Non-invasive CT radiomic biomarkers predict microsatellite stability status in colorectal cancer: a multicenter validation study.

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. CONCLUSION: 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. RELEVANCE STATEMENT: 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. KEY POINTS: 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.

Polymorphism analysis of tri- and tetranucleotide repeat microsatellite markers in Hanwoo cattle.

The Hanwoo traceability system currently utilizes 11 dinucleotide repeat microsatellite (MS) markers. However, dinucleotide repeat markers are known to have a high incidence of polymerase chain reaction (PCR) artifacts, such as stutter bands, which can complicate the accurate reading of alleles. In this study, we examined the polymorphisms of the 11 dinucleotide repeat MS markers currently employed in traceability systems. Additionally, we explored four trinucleotide repeat MS markers and one tetranucleotide repeat MS marker in a sample of 1,106 Hanwoo cattle. We also assessed the potential utility of the tri- and tetranucleotide repeat MS markers. The polymorphic information content (PIC) of the five tri- and tetranucleotide repeat markers ranged from 0.663 to 0.767 (mean: 0.722), sufficiently polymorphic and slightly higher than the mean (0.716) of the current 11 dinucleotide repeat markers. Using all 16 markers, the mean PIC was 0.718. The estimated probability of identity (PI) was 3.13 × 10-12 using the 11 dinucleotide repeat markers, 7.03 × 10-6 using the five tri- and tetranucleotide repeat markers, and 2.39 × 10-17 using all 16 markers; the respective PIhalf-sibs values were 2.69 × 10-9, 1.29 × 10-4, and 3.42 × 10-13; and the respective PIsibs values were 3.89 × 10-5, 9.6 × 10-3, and 3.69 × 10-7. The probability of exclusion1 (PE1) was 0.999864 for the 11 dinucleotide repeat markers, 0.981141 for five of the tri- and tetranucleotide repeat markers, and > 0.99 for all 16 markers; the respective PE2 values were 0.994632, 0.901369, and > 0.99; and the respective PE3 values were 0.998702, > 0.99, and > 0.99. The five investigated tri- and tetranucleotide repeat MS markers can be used in combination with the 11 existing MS markers to improve the accuracy of individual identification and paternity testing in Hanwoo.

Prognostic significance of microsatellite instability in patients with resectable gastric cancer.

BACKGROUND: Microsatellite instability (MSI) gastric cancer (GC) generally has a better prognosis than microsatellite-stable (MSS) GC and has been associated with nonsurvival benefit with the addition of chemotherapy (CMT) compared with surgery alone. However, patients with MSI have distinct clinicopathological characteristics. This study aimed to compare the survival outcomes between patients with MSI GC and those with MSS GC. In addition, this study analyzed the survival outcomes of patients with MSI GC who received CMT. METHODS: This study reviewed all patients with GC who underwent curative gastrectomy. Patients were divided into MSI group and the MSS group. Propensity score matching (PSM) was used to match clinicopathological factors. RESULTS: Among the 378 patients enrolled, 78 (20.6%) had MSI. Older age (P < .001), subtotal gastrectomy (P = .008), pN0 (P = .020), and earlier pTNM stage (P = .012) were associated with MSI GC. Survival analysis showed better disease-free survival (DFS) and overall survival (OS) of patients in the MSI group (P = .012 and P = .019, respectively). After PSM, 78 patients were matched to each group. All variables assigned to the scores were well matched, and both groups became equivalent. After the matching, the differences in DFS and OS according to MSI/MSS status were estimated to be larger than before (DFS: 63.3% vs 41.4%; P = .002; OS: 65.8% vs 42.5%; P = .002). Regarding patients referred for CMT, there was no difference in DFS and OS between patients with MSI GC who underwent CMT and those who underwent surgery alone (P = .255 and P = .178, respectively). CONCLUSION: Even after controlling for clinicopathological characteristics, MSI was identified as a prognostic factor for patient survival. MSI GC showed no significant survival benefit with the addition of CMT.

A pilot study on the detection of microsatellite instability using long mononucleotide repeats in solid tumors.

