-
Biomedicine & Pharmacotherapy =... Jul 2024The unresectable or postoperative recurrence of advanced metastatic colorectal cancer (CRC) is the difficulty of its clinical management, and pharmacological therapy is...
The unresectable or postoperative recurrence of advanced metastatic colorectal cancer (CRC) is the difficulty of its clinical management, and pharmacological therapy is the main source of benefit. Immune checkpoint inhibitors are therapeutic options but are effective in approximately 5 % of patients with deficient mismatch repair (MMR)/microsatellite instability CRC and are ineffective in patients with MMR-proficient (pMMR)/microsatellite stable (MSS) CRCs, which may be associated with the tumor microenvironment (TME). Here, we propose a new combination strategy and evaluate the efficacy of rapamycin (Rapa) combined with anti-PD-1 (αPD-1) in CT26 tumor-bearing mice, azoxymethane (AOM)/dextran sodium sulfate (DSS) inflammation-associated CRC mice, CT26-Luc tumor-bearing mice with postoperative recurrence, and CT26 liver metastasis mice. The results revealed that Rapa improved the therapeutic effect of αPD-1 and effectively inhibited colorectal carcinogenesis, postoperative recurrence, and liver metastasis. Mechanistically, Rapa improved the anticancer effect of αPD-1, associated with Rapa reprograming of the immunosuppressive TME. Rapa effectively depleted α-SMA cancer-associated fibroblasts and degraded collagen in the tumor tissue, increasing T lymphocyte infiltration into the tumor tissue. Rapa induced the downregulation of programed cell death 1 ligand 1 (PD-L1) protein and transcript levels in CT26 cells, which may be associated with the inhibition of the mTOR/P70S6K signaling axis. Furthermore, co-culture of tumor cells and CD8 T lymphocytes demonstrated that Rapa-induced PD-L1 downregulation in tumor cells increased spleen-derived CD8 T lymphocyte activation. Therefore, Rapa improves the anti-tumor effect of αPD-1 in CRCs, providing new ideas for its use to improve combinatorial strategies for anti-PD-1 immunotherapy.
Topics: Animals; Tumor Microenvironment; Colorectal Neoplasms; Sirolimus; B7-H1 Antigen; Mice; Cell Line, Tumor; Immune Checkpoint Inhibitors; Mice, Inbred BALB C; Drug Resistance, Neoplasm; Programmed Cell Death 1 Receptor; Male; Humans; Liver Neoplasms; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38876047
DOI: 10.1016/j.biopha.2024.116883 -
APMIS : Acta Pathologica,... Jun 2024Fifteen percent of all colorectal cancers have detectable defects in the mismatch repair system (dMMR). MMR status is used to identify possible Lynch Syndrome (LS) and...
Fifteen percent of all colorectal cancers have detectable defects in the mismatch repair system (dMMR). MMR status is used to identify possible Lynch Syndrome (LS) and to determine prognosis and choice of treatment. Two standard techniques for determining MMR status are immunohistochemistry (IHC) and analysis for microsatellite instability (MSI) by PCR. Recently, our department introduced Idylla™ MSI assay as an alternative option to IHC, and as part of this, we introduced a decision algorithm. The purpose of this study was to review the use of the new method and our algorithm and to assess possible false-positive results. Retrospectively, we identified 629 cases of colorectal cancer in which either IHC (336 cases) or Idylla™ MSI (293 cases) was performed. Similar results were obtained by the two methods. IHC detected dMMR in 55 cases (16%) and Idylla™ MSI in 52 cases (18%). In all 52 cases of MSI, subsequent IHC was performed. One case was not confirmed by IHC, but was confirmed by another PCR-based method. Overall, we found that the Idylla™ MSI works well as a screening method for dMMR with no false-positive cases detected. The proposed algorithm was useful and easily applicable.
PubMed: 38873700
DOI: 10.1111/apm.13442 -
Oncology Letters Aug 2024Metadherin (MTDH), initially discovered in primary astrocytes of the human fetus through rapid subtraction hybridization and labeled as astrocyte elevated gene-1,...
Metadherin (MTDH), initially discovered in primary astrocytes of the human fetus through rapid subtraction hybridization and labeled as astrocyte elevated gene-1, represents a widely recognized oncogene present in multiple types of cancers. However, the role of MTDH in different types of cancer remains unclear. To address this, a comprehensive analysis of MTDH across various types of cancers was conducted by utilizing multiple databases such as The Cancer Genome Atlas. The present analysis discovered that MTDH exhibits differential expression in different types of cancer and is associated with important factors including tumor mutational burden and microsatellite instability. These findings highlighted the significance of MTDH in the tumor microenvironment and its involvement in the development of immune cells in specific cancers. Furthermore, the results of the present study indicated that the expression of MTDH is strongly correlated with clinical prognosis, mutations and immune cell infiltration. MTDH could serve as a potential indicator of patient prognosis and potentially play a role in modulating the immune system. Given its potential as a novel immunological checkpoint, MTDH may be a viable target for tumor immunotherapy.
