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An increasing body of research indicates that immunotherapy has demonstrated substantial effectiveness in the realm of metastatic colorectal cancer(mCRC), especially among patients with deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) (dMMR/MSI-H mCRC). This study constitutes the inaugural bibliometric and visual analysis of immunotherapy related to mCRC during the last decade. Between 2013 and the conclusion of 2022, we screened 306 articles from Web of Science and subjected them to analysis using CiteSpace and VOSviewer. The United States stood out as the primary contributor in this area, representing 33.33% of the publications, with China following closely at 24.51%. The most prolific institution has the lowest average citation rate. Sorbonne University were the most highly cited institutions. Notably, Frontiers In Oncology published the largest quantity of articles. Andre, Thierry, and Overman, Michael J. were prominent authors known for their prolific output and the high citation rates of their work. The focus areas in this field encompass "tumor microenvironment," "liver metastasis," "tumor-associated macrophages," "combination therapy" and "gut microbiota." Some keywords offer promise as potential biomarkers for evaluating the effectiveness of immunotherapeutic interventions.

Background: The Ras-responsive element binding protein 1 (RREB1) is a transcription factor involved in various biological processes. Notably, RREB1 plays a role in tumor immunity by regulating tumor-related gene expression, shaping the tumor microenvironment, and modulating immune checkpoints. Given these functions, RREB1 has emerged as a potential regulatory target in tumor immunotherapy. However, a comprehensive pan-cancer analysis evaluating RREB1's prognostic value and its role in modulating the immune microenvironment remains unexplored, warranting further investigation to better understand its mechanisms across different cancer types and its implications for personalized immunotherapy., Methods: We analyzed RREB1 expression across 33 cancer types using RNA sequencing data from the TCGA database. RREB1 alterations were further characterized using the cBioPortal database. Clinical and pathological features, along with prognostic significance, were assessed using TCGA clinical data. The involvement of RREB1 in the tumor microenvironment was evaluated using the CIBERSORT and ESTIMATE algorithms. Relationships between RREB1 expression and tumor mutation burden (TMB), as well as microsatellite instability (MSI), were investigated using Spearman's rank correlation coefficient. GSEA was applied to explore the biological functions of RREB1. Additionally, we assessed the link between RREB1 expression and the efficacy of PD-1/PD-L1 inhibitors. Finally, a series of in vitro experiments were performed to evaluate the impact of RREB1 expression on the malignant behavior of osteosarcoma (OS) and lung cancer cell lines., Results: RREB1 was overexpressed in several cancer types and correlated with patient prognosis. RREB1 expression was strongly associated with TMB, MSI, and immune cell infiltration, including regulatory T cells, CD8 + T cells, and macrophages. Furthermore, RREB1 expression was linked to immune responses and the efficacy of immunotherapy. In vitro experiments demonstrated that knockdown of RREB1 significantly inhibited the proliferation and migration of OS cells., Conclusions: RREB1 shows potential as a prognostic marker for certain cancers and may predict the efficacy of immunotherapy. Additionally, RREB1 expression is related to immune-related markers, suggesting its role in prognosis and predicting responses to immune microenvironment therapies in specific tumors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Human epidermal growth factor receptor-2 (HER2), programmed death-ligand 1 (PD-L1), and microsatellite (MS) status are well-established biomarkers in gastroesophageal adenocarcinomas (GEAs). However, it is unclear how the combination of these biomarkers is associated with clinicopathological factors and prognosis. This retrospective study included baseline metastatic GEA patients who were tested for all three biomarkers (HER2, PD-L1, and MS status) at the MD Anderson Cancer Center between 2012 and 2022. Stratification was performed according to the combination of biomarker profiles: triple negative (TN), single positive (SP), and multiple positive (MP). Comparative analyses of clinicopathological factors and survival using combinations of biomarkers were performed. Among the 698 GEA patients analyzed, 251 (36.0%) were classified as TN, 334 (47.9%) as SP, and 113 (16.1%) as MP. The MP group showed a significant association with tumors located in the esophagus (p < .001), well to moderate differentiation (p < .001), and the absence of signet ring cells (p < .001). In the survival analysis, MP group had a significantly longer overall survival (OS) compared to the other groups (MP vs. TN, p < .001 and MP vs. SP, p < .001). Multivariate Cox regression analysis revealed that MP serves as an independent positive prognostic indicator for OS (hazard ratio = 0.63, p < .01). Our findings indicate that MP biomarkers are associated with a favorable prognosis in metastatic GEA. These results are reflective of clinical practice and offer valuable insights into how therapeutics and future biomarkers could influence therapy/prognosis., (© 2024 UICC.)

Treatment of locally advanced rectal cancer involves neoadjuvant chemoradiotherapy (CRT), including induction or consolidation chemotherapy. Introduction of immunotherapy has brought success in several solid tumors and hematological diseases. In colorectal tumors, it was only introduced later. A general predictive biomarker is the deficient mismach repair (dMMR) status and consequent microsatellite instability (MSI-H). In these tumors, immune checkpoint inhibitor (ICI) therapy is the first-choice therapy in metastatic colorectal cancer. ICIs have been used in earlier, non-metastatic stages in several studies, with breakthrough results in the microsatellite-unstable patient group and recently in combination with neoadjuvant CRT in rectal tumor patients with pMMR/MSI-L status. In our report we focused on the recent immune checkpoint inhibitor treatment of metastatic and locally advanced colorectal cancer, as a monotherapy, or combined with chemo- or radiotherapy. We summarize the studies with the most promising results.

The molecular pathological examination of solid tumors is essential not only for supporting histological diagnosis but also for detecting hereditary variations and predictive biomarkers. Analyzing predictive markers is fundamental to personalized cancer therapy, directly affecting patient care through pathological testing. These analyses employ both traditional immunohistochemical staining methods and molecular genetic techniques. In both approaches, preanalytics is of critical importance, necessitating the adoption of standardized and reproducible processes. Molecular diagnostics in colorectal cancer focuses on detecting activating mutations in the MAPK pathway (KRAS, NRAS, BRAF), as well as evaluating microsatellite instability and HER2 amplification. Immunohistochemical methods can effectively identify biomarkers for gastric cancers, including the novel claudin18.2. The responsiveness of gastrointestinal stromal tumors to imatinib requires validation via molecular testing. Patients diagnosed with pancreatic cancer may see enhanced survival rates by targeted therapy addressing microsatellite instability and BRCA mutations. In bile duct malignancies, especially intrahepatic cholangiocarcinoma of the small duct variant, the analysis of IDH1 mutations and FGFR2 fusions presents new treatment prospects.

Background: Pancreatic ductal adenocarcinoma (PDAC) remains a challenging disease due to its aggressiveness, late-stage diagnosis, and limited treatment options. Microsatellite instability-high (MSI-H) cancers are susceptible to immune checkpoint inhibitors. Survival outcomes for patients with MSI-H PDAC are unknown as the disease is rare., Methods: This study included patients with PDACs surgically resected from 1990 to 2023, and those with germline or sporadic pathogenic variants in DNA mismatch repair genes were identified. The study matched MSI-H, mismatch repair-deficient (MMRd), and Lynch syndrome (LS)-associated PDAC cases (on age, gender, and year of surgery) with microsatellite-stable (MSS), mismatch repair-proficient, or non-LS-associated PDAC cases in a 1:2 ratio. A generalized estimating equation Cox model with a robust sandwich estimator was used to compare overall survival (OS) in the matched cohorts., Results: Of 936 cases, 18 were included. Eight cases were MSI-H/MMRd, two were MSI/IHC-indeterminate, seven were MSS, and one was not tested for MSI. Nine patients had LS (MLH1 [n = 1], MSH2 [n = 4], MSH6 [n = 1], PMS2 [n = 3]), and nine patients had sporadic pathogenic variants in DNA MMR genes (MLH1 [n = 4], MSH6 [n = 5]). After matching to 36 control patients, the MSI-H/MMRd/LS PDACs had a significantly better OS (hazard ratio [HR], 0.36 [95% confidence interval [CI], 0.18-0.73; p = 0.005]; 5-year OS: MSI-H 77% [95% CI 58-100%] vs. MSS 27% [95% CI 15-51%])., Conclusion: Before routine use of immune checkpoint inhibitors, the patients with MSI-H, MMRd, and LS-associated PDACs displayed significantly better survival than the patients with MSS, MMR-proficient, non-LS-associated PDACs. It is expected that survival for this cohort will further improve with increased availability of immunotherapy., Competing Interests: Disclosure: Eileen M. O’Reilly reports research funding to Genentech/Roche, BioNTech, AstraZeneca, Arcus, Elicio, Parker Institute, NIH/NCI, and Digestive Care, Break Through Cancer, as well as consulting/DSMB for Arcus, Alligator, Agenus, BioNTech, Ipsen, Merck, Moma Therapeutics, Novartis, Syros, Leap Therapeutics, Astellas, BMS, Fibrogen, Revolution Medicine, Merus Agios (spouse), Genentech-Roche (spouse), Eisai (spouse), Servier (spouse). Jeffrey Drebin reports employment and leadership at American Regent (spouse) and stock and other ownership interests in Alnylam, Arrowhead Pharmaceuticals and Ions pharmaceuticals. Vinod P. Balachandran reports research funding from Genetech/Roche and was an inventor on patent applications related to antigen cross-reactivity and neoantigen quality modeling. Alice C. Wei reports consulting for Histosonics and clinical trial funding from Ipsen. The remaining authors have no conflicts of interest., (© 2024. Society of Surgical Oncology.)

