital from January 2008 to July 2022 were retrospectively collected. The patients were categorized into three groups based on the relative locations of their multiple cancer foci: (1) a right-sided group that comprised patients with multiple cancer foci in the cecum, ascending colon, hepatic flexure of the colon, and transverse colon; (2) a left-sided group that comprised patients with multiple cancer foci in the splenic flexure of the colon, descending colon, sigmoid colon, and rectum; and (3) a left- and right-sided group that comprised patients with multiple cancer foci in the right half of the colon and left half of the colon/rectum. Additionally, the patients were further divided into two groups based on microsatellite status: a high microsatellite instability (MSI-H) and a low MSI/stable MSI (MSI/L&MSS) group. We compared differences in clinical characteristics and prognostic indicators between these groups. The χ 2 test was utilized to compare selected clinical characteristics, whereas Kaplan-Meier survival analyses and log-rank tests were performed to compare their effects on prognosis. Result: Among 278 patients with SSCRC, 256 (92.1%) presented with two cancer foci and 22 (7.9%) with more than two foci. Additionally, 255 patients (91.7%) had adenocarcinomas, whereas the remaining 23 (8.3%) had mucinous adenocarcinomas. Lymph node metastases were identified in 136 patients (48.9%); the cancer foci had infiltrated beyond the muscular layer in 238 (85.6%); and 147 patients (52.9%) were diagnosed with TNM Stage III-IV disease. There were 155 patients (55.8%) in the left-sided group, 55 (19.8%) in the right-sided group, and 68 (24.5%) in the left- and right-sided group. Immunohistochemical examination of all four mismatch repair proteins were performed in 199 cases, revealing that 166 of these patients had MSI/L&MSS and 33 MSI-H disease. In the left-sided, left- and right-sided, and right-sided groups, the proportion of women was 16.8% (26/155), 26.5% (18/68), and 49.1% (27/55), respectively; these differences are statistically significant (χ 2 =22.335, P <0.001). The proportions of patients with more than three cancer foci were 5.2% (8/155), 16.2% (11/68), and 5.5% (3/55), respectively; these differences are statistically significant (χ 2 =8.438, P =0.015). The proportions of mucinous adenocarcinomas were 4.5% (7/155), 8.8% (6/68), and 18.2% (10/55), respectively; these differences are statistically significant (χ 2 =10.026, P =0.007). The proportions of patients with lymph node metastases were 55.5% (86/155), 48.5% (33/68), and 30.9% (17/55); these differences are statistically significant (χ 2 =9.817, P =0.007). The proportions of patients with Stage T3 & T4 disease in each group according to location were 81.3% (126/155), 88.2% (60/68), and 94.5% (52/55), respectively; these differences are statistically significant (χ 2 =6.293, P =0.043). The proportions of TNM Stage III-IV tumors were 59.4% (92/155), 54.4% (37/68), and 32.7% (18/55), respectively; these differences are statistically significant (χ 2 =11.637, P =0.003). Age, size of cancer foci, presence of distant metastasis, adenoma, nerve invasion, and vascular invasion did not differ significantly between the three groups (all P >0.05). Compared with those with MSI-H, patients with MSI/L&MSS disease were more likely to be aged >65 years and male (50.6% [84/166] vs. 15.2% [5/33], χ 2 =13.994, P <0.001; 80.7% [134/166] vs. 54.5% [18/33], χ 2 =10.457, P =0.001), more likely to be in the left-sided group (63.3% [105/166] vs. 24.2% [8/33], χ 2 =18.232, P <0.001), had a higher proportion of cancer foci of diameter <4 cm (54.8% [91/166] vs. 33.3% [11/33], χ 2 =5.086, P =0.024), and a lower proportion of mucinous adenocarcinomas (4.2% [7/166] vs. 27.3% [9/33], χ 2 =19.791, P <0.001), more likely to develop distant metastases (22.3% [37/166] vs. 6.1% [2/33], χ 2 =4.601, P =0.032), more likely to have lymph node metastases (57.2% [95/166) vs. 24.2% [8/33], χ 2 =11.996, P <0.001) and nerve invasion (28.9% [48/166] vs. 6.1% [2/33], χ 2 =7.643, P =0.006), had a higher proportion of TNM Stage III-IV disease (60.2% [100/166] vs. 24.2% [8/33], χ 2 =14.374, P <0.001), and a smaller proportion of family history of tumors (28.9% [48/166] vs. 60.6% [20/33], χ 2 =12.228, P <0.001). All the above-listed differences are statistically significant (all P <0.05). The differences in number of cancer foci, depth of infiltration, presence or absence of adenomas, and vascular invasion were not statistically significant (all P >0.05). In the 33 patients with MSI-H status and mismatch repair protein loss, the highest frequency of deletion was found in PMS-2 (66.7%, 22/33), followed by MLH-1 (57.6%, 19/33), whereas the proportions of MSH-2 (33.3%, 11/33) and MSH-6 (24.2%, 8/33) deletions were relatively low. There were statistically significant differences in the 3-year overall survival rates among the groups according to relative locations of cancer foci. The 3-year overall survival rates were 96.8%, 79.6%, and 88.5% in the right-sided, left- and right-sided, and left-sided groups, respectively ( P =0.021). As to microsatellite status, the 3-year overall survival rate of patients with MSI-H disease was 93.8%, which is significantly better than the 78.4% for those with MSI/L & MSS ( P =0.026). Conclusions: Among sporadic, synchronous, multiple, primary, colorectal carcinomas, those with right-sided disease had the deepest local infiltration, whereas those with left-sided disease had the greatest number of lymph node metastases, most advanced clinical TNM stage, lowest percentage of MSI-H disease, and the poorest prognosis.

Objective: To explore the concordance and causes of different mismatch repair (MMR) and microsatellite instability (MSI) detection results in endometrial carcinoma (EC) molecular typing. Methods: A total of 214 EC patients diagnosed from January 2021 to April 2023 were selected at the Department of Pathology, Peking University Third Hospital. The immunohistochemistry (IHC) results of MMR protein were reviewed. Tumor specific somatic mutations, MMR germline mutations, microsatellite scores and tumor mutation burden (TMB) were detected by next-generation sequencing (NGS) with multi-gene panel. Methylation-specific PCR was used to detect the methylation status of MLH1 gene promoter in cases with deficient MLH1 protein expression. In cases with discrepant results between MMR-IHC and MSI-NGS, the MSI status was detected again by PCR (MSI-PCR), and the molecular typing was determined by combining the results of TMB and MLH1 gene promoter methylation. Results: (1) In this study, there were 22 cases of POLE gene mutation subtype, 55 cases of mismatch repair deficient (MMR-d) subtype, 29 cases of p53 abnormal subtype, and 108 cases of no specific molecular profile (NSMP). The median age at diagnosis of MMR-d subtype (54 years old) and the proportion of aggressive histological types (40.0%, 22/55) were higher than those of NSMP subtype [50 years old and 12.0% (13/108) respectively; all P <0.05]. (2) Among 214 patients, MMR-IHC test showed that 153 patients were mismatch repair proficient (MMR-p), 49 patients were MMR-d, and 12 patients were difficult to evaluate directly. MSI-NGS showed that 164 patients were microsatellite stable (MSS; equal to MMR-p), 48 patients were high microsatellite instability (MSI-H; equal to MMR-d), and 2 patients had no MSI-NGS results because the effective sequencing depth did not meet the quality control. The overall concordance between MMR-IHC and MSI-NGS was 94.3% (200/212). All the 12 discrepant cases were MMR-d or subclonal loss of MMR protein by IHC, but MSS by NGS. Among them, 10 