-
International Journal of Gynecological... Jun 2024Immune checkpoint inhibitor combinations show significant survival advantages compared with chemotherapy for patients with advanced endometrial cancer.
BACKGROUND
Immune checkpoint inhibitor combinations show significant survival advantages compared with chemotherapy for patients with advanced endometrial cancer.
OBJECTIVE
To compare the efficacy, safety, and cost-effectiveness of different immunotherapy combinations for clinician and patient decision-making.
METHODS
The PubMed, Embase, Cochrane, and Web of Science Databases were reviewed from January 1, 2010 to October 30, 2023, for phase III randomized controlled trials of first-line immunotherapy combinations in patients with advanced endometrial cancer. Bayesian network meta-analysis was performed to obtain hazard ratios (HRs) of overall survival and progression-free survival, relative risks (RRs) of adverse events, and corresponding p value. The lifetime Markov model of cost-effectiveness analysis was developed to summarize the cost, life-years, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios at the US$150 000/QALY of willingness-to-pay of six first-line treatment strategies.
RESULTS
Four trials were identified, involving 2577 patients. Dostarlimab plus chemotherapy or durvalumab plus chemotherapy with olaparib was associated with more survival benefits than other immunotherapy regimens and chemotherapy in the mismatch repair-deficient microsatellite instability-high (dMMR/MSI-H) and mismatch repair-proficient microsatellite-stable (pMMR/MSS) population, respectively. Further, pembrolizumab plus chemotherapy versus chemotherapy increased efficacy (cost) by 3.76 QALYs and US$540 817, which yielded incremental cost-effectiveness ratios of US$143 894/QALY in the dMMR/MSI-H population.
CONCLUSION
First-line durvalumab plus chemotherapy with olaparib, and dostarlimab plus chemotherapy, were more beneficial for survival in the pMMR/MSS and dMMR/MSI-H populations, respectively. Only pembrolizumab plus chemotherapy versus chemotherapy was cost-effective for patients with dMMR/MSI-H endometrial cancer in the USA.
PubMed: 38901970
DOI: 10.1136/ijgc-2024-005296 -
World Neurosurgery Jun 2024
Review
PubMed: 38901486
DOI: 10.1016/j.wneu.2024.06.050 -
Computers in Biology and Medicine Jun 2024Thoracic endovascular aortic repair (TEVAR) is a minimally invasive procedure involving the placement of an endograft inside the dissection or an aneurysm to direct...
Thoracic endovascular aortic repair (TEVAR) is a minimally invasive procedure involving the placement of an endograft inside the dissection or an aneurysm to direct blood flow and prevent rupture. A significant challenge in endovascular surgery is the geometrical mismatch between the endograft and the artery, which can lead to endoleak formation, a condition where blood leaks between the endograft and the vessel wall. This study uses computational modeling to investigate the effects of artery curvature and endograft oversizing, the selection of an endograft with a larger diameter than the artery, on endoleak creation. Finite element analysis is employed to simulate the deployment of endografts in arteries with varying curvature and diameter. Numerical simulations are conducted to assess the seal zone and to quantify the potential endoleak volume as a function of curvature and oversizing. A theoretical framework is developed to explain the mechanisms of endoleak formation along with proof-of-concept experiments. Two main mechanisms of endoleak creation are identified: local buckling due to diameter mismatch and global buckling due to centerline curvature mismatch. Local buckling, characterized by excess graft material buckling and wrinkle formation, increases with higher levels of oversizing, leading to a larger potential endoleak volume. Global buckling, where the endograft bends or deforms to conform to the centerline curvature of the artery, is observed to require a certain degree of oversizing to bridge the curvature mismatch. This study highlights the importance of considering both curvature and diameter mismatch in the design and clinical use of endografts. Understanding the mechanisms of endoleak formation can provide valuable insights for optimizing endograft design and surgical planning, leading to improved clinical outcomes in endovascular aortic procedures.
PubMed: 38901185
DOI: 10.1016/j.compbiomed.2024.108745 -
World Journal of Gastroenterology Jun 2024In this editorial we comment on the article by Li published in the recent issue of the . We focus specifically on the application of immune checkpoint inhibitors (ICIs)...
