-
BMC Cancer Jun 2024Colon cancer (CC) is a malignancy associated with significant morbidity and mortality within the gastrointestinal tract. Recurrence and metastasis are the main factors...
BACKGROUND
Colon cancer (CC) is a malignancy associated with significant morbidity and mortality within the gastrointestinal tract. Recurrence and metastasis are the main factors affecting the prognosis of CC patients undergoing radical surgery; consequently, we attempted to determine the impact of immunity-related genes.
RESULT
We constructed a CC risk model based on ZG16, MPC1, RBM47, SMOX, CPM and DNASE1L3. Consistently, we found that a significant association was found between the expression of most characteristic genes and tumor mutation burden (TMB), microsatellite instability (MSI) and neoantigen (NEO). Additionally, a notable decrease in RBM47 expression was observed in CC tissues compared with that in normal tissues. Moreover, RBM47 expression was correlated with clinicopathological characteristics and improved disease-free survival (DFS) and overall survival (OS) among patients with CC. Lastly, immunohistochemistry and co-immunofluorescence staining revealed a clear positive correlation between RBM47 and CXCL13 in mature tertiary lymphoid structures (TLS) region.
CONCLUSION
We conclude that RBM47 was identified as a prognostic-related gene, which was of great significance to the prognosis evaluation of patients with CC and was correlated with CXCL13 in the TLS region.
Topics: Humans; Colonic Neoplasms; Prognosis; Male; Female; Microsatellite Instability; Biomarkers, Tumor; Middle Aged; RNA-Binding Proteins; Aged; Mutation; Gene Expression Regulation, Neoplastic; Disease-Free Survival
PubMed: 38914961
DOI: 10.1186/s12885-024-12507-z -
Hepatobiliary Surgery and Nutrition Jun 2024Immune checkpoint inhibitor (ICI)-based therapy has achieved impressive success in various cancer types. Several ICIs have been unprecedentedly approved as the treatment... (Review)
Review
BACKGROUND AND OBJECTIVE
Immune checkpoint inhibitor (ICI)-based therapy has achieved impressive success in various cancer types. Several ICIs have been unprecedentedly approved as the treatment regimens for advanced hepatocellular carcinoma (HCC) in recent decade. Meanwhile, numerous clinical trials are being performed to exploit more ICIs into initially unresectable HCC and postoperative HCC to expectantly induce adequate tumor downstaging for further resection or implement adjuvant treatment for relapse-free survival, respectively. In this review, we aim to summarize some pragmatic histomorphologic, immunohistochemical, and molecular pathologic parameters which promisingly indicate the response of neoadjuvant/conversion ICI-related therapy and predict the efficacy of adjuvant/therapeutic ICI-related therapy for HCC.
METHODS
We searched PubMed using the terms hepatocellular carcinoma, immunotherapy, immune checkpoint inhibitor, immune checkpoint blockade, conversion therapy, neoadjuvant therapy, adjuvant therapy, biomarker, pathologic evaluation, pathologic assessment till February 2023.
KEY CONTENT AND FINDINGS
Although there is no consensus regarding the pathologic evaluation of relevant HCC specimens, it is encouraging that a few of studies have concentrated on this field, and moreover, the methods and parameters noted on other cancer types are also worthy of reference. For the pathologic assessment of HCC specimens underwent immunotherapy, a suitable sampling scheme, identifying immunotherapy-related pathologic response, and quantification of pathologic response rate should be emphasized. For the patients of HCC who are scheduled to receive immunotherapy, tumor-infiltrating lymphocyte, intratumoral tertiary lymphoid structure, programmed cell death ligand 1, , microsatellite instability and mismatch repair, tumor mutational burden and tumor neoantigen, as well as some other signaling pathways are the potential predictive biomarkers of treatment response of ICI.
CONCLUSIONS
The management of HCC in the era of immunotherapy arises a brand-new pathological challenge that is to provide an immunotherapy-related diagnostic report. Albeit many related researches are preclinical or insufficient, they may tremendously alter the immunotherapy strategy of HCC in future.