cases were loss or subclonal loss of MLH1 and (or) PMS2 protein. Three discrepant cases were classified as POLE gene mutation subtype. In the remaining 9 cases, 5 cases and 3 cases were confirmed as MSI-H and low microsatellite instability (MSI-L) respectively by MSI-PCR, 6 cases were detected as MLH1 gene promoter methylation and 7 cases demonstrated high TMB (>10 mutations/Mb). These 9 cases were classified as MMR-d EC. (3) Lynch syndrome was diagnosed in 27.3% (15/55) of all 55 MMR-d EC cases, and the TMB of EC with MSH2 and (or) MSH6 protein loss or associated with Lynch syndrome [(71.0±26.2) and (71.5±20.1) mutations/Mb respectively] were significantly higher than those of EC with MLH1 and (or) PMS2 loss or sporadic MMR-d EC [(38.2±19.1) and (41.9±24.3) mutations/Mb respectively, all P <0.01]. The top 10 most frequently mutated genes in MMR-d EC were PTEN (85.5%, 47/55), ARID1A (80.0%, 44/55), PIK3CA (69.1%, 38/55), KMT2B (60.0%, 33/55), CTCF (45.5%, 25/55), RNF43 (40.0%, 22/55), KRAS (36.4%, 20/55), CREBBP (34.5%, 19/55), LRP1B (32.7%, 18/55) and BRCA2 (32.7%, 18/55). Concurrent PTEN, ARID1A and PIK3CA gene mutations were found in 50.9% (28/55) of MMR-d EC patients. Conclusions: The concordance of MMR-IHC and MSI-NGS in EC is relatively high.The discordance in a few MMR-d EC are mostly found in cases with MLH1 and (or) PMS2 protein loss or MMR protein subclonal staining caused by MLH1 gene promoter hypermethylation. In order to provide accurate molecular typing for EC patients, MLH1 gene methylation, MSI-PCR, MMR gene germline mutation and TMB should be combined to comprehensively evaluate MMR and MSI status.

Objective: To examine the radiomics model based on high-resolution T2WI and diffusion weighted imaging (DWI) in predicting microsatellite stability in patients with stage Ⅱ and Ⅲ rectal cancer. Methods: From February 2016 to October 2020, 175 patients with stage Ⅱ and Ⅲ rectal cancer who met the inclusion criteria were retrospectively collected. There were 119 males and 56 females, aged (63.9±9.4) years (range: 37 to 85 years), including 152 patients with microsatellite stability and 23 patients with microsatellite instability. All patients were randomly divided into the training group ( n =123) and the validation group ( n =52) with a ratio of 7∶3. The region of interest was labeled on the T2WI and DWI images of each patient using the ITK-SNAP software, and PyRadiomics was used to extract seven kinds of radiomics features. After removing redundant features and normalizing features, the least absolute shrinkage and selection operation were used for feature selection. One clinical model, three radiomics models and one clinical-radiomics model were constructed in the training group based on a support vector machine. The area under receiver operating characteristic curve (AUC), sensitivity, specificity, and accuracy were used to evaluate the performance of the models in the verification group. Results: Three clinical features (age, degree of tumor differentiation, and distance from the lower edge of the tumor to the anal edge) and six radiomics features (two DWI-related features and four T2WI-related features) most related to microsatellite status of rectal cancer patients were selected. The AUC of the clinical-radiomics model in the training group was 0.95. In the validation group, the AUC was 0.81, better than the clinical model (0.68, Z =0.71, P =0.04), and equivalent to the T2WI+DWI model (0.82, Z =0.21, P =0.83). Conclusions: Radiomic features based on preoperative T2WI and DWI were related to microsatellite stability in patients with stage Ⅱ and Ⅲ rectal cancer and showed a high classification efficiency. The model based on the features provided a noninvasive and convenient tool for preoperative determination of microsatellite stability in rectal cancer patients.

