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INTRODUCTION: Personalized and tumor-informed circulating tumor DNA (ctDNA) testing is feasible and allows for molecular residual disease (MRD) identification in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: In this retrospective analysis of commercial cases from multiple US institutions, personalized, tumor-informed, whole-exome sequenced, and germline-controlled ctDNA levels were quantified and analyzed in patients with PDAC. Plasma samples (n = 1329) from 298 clinically validated patients were collected at diagnosis, perioperatively (MRD-window; within 2-12 weeks after surgery, before therapy), and during surveillance (>12 weeks post-surgery if no ACT or starting 4 weeks post-ACT) from November 2019 to March 2023. RESULTS: Of the initially diagnosed patients with stages I-III PDAC who went for resection, the median follow-up time from surgery was 13 months (range 0.1-214). Positive ctDNA detection rates were 29% (29/100) and 29.6% (45/152) during the MRD and surveillance windows, respectively. Positive ctDNA detection was significantly associated with shorter DFS within the MRD window (median DFS of 6.37 months for ctDNA-positive vs 33.31 months for ctDNA-negative patients; HR: 5.45, P

Background: Bronchiolar adenoma (BA) is a rare benign tumor originating in the bronchial mucosal epithelium and occurring primarily in the periphery of the lung. The most prominent histopathological feature of BA is a double-layer bronchial epithelium containing continuous basal cell layers. However, due to the high mutation frequency of the driver gene, there is still debate as to whether BA has the potential for malignant transformation. In frozen sections, basal cells are difficult to identify under the microscope, which makes it difficult to distinguish from mucinous adenocarcinoma, especially when BA malignancies transform into invasive mucinous adenocarcinoma (IMA), which can only be distinguished by histomorphological criteria, greatly increasing the difficulty of diagnosis. Case summary: In this paper, we present a case study of a 59-year-old man whose chest computed tomography (CT) revealed a progressively enlarging, high-density nodule over a four-year period in the outer basal segment of the right lower lobe. Consequently, he underwent thoracoscopic wedge resection of the right lower lobe. The postoperative pathological diagnosis revealed BA with mucous gland structure formation combined with partial basal cell loss, raising the possibility of malignant transformation into IMA. Regular postoperative follow-up showed no recurrence or metastasis. Hybridization Capture-based next-generation sequencing (NGS) analysis detected driver gene mutations in Kirsten Rat Sarcoma viral oncogene homolog (KRAS) and Cyclin-Dependent Kinases (CDK) 6 in the case, thereby inferring the malignant transformation of BA into IMA. Conclusion: In this case, the detection of driver gene KRAS mutation and loss of continuity in the basal cell layer within the mucous glandular structures of the nodule suggests the malignant transformation of BA into IMA, inferring the malignant potential of BA. [ABSTRACT FROM AUTHOR]

Gapmer-type antisense oligonucleotides (ASOs) are an emerging class of therapeutic agents that directly inhibit pathogenic mRNA. In this study, three new 4′-C-substituted thymidine analogs were generated using a synthetic strategy recently established by our group, namely, 4′-C-(N-ethyl) aminoethyl (4′-EAE-T), 4′-C-(N-butyl) aminoethyl (4′-BAE-T), and 4′-C-(N-octyl) aminoethyl (4′-OAE-T). Their properties were evaluated and compared with those of previously reported analogs, including 4′-C-aminoethyl (4′-AE-T) and 4′-C-(N-methyl) aminoethyl (4′-MAE-T). The novel nucleoside analogs were subsequently incorporated into gapmer-type ASOs featuring phosphorothioate (PS) linkages and locked nucleic acids (LNAs) in the wing regions. The incorporation of 4′-EAE-T and 4′-BAE-T analogs resulted in RNA binding affinities similar to that of the previously reported 4′-MAE-T analog, whereas a marked decrease in RNA affinity was noted for 4′-OAE-T, however, this reduction was mitigated when combined with other chemical modifications. Furthermore, the structural modifications conferred enhanced nuclease resistance under bovine serum conditions, with 4′-EAE-T resulting in the highest stability, followed by 4′-BAE-T and 4′-OAE-T. Additionally, oligonucleotides modified with the developed analogs preserved their RNase H cleavage susceptibility, albeit inducing minor alterations in the cleavage pattern. Finally, the oligonucleotides were applied in a gene silencing experiment targeting the KRAS gene, conducted without the use of transfection agents, displaying gene silencing activities comparable to that of the control, with the exception of the 4′-OAE-modified nucleotide, which exhibited low activity. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Is there an association between the somatic loss of PTEN (phosphatase and tensin homolog) and ARID1A (AT-rich interaction domain 1A) and endometriosis disease severity and worse clinical outcomes? SUMMARY ANSWER Somatic PTEN loss in endometriosis epithelium was associated with greater disease burden and subsequent surgical complexity. WHAT IS KNOWN ALREADY Somatic cancer-driver mutations including those involving the PTEN and ARID1A genes exist in endometriosis without cancer; however, their clinical impact remains unclear. STUDY DESIGN, SIZE, DURATION This prospective longitudinal study involved endometriosis tissue and clinical data from 126 participants who underwent surgery at a tertiary center for endometriosis (2013–2017), with a follow-up period of 5–9 years. PARTICIPANTS/MATERIALS, SETTING, METHODS PTEN and ARID1A loss was assessed using established immunohistochemistry (IHC) methods as proxies for somatic loss by two independent raters. PTEN and ARID1A status for each participant was defined as loss (loss in at least one sample for a participant) or retained (no loss in all samples for a participant). Primary analyses examined associations between PTEN and ARID1A loss and disease burden based on anatomic subtype (superficial peritoneal endometriosis (SUP), deep endometriosis (DE), ovarian endometrioma (OMA)) and rASRM stage (I–IV). Secondary analyses explored associations of PTEN and ARID1A loss with demographics, surgical difficulty, and pain scores (baseline and follow-up). Additionally, using previously published data on KRAS codon 12 mutations for this cohort, we investigated associations between variables in the primary and secondary analyses and acquiring two or more somatic events (PTEN loss, ARID1A loss, or KRAS mutation) in this cohort. The risk of reoperation over the 5–9 years was also examined. MAIN RESULTS AND THE ROLE OF CHANCE PTEN loss (68.3%; 86 participants) exceeded ARID1A loss (24.6%; 31 participants). Inter-rater reliability was substantial for PTEN (k  = 0.69; 95% CI: 0.62–0.77) and ARID1A (k  = 0.64; 95% CI: 0.51–0.77). PTEN loss was significantly associated with more severe anatomic subtypes (P  < 0.001; participants with SUP only = 46.4%; participants with DE only or OMA only = 72.7%; participants with mixed subtypes = 85.1%), and higher stages (P  = 0.024; Stage I = 47.8%; Stage II = 73.7%; Stage III = 80.8%; Stage IV = 81.0%). Results were similar for ARID1A loss, albeit with smaller sample size limiting power. PTEN loss was further associated with non-White ethnicities (P  = 0.017) and greater surgical difficulty (more frequent need for ureterolysis) (P  = 0.02). There were no differences in pain scores (baseline or follow-up) based on PTEN or ARID1A status. Reoperation was uncommon (13.5% of the cohort), and patterns in reoperation rates based on the presence of somatic alterations did not reach statistical significance. LIMITATIONS, REASONS FOR CAUTION Sequencing was not performed to determine the type of PTEN and ARID1A somatic mutations resulting in loss of expression. WIDER IMPLICATIONS OF THE FINDINGS These results demonstrate a link between PTEN somatic loss and greater endometriosis disease burden. These findings underscore the potential relevance of PTEN loss and other somatic driver mutations in a future molecular classification of endometriosis. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by Canadian Institutes of Health Research (CIHR) project grant (MOP-142273 and PJT-156084). P.J.Y. was supported by a Health Professional Investigator award from Michael Smith Health Research BC, Canada, and a Canada Research Chair (Tier 2) in Endometriosis and Pelvic Pain. M.S.A. was supported by a Michael Smith Health Research BC Scholar award, and CIHR project grants (369990, 462997, and 456767). The sponsors did not play any role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. C.A. declares receiving payment from Pfizer for a symposium; being on advisory boards for AbbVie and Pfizer; being President and past President of the Canadian Society for the Advancement of Gynecologic Excellence (CanSAGE), co-lead of EndoAct Canada, and a board member of IPPS. M.A.B. has received consulting fees from AbbVie and Pfizer and grants from Ferring outside the scope of this work. D.G.H. is the founder of Canxeia Health but has no current affiliation. M.K. has received consulting fees from Helix Biopharma outside the scope of this work. M.S.A. received reimbursement of travel and registration fees to attend and present at the 2023 and 2024 annual meetings for the Society for Reproductive Investigation (SRI). P.J.Y. declares receiving: payment for a lecture from the International Society for the Study of Women's Sexual Health (ISSWSH); honoraria from the CIHR; support to attend meetings from CanSAGE, ISSWSH, the International Pelvic Pain Society, the World Endometriosis Society (WES), the Society for the Study of Reproduction, and the Vulvodynia Summit; and discounted devices from Ohnut Wearable for a clinical trial. P.J.Y. is a data safety monitoring board member of a clinical trial funded by CIHR; and a strategic advisory board member for the Women's Health Research Institute. P.J.Y. served as a board of directors member for CanSAGE and ISSWSH; was a junior board of directors member for WES; is a current board of directors member for WES; and was a committee chair for the Society of Obstetricians and Gynaecologists of Canada. A subset of these results was presented by the first author at the 71st Society for Reproductive Investigation Annual Scientific Meeting on 15 March 2024. Other authors have nothing to declare. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