Microsatellite instability (MSI) status is a prognostic biomarker for immunotherapy in certain types of cancers, such as colorectal cancers (CRCs) and endometrial cancers (ECs). Tumors that are categorized as having high MSI (MSI-H) express high levels of neoantigens for immune recognition. The typical MSI test measures the length of short mononucleotide repeats (SMR) poly(A) 21-27; however, a limitation of this test is the difficulty in determining the shift size, particularly in endometrial cancer. To investigate an MSI detection assay with improved performance, the present study analyzed the use of poly(A) 40-44 mononucleotide repeats to detect the MSI status of 100 patients with either CRC (n=50) or EC (n=50). Capillary electrophoresis was used to evaluate five long mononucleotide repeat (LMR) markers, including poly(A) 40-A, 40-B, 40-C, 40-D and 44. The concordance rate of the LMR-MSI assay compared with an immunohistochemistry MSI detection assay was 96.0 and 95.1% for CRCs and ECs respectively, with the detection limit of the LMR-MSI assay demonstrated to be 2.5% MSI-H in HCT116 colorectal carcinoma cell lines. The LMR-MSI assay yielded a 95.1% concordance rate in ECs compared with that in the SMR-MSI test (87.8%). The LMR-MSI test identified a significantly higher mean shift size (13 bp) in MSI-H tumors compared with the SMR-MSI test (10 bp), in both EC and CRC tissue samples. Together, the present study suggested that the LMR-MSI test could potentially be a sensitive and practical technology for molecular laboratory testing, particularly in the use of immunotherapy for patients with CRCs and ECs.

Microsatellite instability at U2AF-binding polypyrimidic tract sites perturbs alternative splicing during colorectal cancer initiation.

BACKGROUND: Microsatellite instability (MSI) due to mismatch repair deficiency (dMMR) is common in colorectal cancer (CRC). These cancers are associated with somatic coding events, but the noncoding pathophysiological impact of this genomic instability is yet poorly understood. Here, we perform an analysis of coding and noncoding MSI events at the different steps of colorectal tumorigenesis using whole exome sequencing and search for associated splicing events via RNA sequencing at the bulk-tumor and single-cell levels. RESULTS: Our results demonstrate that MSI leads to hundreds of noncoding DNA mutations, notably at polypyrimidine U2AF RNA-binding sites which are endowed with cis-activity in splicing, while higher frequency of exon skipping events are observed in the mRNAs of MSI compared to non-MSI CRC. At the DNA level, these noncoding MSI mutations occur very early prior to cell transformation in the dMMR colonic crypt, accounting for only a fraction of the exon skipping in MSI CRC. At the RNA level, the aberrant exon skipping signature is likely to impair colonic cell differentiation in MSI CRC affecting the expression of alternative exons encoding protein isoforms governing cell fate, while also targeting constitutive exons, making dMMR cells immunogenic in early stage before the onset of coding mutations. This signature is characterized by its similarity to the oncogenic U2AF1-S34F splicing mutation observed in several other non-MSI cancer. CONCLUSIONS: Overall, these findings provide evidence that a very early RNA splicing signature partly driven by MSI impairs cell differentiation and promotes MSI CRC initiation, far before coding mutations which accumulate later during MSI tumorigenesis.

Characterization of Lithuanian Tomato Varieties and Hybrids Using Phenotypic Traits and Molecular Markers.

The aim of this study was to evaluate phenotypic traits and genetic diversity of the 13 tomato (Solanum lycopersicum L.) varieties and 6 hybrids developed at the Institute of Horticulture Lithuanian Research Centre for Agriculture and Forestry (LRCAF IH). For the molecular characterisation, seven previously published microsatellite markers (SSR) were used. A24 and 26 alleles were detected in tomato varieties and hybrids, respectively. Based on the polymorphism information content (PIC) value, the most informative SSR primers for varieties were TMS52, TGS0007, LEMDDNa and Tom236-237, and the most informative SSR primers for hybrids were SSR248 and TMS52. In UPGMA cluster analysis, tomato varieties are grouped in some cases due to genetic relationships, as the same cluster cultivars 'Viltis' (the parent of cv. 'Laukiai') and 'Ausriai' (the progeny of cv. 'Jurgiai') are present. The grouping of all hybrids in the dendrogram is related to the parental forms, and it shows the usefulness of molecular markers for tomato breeding, as they can be used to trace the origin of hybrids and, eventually, varieties accurately. The knowledge about the genetic background of Lithuanian tomato cultivars will help plan targeted crosses in tomato breeding programs.

Artificial Intelligence Models for the Detection of Microsatellite Instability from Whole-Slide Imaging of Colorectal Cancer.