Objective: To investigate the correlation of stress-inducible phosphoprotein 1 (STIP1) expression level with prognosis of different cancers and its potential role in immunotherapy., Methods: TCGA, TARGET and GTEx databases were used for bioinformatic analysis of STIP1 expression level and its prognostic value in different cancers. We also detected STIP1 expression immunohistochemically in 10 pairs of colorectal cancer and adjacent tissues. We further analyzed the correlation of STIP1 expression level with tumor mutational burden, microsatellite instability, immune cell infiltration, immune regulators and outcomes of different cancers. STIP1- related proteins were identified using protein- protein interaction (PPI) network analysis, and functional enrichment analysis was performed to analyze the regulatory pathways involving STIP1., Results: Bioinformatics analysis showed that STIP1 was highly expressed in most tumors compared with the normal tissues ( P < 0.05), which was confirmed by immunohistochemistry of the 10 pairs of colorectal cancer tissues. STIP1 expression level was correlated with clinical stages of multiple cancers ( P < 0.05), and in some cancer types, an upregulated STIP1 expression was correlated with a poor prognosis of the patients in terms of overall survival, disease-specific survival, disease-free survival and progression-free survival ( P < 0.05). STIP1 expression was significantly correlated with tumor mutational burden, microsatellite instability, immune cell infiltration and immunomodulatory factors in most tumors ( P < 0.05). PPI network analysis indicated that STIP1-related proteins included HSPA4, HSPA8, and HSP90AA1. KEGG enrichment analysis suggested that the high expression of STIP1 in liver cancer was related mainly with valerate metabolism, tryptophan metabolism, and butyrate metabolism pathways; HALLMARK enrichment analysis suggested high STIP1 expression in liver cancer was involved in bile acid and fatty acid metabolism., Conclusion: STIP1 is up-regulated in multiple cancer types and its expression level is correlated with clinical tumor stage, tumor mutational burden, microsatellite instability, immune cell infiltration and immunomodulatory factors.

Objective: To investigate the differences in molecular classification of endometrial carcinoma (EC) between various technical methods and to explore molecular classification schemes suitable for Chinese population. Methods: The study used a comprehensive scheme of next generation sequencing (NGS) and immunohistochemistry for molecular classification of 254 EC cases that were obtained at Department of Pathology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China from April 2021 to March 2022. According to the recommended threshold of Sanger sequencing which was approximate-20% variant allele fraction (VAF), NGS data were extracted to simulate the results of Sanger sequencing. Results: The 254 EC patients had a mean age of 51 years (range, 24 to 89 years). Combination of POLE (9-14 exons), TP53 total exons and microsatellite instability (MSI) detection was a better single scheme than NGS alone, while combination of MSI fragment analysis and conventional immunohistochemistry was the best solution and seemed best aligned with TCGA data and recent studies. POLE ultramuted type, mismatch repair defect type, TP53 mutant type and non-specific molecular characteristic type accounted for 11.4% (29/254), 31.5% (80/254), 22.4% (57/254) and 34.6% (88/254) of the cases, respectively. If Sanger sequencing was adopted for POLE and TP53 detection, the frequencies of these EC types were 9.1% (23/254), 31.5% (80/254), 12.9% (33/254) and 46.6% (118/254), respectively, with greatly increasing non-specific molecular characteristics cases. If POLE was detected by Sanger sequencing and others by immunohistochemistry, they were 9.1% (23/254), 42.2% (92/218), 13.8% (35/254) and 40.9% (105/254), respectively, with increasing the false positive rates of the mismatch repair defect group. Conclusions: Small and medium-sized NGS panels with MSI detection is a better solution than NGS alone. Sanger sequencing is currently available for POLE mutation detection, which is not sensitive enough for TP53 mutation detection, and seems equivalent to the efficiency of TP53 by immunohistochemistry. Further optimization of small and medium-sized NGS panels covering MSI detection and POLE and TP53 full exons may be the best choice for the future to meet national conditions.