In this editorial we comment on the article by Li published in the recent issue of the . We focus specifically on the application of immune checkpoint inhibitors (ICIs) and microsatellite instability (MSI) in gastric cancer (GC). The four pillars of GC management have long been considered, including surgery, chemotherapy, radiotherapy and targeted therapy. However, immunotherapy has recently emerged as a "fifth pillar", and its use is rapidly expanding. There are four principal strategies for tumor immunotherapy: ICIs, tumor vaccines, adoptive immunotherapy and nonspecific immunomodulators. Of them, ICIs are the most advanced and widespread type of cancer immunotherapy for GC. Recent breakthrough results for ICIs have paved the way to a new era of cancer immunotherapy. In particular, inhibition of the PD-1/PD-L1 axis with ICIs, including nivolumab and pembrolizumab, has emerged as a novel treatment strategy for advanced GC. Unfortunately, these therapies are sometimes associated with often subtle, potentially fatal immune-related adverse events (irAEs), including dermatitis, diarrhea, colitis, endocrinopathy, hepatotoxicity, neuropathy and pneumonitis. We must be aware of these irAEs and improve the detection of these processes to prevent inappropriate discharges, emergency department revisits, and downstream complications. Recent studies have revealed that MSI-high or mismatch- repair-deficient tumors, regardless of their primary site, have a promising response to ICIs. So, it is important to detect MSI before applying ICIs for treatment of GC.
Topics: Humans; Microsatellite Instability; Stomach Neoplasms; Immune Checkpoint Inhibitors; B7-H1 Antigen; Programmed Cell Death 1 Receptor; Antibodies, Monoclonal, Humanized; Immunotherapy; Cancer Vaccines
PubMed: 38899328
DOI: 10.3748/wjg.v30.i21.2734 -
Scientific Reports Jun 2024This study probes the utility of biomarkers for microsatellite instability (MSI) detection and elucidates the molecular dynamics propelling colorectal cancer (CRC)...
This study probes the utility of biomarkers for microsatellite instability (MSI) detection and elucidates the molecular dynamics propelling colorectal cancer (CRC) progression. We synthesized a primer panel targeting 725 MSI loci, informed by The Cancer Genome Atlas (TCGA) and ancillary databases, to construct an amplicon library for next-generation sequencing (NGS). K-means clustering facilitated the distillation of 8 prime MSI loci, including activin A receptor type 2A (ACVR2A). Subsequently, we explored ACVR2A's influence on CRC advancement through in vivo tumor experiments and hematoxylin-eosin (HE) staining. Transwell assays gauged ACVR2A's role in CRC cell migration and invasion, while colony formation assays appraised cell proliferation. Western blotting illuminated the impact of ACVR2A suppression on CRC's PI3K/AKT/mTOR pathway protein expressions under hypoxia. Additionally, ACVR2A's influence on CRC-induced angiogenesis was quantified via angiogenesis assays. K-means clustering of NGS data pinpointed 32 MSI loci specific to tumor and DNA mismatch repair deficiency (dMMR) tissues. ACVR2A emerged as a pivotal biomarker, discerning MSI-H tissues with 90.97% sensitivity. A curated 8-loci set demonstrated 100% sensitivity and specificity for MSI-H detection in CRC. In vitro analyses corroborated ACVR2A's critical role, revealing its suppression of CRC proliferation, migration, and invasion. Moreover, ACVR2A inhibition under CRC-induced hypoxia markedly escalated MMP3, CyclinA, CyclinD1, and HIF1α protein expressions, alongside angiogenesis, by triggering the PI3K/AKT/mTOR cascade. The 8-loci ensemble stands as the optimal marker for MSI-H identification in CRC. ACVR2A, a central element within this group, deters CRC progression, while its suppression amplifies PI3K/AKT/mTOR signaling and angiogenesis under hypoxic stress.
