Neoadjuvant immune checkpoint blockade (ICB) has shown unprecedented activity in mismatch repair deficient (MMRd) colorectal cancers, but its effectiveness in MMRd endometrial cancer (EC) remains unknown. In this investigator-driven, phase I, feasibility study (NCT04262089), 10 women with MMRd EC of any grade, planned for primary surgery, received two cycles of neoadjuvant pembrolizumab (200 mg IV) every three weeks. A pathologic response (primary objective) was observed in 5/10 patients, with 2 patients showing a major pathologic response. No patient achieved a complete pathologic response. A partial radiologic response (secondary objective) was observed in 3/10 patients, 5/10 patients had stable disease and 2/10 patients were non-evaluable on magnetic resonance imaging. All patients completed treatment without severe toxicity (exploratory objective). At median duration of follow-up of 22.5 months, two non-responders experienced disease recurrence. In-depth analysis of the loco-regional and systemic immune response (predefined exploratory objective) showed that monoclonal T cell expansion significantly correlated with treatment response. Tumour-draining lymph nodes displayed clonal overlap with intra-tumoural T cell expansion. All pre-specified endpoints, efficacy in terms of pathologic response as primary endpoint, radiologic response as secondary outcome and safety and tolerability as exploratory endpoint, were reached. Neoadjuvant ICB with pembrolizumab proved safe and induced pathologic, radiologic, and immunologic responses in MMRd EC, warranting further exploration of extended neoadjuvant treatment.

By replicating damaged nucleotides, error-prone DNA translesion synthesis (TLS) enables the completion of replication, albeit at the expense of fidelity. TLS of helix-distorting DNA lesions, that usually have reduced capacity of basepairing, comprises insertion opposite the lesion followed by extension, the latter in particular by polymerase ζ (Pol ζ). However, little is known about involvement of Pol ζ in TLS of non- or poorly-distorting, but miscoding, lesions such as O6-methyldeoxyguanosine (O6-medG). Using purified Pol ζ we describe that the enzyme can misincorporate thymidine opposite O6-medG and efficiently extend from terminal mismatches, suggesting its involvement in the mutagenicity of O6-medG. Surprisingly, O6-medG lesions induced by the methylating agent N-methyl-N\'-nitro-N-nitrosoguanidine (MNNG) appeared more, rather than less, mutagenic in Pol ζ-deficient mouse embryonic fibroblasts (MEFs) than in wild type MEFs. This suggested that in vivo Pol ζ participates in non-mutagenic TLS of O6-medG. However, we found that the Pol ζ-dependent misinsertions at O6-medG lesions are efficiently corrected by DNA mismatch repair (MMR), which masks the error-proneness of Pol ζ. We also found that the MNNG-induced mutational signature is determined by the adduct spectrum, and modulated by MMR. The signature mimicked single base substitution signature 11 in the catalogue of somatic mutations in cancer, associated with treatment with the methylating drug temozolomide. Our results unravel the individual roles of the major contributors to methylating drug-induced mutagenesis. Moreover, these results warrant caution as to the classification of TLS as mutagenic or error-free based on in vitro data or on the analysis of mutations induced in MMR-proficient cells.