PubMed: 38872862
DOI: 10.3892/ol.2024.14482 -
Archives of Pathology & Laboratory... Jun 2024The College of American Pathologists (CAP) accreditation requirements for clinical laboratory testing help ensure laboratories implement and maintain systems and...
General Applicability of Existing College of American Pathologists Accreditation Requirements to Clinical Implementation of Machine Learning-Based Methods in Molecular Oncology Testing.
CONTEXT.—
The College of American Pathologists (CAP) accreditation requirements for clinical laboratory testing help ensure laboratories implement and maintain systems and processes that are associated with quality. Machine learning (ML)-based models share some features of conventional laboratory testing methods. Accreditation requirements that specifically address clinical laboratories' use of ML remain in the early stages of development.
OBJECTIVE.—
To identify relevant CAP accreditation requirements that may be applied to the clinical adoption of ML-based molecular oncology assays, and to provide examples of current and emerging ML applications in molecular oncology testing.
DESIGN.—
CAP accreditation checklists related to molecular pathology and general laboratory practices (Molecular Pathology, All Common and Laboratory General) were reviewed. Examples of checklist requirements that are generally applicable to validation, revalidation, quality management, infrastructure, and analytical procedures of ML-based molecular oncology assays were summarized. Instances of ML use in molecular oncology testing were assessed from literature review.
RESULTS.—
Components of the general CAP accreditation framework that exist for traditional molecular oncology assay validation and maintenance are also relevant for implementing ML-based tests in a clinical laboratory. Current and emerging applications of ML in molecular oncology testing include DNA methylation profiling for central nervous system tumor classification, variant calling, microsatellite instability testing, mutational signature analysis, and variant prediction from histopathology images.
CONCLUSIONS.—
Currently, much of the ML activity in molecular oncology is within early clinical implementation. Despite specific considerations that apply to the adoption of ML-based methods, existing CAP requirements can serve as general guidelines for the clinical implementation of ML-based assays in molecular oncology testing.
PubMed: 38871357
DOI: 10.5858/arpa.2024-0037-CP -
Hormone and Metabolic Research =... Jun 2024This study attempted to build a prostate cancer (PC) prognostic risk model with mitochondrial feature genes. PC-related MTGs were screened for Cox regression analyses,...
This study attempted to build a prostate cancer (PC) prognostic risk model with mitochondrial feature genes. PC-related MTGs were screened for Cox regression analyses, followed by establishing a prognostic model. Model validity was analyzed via survival analysis and receiver operating characteristic (ROC) curves, and model accuracy was validated in the GEO dataset. Combining risk score with clinical factors, the independence of the risk score was verified by using Cox analysis, followed by generating a nomogram. The Gleason score, microsatellite instability (MSI), immune microenvironment, and tumor mutation burden were analyzed in two risk groups. Finally, the prognostic feature genes were verified through a q-PCR test. Ten PC-associated MTGs were screened, and a prognostic model was built. Survival analysis and ROC curves illustrated that the model was a good predictor for the risk of PC. Cox regression analysis revealed that risk score acted as an independent prognostic factor. The Gleason score and MSI in the high-risk group were substantially higher than in the low-risk group. Levels of ESTIMATE Score, Immune Score, Stromal Score, immune cells, immune function, immune checkpoint, and immunopheno score of partial immune checkpoints in the high-risk group were significantly lower than in the low-risk group. Genes with the highest mutation frequencies in the two groups were SPOP, TTN, and TP53. The q-PCR results of the feature genes were consistent with the gene expression results in the database. The 10-gene model based on MTGs could accurately predict the prognosis of PC patients and their responses to immunotherapy.
PubMed: 38870985
DOI: 10.1055/a-2330-3696 -
Med (New York, N.Y.) Jun 2024Whether or not the addition of immunotherapy to current standard-of-care treatments can improve efficacy in proficient mismatch repair (pMMR)/microsatellite-stable (MSS)...
BACKGROUND
Whether or not the addition of immunotherapy to current standard-of-care treatments can improve efficacy in proficient mismatch repair (pMMR)/microsatellite-stable (MSS) metastatic colorectal cancer (mCRC), the predominant type of mCRC, is unclear.