PubMed: 38911201
DOI: 10.21037/hbsn-22-527 -
Cell Reports. Medicine Jun 2024Immune checkpoint inhibitors (ICIs) activate anti-cancer immunity by blocking T cell checkpoint molecules such as programmed death 1 (PD-1) and cytotoxic T... (Review)
Review
Immune checkpoint inhibitors (ICIs) activate anti-cancer immunity by blocking T cell checkpoint molecules such as programmed death 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). Although ICIs induce some durable responses in various cancer patients, they also have disadvantages, including low response rates, the potential for severe side effects, and high treatment costs. Therefore, selection of patients who can benefit from ICI treatment is critical, and identification of biomarkers is essential to improve the efficiency of ICIs. In this review, we provide updated information on established predictive biomarkers (tumor programmed death-ligand 1 [PD-L1] expression, DNA mismatch repair deficiency, microsatellite instability high, and tumor mutational burden) and potential biomarkers currently under investigation such as tumor-infiltrated and peripheral lymphocytes, gut microbiome, and signaling pathways related to DNA damage and antigen presentation. In particular, this review aims to summarize the current knowledge of biomarkers, discuss issues, and further explore future biomarkers.
PubMed: 38906149
DOI: 10.1016/j.xcrm.2024.101621 -
Indian Journal of Pathology &... Jun 2024To investigate relationships between microsatellite instability (MSI) and the clinicopathological characteristics of colorectal cancer (CRC) to facilitate the provision...
BACKGROUND
To investigate relationships between microsatellite instability (MSI) and the clinicopathological characteristics of colorectal cancer (CRC) to facilitate the provision of targeted therapy and immunotherapy for CRC related to MSI, and provide a basis for better prognoses.
MATERIALS AND METHODS
Data were obtained from the information system of the Pathology Department of the Fourth Affiliated Hospital of Harbin Medical University, China, from January 01, 2021 to September 30, 2022. Clinicopathological information, including sex, age, tumor size, and associated expression of MSI, was collected.
RESULTS
CRC associated with MSI usually occurred in people aged over 50 years. It was related to tumor diameter, which was 5-10 cm at the most. Most tumors occurred in the right colon and were moderately to poorly differentiated. PCR detected 29 patients, including 24 cases of microsatellite stable (MSS), one case of MSI-low, and four cases of MSI-high. The expression of mismatch repair (MMR) protein in these 29 patients was also investigated via immunohistochemistry (IHC), which detected 25 cases of MSS and four cases of MSI-high. The consistency between IHC and PCR was 96.6%.
CONCLUSION
The expression of MMR is related to age, tumor diameter, tumor location, and tumor differentiation. It was not related to gender, lymphovascular and perineural invasion, lymph node metastasis, TNM stage, or P53 expression. The consistency between IHC and PCR was 96.6%.
PubMed: 38904458
DOI: 10.4103/ijpm.ijpm_651_23 -
Frontiers in Immunology 2024The past decade has witnessed a revolution in cancer treatment, shifting from conventional drugs (chemotherapies) towards targeted molecular therapies and immune-based... (Review)
Review
The past decade has witnessed a revolution in cancer treatment, shifting from conventional drugs (chemotherapies) towards targeted molecular therapies and immune-based therapies, in particular immune-checkpoint inhibitors (ICIs). These immunotherapies release the host's immune system against the tumor and have shown unprecedented durable remission for patients with cancers that were thought incurable, such as metastatic melanoma, metastatic renal cell carcinoma (RCC), microsatellite instability (MSI) high colorectal cancer and late stages of non-small cell lung cancer (NSCLC). However, about 80% of the patients fail to respond to these immunotherapies and are therefore left with other less effective and potentially toxic treatments. Identifying and understanding the mechanisms that enable cancerous cells to adapt to and eventually overcome therapy can help circumvent resistance and improve treatment. In this review, we describe the recent discoveries on the onco-immunological processes which govern the tumor microenvironment and their impact on the resistance to PD-1/PD-L1 checkpoint blockade.
Topics: Humans; Immune Checkpoint Inhibitors; Drug Resistance, Neoplasm; Tumor Microenvironment; Neoplasms; Animals; Immunotherapy; B7-H1 Antigen; Programmed Cell Death 1 Receptor
PubMed: 38903504
DOI: 10.3389/fimmu.2024.1384121 -
Cureus May 2024Small-cell carcinoma of the ovary, the hypercalcemic type (SCCOHT) is a rare, aggressive tumor that primarily affects young females. It is a monogenic disorder caused by...