Topics: Colorectal Neoplasms; Humans; Microsatellite Instability; Activin Receptors, Type II; Disease Progression; Animals; Cell Movement; Mice; Cell Line, Tumor; Cell Proliferation; Biomarkers, Tumor; Signal Transduction; Male; High-Throughput Nucleotide Sequencing; Female; Proto-Oncogene Proteins c-akt
PubMed: 38898042
DOI: 10.1038/s41598-024-62753-1 -
BioRxiv : the Preprint Server For... Jun 2024Huntington's disease (HD), one of >50 inherited repeat expansion disorders (Depienne and Mandel, 2021), is a dominantly-inherited neurodegenerative disease caused by a...
Huntington's disease (HD), one of >50 inherited repeat expansion disorders (Depienne and Mandel, 2021), is a dominantly-inherited neurodegenerative disease caused by a CAG expansion in (The Huntington's Disease Collaborative Research Group, 1993). Inherited CAG repeat length is the primary determinant of age of onset, with human genetic studies underscoring that the property driving disease is the CAG length-dependent propensity of the repeat to further expand in brain (Swami ., 2009; GeM-HD, 2015; Hensman Moss ., 2017; Ciosi ., 2019; GeM-HD, 2019; Hong ., 2021). Routes to slowing somatic CAG expansion therefore hold great promise for disease-modifying therapies. Several DNA repair genes, notably in the mismatch repair (MMR) pathway, modify somatic expansion in HD mouse models (Wheeler and Dion, 2021). To identify novel modifiers of somatic expansion, we have used CRISPR-Cas9 editing in HD knock-in mice to enable screening of expansion-modifier candidates at scale. This has included testing of HD onset modifier genes emerging from human genome-wide association studies (GWAS), as well as interactions between modifier genes, thereby providing new insight into pathways underlying CAG expansion and potential therapeutic targets.
PubMed: 38895438
DOI: 10.1101/2024.06.08.597823 -
Diagnostics (Basel, Switzerland) May 2024Determination of microsatellite instability (MSI)/mismatch repair (MMR) status in cancer has several clinical implications. Our aim was to integrate MSI/MMR status from...
Determination of microsatellite instability (MSI)/mismatch repair (MMR) status in cancer has several clinical implications. Our aim was to integrate MSI/MMR status from patients tested in Greece to assess the prevalence of MSI-high (MSI-H)/deficient MMR (dMMR) per tumor type, testing patterns over time and concordance between MSI and MMR status. We retrospectively recorded MSI/MMR testing data of patients with diverse tumor types performed in pathology and molecular diagnostics laboratories across Greece. Overall, 18 of 22 pathology and/or molecular diagnostics laboratories accepted our invitation to participate. In the 18 laboratories located across the country, 7916 tumor samples were evaluated for MSI/MMR status. MSI/MMR testing significantly increased in patients with colorectal cancer (CRC) and other tumor types overtime ( < 0.05). The highest prevalence was reported in endometrial cancer (47 of 225 patients, 20.9%). MSI-H/dMMR was observed in most tumor types, even in low proportions. Among 904 tumors assessed both for MSI and MMR status, 21 had discordant results (overall discordance rate, 2.3%). We reported MSI-H/dMMR prevalence rates in patients with diverse cancers, while demonstrating increasing referral patterns from medical oncologists in the country overtime. The anticipated high rate of concordance between MSI and MMR status in paired analysis was confirmed.
PubMed: 38893603
DOI: 10.3390/diagnostics14111076 -
Cancers Jun 2024: In cancer care, the MLH1 gene is crucial for DNA mismatch repair (MMR), serving as a vital tumor suppressor. Evaluating MLH1 protein expression status, followed by...