Objective: To analyze the differences and characteristics of microsatellite instability (MSI) in endometrial cancer (EMC), by using colorectal cancer (CRC) as control., Methods: In the study, 228 cases of EMC were collected. For comparative analysis, 770 cases of CRC were collected. Mismatch repair (MMR) expression was detected by immunohistochemistry (IHC), and microsatellite instability (MSI) was analyzed by PCR and capillary electrophoresis fragment analysis (MSI-PCR). MSI-PCR was detected using five mononucleotide repeat markers: BAT-25, BAT-26, NR-21, NR-24, and MONO-27., Results: In EMC, we found 27.19% (62/228) of deficient mismatch repair (dMMR) using IHC, significantly higher than CRC (7.79%, 60/770). Meanwhile, subclonal expression of MMR protein was found in 4 cases of dMMR-EMC and 2 cases of dMMR-CRC. According to the criteria of major micro-satellite shift, we found 16.23% (37/228) of MSI-high (MSI-H), 2.63% (6/228) of MSI-low (MSI-L), and 81.14% (185/228) of microsatellite stability (MSS) in EMC using MSI-PCR. The discor-dance rate between MMR-IHC and MSI-PCR in EMC was 11.84% (27/228). In CRC, we found 8.05% (62/770) of MSI-H, 0.13% (1/770) of MSI-L, and 91.82% (707/770) of MSS. The discordance rate between MMR-IHC and MSI-PCR in CRC was only 0.52% (4/770). However, according to the criteria of minimal microsatellite shift, 12 cases of EMC showed minimal microsatellite shift including 8 cases of dMMR/MSS and 4 cases of dMMR/MSI-L and these cases were ultimately evaluated as dMMR/MSI-H. Then, 21.49% (49/228) of EMC showed MSI-H and the discordance rate MMR-IHC and MSI-PCR in EMC decreased to 6.58% (15/228). No minimal microsatellite shift was found in CRC. Compared with EMC group with major microsatellite shift, cases with minimal microsatellite shift showed younger age, better tumor differentiation, and earlier International Federation of Gynecology and Obstetrics (FIGO) stage. There were significant differences in histological variant and FIGO stage between the two groups ( P < 0.001, P =0.006)., Conclusion: EMC was more prone to minimal microsatellite shift, which should not be ignored in the interpretation of MSI-PCR results. The combined detection of MMR-IHC and MSI-PCR is the most sensitive and specific method to capture MSI tumors.

Immunotherapy has been one of the hot topics in the field of colorectal cancer research in recent years. Patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) are the main beneficiaries of immunotherapy. The response rate of patients with dMMR/MSI-H colorectal cancer receiving neoadjuvant immunotherapy is nearly 100%, of which the pathological complete response rate approximately accounts for 60%-67%. The prospect of neoadjuvant immunotherapy in dMMR or MSI-H colorectal cancer patients, especially in the rectal cancer patients, lies in achieving sustainable clinical complete response so as to achieve organ preservation and avoid adverse effects on reproductive, sexual, bowel and bladder function after surgery and radiotherapy. Studies have shown that part of the colorectal cancer patients of microsatellite stability (MSS) or mismatch repair proficient (pMMR) can respond to neoadjuvant immunotherapy in combination with other treatment methods such as radiotherapy and chemotherapy. In pMMR or MSS colorectal cancer, optimizing neoadjuvant immunotherapy regimens and finding effective efficacy prediction biomarkers are important research directions. In neoadjuvant immunotherapy, overcoming primary and secondary resistance and identifying the pseudoprogression and hyperprogression of neoadjuvant immunotherapy are clinical challenges that require attention. This paper comprehensively reviews the research progress, controversies,challenges and future research directions of neoadjuvant immunotherapy (mainly immune checkpoint inhibitors) in colorectal cancer.

