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Scientific Reports May 2024The innate immune molecule NLR family CARD domain-containing 5 (NLRC5) plays a significant role in endometrial carcinoma (EC) immunosurveillance. However, NLRC5 also...
The innate immune molecule NLR family CARD domain-containing 5 (NLRC5) plays a significant role in endometrial carcinoma (EC) immunosurveillance. However, NLRC5 also plays a protumor role in EC cells. Mismatch repair gene deficiency (dMMR) can enable tumors to grow faster and also can exhibit high sensitivity to immune checkpoint inhibitors. In this study, we attempted to determine whether NLRC5-mediated protumor role in EC is via the regulation of dMMR. Our findings revealed that NLRC5 promoted the proliferation, migration, and invasion abilities of EC cells and induced the dMMR status of EC in vivo and in vitro. Furthermore, the mechanism underlying NLRC5 regulated dMMR was also verified. We first found NLRC5 could suppress nuclear factor-kappaB (NF-κB) pathway in EC cells. Then we validated that the positive effect of NLRC5 in dMMR was restricted when NF-κB was activated by lipopolysaccharides in NLRC5-overexpression EC cell lines. In conclusion, our present study confirmed the novel NLRC5/NF-κB/MMR regulatory mechanism of the protumor effect of NLRC5 on EC cells, thereby suggesting that the NLRC5-mediated protumor in EC was depend on the function of MMR.
Topics: Humans; Female; NF-kappa B; Endometrial Neoplasms; Intracellular Signaling Peptides and Proteins; Cell Line, Tumor; Signal Transduction; Cell Proliferation; Animals; Cell Movement; Disease Progression; Gene Expression Regulation, Neoplastic; Mice; Neoplastic Syndromes, Hereditary; DNA Mismatch Repair; Colorectal Neoplasms; Brain Neoplasms
PubMed: 38822039
DOI: 10.1038/s41598-024-63457-2 -
Journal For Immunotherapy of Cancer May 2024Programmed death-1 (PD-1) inhibitors, including nivolumab, have demonstrated long-term survival benefit in previously treated patients with microsatellite...
Nivolumab plus relatlimab in patients with previously treated microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: the phase II CheckMate 142 study.
BACKGROUND
Programmed death-1 (PD-1) inhibitors, including nivolumab, have demonstrated long-term survival benefit in previously treated patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (CRC). PD-1 and lymphocyte-activation gene 3 (LAG-3) are distinct immune checkpoints that are often co-expressed on tumor-infiltrating lymphocytes and contribute to tumor-mediated T-cell dysfunction. Relatlimab is a LAG-3 inhibitor that has demonstrated efficacy in combination with nivolumab in patients with melanoma. Here, we present the results from patients with MSI-H/dMMR metastatic CRC treated with nivolumab plus relatlimab in the CheckMate 142 study.
METHODS
In this open-label, phase II study, previously treated patients with MSI-H/dMMR metastatic CRC received nivolumab 240 mg plus relatlimab 160 mg intravenously every 2 weeks. The primary end point was investigator-assessed objective response rate (ORR).
RESULTS
A total of 50 previously treated patients received nivolumab plus relatlimab. With median follow-up of 47.4 (range 43.9-49.2) months, investigator-assessed ORR was 50% (95% CI 36% to 65%) and disease control rate was 70% (95% CI 55% to 82%). The median time to response per investigator was 2.8 (range 1.3-33.1) months, and median duration of response was 42.7 (range 2.8-47.0+) months. The median progression-free survival per investigator was 27.5 (95% CI 5.3 to 43.7) months with a progression-free survival rate at 3 years of 38%, and median overall survival was not reached (95% CI 17.2 months to not estimable), with a 56% overall survival rate at 3 years. The most common any-grade treatment-related adverse events (TRAEs) were diarrhea (24%), asthenia (16%), and hypothyroidism (12%). Grade 3 or 4 TRAEs were reported in 14% of patients, and TRAEs of any grade leading to discontinuation were observed in 8% of patients. No treatment-related deaths were reported.