BACKGROUND: Young onset colorectal cancer (YOCRC) is a heterogenous CRC phenotype with an increasing trend globally. This study aims to determine FOXP3+ Treg cells, Mismatch Repair (MMR) proteins, and proto-oncogene B-Raf (BRAF) V600E status among YOCRC patients at Hospital Universiti Sains Malaysia.
METHODS: This was a retrospective study of YOCRC (<50 years) over 8 years (January 2013 to December 2021). Immunohistochemistry staining of FOXP3, BRAFV600E, and MMR protein expression was performed using monoclonal antibodies. The staining intensity and percentage of positive cells were used to evaluate the staining using immunoreactive scoring. All data were analysed using descriptive and correlation statistics. A p-value of ≤ 0.05 was taken as statistically significant.
RESULTS: A total of 65 YOCRC patients were diagnosed, out of which 53.8% had proficient MMR (pMMR) with a mean age of 41, while 46.2% had deficient MMR (dMMR) with a mean age of 35.5. The pMMR with the BRAFV600E+ group expressed higher FOXP3+Tregs (54.2%) than the dMMR with the BRAFV600E+ group (22.9%). Patients with lower FOXP3+Tregs were observed more in dMMR with BRAFV600E- (47%) than in pMMR with BRAFV600E- (5.9%). There was a statistically significant association between the density of expressed FOXP3+Tregs with MMR and BRAFV600E status (p=0.002).
CONCLUSIONS: While most of the YOCRC had pMMR, others exhibited dMMR with loss of one or more MMR proteins. The presence of BRAFV600E demonstrated the YOCRC\'s sporadic nature. A high FOXP3+Treg expression was significantly associated with MMR and BRAFV600E status. Future research must be expanded to cover other hospitals to increase the sample size and include MLH1 hypermethylation testing.

BACKGROUND: Microsatellite instability (MSI) status is a strong predictor of response to immunotherapy of colorectal cancer. Radiogenomic approaches promise the ability to gain insight into the underlying tumor biology using non-invasive routine clinical images. This study investigates the association between tumor morphology and the status of MSI versus microsatellite stability (MSS), validating a novel radiomic signature on an external multicenter cohort.
METHODS: Preoperative computed tomography scans with matched MSI status were retrospectively collected for 243 colorectal cancer patients from three hospitals: Seoul National University Hospital (SNUH); Netherlands Cancer Institute (NKI); and Fondazione IRCCS Istituto Nazionale dei Tumori, Milan Italy (INT). Radiologists delineated primary tumors in each scan, from which radiomic features were extracted. Machine learning models trained on SNUH data to identify MSI tumors underwent external validation using NKI and INT images. Performances were compared in terms of area under the receiving operating curve (AUROC).
RESULTS: We identified a radiomic signature comprising seven radiomic features that were predictive of tumors with MSS or MSI (AUROC 0.69, 95% confidence interval [CI] 0.54-0.84, p = 0.018). Integrating radiomic and clinical data into an algorithm improved predictive performance to an AUROC of 0.78 (95% CI 0.60-0.91, p = 0.002) and enhanced the reliability of the predictions.
CONCLUSIONS: Differences in the radiomic morphological phenotype between tumors MSS or MSI could be detected using radiogenomic approaches. Future research involving large-scale multicenter prospective studies that combine various diagnostic data is necessary to refine and validate more robust, potentially tumor-agnostic MSI radiogenomic models.
CONCLUSIONS: Noninvasive radiomic signatures derived from computed tomography scans can predict MSI in colorectal cancer, potentially augmenting traditional biopsy-based methods and enhancing personalized treatment strategies.
CONCLUSIONS: Noninvasive CT-based radiomics predicted MSI in colorectal cancer, enhancing stratification. A seven-feature radiomic signature differentiated tumors with MSI from those with MSS in multicenter cohorts. Integrating radiomic and clinical data improved the algorithm\'s predictive performance.

BACKGROUND: Neoadjuvant immunotherapy emerges as a promising strategy for patients with localized colon cancer (CC) harboring microsatellite instability/mismatch repair deficiency (MSI/dMMR). The aim of this study is to evaluate the concordance between clinical cTN stage assessed by preoperative computed tomography (CT) scan and pTN stage of MSI/dMMR CC.
METHODS: Consecutive patients diagnosed for localized MSI/dMMR CC and treated with upfront surgery between 2013 and 2022 in two French centers were eligible. Two independent radiologists, blinded to pathological findings, reviewed all preoperative CT scans and assessed cTN stage, with a third radiologist reviewing discordant cases. Radiological predictive diagnostic accuracy for pT4 and pN+ (N+ = N1 or N2) were calculated.
RESULTS: One hundred and thirteen patients were included (right CCs = 79%). CT scan diagnostic performances for pT4 were sensitivity (Se) = 33.3%; specificity (Sp) = 94.0%; positive predictive value (PPV) = 66.7%; and negative predictive value (NPV) = 79.6% and for pN+ were Se = 70.3%; Sp = 59.2%; PPV = 45.6%; and NPV = 80.4%. When pT-pN were combined, 37.5% of tumors identified as cT4 and/or cN+ were actually pT1-3 and pN0, and 23.1% of the pT4 and pN+ population was not identified as such radiologically.
CONCLUSIONS: The ability of preoperative CT scan to predict pT and pN stages is limited for localized MSI/dMMR CCs. Reassessing neoadjuvant strategies\' benefit-risk balance in this population is needed.