Objective To investigate the expression of thioredoxin reductase 3(TXNRD3),a selenoprotein,in 33 human malignant tumors and then analyze its effect on the survival prognosis.Methods We employed the genotype-tissue expression project database,the cancer cell line encyclopedia,and the cancer genome atlas to explore the expression of TXNRD3 gene in 33 human malignant tumors and analyze its impact on the survival prognosis.Further,we explored the correlations of TXNRD3 with immune cells and immune infiltration in the tumor microenvironment,as well as with neoantigens,immune checkpoint genes,tumor mutational burden,and microsatellite instability.Subsequently,human samples were classified into high-and low-expression groups according to TXNRD3 gene expression levels,and the enrichment analysis of biological functions and signaling pathways was performed.Results The analysis with multiple databases showed that TXNRD3 was highly expressed in 15 tumors.The survival analysis showed that TXNRD3 was significantly associated with poor prognosis in pancreatic cancer patients.In addition,the expression level of TXNRD3 was correlated with immune infiltration in tumor microenvironment,neoantigens,immune checkpoint genes,tumor mutational burden,and microsatellite instability.TXNRD3 affected the expression of DNA mismatch repair genes.The gene set enrichment indicated that TXNRD3 was involved in regulating multiple signaling pathways associated with tumor metabolism and tumor immunity.Conclusion TXNRD3 is widely expressed in tumors and has a clinical value for the survival prognosis prediction and treatment of multiple tumors,demonstrating the potential of being a promising biomarker for targeted treatment of multiple tumors.

Objective: To assess the association of genomic instability of epithelial cadherin 1 (CDH1) gene and clinicopathological characteristics of gastric cancer., Methods: In total 120 paraffin-embedded gastric cancer tissue specimen were prepared, and genomic DNA was extracted. The genomic instability of the CDH1 gene was analyzed by immunohistochemistry and silver staining PCR-single-strand conformation polymorphism., Results: The number of information individuals (heterozygotes) was 98 for the D16S752 locus. The detection rates for microsatellite instability (MSI) and loss of heterozygosity (LOH) at the D16S752 locus and the positive rate of CDH1 protein were 19.39%, 16.33% and 51.02%, respectively. The detection rate of MSI in TNM stages I or II was significantly higher than that in stages III or IV (P<0.05) while the detection rate of LOH was significantly lower than that in stages III or IV (P<0.05). The positive rate of CDH1 protein in TNM stages III or IV was significantly lower than that in stages I or II (P<0.05). The detection rate of MSI of cases with lymph node metastasis was significantly lower than that of without lymph node metastasis (P<0.05) while the detection rate of LOH was significantly higher than that without lymph node metastasis (P<0.05). The positive rate of CDH1 protein in patients with lymph node metastasis was significantly lower than that in patients without lymph node metastasis (P<0.05). The positive rate of CDH1 protein in MSI-positive group was significantly higher than that in MSI-negative group (P<0.05), and the positive rate of CDH1 protein in the LOH-positive group was significantly lower than that the LOH-negative group (P<0.05)., Conclusion: The genomic instability of the CDH1 gene is associated with the progression of gastric cancer. MSI at the D16S752 locus may be used as a molecular marker for early gastric cancer, while LOH at this locus mostly occurs in advanced gastric cancer and can be regarded as an effective indicators for malignancy evaluation and prognosis.