Simple Summary: Borderline Ovarian Tumors (BOTs) are a unique group of ovarian growths that fall between benign and malignant categories. These tumours primarily affect younger women, often raising concerns about preserving fertility during treatment. Currently, doctors rely on surgical findings and tumour characteristics to predict outcomes and guide treatment decisions. However, this approach may not always provide a complete picture. Our review explores the potential of using molecular markers, such as BRAF, KRAS, CA125, and others, to better understand and manage BOTs. By identifying these biomarkers, we aim to develop a more personalized approach to treatment, potentially allowing for less aggressive interventions in low-risk cases while ensuring appropriate care for those at higher risk of recurrence or progression. This research could lead to improved decision-making and outcomes for women diagnosed with BOTs. Borderline Ovarian Tumours (BOTs) are a heterogenous group of ovarian neoplasms which have increased mitotic activity but lack stromal invasion. We performed a narrative review of the literature, aiming to identify prognostic molecular biomarkers that can potentially be used for treatment personalisation. We identified and discussed BRAF/KRAS, Cancer Antigen 125 (Ca 125), Calprotectin, p16ink4a, and Microsatellite instability (MSI) as the most studied biomarkers related to BOTs. Overall, BRAF and KRAS mutations are associated with earlier-stage and favourable prognosis; KRASmt may indicate extraovarian disease in serous BOT (sBOT). Ca125, the only currently clinically used biomarker, can be assessed pre-operatively and has an established role in post-operative surveillance, especially when it is raised pre-operatively or a high potential for malignant transformation is suspected post-operatively. p16ink4a expression trends could also indicate the malignant transformation of the tumour. Calprotectin has an inferior specificity to Ca125 and is not yet established as a biomarker, whilst there is very limited evidence available for MSI. As new evidence is coming along with artificial intelligence platforms, these biomarkers can be integrated and used towards the development of a precision model for treatment stratification and counselling in women diagnosed with BOTs. [ABSTRACT FROM AUTHOR]

Simple Summary: Non-small cell lung cancer (NSCLC) patients harboring KRAS mutations are targeted using monoclonal antibody (mAb) or tyrosine kinase inhibitors (TKI) therapies. To impede the KRAS activity, it was proposed to inhibit SRC kinase, an intermediary signal transductor between DDR2 and KRAS, using Dasatinib (Bcr-Abl TKI). However, clinical trials using Dasatinib failed to fully inhibit SRC or sensitize therapies towards SRC inhibitors, and its mechanistic failure remains partially understood. This report identifies AXL as a bypass resistant gene and investigates its role with SRC and KRAS activity. We found that AXL overexpression drives downstream KRAS and Akt pathways, and co-inhibiting AXL and SRC using SGI-7079 and Dasatinib effectively impeded both those pathways. Synergistic inhibition of AXL and SRC led to significant tumor growth suppression in A549 mice xenografts. The results from this study will be beneficial in understanding drug-resistance mechanisms and to strategize effective drug therapies in patients harboring KRAS mutations. Background/Objectives: KRAS-mutated NSCLC has been targeted using monoclonal antibody (mAb) or tyrosine kinase inhibitor (TKI) therapies. However, in time, these mutations appear to develop resistance against the targeted antibodies and TKI treatments. One possible explanation is the activation of pro apoptotic pathways through the AXL–SRC–Akt axis. In this study, we identify AXL as the bypass resistant gene and investigate its role with KRAS and SRC activity. Methods: In this study, we use Dasatinib and SGI-7079 to co-inhibit SRC and AXL respectively. In vitro studies were conducted using four cell lines, and AXL suppression was achieved using siRNA and in CRISPR-Cas9 mediated knockout models. Subsequently, we studied gene-protein expression analysis using Western blot, apoptotic markers using a cytochrome release assay and cytotoxicity using an MTT assay. A549 xenografts were studied for in vivo validation of our proposed hypothesis. Results: The results suggest that dual inhibition of AXL and SRC significantly reversed this resistance, both in in vivo and in vitro studies. Conclusions: Co-inhibition of AXL and SRC synergistically reduced KRAS activity and induced apoptosis in NSCLC. [ABSTRACT FROM AUTHOR]