CONCLUSIONS
Nivolumab plus relatlimab provided durable clinical benefit and was well tolerated in previously treated patients with MSI-H/dMMR metastatic CRC.
TRIAL REGISTRATION NUMBER
NCT02060188.
Topics: Humans; Nivolumab; Colorectal Neoplasms; Microsatellite Instability; Female; Male; Middle Aged; Aged; Antineoplastic Combined Chemotherapy Protocols; Adult; DNA Mismatch Repair; Aged, 80 and over; Neoplasm Metastasis
PubMed: 38821718
DOI: 10.1136/jitc-2023-008689 -
European Journal of Surgical Oncology :... Jul 2024The study aimed to validate the Betella algorithm, focusing on molecular analyses exclusively for endometrial cancer patients, where molecular classification alters risk...
INTRODUCTION
The study aimed to validate the Betella algorithm, focusing on molecular analyses exclusively for endometrial cancer patients, where molecular classification alters risk assessment based on ESGO/ESTRO/ESP 2020 guidelines.
MATERIALS AND METHODS
Conducted between March 2021 and March 2023, the retrospective research involved endometrial cancer patients undergoing surgery and comprehensive molecular analyses. These included p53 and mismatch repair proteins immunohistochemistry, as well as DNA sequencing for POLE exonuclease domain. We applied the Betella algorithm to our population and evaluated the proportion of patients in which the molecular analysis changed the risk class attribution.
RESULTS
Out of 102 patients, 97 % obtained complete molecular analyses. The cohort exhibited varying molecular classifications: 10.1 % as POLE ultra-mutated, 30.3 % as mismatch repair deficient, 11.1 % as p53 abnormal, and 48.5 % as non-specified molecular classification. Multiple classifiers were present in 3 % of cases. Integrating molecular classification into risk group calculation led to risk group migration in 11.1 % of patients: 7 moved to lower risk classes due to POLE mutations, while 4 shifted to higher risk due to p53 alterations. Applying the Betella algorithm, we can spare the POLE sequencing in 65 cases (65.7 %) and p53 immunochemistry in 17 cases (17.2 %).
CONCLUSION
In conclusion, we externally validated the Betella algorithm in our population. The application of this new proposed algorithm enables assignment of the proper risk class and, consequently, the appropriate indication for adjuvant treatment, allowing for the rationalization of the resources that can be allocated otherwise, not only for the benefit of settings with low resources, but of all settings in general.
Topics: Humans; Endometrial Neoplasms; Female; Algorithms; Retrospective Studies; Middle Aged; Aged; Tumor Suppressor Protein p53; DNA Polymerase II; Mutation; Immunohistochemistry; Poly-ADP-Ribose Binding Proteins; Risk Assessment; DNA Mismatch Repair; Aged, 80 and over; Adult; Sequence Analysis, DNA
PubMed: 38820923
DOI: 10.1016/j.ejso.2024.108436 -
CA: a Cancer Journal For Clinicians May 2024Tumor-agnostic therapies represent a paradigm shift in oncology by altering the traditional means of characterizing tumors based on their origin or location. Instead,... (Review)
Review
Tumor-agnostic therapies represent a paradigm shift in oncology by altering the traditional means of characterizing tumors based on their origin or location. Instead, they zero in on specific genetic anomalies responsible for fueling malignant growth. The watershed moment for tumor-agnostic therapies arrived in 2017, with the US Food and Drug Administration's historic approval of pembrolizumab, an immune checkpoint inhibitor. This milestone marked the marriage of genomics and immunology fields, as an immunotherapeutic agent gained approval based on genomic biomarkers, specifically, microsatellite instability-high or mismatch repair deficiency (dMMR). Subsequently, the approval of NTRK inhibitors, designed to combat NTRK gene fusions prevalent in various tumor types, including pediatric cancers and adult solid tumors, further underscored the potential of tumor-agnostic therapies. The US Food and Drug Administration approvals of targeted therapies (BRAF V600E, RET fusion), immunotherapies (tumor mutational burden ≥10 mutations per megabase, dMMR) and an antibody-drug conjugate (Her2-positive-immunohistochemistry 3+ expression) with pan-cancer efficacy have continued, offering newfound hope to patients grappling with advanced solid tumors that harbor particular biomarkers. In this comprehensive review, the authors delve into the expansive landscape of tissue-agnostic targets and drugs, shedding light on the rationale underpinning this approach, the hurdles it faces, presently approved therapies, voices from the patient advocacy perspective, and the tantalizing prospects on the horizon. This is a welcome advance in oncology that transcends the boundaries of histology and location to provide personalized options.