Objective To investigate1 the expression and signifieanee of mismatch repair gene (MMR) in non-meta-static colorectal tissues. Methods Totally 141 patients with non-metastatic colorectal cancer who underwent surgery were selected, and none of them received preoperative radiotherapy or chemotherapy. The expression of lour MMR proteins (MI.HI . MSH2. MSH6. PMS2) in postoperative pathological specimens were detected by routine pathological examination and immunohistoehemistry. One or more of the four proteins were not expressed, namely, the MMR expression was deleted (dMMR), and the clinicopathological features of the patients with normal and dMMR colorectal cancer were compared. Results The deletion rates of MLH1, MSH2. MSH6 and PMS2 were 15. 6% (22/141). 2.8% (4/141). 7.1% (10/141), 15.6% (22/141). and the dMMR rate was 25.5% (36/141). in patients with non-metastatic colorectal cancer MMR expression was correlated with non-metastatic colorectal cancer patients age, location, tumor size and pathological type (all P < 0. 05), and dMMR occurred more frequently in patients younger than 60 years . proximal. mucinous and large tumors (all P <0. 05). Conclusion MMR expression is absent in non-metastatic colorectal cancer, and MMR status is helpful in predicting prognosis and guiding therapy. [ABSTRACT FROM AUTHOR]

Objective To investigate the expression and mutations of DNA mismatch repair ( MMR) of Lynch syn-drome in the members of a Chinese Hui family. Methods The propositus was male, 37 years old, the forth generation, Hui nationality, had rectal poorly differentiated adenocarcinoma. There were six generations existing ( Hui nationality), and a total of 14 patients with colorectal cancer were found including 7 living cases. The peripheral blood and tumor tissue DNA was collected from 6 cases of patients and 5 healthy controls. The microsatellite instability ( MSI ) was detected through DNA sequencing, the expression of MMR protein was measured using immunohistochemistry, and MMR gene muta-tions was detected by PCR amplification. Results The MSI detection of tumor tissues in the family members demonstrated MSI-H.The immunohistochemistry showed that MLH1 protein was negative. Two new missense mutation sites ( c.264G>T and c.265G>T) in the first exon of MLH1 gene were found in 6 patients and 1 normal individual, and c.264G>T mu-tation led to early termination of MLH1 protein translation on this site. Conclusion There is MLH1 mutation in Hui family with Lynch syndrome, that is the missense muntation site c.264G>T in the first exon of MLH1 gene. [ABSTRACT FROM AUTHOR]

Objective: To assess the value of m 7 G-lncRNAs in predicting the prognosis and microenvironment of colorectal cancer (CRC)., Methods: We screened m 7 G-lncRNAs from TCGA to construct an m 7 G-lncRNAs risk model using multivariate Cox analysis, which was validated using ROC and C-index curves. Calibration and nomogram were used to predict the prognosis of CRC patients. Point-bar charts and K-M survival curves were used to assess the correlation of risk scores with the patients' clinical staging and prognosis. CIBERSORT and ESTIMATE were used to explore the association between the tumor microenvironment and immune cell infiltration in patients in high and low risk groups and the correlation of risk scores with microsatellite instability, stem cell index and immune checkpoint expression. A protein-protein interaction network was constructed, and the key targets regulated by m 7 G-lncRNAs were identified and validated in paired samples of CRC and adjacent tissues by immunoblotting., Results: We identified a total of 1722 m 7 G-lncRNAs from TCGA database, from which 12 lncRNAs were screened to construct the risk model. The AUCs of the risk model for predicting survival outcomes at 1, 3 and 5 years were 0.727, 0.747 and 0.794, respectively. The AUC of the nomogram for predicting prognosis was 0.794, and the predicted results were consistent with actual survival outcomes of the patients. The patients in the high-risk group showed more advanced tumor stages and a greater likelihood of high microsatellite instability than those in the low-risk group ( P < 0.05). The tumor stemness index was negatively correlated with the risk score ( r =-0.19; P =7.3e-05). Patients in the high-risk group had higher stromal cell scores ( P =0.0028) and higher total scores ( P =0.007) with lowered expressions of activated mast cells ( r =-0.11; P =0.045) and resting CD4+ T cells ( r =-0.14; P =0.01) and increased expressions of most immune checkpoints ( P < 0.05). ATXN2 ( P = 0.006) and G3BP1 ( P =0.007) were identified as the key targets regulated by m 7 G-lncRNAs, and their expressions were both higher in CRC than in adjacent tissues., Conclusion: The risk model based on 12 m 7 G-lncRNAs has important prognostic value for CRC and can reflect the microenvironment and the efficacy of immunotherapy in the patients.