Small-cell carcinoma of the ovary, the hypercalcemic type (SCCOHT) is a rare, aggressive tumor that primarily affects young females. It is a monogenic disorder caused by germline and/or somatic mutations. Here, we report a case of SCCOHT harboring multiple previously unreported somatic mutations in (c.2866_2867delC>T; c.3543del). A 28-year-old breastfeeding Japanese female presented to a previous hospital with nausea and vomiting. She had no family history of relevant malignancies, including ovarian cancer. Based on an evaluation performed at another institution, she was referred to a gynecologist for suspected ovarian cancer. Imaging studies revealed a 16×15 cm heterogenous enhancing mass within the right ovary without lymph node or distant metastasis. She had mild ascites without peritoneal dissemination, but there was an elevation in the serum calcium level (15.1 mg/dL). The patient underwent cytoreductive surgery and was pathologically diagnosed with SCCOHT. Auxiliary immunohistochemical staining confirmed the loss of SMARCA4 protein expression. The patient was diagnosed with the International Federation of Gynecology and Obstetrics (FIGO) 2014 stage IA (pT1a pN0 M0). The serum calcium levels returned to normal post-surgery. Matched-pair analysis using tumor tissue and peripheral blood revealed multiple somatic mutations in , but no deleterious germline mutations were present. Microsatellite instability was not significant, and the patients had a heterozygous mutation of . She underwent six cycles of irinotecan hydrochloride plus cisplatin chemotherapy and achieved complete remission. The patient was finally examined and evaluated 45 months postoperatively; there was no evidence of the disease. Overall, the genetic findings will not aid in the SCCOHT diagnosis and relevant genetic counseling; however, they may have implications for the treatment of this disease in the future.
PubMed: 38903333
DOI: 10.7759/cureus.60802 -
The Journal of International Medical... Jun 2024Breast cancer, particularly triple-negative breast cancer (TNBC), poses a significant global health burden. Chemotherapy was the mainstay treatment for TNBC patients...
BACKGROUND
Breast cancer, particularly triple-negative breast cancer (TNBC), poses a significant global health burden. Chemotherapy was the mainstay treatment for TNBC patients until immunotherapy was introduced. Studies indicate a noteworthy prevalence (0.2% to 18.6%) of mismatch repair protein (MMRP) deficiency in TNBC, with recent research highlighting the potential of immunotherapy for MMRP-deficient metastatic breast cancer. This study aims to identify MMRP deficiency in TNBC patients using immunohistochemistry.
METHODS
A retrospective cohort study design was used and included TNBC patients treated between 2015 and 2021 at King Hussein Cancer Center. Immunohistochemistry was conducted to assess MMRP expression.
RESULTS
Among 152 patients, 14 (9.2%) exhibited deficient MMR (dMMR). Loss of PMS2 expression was observed in 13 patients, 5 of whom showed loss of MLH1 expression. Loss of MSH6 and MSH2 expression was observed in one patient. The median follow-up duration was 44 (3-102) months. Despite the higher survival rate (80.8%, 5 years) of dMMR patients than of proficient MMR patients (62.3%), overall survival did not significantly differ between the two groups.
CONCLUSION
Approximately 9% of TNBC patients exhibit dMMR. dMMR could be used to predict outcomes and identify patients with TNBC who may benefit from immunotherapy.
Topics: Humans; Female; Triple Negative Breast Neoplasms; Middle Aged; Adult; Retrospective Studies; Mismatch Repair Endonuclease PMS2; Aged; DNA-Binding Proteins; DNA Mismatch Repair; MutL Protein Homolog 1; MutS Homolog 2 Protein; Biomarkers, Tumor; Survival Rate; Immunohistochemistry; Aged, 80 and over; Prognosis
PubMed: 38902203
DOI: 10.1177/03000605241259747 -
International Journal of Gynecological... Jun 2024Immune checkpoint inhibitor combinations show significant survival advantages compared with chemotherapy for patients with advanced endometrial cancer.
BACKGROUND
Immune checkpoint inhibitor combinations show significant survival advantages compared with chemotherapy for patients with advanced endometrial cancer.
OBJECTIVE
To compare the efficacy, safety, and cost-effectiveness of different immunotherapy combinations for clinician and patient decision-making.
METHODS
The PubMed, Embase, Cochrane, and Web of Science Databases were reviewed from January 1, 2010 to October 30, 2023, for phase III randomized controlled trials of first-line immunotherapy combinations in patients with advanced endometrial cancer. Bayesian network meta-analysis was performed to obtain hazard ratios (HRs) of overall survival and progression-free survival, relative risks (RRs) of adverse events, and corresponding p value. The lifetime Markov model of cost-effectiveness analysis was developed to summarize the cost, life-years, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios at the US$150 000/QALY of willingness-to-pay of six first-line treatment strategies.
RESULTS
Four trials were identified, involving 2577 patients. Dostarlimab plus chemotherapy or durvalumab plus chemotherapy with olaparib was associated with more survival benefits than other immunotherapy regimens and chemotherapy in the mismatch repair-deficient microsatellite instability-high (dMMR/MSI-H) and mismatch repair-proficient microsatellite-stable (pMMR/MSS) population, respectively. Further, pembrolizumab plus chemotherapy versus chemotherapy increased efficacy (cost) by 3.76 QALYs and US$540 817, which yielded incremental cost-effectiveness ratios of US$143 894/QALY in the dMMR/MSI-H population.