Background: In recent years, as the availability of precision therapies expands, there is increasing reliance on genomic profiling assays to help identify the most appropriate treatment options for patients with advanced cancers. We retrospectively investigated the results of comprehensive genomic profiling tests from the time insurance coverage began until recently and examined the status of genetic analysis., Methods: We retrospectively reviewed the analysis results of 300 patients with advanced solid tumors who consented to comprehensive genomic profiling tests from October 2019 to December 2022., Results: Of the 300 patients who underwent comprehensive genomic profiling tests, analysis results for 274 patients were obtained, and were reviewed by the Clinical Genome Expert Panel. Six specimens (2%) were discontinued due to patient deaths and deteriorations in general condition. The three most frequently occurring actionable genomic alterations observed were TP53 (47.4%), KRAS (28.1%) and CDKN2A (20.4%). The most common druggable variant was CDKN2A, which was noted in 52 (19%) of 274 patients. The next most common were PIK3CA, BRAF, KRAS and PTEN. The cancer types that showed a greater median number of actionable alterations comprised thyroid cancer, pancreatic cancer and colorectal cancer., Conclusions: In conclusion, comprehensive genomic profiling tests have the potential to be valuable in identifying genomic abnormalities. Even if there is no effective treatment at present, it may lead to a treatment in the future. Comprehensive genomic profiling tests should be considered for any cancer., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Approximately 20% of patients living with colorectal cancer (CRC) have activating mutations in their tumors in the PIK3CA oncogene. Two or more activating mutations (multi-hit) for the PIK3CA allele increase PI3K⍺ signaling compared to single-point mutations, resulting in exceptional response to PI3K⍺ inhibition. We aimed to identify the prevalence of PIK3CA multi-hit mutations in metastatic CRC to identify patients who may benefit from PI3K inhibitors., Methods: The Foundation Medicine database (Boston, MA, USA) was analyzed for patients with CRC who underwent genomic profiling on tumor DNA isolated during routine clinical care from 2013 to 2021. Molecular and clinical variables were abstracted for patients with PIK3CA mutations., Results: We identified 49 051 patients with CRC who underwent Foundation Medicine testing. 710/41154 (1.7%) patients had multi-hit PIK3CA mutations, of which 53% were male (n = 448) with a median age of 60. Microsatellite status was available for 697 patients with multi-hit PIK3CA and 17.6% (123/697) were microsatellite instability-high. Clinically relevant mutations in KRAS and BRAFV600E were seen in 459/710 (64.7%) and 65/710 (9.1%), respectively. The 4 most common PIK3CA variants were H1047R (9.8%), E545K (9.2%), E542K (9.0%), and R88Q (7.1%). The most common variant pair was E542K-E545K (4.7%)., Conclusions: Multi-hit mutations in PIK3CA are seen in 1.7% of advanced CRC, a meaningful prevalence given the high burden of CRC worldwide, and may represent a subset of patients that have enhanced sensitivity to PI3K inhibition. Future investigation regarding the clinical utility of PI3K inhibitors is warranted in multi-hit PIK3CA CRC., (© The Author(s) 2024. Published by Oxford University Press.)

Growth differentiation factor 15 (GDF15) is a member of the transforming growth factor beta (TGF-β) superfamily and is related to metabolism, injury, and aging. GDF15 has both tumor-promoting and tumor-suppressing effects. However, its role in colorectal cancer (CRC) with high microsatellite instability (MSI-H) must be further clarified. In our study, we found that GDF15 is generally elevated in pancarcinoma, particularly in colorectal cancer, and serves as an early indicator of the development of colorectal cancer. IHC and WB confirmed that GDF15 was elevated in MSI-H CRC clinical tissues and MSI-H CRC cell lines (HCT-116 and LoVo). Suppressing GDF15 by siRNA resulted in a substantial decrease in cell viability and proliferation. Furthermore, suppressing GDF15 can increase the sensitivity of MSI-H CRC cells to 5-fluorouracil (5-FU), which decreases cell viability and increases the apoptosis rate. In vivo experiments also demonstrated that mouse xenografts with suppressed GDF15 expression were more susceptible to 5-FU chemotherapy. We examined alterations in mitochondria via electron microscopy and changes in the mitochondrial membrane potential, ferroptosis-related signals (MDA, Fe 2+ ), and SLC7A11/GSH/GPX4 protein pathway. Our research indicates that inhibiting GDF15 affects ferroptosis-related pathways, leading to ferroptosis and improving the MSI-H CRC response to 5-FU therapy. As a result, GDF15 could be a promising target for diagnosing and treating MSI-H CRC, potentially enhancing the overall effectiveness of therapy for patients with MSI-H CRC., Competing Interests: Declarations. Conflict of interest: There are no conflicts of interest associated with this manuscript. Informed consent: Informed consent was obtained from all the subjects involved in the study., (© 2024. The Author(s).)

Background: Microsatellite instability (MSI) is a well-established predictive biomarker for immune checkpoint inhibitor (ICI) response in metastatic colon cancer. Both high MSI and tumor mutational burden (TMB) are markers of genomic instability. However, the prognostic and predictive value of TMB in patients with microsatellite stable (MSS) tumors remains unclear., Methods: We evaluated the prognostic significance of TMB levels in MSS metastatic colon cancer patients undergoing standard treatments. Tumor responses were assessed using RECIST v1.1 criteria. Comprehensive clinical and molecular profiling was conducted, including next-generation sequencing (NGS) for TMB evaluation with the TruSight Oncology® kit. Overall survival (OS) was the primary endpoint. Multivariate Cox regression analysis was utilized to assess the relationship among potential prognostic factors., Results: Among 102 MSS metastatic colon cancer patients, high TMB (> 10 mut/mb) was associated with a significantly longer median OS compared to low TMB (70.0 vs 45.0 months, respectively; HR: 0.45; 95% CIs 0.21 to 0.96; P = 0.0396). Multivariate analysis, adjusting for age, gender, number of metastatic sites, response to first-line chemotherapy, RAS mutational status, and liver involvement, identified TMB as an independent prognostic factor, along with response to first-line chemotherapy., Conclusions: Our results highlight the prognostic significance of TMB in MSS metastatic colon cancer patients, suggesting its potential role in patient stratification and treatment decision-making., Competing Interests: Declarations. Ethics approval and consent to participate: In accordance with local and national laws, ethics approval and consent to participate were exempted due to the retrospective/observational and non-interventional nature of the work. However, all patients involved in this study provided written informed consent before undergoing treatment administration and molecular assessments. Consent for publication: Not applicable. Competing interests: Roberto Sirica, Giovanni Savarese, and Monica Ianniello are employed by AMES, Centro Polidiagnostico Strumentale srl, 80013 Naples, Italy. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024. The Author(s).)

The molecular-based detection of microsatellite instability (MSI) in endometrial cancer is complex, due to the low sensitivity of PCR and a lack of standardization in next-generation sequencing (NGS) methods. In the present study, sequenced data were obtained from an NGS panel following the addition of five commonly used microsatellite loci. Subsequently, a novel algorithm, namely MSIPeak, was developed for data analysis. Results of the present study demonstrated that MSI data obtained using MSIPeak were presented in a peak, using a threshold of 1.10 to distinguish stable and unstable loci. MSIPeak was further validated using synthetic DNA samples and endometrial cancer tissue and the results were compared with the immunohistochemical analysis-determined mismatch repair status. The PCR results demonstrated a 3-base-pair (bp) deletion in synthetic DNA samples, compared with 1- and 2-bp deletion controls. Results obtained using MSIPeak demonstrated notable differences in peak profiles and positive scores in synthetic DNA samples with 1-, 2- and 3-bp deletions, compared with controls. Thus, the results of the present study demonstrated that NGS-based MSI detection exhibited a higher sensitivity compared with PCR. In addition, NGS-based MSI detection exhibited higher levels of repeatability and applicability compared with other MSI-NGS-based methods, such as MSISensor2 and MANTIS. Collectively, the results of the present study highlighted that the combination of MSIPeak and NGS exhibits potential in the detection of cancer., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Zhou et al.)