PubMed: 38814103
DOI: 10.3322/caac.21844 -
NPJ Digital Medicine May 2024Molecular classification, particularly microsatellite instability-high (MSI-H), has gained attention for immunotherapy in endometrial cancer (EC). MSI-H is associated...
Molecular classification, particularly microsatellite instability-high (MSI-H), has gained attention for immunotherapy in endometrial cancer (EC). MSI-H is associated with DNA mismatch repair defects and is a crucial treatment predictor. The NCCN guidelines recommend pembrolizumab and nivolumab for advanced or recurrent MSI-H/mismatch repair deficient (dMMR) EC. However, evaluating MSI in all cases is impractical due to time and cost constraints. To overcome this challenge, we present an effective and efficient deep learning-based model designed to accurately and rapidly assess MSI status of EC using H&E-stained whole slide images. Our framework was evaluated on a comprehensive dataset of gigapixel histopathology images of 529 patients from the Cancer Genome Atlas (TCGA). The experimental results have shown that the proposed method achieved excellent performances in assessing MSI status, obtaining remarkably high results with 96%, 94%, 93% and 100% for endometrioid carcinoma G1G2, respectively, and 87%, 84%, 81% and 94% for endometrioid carcinoma G3, in terms of F-measure, accuracy, precision and sensitivity, respectively. Furthermore, the proposed deep learning framework outperforms four state-of-the-art benchmarked methods by a significant margin (p < 0.001) in terms of accuracy, precision, sensitivity and F-measure, respectively. Additionally, a run time analysis demonstrates that the proposed method achieves excellent quantitative results with high efficiency in AI inference time (1.03 seconds per slide), making the proposed framework viable for practical clinical usage. These results highlight the efficacy and efficiency of the proposed model to assess MSI status of EC directly from histopathological slides.
PubMed: 38811811
DOI: 10.1038/s41746-024-01131-7 -
Frontiers in Oncology 2024Comprehensive molecular profiling of tissue samples that can help guide therapy management is not widely available across the globe.
BACKGROUND
Comprehensive molecular profiling of tissue samples that can help guide therapy management is not widely available across the globe.
METHODS
Comprehensive molecular profiling through Caris Molecular Intelligence involves the analysis of DNA through next-generation sequencing, chromogenic or fluorescent in situ hybridization, pyrosequencing, and copy number alterations; RNA through whole-transcriptome sequencing and multiplex PCR of RNA; and protein through immunohistochemistry.
RESULTS
Here we describe the experience of molecular profiling of tumor tissue samples from patients diagnosed with advanced solid tumors and treated in two countries, the United Arab Emirates and Thailand. Tumor cancer cases submitted to Caris Life Sciences (Phoenix, Arizona, USA) for molecular profiling from the UAE and Thailand were retrospectively analyzed (data accessed between 2019 and 2020) for their molecular alterations and clinical biomarkers, without regard to ethnicity. A total of 451 samples from 35 distinct types of advanced cancers were examined for mutations, amplifications, overexpression, exon copy number alterations, microsatellite instability, deficient mismatch repair, tumor mutational burden, and fusions. Interrogating each step of the biological pathway, from DNA to RNA to distinct protein, identified an alteration with an associated therapy for 75% of these tumor samples. The most common alterations identified included elevated PDL-1 that can be targeted with an immune checkpoint inhibitors and amplification of HER2 for which a variety of anti HER2 therapies are available.