: In cancer care, the MLH1 gene is crucial for DNA mismatch repair (MMR), serving as a vital tumor suppressor. Evaluating MLH1 protein expression status, followed by analysis of MLH1 promoter methylation, has become a key diagnostic and prognostic approach. Our study investigates the complex link between MLH1 methylation and prognosis in endometrial adenocarcinoma (EA) patients. : MLH1 methylation status was accessed by a Pyrosequencing (PSQ) assay. Qualitative positivity for methylation was established if it exceeded the 11% cut-off; as well, a quantitative methylation analysis was conducted to establish correlations with clinicopathological data, relapse-free survival, and disease-free survival. Our study revealed that 33.3% of patients without MLH1 methylation experienced relapses, surpassing the 23.3% in patients with methylation. Furthermore, 16.7% of patients without methylation succumbed to death, with a slightly higher rate of 17.6% in methylated patients. Qualitative comparisons highlighted that the mean methylation rate in patients experiencing relapse was 35.8%, whereas in those without relapse, it was 42.2%. This pattern persisted in disease-specific survival (DSS), where deceased patients exhibited a higher mean methylation level of 49.1% compared to living patients with 38.8%. : Our findings emphasize the efficacy of PSQ for evaluating MLH1 methylation. While unmethylation appears to be associated with a higher relapse rate, the survival rate does not seem to be influenced by methylation. Quantitative percentages suggest that elevated MLH1 methylation is linked to relapse and mortality, though a study with a larger sample size would be essential for statistically significant results.
PubMed: 38893238
DOI: 10.3390/cancers16112119 -
Cancers May 2024Patients with pancreatic cancer (PC) showing mismatch repair (MMR) deficiency may benefit from immunotherapy. Microsatellite instability (MSI) is a hallmark of MMR...
Patients with pancreatic cancer (PC) showing mismatch repair (MMR) deficiency may benefit from immunotherapy. Microsatellite instability (MSI) is a hallmark of MMR deficiency (MMR-D). Here, we estimated the prevalence of MSI in PC, investigated germline and somatic mutations in the three MMR genes (, , and ), and assessed the relationship between MMR genes mutations and MSI status in PC. Clinical specimens from PC patients were analyzed using targeted next-generation sequencing, including paired normal and tumor specimens from 155 patients, tumor-only specimens from 86 patients, and normal-only specimens from 379 patients. The MSI status of 235 PCs was assessed via PCR. Pathogenic/likely pathogenic (P/LP) germline variants in the MMR genes were identified in 1.1% of patients, while somatic variants were found in 2.6% of patients. No MSI-H tumors were detected. One patient carried two variants (P (VAF = 0.57) and LP (VAF = 0.25)) simultaneously; however, their germline/somatic status remains unknown due to the investigation focusing solely on the tumor and MSI analysis was not performed for this patient. MSI is rare in PC, even in tumors with MMR genes mutations. Our findings underscore the importance of assessing tumor MMR-D status in PC patients with confirmed Lynch syndrome when deciding whether to prescribe immunotherapy.
PubMed: 38893230
DOI: 10.3390/cancers16112111 -
Cancers May 2024Endometrial cancer is one the most prevalent gynecological cancers and, unfortunately, has a poor prognosis due to low response rates to traditional treatments. However,... (Review)
Review
Endometrial cancer is one the most prevalent gynecological cancers and, unfortunately, has a poor prognosis due to low response rates to traditional treatments. However, the progress in molecular biology and understanding the genetic mechanisms involved in tumor processes offers valuable information that has led to the current classification that describes four molecular subtypes of endometrial cancer. This review focuses on the molecular mechanisms involved in the pathogenesis of endometrial cancers, such as genetic mutations, defects in the DNA mismatch repair pathway, epigenetic changes, or dysregulation in angiogenic or hormonal signaling pathways. The preclinical genomic and molecular investigations presented allowed for the identification of some molecules that could be used as biomarkers to diagnose, predict, and monitor the progression of endometrial cancer. Besides the therapies known in clinical practice, targeted therapy is described as a new cancer treatment that involves identifying specific molecular targets in tumor cells. By selectively inhibiting these targets, key signaling pathways involved in cancer progression can be disrupted while normal cells are protected. The connection between molecular biomarkers and targeted therapy is vital in the fight against cancer. Ongoing research and clinical trials are exploring the use of standard therapy agents in combination with other treatment strategies like immunotherapy and anti-angiogenesis therapy to improve outcomes and personalize treatment for patients with endometrial cancer. This approach has the potential to transform the management of cancer patients. In conclusion, enhancing molecular tools is essential for stratifying the risk and guiding surgery, adjuvant therapy, and cancer treatment for women with endometrial cancer. In addition, the information from this review may have an essential value in the personalized therapy approach for endometrial cancer to improve the patient's life.
PubMed: 38893147
DOI: 10.3390/cancers16112027