With the advent of whole-slide imaging (WSI), a technology that can digitally scan whole slides in high resolution, pathology is undergoing a digital revolution. Detecting microsatellite instability (MSI) in colorectal cancer is crucial for proper treatment, as it identifies patients responsible for immunotherapy. Even though universal testing for MSI is recommended, particularly in patients affected by colorectal cancer (CRC), many patients remain untested, and they reside mainly in low-income countries. A critical need exists for accessible, low-cost tools to perform MSI pre-screening. Here, the potential predictive role of the most relevant artificial intelligence-driven models in predicting microsatellite instability directly from histology alone is discussed, focusing on CRC. The role of deep learning (DL) models in identifying the MSI status is here analyzed in the most relevant studies reporting the development of algorithms trained to this end. The most important performance and the most relevant deficiencies are discussed for every AI method. The models proposed for algorithm sharing among multiple research and clinical centers, including federal learning (FL) and swarm learning (SL), are reported. According to all the studies reported here, AI models are valuable tools for predicting MSI status on WSI alone in CRC. The use of digitized H&E-stained sections and a trained algorithm allow the extraction of relevant molecular information, such as MSI status, in a short time and at a low cost. The possible advantages related to introducing DL methods in routine surgical pathology are underlined here, and the acceleration of the digital transformation of pathology departments and services is recommended.

Preimplantation Genetic Testing of Spinocerebellar Ataxia Type 3/Machado-Joseph Disease-Robust Tools for Direct and Indirect Detection of the ATXN3 (CAG)n Repeat Expansion.

Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is a neurodegenerative disorder caused by the ATXN3 CAG repeat expansion. Preimplantation genetic testing for monogenic disorders (PGT-M) of SCA3/MJD should include reliable repeat expansion detection coupled with high-risk allele determination using informative linked markers. One couple underwent SCA3/MJD PGT-M combining ATXN3 (CAG)n triplet-primed PCR (TP-PCR) with customized linkage-based risk allele genotyping on whole-genome-amplified trophectoderm cells. Microsatellites closely linked to ATXN3 were identified and 16 markers were genotyped on 187 anonymous DNAs to verify their polymorphic information content. In the SCA3/MJD PGT-M case, the ATXN3 (CAG)n TP-PCR and linked marker analysis results concurred completely. Among the three unaffected embryos, a single embryo was transferred and successfully resulted in an unaffected live birth. A total of 139 microsatellites within 1 Mb upstream and downstream of the ATXN3 CAG repeat were identified and 8 polymorphic markers from each side were successfully co-amplified in a single-tube reaction. A PGT-M assay involving ATXN3 (CAG)n TP-PCR and linkage-based risk allele identification has been developed for SCA3/MJD. A hexadecaplex panel of highly polymorphic microsatellites tightly linked to ATXN3 has been developed for the rapid identification of informative markers in at-risk couples for use in the PGT-M of SCA3/MJD.

Enhanced Commendable Sensitivity and Specificity for MSI in Colorectal Cancer by a New PCR-HRM Based 8-Loci MSI Assay.

BACKGROUND: This study evaluated the performance of the PCR-HRM assay by comparing it with immunohistochemistry (IHC) for mismatch repair (MMR) proteins and the PCR capillary electrophoresis (PCR-CE) methods. RESULTS: A total of 224 patients with colorectal cancer participated in the study, with nearly half having mismatch repair deficiency (dMMR) tissues and the remainder possessing pMMR tissues. There was a 97.77% concordance between the PCR-HRM assay and IHC, and a 97.56% concordance between PCR-HRM and the PCR-CE assay. In comparison with IHC for dMMR proteins, the PCR-HRM demonstrated a sensitivity of 96.36% and a specificity of 99.12%. When juxtaposed with the PCR-CE assay, its sensitivity was 98.96% and specificity stood at 96.33%. The mutations observed in the microsatellite loci were uniformly distributed across all eight loci. Discrepant outcomes were more frequent in instances of MLH1 and PMS2 deficiency. Furthermore, the germline mutation status of MLH1, MSH2, PMS2, and MSH6 in 62 patients was ascertained using next-generation sequencing. All patients displaying MMR gene pathogenic mutations (N = 14) were identified as MSI-H by PCR-HRM, whereas those with MSS tissues (N = 43) did not exhibit MMR gene pathogenic mutations. Thus, the PCR-HRM method proficiently pinpoints tumors with verified germline MMR mutations, indicative of Lynch syndrome. CONCLUSION: Conclusively, the PCR-HRM assay emerges as a swift and congruent diagnostic tool for microsatellite instability, boasting commendable sensitivity and specificity in colorectal cancer.