In recent years, immune checkpoint inhibitors (ICIs) have been widely used in malignant solid tumors with remarkable efficacy. However, in colorectal cancer (CRC), ICIs have shown significant therapeutic effects only in patients with highly microsatellite unstable/mismatch repair-deficient metastatic CRC and these patients are only a minority of all CRC patients. In contrast, the majority of patients, those with microsatellite stable (MSS)/mismatch repair-complete (pMMR)-type metastatic CRC, could hardly benefit from ICI monotherapies, and immune combination therapies have become the key to solveing this clinical challenge. This article introduces the common patterns and possible mechanisms of immune-combination therapies for MSS/pMMR-type CRC, the exploration and progress made in the application of immune-combination therapies, as well as the possible predictive markers of efficacy of immune therapies. The prospects and directions of ICIs in the treatment of MSS/pMMR-type CRC are also discussed.
近年来，免疫检查点抑制剂（ICIs）在恶性实体肿瘤中应用广泛且疗效显著。然而，在结直肠癌（CRC）中，ICIs仅对占少数的微卫星高度不稳定/错配修复缺失型转移性CRC表现出显著的治疗效果，而占大多数的微卫星稳定（MSS）/错配修复完整（pMMR）型转移性CRC几乎不能从ICIs单药治疗中获益，免疫联合治疗成为破解这一临床难题的关键。文章介绍了MSS/pMMR型CRC免疫联合治疗的常见模式和可能机制，总结归纳了MSS/pMMR型CRC免疫联合治疗方面所做的探索和取得的进展以及免疫治疗疗效的可能预测标志物，对ICIs在MSS/pMMR型CRC治疗中的应用前景进行了展望。.

OBJECTIVE: No consensus on the definition of right and left colorectal cancer (CRC) exists, nor studies offering histological or molecular basis for such categorisation. This study investigated the regional variations in the histological and molecular characteristics of CRCs, with the objective of determining an optimal division point between right and left CRCs.
METHODS: An observational study of consecutive patients who underwent CRC resection (1995-2022) at Concord Hospital, Sydney was performed. Clinicopathological data were extracted from a prospective database and seven permutations of right-left divisions considered. Logistic regression tested association between the right-left divisions and pathological characteristics. Receiver operating characteristic and area under the curve (AUC) analyses determined the discriminative ability of each division to predict 18 pathology characteristics.
RESULTS: 3753 patients underwent a CRC resection (2120 male; mean 69.5yrs [SD12.6]). There was regional variation in tumours with respect to tumour infiltrating lymphocytes (TILs), mismatch repair deficiency (dMMR), and mutant BRAF (mBRAF). Left-sided tumours were less likely to demonstrate TILs (P < 0.001), be dMMR (P < 0.001), and express mBRAF (P < 0.001). Division at the descending-sigmoid junction yielded highest discriminative abilities: TILs - AUC 0.66, dMMR - AUC 0.76, and mBRAF - AUC 0.73.
CONCLUSIONS: This is the first study to provide a pathological basis on which right- and left-sided cancers may be defined, and found the optimal division point between the right and left colorectum to be at the descending-sigmoid junction. Further research is needed to determine whether this can facilitate individualised patient management.