Background: In resectable gastric/gastroesophageal junction adenocarcinoma (GAC/GEJAC), microsatellite instability (MSI-H) confers improved survival, but limited benefit from chemotherapy. Immunotherapy may eliminate the need of chemotherapy or surgery., Patients and Methods: INFINITY is a multicentre, multicohort phase II trial (NCT04817826) investigating in Cohort 1 the activity and safety of tremelimumab+durvalumab (T300/D) as neoadjuvant treatment for dMMR/MSI-H, resectable GAC/GEJAC. Primary endpoint was pathologic complete response (pCR) rate; Secondary endpoints: progression-free survival (PFS), overall survival (OS), quality of life (QoL), and translational analyses. In Cohort 2, the activity and safety of T300/D was explored as definitive treatment in patients achieving clinical complete response (cCR). Primary endpoint was 2-year cCR rate, Secondary endpoints: PFS, OS, QoL, gastrectomy-free survival (GFS) and translational analyses., Results: In Cohort 1, 18 patients were recruited and 15 evaluable. pCR and major-complete pathological response were 60% and 80%. Since pCR rate in T4 tumors was 17%, this subgroup of patients was excluded from enrollment in Cohort 2. At 28.1 months median follow-up, 24-month GC-specific PFS and OS rates were 85% and 92%. In Cohort 2, 18 patients were enrolled and 17 evaluable, 13 had cCR and started non-operative management (NOM). At 11.5 months median follow up, 1 patient had local regrowth and underwent salvage surgery, 12-month GFS was 64.2%., Conclusions: The INFINITY study provided promising activity results of a chemo-free T300/D combination regimen as pre-operative treatment in dMMR/MSI GAC/GEJAC and the first available feasibility results of a NOM strategy in this disease setting, worth of further validation in larger cohorts., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Microsatellite instability (MSI) is an important genomic biomarker for cancer diagnosis and treatment, and sequencing-based approaches are often applied to identify MSI because of its fastness and efficiency. These approaches, however, may fail to identify MSI on one or more sub-clones for certain cancers with a high degree of heterogeneity, leading to erroneous diagnoses and unsuitable treatments. Besides, the computational cost of identifying sub-clonal MSI can be exponentially increased when multiple sub-clones with different length distributions share MSI status. Herein, this paper proposes "scMSI", an accurate and efficient estimation of sub-clonal MSI to identify the microsatellite status. scMSI is an integrative Bayesian method to deconvolute the mixed-length distribution of sub-clones by a novel alternating iterative optimization procedure based on a subtle generative model. During the process of deconvolution, the optimized division of each sub-clone is attained by a heuristic algorithm, aligning with clone proportions that adhere optimally to the sample's clonal structure. To evaluate the performance, 16 patients diagnosed with endometrial cancer, exhibiting positive responses to the treatment despite having negative MSI status based on sequencing-based approaches, were considered. Excitingly, scMSI reported MSI on sub-clones successfully, and the findings matched the conclusions on immunohistochemistry. In addition, testing results on a series of experiments with simulation datasets concerning a variety of impact factors demonstrated the effectiveness and superiority of scMSI in detecting MSI on sub-clones over existing approaches. scMSI provides a new way of detecting MSI for cancers with a high degree of heterogeneity., Competing Interests: I have read the journal’s policy, and the authors of this manuscript have the following competing interests: YW and XY are employed by GenePlus Beijing Institute. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright: © 2024 Liu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Gastric cancer is the fifth most common cancer worldwide and the fourth most common cause of cancer-related death. Two molecular subtyping classifications were recently introduced: The Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group (ACRG) classifications., Methods: We classified a cohort of 283 gastric cancer patients undergoing surgery at Helsinki University Hospital between 2000 and 2009. We constructed a tumour tissue microarray immunostained for the following markers: microsatellite instability (MSI) markers MSH2, MSH6, MLH1, and PMS2; p53; E-cadherin; and EBERISH., Results: In the univariate survival analysis for disease-specific survival, the Epstein-Barr virus (EBV) -positive subtype exhibited the worst prognosis with a hazard ratio (HR) of 2.49 (95% confidence interval [CI] 1.19-5.25, p = 0.016) compared with the most benign subtype, chromosomal instability (CIN). Using TCGA's classification, the genetically stable (GS) and MSI subtypes exhibited a worse survival compared with CIN (HR 1.73 [95% CI 1.15-2.60], p = 0.009 and HR 1.74 [95% CI 1.06-2.84], p = 0.027, respectively). Using the ACRG classification, the p53 aberrant subtype exhibited the best prognosis, whereas wild-type p53, MSI, and the epithelial-mesenchymal transition (EMT) subtypes exhibited poorer prognoses (EMT: HR 1.90 [95% CI 1.30-2.77], p < 0.001) when compared with aberrant p53., Conclusions: Immunohistochemical analysis can identify prognostically different molecular subtypes of gastric cancer. The method is inexpensive and fast, yet reveals significant information for clinical decision-making. However, our study did not find that either molecular subtyping performed better than the other classification. Thus, further development of the most optimal grouping of different molecular subtypes is still needed., Competing Interests: Declarations. Ethics approval and consent to participate: Appropriate ethical permits were granted by the National Supervisory Authority of Health and Welfare (permit for research conducted with human samples: Valvira Dnro 1004/06.01.03.01/2012), the hospital district of Helsinki and Uusimaa (permit number HUS/23/2024), and the Ethics Committee of Medicine of the Helsinki University Central Hospital (permit number HUS/1223/2021). Patient information, samples, and data were handled and stored in accordance with the Declaration of Helsinki and other local regulations. The National Supervisory Authority of Health and Welfare granted permission to study the archived tissue samples without requiring individual informed consent (Valvira Dnro 1004/06.01.03.01/2012). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Deficient mismatch repair or microsatellite instability is a major predictive biomarker for the efficacy of immune checkpoint inhibitors of colorectal cancer. However, routine testing has not been uniformly implemented due to cost and resource constraints., Methods: We developed and validated a deep learning-based classifiers to detect mismatch repair-deficient status from routine colonoscopy images. We obtained the colonoscopy images from the imaging database at Endoscopic Center of the Sixth Affiliated Hospital, Sun Yat-sen University. Colonoscopy images from a prospective trial (Neoadjuvant PD-1 blockade by toripalimab with or without celecoxib in mismatch repair-deficient or microsatellite instability-high locally advanced colorectal cancer) were used to test the model., Results: A total of 5226 eligible images from 892 tumors from the consecutive patients were utilized to develop and validate the deep learning model. 2105 colorectal cancer images from 306 tumors were randomly selected to form model development dataset with a class-balanced approach. 3121 images of 488 proficient mismatch repair tumors and 98 deficient mismatch repair tumors were used to form the independent dataset. The model achieved an AUROC of 0.948 (95% CI 0.919-0.977) on the test dataset. On the independent validation dataset, the AUROC was 0.807 (0.760-0.854), and the NPV in was 94.2% (95% CI 0.918-0.967). On the prospective trial dataset, the model identified 29 tumors among the 33 deficient mismatch repair tumors (87.88%)., Conclusions: The model achieved a high NPV in detecting deficient mismatch repair colorectal cancers. This model might serve as an automatic screening tool., Competing Interests: Declarations. Disclosures: Yue Cai, Xijie Chen, Junguo Chen, James Liao, Ming Han, Dezheng Lin, Xiaoling Hong, Huabin Hu and Jiancong Hu have no conficts of interest or fnancial ties to disclose. Ethical approval: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Besides, the current study was approved by the Institutional Review Board of the Sixth Affiliated Hospital, Sun Yat-sen University. Signed informed consent was not obtained due to the retrospective nature of the study., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: We have previously shown that DNA based, single test molecular classification by next generation sequencing (NGS) (Proactive Molecular risk classifier for Endometrial cancer (ProMisE) NGS) is highly concordant with the original ProMisE classifier and maintains prognostic value in endometrial cancer. Our aim was to validate ProMisE NGS in an independent cohort and assess the performance of ProMisE NGS in real world clinical practice to address if there were any practical challenges or learning points for implementation., Methods: We evaluated DNA extracted from an external research cohort of 211 endometrial cancer cases diagnosed in 2016 from Germany, Switzerland, and Austria, across seven European centers, comparing standard molecular classification (NGS for POLE status, immunohistochemistry for mismatch repair and p53) with ProMisE NGS (NGS for POLE and TP53, microsatellite instability assay) for concordance metrics and Kaplan-Meier survival statistics across molecular subtypes. In parallel, we assessed all patients who had undergone a new NGS based molecular classification test (n=334) comparing molecular subtype assignment with the original ProMisE classifier., Results: A total of 545 endometrial cancers were compared. Prognostic differences in progression free, disease specific, and overall survival between the four molecular subtypes were observed for the NGS classifier, recapitulating the survival curves of original ProMisE. In 28 of 545 (5%) discordant cases (8/211 (4%) in the validation set, 20/334 (6%) in the real world cohort), molecular subtype was able to be definitively assigned in all, based on review of the histopathological features and/or additional immunohistochemistry. DNA based molecular classification identified twice as many 'multiple classifier' endometrial cancers; 37 of 545 (7%) compared with 20 of 545 (4%) with original ProMisE., Conclusion: External validation confirmed that single test, DNA based molecular classification was highly concordant (95%) with original ProMisE classification, with prognostic value maintained, representing an acceptable alternative for clinical practice. Careful consideration of reasons for discordance and knowledge of how to correctly assign multiple classifier endometrial cancers is imperative for implementation., Competing Interests: Competing interests: MKM, JR, and AL are previous employees of Imagia Canexia Health. DGH is a previous founder and Chief Medical Officer of Imagia Canexia Health., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Opinion Statement: The biological heterogeneity of colorectal cancer makes its molecular characteristics essential for therapeutic decision-making and prognostic evaluation. Recent advancements in consensus molecular subtyping, based on gene expression profiling, have provided deeper insights into the heterogeneity of CRC. CMS1, known as the immune subtype, is characterized by robust immune activity and microsatellite instability. CMS2, the canonical subtype, exhibits significant activation of the WNT and MYC signaling pathways. CMS3, the metabolic subtype, features unique metabolic dysregulations. CMS4, the mesenchymal subtype, is recognized for its stromal invasion and angiogenesis, which are associated with a poorer prognosis. This review delivers a thorough analysis of the biological and clinical responses of each CMS subtype in colorectal cancer, highlighting their therapeutic vulnerabilities. It integrates data and clinical trial results to suggest potential new therapies for each subtype. The goal is to improve therapeutic efficacy, minimize treatment disparities, and offer CRC patients more precise treatment options., Competing Interests: Declarations. Approval of the research protocol by an Institutional Reviewer Board: N/A. Informed Consent: N/A. Registry and the Registration No. of the study/trial: N/A. Animal Studies: N/A. Competing interests: The authors declare no competing interests. Human and Animal Rights and Informed Consent: This article does not contain any studies with human or animal subjects performed by any of the authors., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

WRN helicase is a crucial target of synthetic death in cancer and has a unique advantage in the treatment of microsatellite unstable cancers. Our previous studies have found that quinazoline derivatives showed the WRN-dependent antiproliferative activity. In this study, a series of new quinazoline derivatives were designed and synthesized by optimizing the structure, and evaluating the targeting and sensitivity to WRN helicase. Cell growth inhibition experiments on WRN overexpressing PC3 cells (PC3-WRN) showed that the antiproliferative activity of some compounds was significantly dependent on WRN helicase. Moreover, the antitumor activity of 9in vivo was significantly decreased in the nude mouse model constructed with WRN knockdown PC3 cells (PC3-shWRN) compare (P < 0.01) to the control group. The molecular docking and CETSA results showed that 9 directly binds to WRN protein. Mechanism studies have confirmed that 9 targeted WRN, and may affect the binding between WRN and other key regulators, to destroy the repair function and regulate genomic stability. In addition, 9 also has suitable pharmacokinetic parameters and low toxicity in vivo. This result indicates that the quinazoline derivative 9 could be a novel WRN function inhibitor for the treatment of prostate cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

The Repeat Expansion Diseases (REDs) are a large group of human genetic disorders that result from an increase in the number of repeats in a disease-specific tandem repeat or microsatellite. Emerging evidence suggests that the repeats trigger an error-prone form of DNA repair that causes the expansion mutation by exploiting a limitation in normal mismatch repair. Furthermore, while much remains to be understood about how the mutation causes pathology in different diseases in this group, there is evidence to suggest that some of the downstream consequences of repeat expansion trigger the DNA damage response in ways that contribute to disease pathology. This review will discuss these subjects in the context of the Fragile X-related disorders (aka the FMR1 disorders) that provide a particularly interesting example of the intersection between the repeats and the DNA damage response that may also be relevant for many other diseases in this group., Competing Interests: Declaration of Competing Interest All of the authors have nothing to declare., (Published by Elsevier B.V.)