CONCLUSION
First-line durvalumab plus chemotherapy with olaparib, and dostarlimab plus chemotherapy, were more beneficial for survival in the pMMR/MSS and dMMR/MSI-H populations, respectively. Only pembrolizumab plus chemotherapy versus chemotherapy was cost-effective for patients with dMMR/MSI-H endometrial cancer in the USA.
PubMed: 38901970
DOI: 10.1136/ijgc-2024-005296 -
Reproductive Sciences (Thousand Oaks,... Jun 2024The significance of NSUN2 in carcinogenesis is gradually being recognized, yet a comprehensive analysis across pan-cancer remains a pivotal void in existing research. In...
The significance of NSUN2 in carcinogenesis is gradually being recognized, yet a comprehensive analysis across pan-cancer remains a pivotal void in existing research. In our investigation, we capitalized on the UCSC Xena platform to evaluate NSUN2 expression levels and their prognostic implications across a range of cancer types. Furthermore, we employed the cBioPortal database to delve into the genomic variations of NSUN2 within human cancers. Our study encompassed the use of molecular docking, genomic tumor profiling, and an assessment of the gene's responsiveness to pharmacological treatments. Additionally, we utilized algorithmic techniques to measure the relationship between NSUN2 expression and key clinical biomarkers, such as microsatellite instability (MSI), tumor mutational burden (TMB), and immune cell infiltration. Our results have established a notable association between NSUN2 and endometrial cancer (UCEC), thereby confirming its clinical significance through an analysis of tumoral expression patterns, mutational spectra, methylation profiles, and drug sensitivity. Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) were crucial tools in elucidating the biological roles of NSUN2 in endometrial cancer. Consistently, elevated NSUN2 expression was associated with unfavorable clinical outcomes and was primarily observed in the context of genetic amplifications. Across 22 distinct tumor types, our analysis revealed a notable correlation between NSUN2 expression and various metrics related to immune cell infiltration, tumor stroma, and immune scores. Notably, higher levels of NSUN2 expression have been linked to a reduced response to certain chemotherapeutic agents, including PHA-793887. In UCEC, a positive correlation between NSUN2 methylation and gene expression hints at a potential epigenetic regulatory mechanism underlying cancer progression. Our study highlights the potential of NSUN2 as a key oncogene and its promising role as a therapeutic target as well as a prognostic biomarker for endometrial cancer. This underscores its potential importance in predicting responses to immunotherapy.
PubMed: 38900401
DOI: 10.1007/s43032-024-01625-5 -
World Journal of Gastroenterology Jun 2024In this editorial we comment on the article by Li published in the recent issue of the . We focus specifically on the application of immune checkpoint inhibitors (ICIs)...
In this editorial we comment on the article by Li published in the recent issue of the . We focus specifically on the application of immune checkpoint inhibitors (ICIs) and microsatellite instability (MSI) in gastric cancer (GC). The four pillars of GC management have long been considered, including surgery, chemotherapy, radiotherapy and targeted therapy. However, immunotherapy has recently emerged as a "fifth pillar", and its use is rapidly expanding. There are four principal strategies for tumor immunotherapy: ICIs, tumor vaccines, adoptive immunotherapy and nonspecific immunomodulators. Of them, ICIs are the most advanced and widespread type of cancer immunotherapy for GC. Recent breakthrough results for ICIs have paved the way to a new era of cancer immunotherapy. In particular, inhibition of the PD-1/PD-L1 axis with ICIs, including nivolumab and pembrolizumab, has emerged as a novel treatment strategy for advanced GC. Unfortunately, these therapies are sometimes associated with often subtle, potentially fatal immune-related adverse events (irAEs), including dermatitis, diarrhea, colitis, endocrinopathy, hepatotoxicity, neuropathy and pneumonitis. We must be aware of these irAEs and improve the detection of these processes to prevent inappropriate discharges, emergency department revisits, and downstream complications. Recent studies have revealed that MSI-high or mismatch- repair-deficient tumors, regardless of their primary site, have a promising response to ICIs. So, it is important to detect MSI before applying ICIs for treatment of GC.
Topics: Humans; Microsatellite Instability; Stomach Neoplasms; Immune Checkpoint Inhibitors; B7-H1 Antigen; Programmed Cell Death 1 Receptor; Antibodies, Monoclonal, Humanized; Immunotherapy; Cancer Vaccines
PubMed: 38899328
DOI: 10.3748/wjg.v30.i21.2734