Lynch syndrome-associated and sporadic microsatellite unstable colorectal cancers: different patterns of clonal evolution yield highly similar tumours.

Microsatellite unstable colorectal cancer (MSI-CRC) can arise through germline mutations in mismatch repair (MMR) genes in individuals with Lynch syndrome (LS), or sporadically through promoter methylation of the MMR gene MLH1. Despite the different origins of hereditary and sporadic MSI tumours, their genomic features have not been extensively compared. A prominent feature of MMR-deficient genomes is the occurrence of many indels in short repeat sequences, an understudied mutation type due to the technical challenges of variant calling in these regions. In this study, we performed whole genome sequencing and RNA-sequencing on 29 sporadic and 14 hereditary MSI-CRCs. We compared the tumour groups by analysing genome-wide mutation densities, microsatellite repeat indels, recurrent protein-coding variants, signatures of single base, doublet base, and indel mutations, and changes in gene expression. We show that the mutational landscapes of hereditary and sporadic MSI-CRCs, including mutational signatures and mutation densities genome-wide and in microsatellites, are highly similar. Only a low number of differentially expressed genes were found, enriched to interferon-γ regulated immune response pathways. Analysis of the variance in allelic fractions of somatic variants in each tumour group revealed higher clonal heterogeneity in sporadic MSI-CRCs. Our results suggest that the differing molecular origins of MMR deficiency in hereditary and sporadic MSI-CRCs do not result in substantial differences in the mutational landscapes of these tumours. The divergent patterns of clonal evolution between the tumour groups may have clinical implications, as high clonal heterogeneity has been associated with decreased tumour immunosurveillance and reduced responsiveness to immunotherapy.

Medullary carcinomas of the nonampullary small intestine: association with coeliac disease, mismatch repair deficiency, PD-L1 expression, and favourable prognosis.

AIM: Gastrointestinal medullary carcinoma is a rare histologic subtype of adenocarcinoma. As nonampullary small bowel medullary carcinomas (SB-MCs) are poorly characterized, we aimed to analyse their clinicopathologic and immunohistochemical features and to compare them with nonmedullary small bowel adenocarcinomas (NM-SBAs). METHODS AND RESULTS: Surgically resected SBAs collected through the Small Bowel Cancer Italian Consortium were classified as SB-MCs (carcinomas with ≥50% of tumour fulfilling the typical histologic criteria of MC) or NM-SBAs. Immunohistochemistry for cytokeratin (CK)7, CK20, CDX2, programmed death-ligand 1 (PD-L1) and mismatch repair proteins was performed in both SB-MCs and NM-SBAs. SB-MCs were also tested for CK8/18, synaptophysin, SMARCB1, SMARCA2, SMARCA4, and ARID1A and for Epstein-Barr virus (EBV)-encoded RNAs by in-situ hybridization. MLH1 promoter methylation status was evaluated in MLH1-deficient cases. Eleven SB-MCs and 149 NM-SBAs were identified. One (9%) SB-MC was EBV-positive, while 10 (91%) harboured mismatch repair deficiency (dMMR). MLH1 promoter hypermethylation was found in all eight dMMR SB-MCs tested. Switch/sucrose nonfermentable deficiency was seen in two (18%) SB-MCs, both with isolated loss of ARID1A. Compared with NM-SBAs, SB-MCs exhibited an association with coeliac disease (P < 0.001), higher rates of dMMR (P < 0.001), and PD-L1 positivity by both tumour proportion score and combined positive score (P < 0.001 for both), and a lower rate of CK20 expression (P = 0.024). Survival analysis revealed a better prognosis of SB-MC patients compared to NM-SBA cases (P = 0.02). CONCLUSION: SB-MCs represent a distinct histologic subtype, with peculiar features compared to NM-SBAs, including association with coeliac disease, dMMR, PD-L1 expression, and better prognosis.

Efficacy and challenges of anti-PD1 in MSI-H mCRC: a case report on concurrent infections and ir-AIHA.