CONCLUSION
Comprehensive molecular profiling in patients with advanced malignancies can help optimize therapeutic management allowing for improved prognostic outcome.
PubMed: 38800398
DOI: 10.3389/fonc.2024.1374087 -
BioRxiv : the Preprint Server For... May 2024TDP43 is an RNA/DNA binding protein increasingly recognized for its role in neurodegenerative conditions including amyotrophic lateral sclerosis (ALS) and frontotemporal...
TDP43 is an RNA/DNA binding protein increasingly recognized for its role in neurodegenerative conditions including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). As characterized by its aberrant nuclear export and cytoplasmic aggregation, TDP43 proteinopathy is a hallmark feature in over 95% of ALS/FTD cases, leading to the formation of detrimental cytosolic aggregates and a reduction in nuclear functionality within neurons. Building on our prior work linking TDP43 proteinopathy to the accumulation of DNA double-strand breaks (DSBs) in neurons, the present investigation uncovers a novel regulatory relationship between TDP43 and DNA mismatch repair (MMR) gene expressions. Here, we show that TDP43 depletion or overexpression directly affects the expression of key MMR genes. Alterations include MLH1, MSH2, MSH3, MSH6, and PMS2 levels across various primary cell lines, independent of their proliferative status. Our results specifically establish that TDP43 selectively influences the expression of MLH1 and MSH6 by influencing their alternative transcript splicing patterns and stability. We furthermore find aberrant MMR gene expression is linked to TDP43 proteinopathy in two distinct ALS mouse models and post-mortem brain and spinal cord tissues of ALS patients. Notably, MMR depletion resulted in the partial rescue of TDP43 proteinopathy-induced DNA damage and signaling. Moreover, bioinformatics analysis of the TCGA cancer database reveals significant associations between TDP43 expression, MMR gene expression, and mutational burden across multiple cancers. Collectively, our findings implicate TDP43 as a critical regulator of the MMR pathway and unveil its broad impact on the etiology of both neurodegenerative and neoplastic pathologies.
PubMed: 38798341
DOI: 10.1101/2024.05.16.594552 -
Relative Energy Deficiency in Sport (RED-S) and Knee Injuries: Current Concepts for Female Athletes.Journal of ISAKOS : Joint Disorders &... May 2024In athletes, a mismatch between caloric intake and energy expended in exercise can result in Low Energy Availability (LEA). LEA can lead to Relative Energy Deficiency in...
In athletes, a mismatch between caloric intake and energy expended in exercise can result in Low Energy Availability (LEA). LEA can lead to Relative Energy Deficiency in Sport (RED-S), where the athlete suffers from physiological derangements and decreased sport performance. The prevalence of RED-S is higher in females than males. RED-S more comprehensively describes the syndrome originally known as "Female Athlete Triad" (FAT). FAT encompasses the triad of LEA (with or without disordered eating), menstrual dysfunction and low bone mineral density. RED-S includes other physiological derangements such as poor cardiovascular health, abnormalities of metabolic rate, immunity, and protein synthesis. Females are already at a higher risk of knee injuries, which has been attributed to a multitude of factors such as hormonal influences, differences in musculoskeletal anatomy and neuromuscular control compared to males. The literature demonstrates an even higher risk of knee injuries in female athletes with symptoms of RED-S. We propose the various factors that influence this risk. A reduction in anabolic hormones can affect muscle development and tendon repair. A relationship between poor neuromuscular control and knee injury has been established, and this can be further worsened in patients with menstrual dysfunction. Chronic deficiency in nutrients such as collagen and vitamin D can result in poorer recovery from microtrauma in tendon and ligaments. All these factors may contribute to increasing the risk of knee injuries, which may include anterior cruciate ligament tears, patella tendinopathy and patellofemoral pain syndrome. This review aims to educate sports clinicians to have a high index of suspicion when treating knee injuries in females; to screen and then manage for RED-S if present, for holistic patient care.