Deficient (d) DNA mismatch repair (MMR) is a biomarker predictive of better response to PD-1 blockade immunotherapy in solid tumors. dMMR can be caused by mutations in MMR genes or by protein inactivation, which can be detected by sequencing and immunohistochemistry, respectively. To investigate the role of dMMR in diffuse large B-cell lymphoma (DLBCL), MMR gene mutations and expression of MSH6, MSH2, MLH1, and PMS2 proteins were evaluated by targeted next-generation sequencing and immunohistochemistry in a large cohort of DLBCL patients treated with standard chemoimmunotherapy, and correlated with the tumor immune microenvironment characteristics quantified by fluorescent multiplex immunohistochemistry and gene-expression profiling. The results showed that genetic dMMR was infrequent in DLBCL and was significantly associated with increased cancer gene mutations and favorable immune microenvironment, but not prognostic impact. Phenotypic dMMR was also infrequent, and MMR proteins were commonly expressed in DLBCL. However, intratumor heterogeneity existed, and increased DLBCL cells with phenotypic dMMR correlated with significantly increased T cells and PD-1+ T cells, higher average nearest neighbor distance between T cells and PAX5+ cells, upregulated immune gene signatures, LE4 and LE7 ecotypes and their underlying Ecotyper-defined cell states, suggesting the possibility that increased T cells targeted only tumor cell subsets with dMMR. Only in patients with MYC¯ DLBCL, high MSH6/PMS2 expression showed significant adverse prognostic effects. This study shows the immunologic and prognostic effects of genetic/phenotypic dMMR in DLBCL, and raises a question on whether DLBCL-infiltrating PD-1+ T cells target only tumor subclones, relevant for the efficacy of PD-1 blockade immunotherapy in DLBCL.

Lynch syndrome (LS) is a prevalent genetic condition associated with colorectal cancer (CRC). Accurate identification of LS patients is challenging, and a universal tumor screening approach has been recommended. We present the methodology and results of universal LS screening in our hospital\'s Pathology Department. This retrospective study analyzed CRC tumors from a 5-year period (2017-2021). Immunohistochemistry was used to assess MMR protein expression, followed by BRAF V600E analysis and MLH1 promoter methylation. Statistical analysis examined associations between clinicopathologic variables MMR status and LS-suspected tumors. The study analyzed 939 colorectal carcinomas, with 8.7% exhibiting mismatch repair (MMR) deficiency, significantly lower than previous research. After applying the algorithm, 24 LS-suspected cases were identified, accounting for 2.6% of tested patients and 29.3% of MMR-deficient tumors. Our study establishes the feasibility of universal testing for all new cases of CRC in detecting individuals at risk for LS, even in the absence of clinical information. To gain a comprehensive understanding of the MMR status in our population, further investigations are warranted.

Mismatch repair proficient (MMRp) tumors of colorectal origin are one of the prevalent yet unpredictable clinical challenges. Despite earnest efforts, optimal treatment modalities have yet to emerge for this class. The poor prognosis and limited actionability of MMRp are ascribed to a low neoantigen burden and a desert-like microenvironment. This review focuses on the critical roadblocks orchestrated by an immune evasive mechanistic milieu in the context of MMRp. The low density of effector immune cells, their weak spatiotemporal underpinnings, and the high-handedness of the IL-17-TGF-β signaling are intertwined and present formidable challenges for the existing therapies. Microbiome niche decorated by Fusobacterium nucleatum alters the metabolic program to maintain an immunosuppressive state. We also highlight the evolving strategies to repolarize and reinvigorate this microenvironment. Reconstruction of anti-tumor chemokine signaling, rational drug combinations eliciting T cell activation, and reprograming the maladapted microbiome are exciting developments in this direction. Alternative vulnerability of other DNA damage repair pathways is gaining momentum. Integration of liquid biopsy and ex vivo functional platforms provide precision oncology insights. We illustrated the perspectives and changing landscape of MMRp-CRC. The emerging opportunities discussed in this review can turn the tide in favor of fighting the treatment dilemma for this elusive cancer.