Background/objectives: Patients with recurrent or metastatic endometrial cancer (EC) have poor prognoses with limited therapeutic options following immunotherapy or immunochemotherapy treatments. Inhibitors of KRAS mutations (KRAS-mut) have shown efficacy in early solid tumor studies, but data in EC are lacking. This study describes the frequency of KRAS-mut relative to other oncogenic alterations in EC to identify genomic characteristics of KRAS-mut tumors that could lead to novel therapeutic options., Methods: A molecular database of 7870 ECs was queried for presence of oncogenic mutations and immunotherapy biomarkers. Comparisons were performed using Fisher-Exact/ChiSquare (p-values) and adjusted for multiple tests by Benjamini-Hochberg (q) and pairwise nonparametric analysis using Wilcoxon Method., Results: KRAS-mut is a relatively frequent genotype in EC, detected in 16% of cases. Codon 12 was most frequently mutated, with G12D (31%) and G12V (27%) the most common subtypes. Biomarkers of immunotherapy response co-occur with KRAS-mut. Microsatellite instability-high and tumor mutational burden-high status were observed in 34.1% and 36.5% in KRAS-mut compared to 19.8% and 16.9% in KRAS-WT, respectively (p < 0.05). PD-L1 >1% was detected in 8.4% vs 6.4% of KRAS-mut vs KRAS-WT (p < 0.05). BRCA1/2 mutations were detected with similar low frequency (5.9% vs 4.9%) among KRAS-mut and KRAS-WT ECs (p > 0.05). KRAS-mut was inversely associated with Her-2 overexpression (1.8% KRAS-mut vs 13% KRAS-WT. (p < 0.001)., Conclusions: KRAS-mut represents a genotypically distinct group of ECs. Overlap exists with genomic predictors (TMB-high, MSI-high) of immunotherapy response, suggesting a possible biomarker-driven combination option with immunotherapy. Clinical trials to evaluate these strategies should be developed., Competing Interests: Declaration of competing interest RWH has Speaking Honoraria with AstraZeneca, Eisai, Merck, Natera, and Tesaro/GSK; and Consulting or Advisory Roles with Caris, Genelux, Natera, ImmunoGen, and GSK. PHT has done advisory boards or consulting work with Iovance, Astra Zeneca, Glaxo Smith Kline, Clovis Oncology, Zentalis, Novocure, Seagen, Abbvie, R Pharm, Aadi Pharmaceuticals, Caris, Merck, Imunon, Verastem; and has institutional grant funding from Merck and Glaxo Smith Kline. TJH has done advisory boards or consulting work with Aadi, Astra Zeneca, AbbVie (Immunogen), Caris, Clovis, Corcept, Eisai, Genmab, GSK, GOG Foundation, Merck, Pfizer (Seagen), Roche (Genentech). There are no conflicts to report for other co-authors., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Combination regorafenib, ipilimumab, and nivolumab (RIN) was evaluated in a phase 1 nonrandomized study (NCT04362839) of refractory microsatellite stable (MSS) metastatic colorectal cancer. Promising antitumor activity was previously reported in the non-liver metastatic (NLM) population. This updated analysis describes long-term survival outcomes in the NLM cohort and highlights durable remissions with potential cure following completion of RIN therapy., Methods: Between May 2020 and January 2022, 39 patients with refractory MSS metastatic colorectal cancer were enrolled. Patients received RIN until progression, unacceptable toxicity, or completion at two years. The primary endpoint was recommended phase 2 dose (RP2D) selection. Secondary endpoints were safety, overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) at the RP2D level., Results: 22 patients with refractory non-liver metastatic MSS colorectal cancer were treated at the RP2D of RIN. ORR was 36.4 % (8/22 patients), and median PFS was 5.0 months (95 % CI: 3-9). After a median follow-up of 42 months, the 1-, 2-, and 3-year PFS rates were 24.1 %, 24.1 %, and 19.3 % by RECIST. The median OS was 27.5 months (95 % CI: 14.0 to NE). At data cutoff, 6 patients had ongoing clinical benefit, including 3 responders who remain disease-free > 18 months after treatment completion., Conclusion: With extended follow-up, RIN combination therapy demonstrated durable clinical benefit in a subset of patients with NLM MSS metastatic colorectal cancer, including potential cure in 3 responders who remain disease-free > 18 months after treatment completion., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. MF reports research funding from AgenusBio (institution), Bristol-Myers Squibb (institution), Genentech (institution), and Verastem (institution); consulting/advisory relationships with AbbVie, AstraZeneca, Bristol-Myers Squibb, Incyte Corporation, Janssen, Pfizer, and Taiho Oncology; and scientific advisory board for Bayer Corporation, Eisai, Entos, Inc., GlaxoSmithKline, Merck, Mirati Therapeutics, Inc., Nouscom, and Roche/Genentech. The other authors have no conflicts of interest to report., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Neoadjuvant immune checkpoint inhibition (ICI) is a new approach to treat patients with colorectal cancer (CRC). The effects of combined neoadjuvant ICI in locally advanced, DNA mismatch repair (dMMR)-deficient/microsatellite instable (MSI) CRC were recently reported by de Gooyer et al. from the NICHE-3 trial. Further studies will determine whether these impressive pathological responses lead to long-term clinical benefit., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Fusobacterium nucleatum (Fn) is significantly associated with poor prognosis in colorectal carcinoma (CRC), however, mechanisms of Fn in DNA mismatch repair (MMR) and microsatellite instability (MSI) in CRC have not been fully elucidated. Clinical samples are collected to analyze the relationship between Fn abundance and microsatellite stability. Tumor cells are treated with Fn to detect the expression of proteins related to toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (Myd88), mutS homolog 6 (MSH6), and nuclear factor-κB (NF-κB) signaling pathways, respectively. Combined with the prediction results from TargetScan, the regulatory role of microRNA upstream of MSH6 is demonstrated. The effect of this regulatory axis on CRC development is demonstrated using a nude mouse tumor model. Compared with microsatellite stability (MSS)-type CRC patients, MSI-type showed higher Fn abundance. Fn treatment of CRC cells activated TLR4/Myd88/NF-κB signaling pathway, transcriptionally activating miRNA-155-5p expression, thereby negatively regulating MSH6. Fn treatment accelerated the malignant progression of CRC in mice, and this process is inhibited by miRNA-155-5p antagomir. Fn in CRC upregulated miRNA-155-5p by activating TLR4/NF-κB signaling to inhibit MSH6, and this regulatory pathway may affect MSS of cancer cells., (© 2024 Wiley‐VCH GmbH.)

Approximately 15% of locally advanced colorectal cancers (CRC) have DNA mismatch repair deficiency (dMMR), resulting in high microsatellite instability and a high tumour mutational burden. These cancers are frequently sensitive to therapy with immune-checkpoint inhibitors (ICIs) in the metastatic setting. This sensitivity seems to be even more pronounced in locally advanced disease, and organ preservation has become a realistic aim in ongoing clinical trials involving patients with dMMR rectal cancer. By contrast, metastatic CRCs with proficient DNA mismatch repair (pMMR) are generally resistant to ICIs, although a proportion of locally advanced pMMR tumours seem to have a high degree of sensitivity to ICIs. In this Review, we describe the current and emerging clinical evidence supporting the use of neoadjuvant ICIs in patients with dMMR and pMMR CRC, and the potential advantages (based on a biological rationale) of such an approach. We discuss how neoadjuvant 'window-of-opportunity' trials are being leveraged to progress biomarker discovery and we provide an overview of potential predictive biomarkers of response to ICIs, exploring the challenges faced when evaluating such biomarkers in biopsy-derived samples. Lastly, we describe how these discoveries might be used to drive a rational approach to trialling novel immunotherapeutic strategies in patients with pMMR CRC, with the ultimate aim of disease eradication and the generation of long-term immunosurveillance., Competing Interests: Competing interests C.J.M.W. has received institutional research funding from GSK, Merck Serono, and Roche Diagnostics and honoraria from Merck Serono, Roche Diagnostics, Servier and Tactics MD. A.M.P. has received institutional research funding from GSK. P.M.K. has received institutional research funding from Agenus. J.F.S. has received institutional research funding from Amgen, GSK, Merck Serono, and Pierre Fabre Medicament and honoraria from AstraZeneca, Biocartis, BMS, GSK, Jazz Pharmaceuticals, Merck Serono, Pierre Fabre Medicament, Roche Diagnostics, Sanofi, Seagen, Servier and Takeda. C.S.R. has received institutional research funding from GSK. G.W.M. has received institutional research funding from AstraZeneca. S.T. has received institutional research funding from GSK., (© 2024. Springer Nature Limited.)