Anti-programmed cell death protein 1 (PD-1) therapy has demonstrated notable efficacy in treating patients with deficient mismatch repair/high microsatellite instability (dMMR/MSI-H) metastatic colorectal cancer (mCRC). However, its clinical application is fraught with challenges and can lead to significant immune-related adverse events (ir-AEs). In this report, we present a complicated case of an mCRC patient with MSI-H and mutations in ß2M and LRP1B proteins, complicated by concurrent bacteremia and liver fluke infection, who received first-line anti-PD1 therapy. The patient exhibited a positive response to anti-PD1 treatment, even in the presence of concomitant antibiotic and anti-parasitic interventions. Additionally, the patient experienced immunotherapy-related autoimmune hemolytic anemia (ir-AIHA), a rare hematological ir-AE, which was effectively treated later on. Immunotherapy represents a pivotal and highly effective approach to tumor treatment. Baseline assessment of the MMR and MSI status is a crucial step before initiating immunotherapy, and regular ongoing assessments during the treatment course can facilitate early recognition of any secondary complications, enabling prompt intervention and ensuring optimal therapeutic outcomes. Overall, a multidisciplinary diagnostic and therapeutic algorithm can help maximize the therapeutic benefits of immunotherapy.

A prediction model based on deep learning and radiomics features of DWI for the assessment of microsatellite instability in endometrial cancer.

BACKGROUND: To explore the efficacy of a prediction model based on diffusion-weighted imaging (DWI) features extracted from deep learning (DL) and radiomics combined with clinical parameters and apparent diffusion coefficient (ADC) values to identify microsatellite instability (MSI) in endometrial cancer (EC). METHODS: This study included a cohort of 116 patients with EC, who were subsequently divided into training (n = 81) and test (n = 35) sets. From DWI, conventional radiomics features and convolutional neural network-based DL features were extracted. Random forest (RF) and logistic regression were adopted as classifiers. DL features, radiomics features, clinical variables, ADC values, and their combinations were applied to establish DL, radiomics, clinical, ADC, and combined models, respectively. The predictive performance was evaluated through the area under the receiver operating characteristic curve (AUC), total integrated discrimination index (IDI), net reclassification index (NRI), calibration curves, and decision curve analysis (DCA). RESULTS: The optimal predictive model, based on an RF classifier, comprised four DL features, three radiomics features, two clinical variables, and an ADC value. In the training and test sets, this model exhibited AUC values of 0.989 (95% CI: 0.935-1.000) and 0.885 (95% CI: 0.731-0.967), respectively, demonstrating different degrees of improvement compared with the clinical, DL, radiomics, and ADC models (AUC-training = 0.671, 0.873, 0.833, and 0.814, AUC-test = 0.685, 0.783, 0.708, and 0.713, respectively). The NRI and IDI analyses revealed that the combined model resulted in improved risk reclassification of the MSI status compared to the clinical, radiomics, DL, and ADC models. The calibration curves and DCA indicated good consistency and clinical utility of this model, respectively. CONCLUSIONS: The predictive model based on DWI features extracted from DL and radiomics combined with clinical parameters and ADC values could effectively assess the MSI status in EC.

Complete Response to Pembrolizumab in a Patient with Castration-Resistant Prostate Cancer with Both BRCA Positivity and a High Frequency of Microsatellite Instability: A Case Report.

Introduction: There have been few reports of patients for whom a cancer gene panel test for solid tumors revealed the simultaneous presence of BRCA mutation and microsatellite instability (MSI)-high status. BRCA mutations have been reported in 13% of castration-resistant prostate cancer (CRPC) patients, and 3.1% of prostate cancer cases are MSI-high/mismatch repair deficient. Case Presentation: A 71-year-old man with a history of urinary retention was referred to our department for clinically suspected prostate cancer and a high prostate-specific antigen (PSA) level (141 ng/mL). MRI revealed features of prostate cancer invading the bladder, seminal vesicles, and rectum. A histopathological examination of a transperineal needle biopsy specimen obtained from the prostate revealed adenocarcinoma. Bone scintigraphy revealed multiple metastases. The patient was treated with abiraterone acetate combined with androgen deprivation therapy followed by local radiation. Rectal wall thickening and lymph node metastasis were also observed, and docetaxel was administered. A cancer gene panel test was positive results for BRCA2 mutation with a MSI-high. After six courses of docetaxel, lymph node enlargement was observed and olaparib was initiated. Two months later, the metastatic lesions showed enlargement and the PSA level increased. Subsequently, pembrolizumab was administered. At 2 to the patient months after the initiation of pembrolizumab administration, PSA levels decreased to <0.025 ng/mL and the rectal lesions and lymph node metastases disappeared. The patient was continuing to receive pembrolizumab without any apparent adverse events or exacerbations, 9 months after initiation. Conclusion: We herein report a case in which pembrolizumab treatment resulted in a complete response in a CRPC patient with both a BRCA2 mutation and an MSI-high status.