Objective: To conduct a pan-cancer analysis of the expression of long non-coding RNA (lncRNA) MIR22HG and explore its association with clinical characteristics., Methods: We analyzed the expression of MIR22HG in different tumors and its association with clinical staging, lymph node metastasis, tumor mutation burden (TMB) and microsatellite instability (MSI) using R package based on the Cancer Genome Atlas (TCGA) datasets. The relationship between MIR22HG expression and infiltrating immune cells was analyzed using TIMER algorithm. The association of MIR22HG gene alteration frequency with the clinical outcomes was examined using cBioPortal online software. Data form Genomics of Drug Sensitivity in Cancer (GDSC) were used to analyze the relationship between MIR22HG and the sensitivity of chemotherapy drugs. We specifically analyzed MIR22HG expression in hepatocellular carcinoma (HCC) and its correlation with sorafenib treatment using GEO database and verified the results in 12 pairs of HCC specimens. Kaplan-Meier analysis was performed to analyze the correlation of MIR22HG with the outcomes of sorafenib treatment. We also tested the effects of MIR22HG overexpression and knockdown on IC 50 of sorafenib in HCC cells., Results: MIR22HG was downregulated in most tumors ( P < 0.05), where its deletion mutations were frequent, and associated with a poor prognosis ( P < 0.05). In many tumors, MIR22HG expression level was correlated with clinical stage, lymph node metastasis, TMB, MSI, immune cell infiltration, immune checkpoint-related genes, and sensitivity to common chemotherapeutic drugs ( P < 0.05). Among the 6 common infiltrating immune cells in cancers, neutrophil infiltration had the strongest correlation with MIR22HG expression level, especially in breast cancer, rectal cancer and kidney renal papillary cell carcinoma ( P < 0.05). MIR22HG was downregulated in HCC in association with HCC progression ( P < 0.05). In HCC patients, a low MIR22HG expression was associated with a favorable outcome after sorafenib treatment (HR=2.94, P =0.075) and was capable of predicting the response to sorafenib treatment (AUC=0.8095). Compared with the negative control, MIR22HG overexpression obviously reduced sorafenib sensitivity (with IC 50 of 7.731 vs 15.61) while MIR22HG knockdown increased sorafenib sensitivity of HCC cells (with IC 50 of 7.986 vs 5.085)., Conclusion: MIR22HG expression level is correlated with clinical stage, lymph node metastasis, TMB, MSI, immune cell infiltration, and chemosensitivity in most cancer, suggesting its potential as an immunotherapeutic target and also a prognostic biomarker for tumors.

Microsatellite instability-high (MSI-H) colorectal cancer accounts for approximately 10%-15% of all colorectal cancer patients, while in metastatic diseases the MSI-H population accounts for only 5% of patients. Previous studies have shown that early-stage MSI-H colorectal cancer patients have a good prognosis, but those with advanced disease have a poor prognosis and are not sensitive to chemotherapy. The advent of PD-1 antibodies has significantly improved the prognosis and changed treatment landscape in this population, not only achieving good outcomes in late-line therapy, but also significantly outperforming traditional chemotherapy combined with targeted therapy in first-line therapy. How to overcome primary and secondary drug resistance is a key issue in improving the outcome of MSI-H metastatic colorectal cancer, and commonly used approaches include changing chemotherapy regimens, combining with other immunotherapies, combining with anti-angiogenesis, and local treatments (surgery, radiotherapy, or interventional therapy). It is worth noting that immunotherapy has certain lifelong or even lethal toxicity, and the indications for neoadjuvant immunotherapy must be evaluated with caution. Neoadjuvant immunotherapy in MSI-H advantaged population can achieve high rates of pathological complete remission (pCR) and clinical complete remission (cCR). Therefore, for MSI-H patients with a strong intention to preserve anal sphincter and a strict evaluation of cCR after neoadjuvant immunotherapy, the Watch-and-Wait strategy offers an opportunity to preserve sphincter function and improve long-term survival quality in a subset of mid-to-low rectal cancers. Research on adjuvant immunotherapy in the field of colorectal cancer is also in full swing, and the results are worth waiting for.