Background: Metastatic castration-resistant prostate cancer (mCRPC) typically exhibits resistance to immune checkpoint inhibitors (ICIs). However, a subset of mCRPC patients displays a more immunogenic profile. This study examines efficacy and safety of dual ICI therapy in molecularly selected mCRPC., Patients and Methods: This single-arm, phase II trial included 69 molecularly selected mCRPC patients with mismatch repair deficiency (dMMR), non-synonymous tumour mutational burden ≥7.1 muts/Mb (hTMB), a BRCA2 mutation (BRCAm), or biallelic CDK12 inactivation (CDK12i). Efficacy was assessed in ICI-naïve patients (cohort A) with RECIST 1.1 (A1) and Prostate Cancer Working Group 3 (A2) measurable disease. Safety was evaluated in cohorts A and B (prior ICI monotherapy). Treatment included nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks for four cycles, followed by nivolumab 480 mg every 4 weeks for up to 1 year. The primary endpoint was disease control rate beyond 6 months (DCR > 6), aiming to surpass a DCR > 6 of 22%., Results: Patients initiated treatment between January 2021 and February 2024. Cohort A included 65 patients. Of these, 21 had dMMR (32%), 8 had hTMB (12%), 20 had BRCAm (31%), and 16 had CDK12i (25%). DCR > 6 was achieved in 38% of patients [95% confidence interval (CI) 27% to 51%], and was highest in dMMR (81%), followed by hTMB (25%), CDK12i (19%), and BRCAm (15%). Objective response rate in cohort A was 38% (95% CI 22% to 55%) and 47% (95% CI 34% to 60%) exhibited a 50% decline in prostate-specific antigen levels. Median progression-free survival (PFS) was 4.0 months (95% CI 3.5-12.0 months) in cohort A, and 32.7 months (95% CI 21.8 months-not reached) in dMMR patients. Treatment-related adverse events (TRAEs) led to permanent discontinuation in 14 of 69 patients (20%). Grade ≥3 TRAEs occurred in 48% of patients, with diarrhoea and elevated transaminases each in 10%. There was one treatment-related death due to a bowel perforation and a second following euthanasia after grade 4 toxicity., Conclusions: This trial of dual ICIs in molecularly selected mCRPC met its primary endpoint, showing DCR > 6 in 38% of patients. Dual ICIs exhibited modest responses in the hTMB, BRCAm, and CDK12i subgroups, but demonstrated exceptional efficacy in dMMR., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: Endometrial carcinoma (EC) has different molecular subtypes associated with varied prognosis. We sought to characterize the molecular features of ECs with POLE hotspot mutations and concurrent mismatch repair (MMR) deficiency/high microsatellite instability (MSI)., Methods: We identified POLE-mutated (POLEmut), MMR-deficient (MMRd)/MSI-high (MSI-H), or combined POLEmut/MMRd ECs subjected to clinical tumor-normal panel sequencing between 2014 and 2023. Clonality of somatic mutations, MSI scoring, tumor mutational burden (TMB), proportion of somatic insertions and deletions (indels), and single base substitution (SBS) mutational signatures were extracted., Results: We identified 41 ECs harboring POLE exonuclease domain hotspot mutations, 138 MMRd and/or MSI-H ECs, and 14 POLEmut/MMRd ECs. Among the 14 POLEmut/MMRd ECs, 11 (79 %) exhibited clonal POLE hotspot mutations; 4 (29 %) had a dominant POLE-related mutational signature, 4 (29 %) displayed dominant MMRd-related signatures, and 6 (43 %) had mixtures of POLE, aging/clock, MMRd, and POLEmut/MMRd-related SBS mutational signatures. The number of single nucleotide variants was higher in POLEmut/MMR-proficient (MMRp) and in POLEmut/MMRd ECs compared to POLE wild-type (wt)/MMRd EC (both p < 0.001). Small indels were enriched in POLEwt/MMRd ECs (p < 0.001). TMB was highest in POLEmut/MMRd EC compared to POLEmut/MMRp and POLEwt/MMRd ECs (both p < 0.001). Of 14 patients with POLEmut/MMRd EC, 21 % had a recurrence, versus 10 % of those with POLEmut/MMRp EC. Similar findings were noted in 3 POLEmut ECs in patients with Lynch syndrome; akin to somatic POLEmut ECs, these tumors had high TMB., Conclusion: POLEmut/MMRd ECs may be genetically distinct. Further studies are needed to assess the impact on outcomes and treatment response within this population., Competing Interests: Declaration of competing interest Dr. Weigelt reports funding by REPARE Therapeutics, and employment of an immediate family member at AstraZeneca, outside the submitted work. Dr. Momeni-Boroujeni reports consulting work at Scorpion Therapeutics. Dr. Abu-Rustum reports research funding paid to the institution from GRAIL. Dr. Liu reports research funding to the institution from AstraZeneca, GSK/Tesaro, Repare Therapeutics and Artios Pharma unrelated to this work, and payment/honoraria from Topline Bio and HMP Education. The other authors do not have potential conflicts of interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Colorectal cancer (CRC) with BRAF V600E mutation presents a formidable scientific and clinical challenge due to its aggressive nature and poor response to standard therapeutic approaches. BRAF V600E mutation-induced conspicuous activation of the MAPK pathway contributes to the relentless tumor progression. Nevertheless, the efficacy of multi-targeted MAPK pathway inhibition remains suboptimal in clinical practice. Patients with high microsatellite instability (MSI-H) have shown favorable results with immune checkpoint inhibitors (ICIs). The combination of the MAPK pathway inhibition with ICIs has recently emerged as a promising regimen to improve clinical outcomes in the microsatellite stable (MSS) subgroup of BRAF V600E-mutant metastatic CRC patients. In this review, we elucidate the unique tumor biology of BRAF V600E-mutant CRC, with a particular focus on the immune features underlying the rationale for ICI treatments in the MSI-H and MSS subpopulations, then highlight the trends in clinical trials of the ICI therapy for BRAF V600E-mutant metastatic CRC., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Cutaneous melanoma (CM) is the most common type in Caucasians, while acral melanoma (AM) and mucosal melanoma (MM), which are resistant to immunotherapies and BRAF/MEK-targeted therapies, are more common in East Asians. Genomic profiling is essential for treating melanomas, but such data are lacking in Japan., Methods: Comprehensive genomic profiling data compiled in the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) were analyzed., Results: A total of 380 melanomas was analyzed, including 136 CM, 46 AM, 168 MM, and 30 uveal melanoma (UM). MM included conjunctival, sinonasal, oral, esophageal, anorectal, and vulvovaginal melanomas. No significant difference in the median tumor mutational burden (TMB) of CM (3.39 mutations/megabase), AM (2.76), and MM (3.78) was the key finding. Microsatellite instability-high status was found in one case. BRAF V600E/K was found in only 45 patients (12%). Key driver mutations in CM were BRAF (38%), NRAS (21%), NF1 (8%), and KIT (10%), with frequent copy number alterations (CNAs) of CDKN2A, CDKN2B, and MYC. AM was characterized by altered KIT (30%), NRAS (26%), and NF1 (11%) and CDKN2A, CDKN2B, CDK4, MDM2, and CCND1 CNAs. MM was characterized by altered NRAS (24%), KIT (21%), and NF1 (17%) and MYC, KIT, and CDKN2A CNAs, with differences based on anatomical locations. UM bore GNAQ or GNA11 driver mutations (87%) and frequent mutations in SF3B1 or BAP1., Conclusion: The distinct genomic profiling in Japanese patients, including lower TMB, compared to Caucasians, is associated with poorer treatment outcomes. This result underscores the need for more effective therapeutic agents., Competing Interests: Declarations. Conflict of interest: Tokimasa Hida received research funds from Maruho Takagi Dermatology Foundation and Suhara Memorial Foundation. The other authors declare that there are no conflicts of interest regarding this work. Ethics approval and consent for participation and publication: The Institutional Review Board of Sapporo Medical University Hospital (#282-224) and the C-CAT Information Utilization Review Board (CDU2023-033N) approved this study. Informed consent was obtained from all patients at each institution, allowing their data to be deposited in the C-CAT database for research purposes., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Background: Microsatellite Instability (MSI) and Tumor Mutational Burden (TMB) are associated with immune checkpoint inhibitor (ICI) efficacy. We examined the association between TMB and MSI status with survival in patients with urothelial carcinoma (UC) treated with ICI., Methods: Patients from 15 institutions were treated with ICI monotherapy. Primary endpoint was overall survival and secondary endpoints included observed response rate (ORR), and progression-free (PFS) calculated from ICI initiation. TMB was analyzed as dichotomous (≥10 vs. <10 mut/Mb) and continuous variable., Results: We identified 411 patients: 203 were treated with ICI 1L/upfront; 104 with 2 + L. For the 1L/upfront: median [m] OS was numerically longer in patients with TMB ≥10 versus TMB <10: mOS 35 versus 26 months (HR = 0.6) and with MSI-H and MSI-S (mOS NR vs. 22 months), though neither association was statistically significant. A statistically significant association was found between TMB (continuous variable) and OS (HR = 0.96, P = .01). For 2 + L: mOS was numerically longer in patients with TMB ≥10 versus TMB <10: (20 vs. 12 months; HR = 0.9); mOS was 12 and 17 months for patients with MSI-H and MSI-S, respectively. Eighty-nine patients received maintenance avelumab (mAV): mOS was longer in patients with TMB ≥10 versus TMB <10: 61 versus 17 months; (HR = 0.2, P = .02) and with MSI-H and MSI-S (NR vs. 24 months)., Conclusions: Although not reaching statistical significance in several subsets, patients with high TMB and MSI-H had numerically longer OS with ICI, especially with mAV. Further validation is needed., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Mismatch repair deficient (dMMR) gastroesophageal cancers (GEC) are a distinct subgroup. Among patients with locally advanced disease, previous trial data suggest a good response to neoadjuvant immune checkpoint inhibitors (nICI)., Patients and Methods: Since 2019, our institution has routinely performed MMR testing for new GEC cases. Patients diagnosed with GEC (2019-2024) were included in the study. Quantitative data are described as the median and interquartile range (IQR); qualitative data are described as quantities and percentages., Results: A total of 24 patients with dMMR GEC were identified following implementation of routine immunohistochemical testing; 14 were potentially resectable with a median follow-up of 14 months (IQR 8-27). All patients underwent pre-treatment positron emission tomography (PET; median SUV 20.9). Among the 14 potentially resectable patients, 4 underwent immediate surgery, 10 were treated with nICI, and 5 underwent surgical resection to date. All regimens included PD-1 inhibitors, with 70% receiving pembrolizumab. Re-staging PET was performed in five patients; the median post-nICI SUV was 5.1 (range 4.7-6.3). All resected specimens had gross ulceration after nICI, but 60% (N = 3) had a pathologic complete response (pCR) following nICI; one patient had a near-complete response (nCR) and one patient had a partial response (pPR). Reduction in SUV was 75% and 82% in the pCR patients, 25% in the nCR patient, and 43% in the pPR patient., Conclusions: dMMR GECs are responsive to nICI in this limited experience, mirroring early clinical trial data. Given persistent metabolic activity and visible ulceration despite pCR, studies should continue to optimize tools for estimating post-nICI pCR in these patients., (© 2024. Society of Surgical Oncology.)

Purpose: To assess immunogenic effects in unembolized contralateral tumor after single lobar yttrium-90 transarterial radioembolization ( 90 Y-TARE) of colorectal liver metastases (CRLMs)., Material and Methods: The analysis comprised 10 patients with microsatellite stable (MSS) CRLM scheduled for staged treatment in the prospective AROMA trial. Eligibility criteria included bilobar metastatic disease with >5 lesions without any treatment within 3 weeks. Baseline biopsy was followed by initial 90 Y-TARE treatment of 1 liver lobe, followed by a second biopsy of yet untreated tumors in the other liver lobe at a median of 13 days (range, 4-49 days) immediately before second treatment. Tumor biopsies and peripheral blood mononuclear cells (PBMCs) were collected before treatments for immune cell analysis. Patients were stratified into responders and nonresponders based on tumor control or progression during follow-up., Results: At baseline, responders (n = 4) displayed lower concentrations of FoxP3 + cells and colocation of CD4 + FoxP3 + cells than nonresponders (both P = .02) in tumor tissues. At second biopsy, nonresponders showed a higher CD68 + macrophage density (P = .0014) than responders. Responders displayed fewer CD4 + FoxP3 + T cells than CD8 + T cells at all time points (P = .02 and P = .0428). Nonresponders demonstrated a trending increase in CD68 + macrophages (P = .062), as well as a higher CD8 + PD1 + /CD8 + ratio (P = .062). PBMCs of nonresponders displayed lower CD8 + PD1 + T cells and CD8 + PD1 + /CD8 + ratio at both time points., Conclusions: 90 Y-TARE induces local immunogenic effects in nonexposed MSS CRLM, as well as systemic exhaustion of immune cells in nonresponders. Clinical implications such as a prognostic role or synergism of 90 Y-TARE and checkpoint inhibition in MSS CRLM warrant further investigation., (Copyright © 2024 SIR. Published by Elsevier Inc. All rights reserved.)