Performance assessment of computational tools to detect microsatellite instability.

Microsatellite instability (MSI) is a phenomenon seen in several cancer types, which can be used as a biomarker to help guide immune checkpoint inhibitor treatment. To facilitate this, researchers have developed computational tools to categorize samples as having high microsatellite instability, or as being microsatellite stable using next-generation sequencing data. Most of these tools were published with unclear scope and usage, and they have yet to be independently benchmarked. To address these issues, we assessed the performance of eight leading MSI tools across several unique datasets that encompass a wide variety of sequencing methods. While we were able to replicate the original findings of each tool on whole exome sequencing data, most tools had worse receiver operating characteristic and precision-recall area under the curve values on whole genome sequencing data. We also found that they lacked agreement with one another and with commercial MSI software on gene panel data, and that optimal threshold cut-offs vary by sequencing type. Lastly, we tested tools made specifically for RNA sequencing data and found they were outperformed by tools designed for use with DNA sequencing data. Out of all, two tools (MSIsensor2, MANTIS) performed well across nearly all datasets, but when all datasets were combined, their precision decreased. Our results caution that MSI tools can have much lower performance on datasets other than those on which they were originally evaluated, and in the case of RNA sequencing tools, can even perform poorly on the type of data for which they were created.

Clinical and Molecular Variables Associated With Early Progression to Checkpoint Inhibitors in MSI-High Metastatic Colorectal Cancer: A Retrospective Cohort Study.

BACKGROUND: About one third of patients with deficient mismatch repair/microsatellite instability-high metastatic colorectal cancer (dMMR/MSI-H mCRC) experience primary resistance or early progression on immune checkpoint inhibitors (ICI), while others benefit from exceptionally long-lasting responses. In this single-centre retrospective study, we aimed to identify variables associated with improved overall survival (OS) as well as early disease progression. METHODS: All dMMR/MSI-H mCRC patients treated with ICI between 2014 and 2022 were included. Baseline patient demographics, tumour characteristics as well response and outcome data were recorded. OS was estimated using the Kaplan-Meier method. Uni- and multivariate cox regression analysis was used to identify parameters associated with improved OS. Clinicopathological factors associated with early progression (≤ 12 months after treatment initiation) were assessed using uni- and multivariate logistic regression analysis. RESULTS: About 84 ICI-treated dMMR/MSI-H mCRC patients were included. Progressive disease occurred in 37 (44%) patients, but only in 11 (19%) patients with disease control at 12 months. Median OS was 80 months and improved outcome was associated with a lower neutrophile-to-lymphocyte ratio (NLR) (P = .004) and the presence of immune-related adverse events (irAEs) (P = .015). Early progression was associated with poor performance status (P = .036), a higher blood CRP level (P = .033) and absence of irAEs (P = .002). CONCLUSION: Disease progression in ICI-treated dMMR/MSI-H mCRC rarely occurs in patients experiencing disease control for at least 12 months. Performance status, presence of immune-related adverse events, CRP levels, CEA levels and NLR can be helpful to identify those patients that may benefit from ICI treatment, guiding clinicians in therapeutic decisions.

Elucidating the pan-oncologic landscape of S100A9: prognostic and therapeutic corollaries from an integrative bioinformatics and Mendelian randomization analysis.