METHODS
This randomized, double-blind, phase 2 part of a phase 2/3 trial was conducted at 23 hospitals across China (ClinicalTrials.gov: NCT04547166). Patients with unresectable metastatic/recurrent colorectal adenocarcinoma and no prior systemic therapy were randomly assigned 1:1 to receive every-3-weeks intravenous serplulimab (300 mg) plus HLX04 (7.5 mg/kg) and XELOX (serplulimab group) or placebo (300 mg) plus bevacizumab (7.5 mg/kg) and XELOX (placebo group). The primary endpoint was independent radiology review committee (IRRC)-assessed progression-free survival (PFS). Secondary endpoints included other efficacy endpoints and safety.
FINDINGS
Between July 16, 2021, and January 20, 2022, 114 patients were enrolled and randomly assigned to the serplulimab (n = 57) or placebo (n = 57) group. All patients had stage IV CRC, and 95.7% of the patients with available microsatellite instability (MSI) status were MSS. With a median follow-up duration of 17.7 months, median PFS was prolonged in the serplulimab group (17.2 vs. 10.7 months; hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.31-1.14). Although the median overall survival (OS) was not reached for either group, a trend of an OS benefit was observed for the serplulimab group (HR, 0.77; 95% CI, 0.41-1.45). 36 (65.5%) and 32 (56.1%) patients in the serplulimab and placebo groups had grade ≥3 treatment-related adverse events, respectively.
CONCLUSIONS
Serplulimab plus HLX04 and XELOX exhibits promising efficacy and is safe and tolerable in patients with treatment-naive mCRC.
FUNDING
This work was funded by Shanghai Henlius Biotech, Inc.
PubMed: 38870931
DOI: 10.1016/j.medj.2024.05.009 -
Journal of Health, Population, and... Jun 2024This study aimed to conduct a bibliometric analysis of research articles on the relationship between inflammatory bowel disease (IBD) and colorectal cancer (CRC) using...
OBJECTIVE
This study aimed to conduct a bibliometric analysis of research articles on the relationship between inflammatory bowel disease (IBD) and colorectal cancer (CRC) using CiteSpace to summarize the current research status, hotspots, and trends in this field and present the results visually.
METHOD
Research articles on the relationship between IBD and CRC published from 2000 to 2023 and in English were selected from the Web of Science Core Collection (Woscc) database. The articles were downloaded as "full record and references". CiteSpace was used to conduct cooperative, cluster, co-citation, and burst analyses.
RESULTS
The literature search revealed 4244 articles; of which, 5 duplicates were removed, resulting in the inclusion of 4239 articles in this study. The United States of America had the highest number of publications, with Mayo Clinic and Harvard University being the most active institutions, and Bas Oldenburg being the most active author. Collaboration among core authors was inadequate. JA Eaden was the most cited author, and CRC was the most common keyword. Burst analysis indicated that Sun Yat-sen University might be one of the institutions with a large contribution to this research field in the future. Cluster analysis showed that earlier research focused more on microsatellite instability, whereas "gut microbiota" and "oxidative stress" are considered current research hotspots and trends.
CONCLUSION
At present, the primary focus areas of research are "gut microbiota" and "oxidative stress". With the improvement of healthcare policies and standards, regular endoscopic monitoring of patients with IBD has become an indispensable diagnostic and therapeutic practice. More drugs will be developed to reduce the risk of progression from IBD to CRC. The findings of this study provide valuable insights into the relationship between IBD and CRC for researchers in the same field.
Topics: Bibliometrics; Humans; Inflammatory Bowel Diseases; Colorectal Neoplasms; Biomedical Research; Global Health
PubMed: 38867343
DOI: 10.1186/s41043-024-00577-5 -
Nature Reviews. Cancer Jul 2024Although more than a decade has passed since the approval of immune checkpoint inhibitors (ICIs) for the treatment of melanoma and non-small-cell lung, breast and... (Review)
Review
Although more than a decade has passed since the approval of immune checkpoint inhibitors (ICIs) for the treatment of melanoma and non-small-cell lung, breast and gastrointestinal cancers, many patients still show limited response. US Food and Drug Administration (FDA)-approved biomarkers include programmed cell death 1 ligand 1 (PDL1) expression, microsatellite status (that is, microsatellite instability-high (MSI-H)) and tumour mutational burden (TMB), but these have limited utility and/or lack standardized testing approaches for pan-cancer applications. Tissue-based analytes (such as tumour gene signatures, tumour antigen presentation or tumour microenvironment profiles) show a correlation with immune response, but equally, these demonstrate limited efficacy, as they represent a single time point and a single spatial assessment. Patient heterogeneity as well as inter- and intra-tumoural differences across different tissue sites and time points represent substantial challenges for static biomarkers. However, dynamic biomarkers such as longitudinal biopsies or novel, less-invasive markers such as blood-based biomarkers, radiomics and the gut microbiome show increasing potential for the dynamic identification of ICI response, and patient-tailored predictors identified through neoadjuvant trials or novel ex vivo tumour models can help to personalize treatment. In this Perspective, we critically assess the multiple new static, dynamic and patient-specific biomarkers, highlight the newest consortia and trial efforts, and provide recommendations for future clinical trials to make meaningful steps forwards in the field.