Background: Stage II colon cancer (CC) exhibits considerable prognostic heterogeneous. Our objective was to assess survival but also the prognosis impact of microsatellite instability (MSI) in patients with stage IIC (T4bN0M0) CC., Patients and Methods: We conducted a retrospective observational study including all patients who had primary stage IIC CC resection between 2010 and 2020 in 2 expert centers. The primary endpoint was overall survival (OS) and disease-free survival (DFS) and time-to-relapse (TTR) were secondary endpoints., Results: Sixty-six patients, median age of 74 years [30-95], were included, with 37.9% presenting MSI (n = 25). Organ invasion involved the last ileal loop (n = 17), another colonic segment (n = 15), omentum (n = 13), visceral peritoneum (n = 13), and the bladder (n = 4). Surgical quality criteria showed complete monobloc resection in all patients and 93.9% R0 resection. After a median follow-up of 5 years [3.5-6.6], the entire population showed a 5-year OS of 65.2% [53.0-80.3] and 5-year DFS of 53.5% [41.1-69.6], with 18.9% [6.8-29.4] experiencing relapses at 5 years. The MSI phenotype correlated with improved 5-year OS (75.5% [56.5-100] vs. 59.5% [44.9-79.0], HR 0.41 [0.17-0.99]; P = .04), but DFS and TTR did not differ. Adjuvant chemotherapy was administered to 34.9% of patients. Univariate analysis identified age > 65 years, MSI status, and the number of nodes as factors associated with OS., Conclusion: These data underline, in relation to a low rate of relapse, the lack of consensus regarding the appropriate indication for adjuvant chemotherapy in this high-risk stage II population., Competing Interests: Disclosure The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: TS received personal fees from Merck Serono. OD received personal fees from Bristol-Myers-Squibb, Merck & Co Inc, Merck-Serono, Sanofi, and Servier. RC received personal fees from Bristol-Myers Squibb, Exeliom Biosciences, and Enterome. TA reported attending advisory board meetings and/or receiving consulting fees from Abbvie, Aptitude Health, Bristol Myers Squibb, Gritstone Oncology, Gilead, GlaxoSmithKline, Merck & Co Inc, Nordic Oncology, Seagen, Servier, and Takeda; honoraria for lectures, presentations, or speakers bureaus from Bristol Myers Squibb, GlaxoSmithKline, Merck & Co Inc, Merck Serono, Roche, Sanofi, Seagen, Servier, and Takeda; support for meetings from Merck & Co Inc and and a DMC member role for Inspirna. All other authors have no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The systemic inflammatory response (SIR), defined as elevated levels of circulating C-reactive protein (CRP), is an important predictor of impaired survival in colorectal cancer. The aim of this study was to explore the prognostic role of SIR and its association with tumour mismatch repair status and the immune response. Immune activity profiles of mononuclear cells isolated from CRC tissues and blood in the U-CAN exploration cohort (n = 69), were analysed by flow cytometry. In the U-CAN validation cohort (n = 257), T-helper cells (T-bet + ), cytotoxic T cells (CD8 + ), regulatory T cells (FoxP3 + ), B cells (CD20 + ), and macrophages (CD68 + ) were analysed by multispectral imaging. Microsatellite instability was determined using five mononucleotide-repeat microsatellite markers. Patients with high CRP levels (> 10 mg/l) were significantly more often diagnosed with high-grade tumours and tumours exhibiting microsatellite instability. However, some patients with high CRP levels were found to have microsatellite-stable tumours. Furthermore, high CRP levels were associated with specific tumour immune traits including an augmented macrophage response and were significantly linked to poorer cancer-specific survival, particularly in patients with microsatellite-stable tumours. In conclusion, our findings suggest an interplay between SIR and mismatch repair status in CRC prognosis which needs to be further explored., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Supplementary Information accompanies this paper. Supplementary Table S1: Multivariable Cox regression analysis in Stage I-III patients from the U-CAN validation cohort., (© 2024. The Author(s).)

Background: Recently, screening of colorectal cancer (CRC) patients for mismatch repair/microsatellite instability (MMR/MSI) status is widely practiced due to its potential predictive and prognostic roles and a screening tool to reveal Lynch Syndrome (LS). The purpose of the study was to evaluate concordance between immunohistochemistry (IHC) and MSI analysis methods for detection of MMR/MSI status in colorectal cancer patients in Kuantan, Pahang., Methods: Fifty selected CRC cases of deficient mismatch repair (dMMR) and proficient mismatch repair (pMMR) which were identified immunohistochemically in the previous study were subjected to MSI analysis. MSI Analysis System 1.2 (Promega) was utilized., Results: The results of MSI analysis method showed MSI-High: 26% (13/50), MSI-Low: 6% (3/50), and Microsatellite Stable: 68% (34/50). The concordance was perfect (0.896, Kappa value) between MSI analysis and IHC methods for the assessment of MMR/MSI status in CRC patients. The discordance was only 4% (2/50). MSI analysis identified all dMMR cases determined by IHC except one case. The obtained frequency of dMMR and pMMR patients was 11.4% (14/123) and 88.6% (109/123) by IHC method, respectively., Conclusion: Our findings support the universal practice of evaluating the MMR/MSI status in all newly diagnosed CRC patients. Based on the perfect concordance of two methods, the method of choice is based on the availability of expertise and equipments. IHC is highly appreciable method due to its feasibility and reproducibility., Competing Interests: Declarations. Ethical approval: All methods were carried out in accordance with relevant guidelines and regulations from National Medical Research Register (NMRR) of Malaysia and IIUM Research Ethic Committee (IREC); [NMRR-18-3675-45439(IIR)] and (IREC 2019 − 180), respectively. Since the research was conducted on FFPE blocks and no personal information is disclosed and the subjects are not identified, thus, no informed consent was taken from patients, a waiver of informed was obtained from International Islamic University Malaysia (IIUM). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Patients with microsatellite-instability-high (MSI-H) or mismatch-repair-deficient (dMMR) metastatic colorectal cancer have poor outcomes with standard chemotherapy with or without targeted therapies. Nivolumab plus ipilimumab has shown clinical benefit in nonrandomized studies of MSI-H or dMMR metastatic colorectal cancer., Methods: In this phase 3 open-label trial, we randomly assigned patients with unresectable or metastatic colorectal cancer and MSI-H or dMMR status according to local testing to receive, in a 2:2:1 ratio, nivolumab plus ipilimumab, nivolumab alone, or chemotherapy with or without targeted therapies. The dual primary end points, assessed in patients with centrally confirmed MSI-H or dMMR status, were progression-free survival with nivolumab plus ipilimumab as compared with chemotherapy as first-line therapy and progression-free survival with nivolumab plus ipilimumab as compared with nivolumab alone in patients regardless of previous systemic treatment for metastatic disease. At this prespecified interim analysis, the first primary end point (involving nivolumab plus ipilimumab vs. chemotherapy) was assessed., Results: A total of 303 patients who had not previously received systemic treatment for metastatic disease were randomly assigned to receive nivolumab plus ipilimumab or chemotherapy; 255 patients had centrally confirmed MSI-H or dMMR tumors. At a median follow-up of 31.5 months (range, 6.1 to 48.4), progression-free survival outcomes (the primary analysis) were significantly better with nivolumab plus ipilimumab than with chemotherapy (P<0.001 for the between-group difference in progression-free survival, calculated with the use of a two-sided stratified log-rank test); 24-month progression-free survival was 72% (95% confidence interval [CI], 64 to 79) with nivolumab plus ipilimumab as compared with 14% (95% CI, 6 to 25) with chemotherapy. At 24 months, the restricted mean survival time was 10.6 months (95% CI, 8.4 to 12.9) longer with nivolumab plus ipilimumab than with chemotherapy, a finding consistent with the primary analysis of progression-free survival. Grade 3 or 4 treatment-related adverse events occurred in 23% of the patients in the nivolumab-plus-ipilimumab group and in 48% of the patients in the chemotherapy group., Conclusions: Progression-free survival was longer with nivolumab plus ipilimumab than with chemotherapy among patients who had not previously received systemic treatment for MSI-H or dMMR metastatic colorectal cancer. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 8HW ClinicalTrials.gov number, NCT04008030.)., (Copyright © 2024 Massachusetts Medical Society.)

Background/Objectives: Mismatch repair (MMR) deficiency can be indicative of Lynch syndrome (LS) and guide treatment with immune checkpoint inhibitors. Colorectal cancers (CRCs) and endometrial cancers (ECs) are routinely screened to identify LS, primarily using immunohistochemistry (IHC) or microsatellite instability (MSI) testing, but concordance between these methods is variable in ECs. Here, we investigate this variability in 361 ECs from the Ohio OCCPI/OPTEC ( n = 196) and Manchester PETALS ( n = 165) trials, where concordance between assays differed significantly. Methods: Samples were re-tested using the amplicon-sequencing-based Newcastle MSI assay (NCL&#95;MSI), and analysed with respect to existing IHC, MSI and MLH1 promoter hypermethylation data. Results: NCL&#95;MSI showed consistency with the Ohio results (94% and 97% concordance with IHC and original MSI assays, respectively) and increased concordance within the Manchester cohort from 78% to 86% (MSI) and 84% (IHC). Among discordant Manchester samples, NCL&#95;MSI was significantly associated with MLH1 promoter methylation status ( p = 0.0028) and had the highest concordance with methylation, (62/69 samples, 90%), indicating utility as a screening tool in this tumour type. However, tumours with germline MSH6 defects were only detected efficiently with IHC; seven out of eight LS tumours classified as MSS by either MSI assay had isolated MSH6 loss, compared to four out of twelve classified as MSI-H by both ( p = 0.028). Furthermore, reduced MSI signal was observed in tumours with isolated MSH6 loss ( p = 0.009 Ohio, p = 6.2 × 10 -5 Manchester) and in both ECs and CRCs with germline defects, although this only reached significance in CRCs ( p = 0.002). Conclusions: These results provide further evidence that ECs with MSH6 loss in particular and LS tumours in general have an attenuated MSI signal, providing support for current guidelines specifically recommending IHC for LS detection and immune checkpoint therapy assessment in EC.

Purpose: To develop and validate deep learning (DL) models using preoperative contrast-enhanced CT images for tumor auto-segmentation and microsatellite instability (MSI) prediction in colorectal cancer (CRC)., Materials and Methods: Patients with CRC who underwent surgery or biopsy between January 2018 and April 2023 were retrospectively enrolled. Mismatch repair protein expression was determined via immunohistochemistry or fluorescence multiplex polymerase chain reaction-capillary electrophoresis. Manually delineated tumor contours using arterial and venous phase CT images by three abdominal radiologists are served as ground truth. Tumor auto-segmentation used nnU-Net. MSI prediction employed ViT or convolutional neural networks models, trained and validated with arterial and venous phase images (image model) or combined clinical-pathological factors (combined model). The segmentation model was evaluated using patch coverage ratio, Dice coefficient, recall, precision, and F1-score. The predictive models' efficacy was assessed using areas under the curves and decision curve analysis., Results: Overall, 2180 patients (median age: 61 years ± 17 [SD]; 1285 males) were divided into training (n = 1159), validation (n = 289), and independent external test (n = 732) groups. High-level MSI status was present in 435 patients (20%). In the external test set, the segmentation model performed well in the arterial phase, with patch coverage ratio, Dice coefficient, recall, precision, and F1-score values of 0.87, 0.71, 0.72, 0.74, and 0.71, respectively. For MSI prediction, the combined models outperformed the clinical model (AUC = 0.83 and 0.82 vs 0.67, p < 0.001) and two image models (AUC = 0.75 and 0.77, p < 0.001). Decision curve analysis confirmed the higher net benefit of the combined model compared to the other models across probability thresholds ranging from 0.1 to 0.45., Conclusion: DL enhances tumor segmentation efficiency and, when integrated with contrast-enhanced CT and clinicopathological factors, exhibits good diagnostic performance in predicting MSI in CRC., Competing Interests: Declarations. Conflict of interest: The authors have not disclosed any conflict of interests. Ethical standard research involves human participants: All data were from routine clinical test, and there was no clinical intervention for the participants in the study. Informed consent: Informed consent was obtained from all participants for routine clinical testing. However, due to the retrospective design of this study, the requirement for informed consent to participate in the study was waived by the Institutional Review Board., (© 2024. Italian Society of Medical Radiology.)