PubMed: 38795863
DOI: 10.1016/j.jisako.2024.05.012 -
Cancers May 2024Sinonasal intestinal-type adenocarcinoma (ITAC) is a very rare, closely occupational-related tumor with strong histological similarities to colorectal cancer (CRC). In...
Tumor Budding, p53, and DNA Mismatch Repair Markers in Sinonasal Intestinal-Type Adenocarcinoma: A Retrospective Study Supports the Adverse Prognostic Impact of Tumor Budding.
Sinonasal intestinal-type adenocarcinoma (ITAC) is a very rare, closely occupational-related tumor with strong histological similarities to colorectal cancer (CRC). In the latter, tumor budding (TB) is widely recognized as a negative prognostic parameter. The aim of this study was to evaluate the prognostic role of TB in ITAC and to correlate it with other established or emerging biomarkers of the disease, such as p53 and deficient DNA mismatch repair (MMR) system status/microsatellite instability (MSI). We retrospectively analyzed 32 consecutive specimens of patients with ITAC diagnosis treated in two institutions in Northern Italy. We reviewed surgical specimens for TB evaluation (low-intermediate/high); p53 expression and MMR proteins were evaluated via immunohistochemistry. Results were retrospectively stratified using clinical data and patients' outcomes. According to bud counts, patients were stratified into two groups: intermediate/high budding (>4 TB) and low budding (≤4 TB). Patients with high TB (>4) have an increased risk of recurrence and death compared to those with low TB, with a median survival of 13 and 54 months, respectively. On multivariate analysis, considering TB, therapy, and stage as covariates, TB emerged as an independent prognostic factor net of the stage of disease or type of therapy received. No impact of p53 status as a biomarker of prognosis was observed and no alterations regarding MMR proteins were identified. The results of the present work provide further significant evidence on the prognostic role of TB in ITAC and underline the need for larger multicenter studies to implement the use of TB in clinical practice.
PubMed: 38791973
DOI: 10.3390/cancers16101895 -
Cancers May 2024The Cancer Genome Atlas (TCGA) has radically changed the history of endometrial cancer by outlining a new classification, based on its molecular characteristics. In the... (Review)
Review
The Cancer Genome Atlas (TCGA) has radically changed the history of endometrial cancer by outlining a new classification, based on its molecular characteristics. In the field of oncology, we are approaching the new era of molecular biology, particularly regarding endometrial cancer, with the increasing importance of targeted therapy. This paper is a review of phase III randomized controlled trials published in English between January 2019 and December 2023, comparing drugs of interest with standard adjuvant treatment and molecular subtypes in endometrial cancer. The use of immunotherapy alone or in combination with chemotherapy as therapy in patients with recurrent or advanced primary or metastatic endometrial cancer significantly improves the prognosis of these patients. The results show greater efficacy of all proposed treatments for mismatch repair deficiency (dMMR/MSI-H) patients compared to mismatch repair proficiency (pMMR) patients. Progression-free survival (PFS) and overall survival (OS) are better in dMMR patients in all studies analysed. Immunotherapy has the potential to revolutionize the gynaecological cancer treatment landscape, offering a new pathway and new hope for endometrial cancer patients, improving their outcomes in the future. Given the exciting results obtained in dMMR/MSI-H patients, MMR status should be investigated in every patient with advanced endometrial cancer at the time of diagnosis.
PubMed: 38791945
DOI: 10.3390/cancers16101866