The calcium-binding protein S100A9 has emerged as a pivotal biomolecular actor in oncology, implicated in numerous malignancies. This comprehensive bioinformatics study transcends traditional boundaries, investigating the prognostic and therapeutic potential of S100A9 across diverse neoplastic entities. Leveraging a wide array of bioinformatics tools and publicly available cancer genomics databases, such as TCGA, we systematically examined the S100A9 gene. Our approach included differential expression analysis, mutational burden assessment, protein interaction networks, and survival analysis. This robust computational framework provided a high-resolution view of S100A9's role in cancer biology. The study meticulously explored S100A9's oncogenic facets, incorporating comprehensive analyses of its relationship with prognosis, tumor mutational burden (TMB), microsatellite instability (MSI), DNA methylation, and immune cell infiltration across various tumor types. This study presents a panoramic view of S100A9 expression across a spectrum of human cancers, revealing a heterogeneous expression landscape. Elevated S100A9 expression was detected in malignancies such as BLCA (Bladder Urothelial Carcinoma), CESC (Cervical squamous cell carcinoma and endocervical adenocarcinoma), COAD (Colon adenocarcinoma), ESCA (Esophageal carcinoma), and GBM (Glioblastoma multiforme), while reduced expression was noted in BRCA (Breast invasive carcinoma), HNSC (Head and Neck squamous cell carcinoma), and KICH (Kidney Chromophobe). This disparate expression pattern suggests that S100A9's role in cancer biology is multifaceted and context-dependent. Prognostically, S100A9 expression correlates variably with patient outcomes across different cancer types. Furthermore, its expression is intricately associated with TMB and MSI in nine cancer types. Detailed examination of six selected tumors-BRCA, CESC, KIRC (Kidney renal clear cell carcinoma), LUSC (Lung squamous cell carcinoma), SKCM (Skin Cutaneous Melanoma); STAD (Stomach adenocarcinoma)-revealed a negative correlation of S100A9 expression with the infiltration of most immune cells, but a positive correlation with neutrophils, M1 macrophages, and activated NK cells, highlighting the complex interplay between S100A9 and the tumor immune environment. This bioinformatics synthesis posits S100A9 as a significant player in cancer progression, offering valuable prognostic insights. The data underscore the utility of S100A9 as a prognostic biomarker and its potential as a therapeutic target. The therapeutic implications are profound, suggesting that modulation of S100A9 activity could significantly impact cancer management strategies.

How inquilinism shaped breeding systems in a termite host-inquiline relationship.

Social insects have developed a broad diversity of nesting and foraging strategies. One of these, inquilinism, occurs when one species (the inquiline) inhabits the nest built and occupied by another species (the host). Obligatory inquilines must overcome strong constraints upon colony foundation and development, due to limited availability of host colonies. To reveal how inquilinism shapes reproductive strategies in a termite host-inquiline dyad, we carried out a microsatellite marker study on Inquilinitermes inquilinus and its host Constrictotermes cavifrons. The proportion of simple, extended and mixed families was recorded in both species, as well as the presence of neotenics, parthenogenesis and multiple foundations. Most host colonies (95%) were simple families and all were monodomous. By contrast, the inquiline showed a higher proportion of extended (30%) and mixed (5%) families, and frequent neotenics (in 25% of the nests). This results from the simultaneous foundation in host nests of numerous incipient colonies, which, as they grow, may compete, fight, or merge. We also documented the use of parthenogenesis by female-female pairs. In conclusion, the classical monogamous colony pattern of the host species suggests uneventful development of simple foundations dispersed in the environment, in accordance with the wide distribution of their resources. By contrast, the multiple reproductive patterns displayed by the inquiline species reveal strong constraints on foundation sites: founders first concentrate into host nests, then must attempt to outcompete or absorb the neighbouring foundations to gain full control of the resources provided by the host nest.

Oncological characteristics, treatments and prognostic outcomes in MMR-deficient colorectal cancer.

Colorectal cancer (CRC) ranks as the third most prevalent cancer globally. It's recognized that the molecular subtype of CRC, characterized by mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H), plays a critical role in determining appropriate treatment strategies. This review examines the current molecular classifications, focusing on dMMR/MSI-H CRC and its subtypes: Lynch syndrome (LS), Lynch-like syndrome (LLS), and sporadic cases. Despite advances in understanding of these genetic backgrounds, clinical trials have not conclusively differentiated the efficacy of immune checkpoint inhibitors among these subgroups. Therefore, while this review details the molecular characteristics and their general implications for treatment and prognosis, it also highlights the limitations and the need for more refined clinical studies to ascertain tailored therapeutic strategies for each subtype. Furthermore, this review summarizes completed and ongoing clinical studies, emphasizing the importance of developing treatments aligned more closely with molecular profiles. By discussing these aspects, the review seeks to provide a comprehensive analysis of oncological characteristics, presenting a detailed understanding of their implications for treatment and prognosis in dMMR/MSI-H CRC.