Background: Currently, PD-(L)1 blockade-based neoadjuvant treatment has shown promising outcomes in patients with potentially resectable gastric cancer. In this real-world study, we aimed to retrospectively observe the efficacy including tumor response and event-free survival (EFS), and safety of PD-(L)1 blockade-based neoadjuvant treatment versus chemotherapy alone in potentially resectable gastric cancer patients with microsatellite instability-high (MSI-H) or mismatch-repair deficient (dMMR) status., Methods: We retrospectively collected the clinical data of patients with potentially resectable gastric cancer and MSI-H/dMMR status who received neoadjuvant treatment followed by D2 gastrectomy at the Affiliated Hospital of Qingdao University from January 2019 to June 2023. The outcomes of interest mainly included overall complete response (CR) rates, radiographical and pathological tumor response, treatment-related adverse events (TRAEs), and EFS., Results: In total, 30 patients were included in the analysis; 23 patients received neoadjuvant PD-(L)1 blockade plus chemotherapy or PD-(L)1 blockade monotherapy, and seven patients received neoadjuvant chemotherapy. In the PD-(L)1 blockade-based treatment group, 7 of 23 patients (30.4%, 95% CI 0.141-0.530) achieved pathological CR (pCR), while three patients with radiographical CR did not undergo surgery. In contrast, 1 of 7 (14.3%) patients in the neoadjuvant chemotherapy group achieved pCR. The overall CR rate was 43.5% (10 of 23, 95% CI 0.239-0.651) in the PD-(L)1 blockade-based treatment group and 14.3% (1 of 7, 95% CI 0.026-0.513) in the chemotherapy group. The neoadjuvant PD-(L)1 blockade-based treatment regimen was mild and well tolerated. By the latest follow-up, median EFS time was not reached in both cohorts., Conclusion: In potentially resectable gastric cancer patients with MSI-H/dMMR status, PD-(L)1 blockade-based neoadjuvant treatment regimen provided promising clinical benefits and was well tolerated., Competing Interests: Declarations. Ethics approval and consent to participate: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study was approved by the Institutional Review Board of the Affiliated Hospital of Qingdao University (Approval No. QYFYWZLL27969, Qingdao, China). All the enrolled patients have read and signed the informed consents. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Co-occurring mutations in pairs of genes can pinpoint clinically relevant subgroups of cancer. Most colorectal cancers (CRCs) are microsatellite stable (MSS) and have few frequent mutations. Large patient cohorts and broad genomic coverage are needed for comprehensive co-mutation profiling., Methods: Co-mutations were identified in a population-based Swedish cohort analyzed by whole-genome sequencing (n=819 stage I-IV MSS CRCs). Prognostic value was further evaluated in a publicly available dataset of clinically sequenced metastatic CRCs (MSK-IMPACT; n=934 MSS). Multivariable Cox proportional hazards analyses with clinicopathological parameters were performed for locoregional (stage I-III) and metastatic (stage IV and recurrent) cancers separately., Results: Prevalent co-mutations were detected in 23 unique gene pairs, 20 of which included APC, TP53, KRAS and/or PIK3CA. Several co-mutations involving APC were associated with good overall survival in locoregional CRC, including APC-TCF7L2 (multivariable HR: 0.49, 95% CI 0.27-0.89). This co-mutation was prognostic also in metastatic cancers (multivariable HR: 0.49 and 0.37, 95% CI: 0.24-0.98 and 0.17-0.82 in the Swedish and MSK cohorts, respectively). APC-SOX9 co-mutations were mutually exclusive with APC-TCF7L2, and the co-mutations combined had stronger prognostic associations than APC alone in both metastatic cohorts. BRAF p.V600E-RNF43 co-mutations were associated with poor overall and recurrence-free survival in locoregional CRC (multivariable HR: 4.13 and 3.2, 95% CI: 1.78-9.54 and 1.53-8.04, respectively)., Conclusions: We report a genome-wide evaluation of co-occurring mutations in MSS CRCs, and suggest that co-mutations can improve the prognostic stratification compared to single mutations alone., Competing Interests: Declarations. Ethics approval and consent to participate: This study was conducted using publicly available data from two previously published studies: Nunes et al., Nature 2024 [6] and Yaeger et al., Cancer Cell 2018 [7]. Ethical approvals were obtained from the respective institutional review boards, and all participants provided informed consent, as described in the original publications. No new data was collected specifically for this study, and no additional ethical approval was required. All analyses complied with the Declaration of Helsinki. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

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.

Background: For female patients with Lynch syndrome (LS), endometrial cancer (EC) is often their first cancer diagnosis. A testing pathway of somatic tumour testing triage followed by germline mismatch repair (MMR) gene testing is an effective way of identifying the estimated 3% of EC caused by LS., Methods: A retrospective national population-based observational study was conducted using comprehensive national data collections of functional, somatic and germline MMR tests available via the English National Cancer Registration Dataset. For all EC diagnosed in 2019, the proportion tested, median time to test, yield of abnormal results and factors influencing testing pathway initiation were examined., Results: There was an immunohistochemistry (IHC) or microsatellite instability (MSI) test recorded for 17.8% (1408/7928) of patients diagnosed with EC in 2019. Proportions tested varied by Cancer Alliance and age. There was an MLH1 promoter hypermethylation test recorded for 43.1% (149/346) of patients with MLH1 protein IHC loss or MSI. Of patients with EC eligible from tumour-testing, 25% (26/104) had a germline MMR test recorded. Median time from cancer diagnosis to germline MMR test was 315 days (IQR 222-486)., Conclusion: This analysis highlights the regional variation in recorded testing, patient attrition, delays and missed opportunities to diagnose LS, providing an informative baseline for measuring the impact of the national guidance from the National Institute for Health and Care Excellence on universal reflex LS testing in EC, implemented in 2020., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background: Microsatellite instability (MSI) has prognostic value and impacts therapy strategies in several malignancies. Data regarding MSI in melanoma are scarce. The aim of this study was to assess MSI through the analysis of MMR protein expression in patients with melanoma., Methods: An observational retrospective single-center study was designed based on patients with primary melanoma. We assessed MSI through immunohistochemical staining with anti-MLH1, anti-MSH2, anti-MSH6, and anti-PMS2 on full-thickness excision tissue., Results: Ninety-three patients were included in this study. The complete absence of nuclear staining in tumoral cells was extremely rare, with only one melanoma not expressing MSH6. Most melanomas showed an expression index for MLH1 (77.7%), MSH2 (87.2%), and PMS2 (78.6%) ≥ 75%. Most melanomas (57.8%) exhibited an MSH6 expression index in the range of 1%-74%. A low MSH6 expression index and a reduced combined MMR protein expression index (MMR-e) were significantly associated with higher melanoma-specific survival. A mild PMS2 staining intensity was significantly associated with a higher melanoma-specific survival. The patients with high MMR-e who received immunotherapy progressed and died more frequently than those with reduced MMR-e (75% vs. 33.3%)., Conclusion: More studies are needed to further define the role of MSI in melanoma prognosis and response to immunotherapy., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Thyroid cancer management is rapidly changing. The identification of actionable biomarkers through both germline and somatic testing are now an integral part of directing patient management. However, deficiencies and disparities within existing thyroid cancer biomarker test approaches are resulting in inconsistent application for patient care. An expert panel was convened to create consensus biomarker testing algorithms and recommendations on actionable biomarker testing for patients diagnosed with medullary thyroid cancer, non-anaplastic follicular cell-derived thyroid cancer, or anaplastic follicular cell-derived thyroid cancer who may benefit from targeted therapies. A review of international guidelines was performed to determine the current state, and a literature review was carried out to further evaluate the evidence supporting the use of actionable biomarkers in patients diagnosed with thyroid cancer. Thyroid biomarker-related gaps impacting patient care were also discussed, with an emphasis on the importance of a multidisciplinary team approach for optimal patient care. The recommendations are presented with the aim to help physicians navigate the current thyroid cancer biomarker testing landscape with its many challenges, balancing aspirational care with what is practical and feasible in terms of economic realities and jurisdictional constraints. By remaining therapy-agnostic, these algorithms and recommendations are broadly applicable., Competing Interests: Declarations. Ethics Approval: Not applicable for this publication. Consent for Publication: All authors approved the final version and publication of the manuscript. Competing Interests: All authors report honoraria (facilitated via Precision RxDx) from Eli Lilly Canada for participation in working group meetings related to this project. Dr. Ozgur Mete is the Editor-in-Chief of Endocrine Pathology. This article is handled by an independent senior editor as per Springer Nature’s policies. Dr. Mete received honorarium for serving as an advisory board member for Bayer. Dr. Andrée Boucher has received research support from Eisai and has been compensated for being a speaker and serving as a board member or on an advisory panel for Bayer and Eisai. Dr. Omar Abdel-Rahman has received consulting fees from Amgen, Eisai, Ipsen, Lilly, and Roche, honoraria from Bayer. Dr. Houda Bahig has received grants from AstraZeneca, Sanofi and Varian Medical Systems, as well as consulting fees from AstraZeneca and EMD Serono. Dr. Cheryl Ho received grants from AstraZeneca and Roche which were paid to her institution. She received honoraria for advisory board attendance from AbbVie, Amgen, AstraZeneca, Bayer, BMS, Janssen, Jazz, Merck, Novartis, Pfizer, Roche, and Sanofi. Dr. Kasmintan A. Schrader has a consulting and advisory relationship with and has received honoraria from AstraZeneca Canada and Pfizer and research funding from AstraZeneca Canada and Merck. Dr. Eric Winquist received grants from Eli Lilly, Merck, and Novartis which were paid to his institution. He received consulting fees for advisory boards from Bayer, BMS, Eisai, EMD Serono, Merck, and Roche; honoraria from EMD Serono and support for attending meetings from Eisai. Dr. Jonn Wu served as an Executive board member, International Society of Oral Oncology, from 2019 to 2023. Dr. Shereen Ezzat has served as advisory board member/consultant for Bayer, Eisai, Eli Lilly, Ipsen, Novartis, Medunik Canada, Merck, Pfizer, and Recordati Rare Diseases. Dr. Nicole Chau has received research funding from BeiGene, BMS, ERASCA, Merck, and Roche which were paid to her institution. She received consulting fees for advisory boards from Bayer, BMS, Eisai, Eli Lilly, EMD Serono, Ipsen, Merck, Novartis, Pfizer, and Roche. Dr. Olfat Kamel Hasan, Dr. Bernard Lemieux, and Dr. Ralph Wong have no conflicts of interest to declare that are relevant to the content of this article., (© 2024. The Author(s).)