Topics: Humans; Immune Checkpoint Inhibitors; Biomarkers, Tumor; Neoplasms; Tumor Microenvironment; Microsatellite Instability
PubMed: 38867074
DOI: 10.1038/s41568-024-00705-7 -
Annals of Oncology : Official Journal... Jun 2024Part 1 of the RUBY trial (NCT03981796) evaluated dostarlimab plus carboplatin-paclitaxel compared with placebo plus carboplatin-paclitaxel in patients with primary...
BACKGROUND
Part 1 of the RUBY trial (NCT03981796) evaluated dostarlimab plus carboplatin-paclitaxel compared with placebo plus carboplatin-paclitaxel in patients with primary advanced or recurrent endometrial cancer. At the first interim analysis, the trial met one of its dual-primary endpoints with statistically significant progression-free survival benefits in the mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) and overall populations. Overall survival (OS) results are reported from the second interim analysis.
PATIENTS AND METHODS
RUBY is a phase 3, global, double-blind, randomized, placebo-controlled trial. Part 1 of RUBY enrolled eligible patients with primary advanced stage III or IV or first recurrent endometrial cancer who were randomly assigned (1:1) to receive either dostarlimab (500 mg) or placebo, plus carboplatin-paclitaxel every 3 weeks for 6 cycles followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. OS was a dual-primary endpoint.
RESULTS
A total of 494 patients were randomized (245 in dostarlimab arm; 249 in placebo arm). In the overall population, with 51% maturity, RUBY met the dual-primary endpoint for OS at this second interim analysis, with a statistically significant reduction in the risk of death (HR = 0.69; 95% CI, 0.54-0.89; P = 0.0020) in patients treated with dostarlimab plus carboplatin-paclitaxel versus carboplatin-paclitaxel alone. The risk of death was lower in the dMMR/MSI-H population (HR = 0.32; 95% CI, 0.17-0.63; nominal P = 0.0002) and a trend in favor of dostarlimab was seen in the mismatch repair proficient/microsatellite stable (MMRp/MSS) population (HR = 0.79; 95% CI, 0.60-1.04; nominal P = 0.0493). The safety profile for dostarlimab plus carboplatin-paclitaxel was consistent with the first interim analysis.
CONCLUSIONS
Dostarlimab in combination with carboplatin-paclitaxel demonstrated a statistically significant and clinically meaningful overall survival benefit in the overall population of patients with primary advanced or recurrent endometrial cancer while demonstrating an acceptable safety profile.
PubMed: 38866180
DOI: 10.1016/j.annonc.2024.05.546 -
Pathologie (Heidelberg, Germany) Jul 2024Patients with Lynch syndrome, one of the most common hereditary tumor predisposition syndromes, harbor an increased risk for a broad spectrum of especially... (Review)
Review
Patients with Lynch syndrome, one of the most common hereditary tumor predisposition syndromes, harbor an increased risk for a broad spectrum of especially gastrointestinal and gynecological tumors. Causative for the syndrome are variants in DNA mismatch repair genes, which are passed on to the offspring at a 50% chance (autosomal dominant inheritance). The tumor tissue of these patients usually shows microsatellite instability, which is of increasing relevance regarding prognosis and therapeutic decisions. The detection of a causative genetic variant in a patient enables predictive testing of family members to provide relief to noncarriers and provide carriers with intensified risk-adapted surveillance. In addition, chemoprevention with aspirin (acetylsalicylic acid) has been proven useful for chemoprevention in studies. Therefore, the diagnosis of Lynch syndrome is important for patients and their relatives.
Topics: Humans; Colorectal Neoplasms, Hereditary Nonpolyposis; Female; DNA Mismatch Repair; Microsatellite Instability; Aspirin; Genetic Predisposition to Disease
PubMed: 38864870
DOI: 10.1007/s00292-024-01339-0