Colorectal cancer (CRC) arises through a combination of genetic and epigenetic alterations that affect key pathways involved in tumor growth and progression. This review examines the major molecular pathways driving CRC, including Chromosomal Instability (CIN), Microsatellite Instability (MSI), and the CpG Island Methylator Phenotype (CIMP). Key mutations in genes such as APC, KRAS, NRAS, BRAF, and TP53 activate signaling pathways like Wnt, EGFR, and PI3K/AKT, contributing to tumorigenesis and influencing responses to targeted therapies. Resistance mechanisms, including mutations that bypass drug action, remain challenging in CRC treatment. This review highlights the role of molecular profiling in guiding the use of targeted therapies such as tyrosine kinase inhibitors and immune checkpoint inhibitors. Novel combination treatments are also discussed as strategies to improve outcomes and overcome resistance. Understanding these molecular mechanisms is critical to advancing personalized treatment approaches in CRC and improving patient prognosis.

Microsatellite instability-high (MSI-H) gastric cancer (GC) exhibits high tumor-infiltrating lymphocyte (TIL) density. Despite the recognized significance of the immune microenvironment in MSI-H GC, our understanding of TIL remains limited. This study aimed to investigate the clinicopathologic and prognostic implications of T cell subsets in MSI-H GC. Single immunohistochemistry (IHC) for CD8, TCF1, and CD103, and double IHC for CD8/TCF1 and CD8/CD103 were performed in 382 surgically resected MSI-H GC samples. Densities of single or double positive immune cells were quantified and correlated with clinicopathologic features and overall survival (OS). TCF1 + cell densities showed weak correlations with CD8 + and CD103 + cell densities, while CD8+/TCF1 + cell density moderately correlated with CD8+/CD103 + cell density (R 2  = 0.539, p < 0.001). Single IHC analyses showed no significant associations between CD8+, TCF1+, or CD103 + cell densities and OS (p > 0.05). Notably, elevated CD8+/TCF1 + cell density and a high CD8+/TCF1 + to CD8 + ratio correlated with less aggressive clinicopathologic features and improved OS (p = 0.017 and 0.001, respectively). Multivariable Cox-regression identified CD8+/TCF1 + to CD8 + ratio as an independent prognostic factor (p = 0.028). We demonstrated the prognostic significance of CD8+/TCF1 + to CD8 + ratio using double IHC in a large cohort of MSI-H GC., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Introduction: Understanding the mutational landscape of colon cancer (CC) is crucial for targeted therapy development. Microsatellite instability (MSI-H), rat sarcoma (RAS), and B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutations (MT) are pivotal markers. Further investigation into clinicopathological features of RAS and BRAF MT in microsatellite stable (MSS) and MSI-H tumors is warranted., Methods: A retrospective analysis of 4883 localized CC patients (pts.) was conducted. Molecular profiling assessed MSI, KRAS, NRAS, and BRAF MT. Correlation with clinicopathological data employed ANOVA and Chi-square tests. Disease-free survival (DFS) and overall survival (OS) were analyzed adjusting for age, gender, sidedness, UICC stage, Charlson Comorbidity Index (CCI). A Cox model incorporated all variables as covariates., Results: This analysis included 4883 pts. (2302 female/2572 male, 3865 (79.2%) MSS, 1018 (20.8%) MSI-H). MSS pts. had more All-Wild Type (WT), KRAS MT, and NRAS MT tumors vs. MSI-H pts. (42.1% vs. 21.1%; 39.8% vs. 15.4%; 3.6% vs. 0.7%; p<0.001 for each). BRAF MT tumors (95.5% BRAF V600E MT) were more prevalent in MSI-H individuals (62.8% vs. 8.1%, p<0.001). KRAS and BRAF MT tumors were more frequently right-sided, while BRAF MT tumors were associated with female gender, advanced disease stage, lymph node positivity, and poorer differentiation in the MSS subset (p<0.001). Common KRAS mutations included p.G12D (30.44%) and p.G12V (21.3%) in MSS and p.G13D (28.9%) and p.G12D (22.37%) in MSI-H. NRAS MT tumors were dominated by codon 61 mutations (51.7%). Survival analysis revealed worst prognosis in BRAF MT MSS tumors (DFS: HR 1.74 (95% CI 1.15-2.62, p=0.009; OS: HR 1.61 (95% CI 0.99-2.6), p=0.055). The 3-years DFS and 5-years OS rates were lowest in this subset (61.6% and 57.7% respectively)., Discussion: These findings highlight the complex interplay between molecular subtypes, clinicopathological features, and survival outcomes in early CC. Further research is needed to elucidate underlying mechanisms and develop personalized treatment strategies., Competing Interests: JC: Advisory Boards: AstraZeneca GmbH, Sanofi-Aventis Deutschland GmbH, Honoraria and Travel Support: AstraZeneca GmbH, Qiagen GmbH, Janssen-Cilag GmbH, MSD Sharp & Dohme GmbH, Merck Healthcare Germany, BS: Trial support institution/study grant institution: BioNTech, SH: Advisory Boards: Fa. Mediglobe ( EUS-KI Project), LM: Travel support: Octapharm, Pierre Fabre, ARS: Honoria: Amgen, Roche, Merck Serono, Bristol-Myers Squibb, MSD, MCI Group, AstraZeneca, Advisory board member: Amgen, AstraZeneca; Bristol-Myers Squibb, Daiichi-Sankyo, Janssen-Cilag, Merck Serono, MSD, Travel support: Roche, Amgen, Pierre Fabre Studies (trial support institution/study grant institution): Roche, Ipsen, Funding for scientific research: Roche, Celgene, Ipsen, Amgen, Alexion Pharmaceuticals, Astra Zeneca, Lilly, Servier, AIO Studien gGmbH, Rafael Pharmaceutics, Erytech Pharma, BioNTech, AT: Trial support institution/study grant institution: BioNTech. The remaining author(s) declare(s) that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ekmekciu, Zucha, Christmann, Wisser, Heuer, Sargin, Hollerbach, Lamberti, Müller, Lugnier, Verdoodt, Denz, Terzer, Feder, Reinacher-Schick, Tannapfel and Tischoff.)

Background: High microsatellite instability (MSI) represents a small subgroup of gastric cancer (GC) with favorable prognostic and predictive significance. This study aimed to investigate locoregional lymph node (LN) involvement, overall survival (OS), disease-free survival (DFS), and the interplay between molecular subtypes and histologic profiles regarding survival outcomes in MSI GC vs microsatellite stability (MSS) GC., Methods: This study included 72 patients with GC who underwent surgery with or without chemotherapy from 2017 to 2023. Clinicopathologic characteristics, OS, and DFS were compared between LN-positive and LN-negative patients stratified by microsatellite status, treatments, molecular profiles, and tumor cell types., Results: MSI GC was more common in older patients (79.0 vs 70.2 years; P <.001), more common in females (73.68% vs 43.32%; P =.023), and associated with intestinal-type histology (94.5% vs 49.0%; P =.002). Positive LN involvement and lymphovascular invasion (LVI) were lower in the MSI group than in the MSS group (positive LN: 2.73 vs 4.15, respectively; P =.366; LVI: 36.8% vs 64.5%, respectively; P =.039). Patients with MSI showed slightly better OS and DFS than those with MSS (OS: 84.20% vs 66.00%, respectively; P =.108; DFS: 84.62% vs 63.89%, respectively; P =.120). In addition, compared with patients with MSS GC, those with MSI GC had improved OS and DFS in the LN-positive group (OS: 72.7% vs 61.3%, respectively; P =.255; DFS: 75.0% vs 50.0%, respectively; P =.148) and LN-negative group (OS: 100.0% vs 85.7%, respectively; P =.149; DFS: 100.0% vs 85.7%, respectively; P =.376). In patients not receiving chemotherapy, the MSI/intestinal-type group had the highest OS and DFS (77.0% and 87.5%, respectively; P =.024), whereas the MSS/mixed-type group had the lowest OS and DFS (25.0% and 100.0%, respectively; P =.290). In patients receiving chemotherapy, the MSI/intestinal-type group had the highest OS and DFS (100.0% and 100.0%, respectively; P =.741), whereas the MSS/mixed-type group had the lowest OS and DFS (66.7% and 50.0%, respectively; P =.397)., Conclusion: First, patients with MSI GC have a significantly lower risk of locoregional LN involvement and better OS and DFS than those with MSS GC. Second, treatment responses differ based on MSI status: patients with MSI tumors benefit more from upfront surgical interventions, whereas those with MSS, particularly mixed histotypes, demonstrate improved outcomes with preoperative chemotherapy. These results advocate for a tailored therapeutic approach that considers microsatellite status, Lauren classification, and patient clinical conditions., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Circulating tumor DNA (ctDNA) represents a powerful measure of minimal residual disease (MRD) in colorectal cancer (CRC). Although immunotherapy has been widely established in metastatic CRC that is mismatch repair deficient or microsatellite instability-high (dMMR/MSI-H), its role in non-metastatic CRC is rapidly evolving. In resected, dMMR/MSI-H stage II CRC, adjuvant fluoropyrimidine has no benefit and is not recommended. There is growing evidence to suggest diminished benefit from neoadjuvant chemotherapy and chemoradiation in localized CRC that is dMMR/MSI-H. We present two cases of dMMR/MSI-H stage III CRC treated with definitive surgery wherein adjuvant oxaliplatin-based chemotherapy led to a failure to clear postoperative plasma ctDNA levels, prompting a change to immune checkpoint blockade with pembrolizumab and resultant ctDNA clearance. We illustrate that chemotherapy may achieve suboptimal disease control in localized colon cancer that is dMMR/MSI-H, while plasma ctDNA offers a window of opportunity to gauge the efficacy of oxaliplatin-based adjuvant chemotherapy to clear microscopic disease in resected, dMMR/MSI-H stage III colon cancer. These findings are important to contextualize given that relapse is inevitable with failure to clear MRD in the postoperative stage I-III CRC setting whereby chemotherapy remains the standard adjuvant therapy in resected, dMMR/MSI-H stage III colon cancer.