Simple Summary: KRAS mutations are key drivers of colorectal cancer progression and resistance to treatment, significantly limiting therapeutic options for affected patients. Found in 30–40% of cases, these mutations promote persistent activation of oncogenic pathways such as MAPK/ERK and PI3K/AKT, contributing to tumor growth, poor prognosis, and reduced responsiveness to anti-EGFR therapies. This study aims to elucidate the biological role, clinical significance, and therapeutic potential of targeting KRAS mutations. Recent breakthroughs include the development of targeted inhibitors, such as sotorasib and adagrasib for G12C mutations, and experimental therapies for G12D. However, therapeutic responses in colorectal cancer remain suboptimal compared to other malignancies, largely due to resistance mechanisms and tumor heterogeneity. Promising strategies, including combination therapies, vaccines, and nucleic acid-based treatments, offer hope for improved outcomes. These findings underscore the importance of advancing personalized approaches to enhance care for patients with KRAS-mutant colorectal cancer. Background/Objectives: Colorectal cancer (CRC) remains a leading cause of cancer mortality globally, with KRAS mutations occurring in 30–40% of cases, contributing to poor prognosis and resistance to anti-EGFR therapy. This review explores the biological significance, clinical implications, and therapeutic targeting of KRAS mutations in CRC. Methods: A comprehensive analysis of the existing literature and clinical trials was performed, highlighting the role of KRAS mutations in CRC pathogenesis, their impact on prognosis, and recent advancements in targeted therapies. Specific attention was given to emerging therapeutic strategies and resistance mechanisms. Results: KRAS mutations drive tumor progression through persistent activation of MAPK/ERK and PI3K/AKT signaling pathways. These mutations influence the tumor microenvironment, cancer stem cell formation, macropinocytosis, and cell competition. KRAS-mutant CRC exhibits poor responsiveness to anti-EGFR monoclonal antibodies and demonstrates primary and acquired resistance to KRAS inhibitors. Recent breakthroughs include the development of KRAS G12C inhibitors (sotorasib and adagrasib) and promising agents targeting G12D mutations. However, response rates in CRC remain suboptimal compared to other cancers, necessitating combination therapies and novel approaches, such as vaccines, nucleic acid-based therapeutics, and macropinocytosis inhibitors. Conclusions: KRAS mutations are central to CRC pathogenesis and present a significant therapeutic challenge. Advances in KRAS-targeted therapies offer hope for improved outcomes, but resistance mechanisms and organ-specific differences limit efficacy. Continued efforts in personalized treatment strategies and translational research are critical for overcoming these challenges and improving patient survival. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to confirm whether Kirsten rat sarcoma viral oncogene (KRAS) mutations affect the therapeutic efficacy of non-small cell lung cancer (NSCLC) and, if so, to explore what the possible mechanisms might be. Methods: We retrospectively analyzed the efficacy of immunochemotherapy in KRAS-mutant NSCLC patients compared to driver-negative patients. Online data platforms were used to find immunotherapy cases, and survival analysis compared treatments' efficacy. Cytotoxicity assays measured chemosensitivity in KRAS-mutant versus wild-type NSCLC to drugs like paclitaxel, carboplatin, and pemetrexed. Bioinformatics confirmed the KRAS-SLC7A11 link and cell experiments tested SLC7A11's role in chemoresistance. Animal studies verified the antitumor effects of SLC7A11 inhibitors with chemotherapy. Results: Patients with KRAS-mutated NSCLC have a shorter therapeutic effectiveness duration with immunochemotherapy than patients with driver gene-negative status. The efficacy of immunotherapy alone is similar between the two groups. The KRAS mutation can enhance chemoresistance by upregulating SLC7A11, and inhibiting SLC7A11 can increase the sensitivity of KRAS-mutated NSCLC to chemotherapy. Conclusion: This study suggests that KRAS-mutant NSCLC can enhance its acquired chemoresistance by overexpressing SLC7A11, leading to poorer therapeutic outcomes. Targeting the KRAS-SLC7A11 axis could increase sensitivity to chemotherapeutic drugs, providing theoretical support for future treatment directions. [ABSTRACT FROM AUTHOR]

Cholesterol metabolism is abnormally active in tumour cells. Metabolic enzymes related to cholesterol metabolism are upregulated in tumours, but their nonmetabolic functions remain unclear. We found that MVK (mevalonate kinase) is upregulated in lung adenocarcinoma tissues vs. normal tissues and that its expression can be induced by constitutively activated Kras. By investigating the molecular mechanisms involved, we discovered that MVK interacts with TBK1, inhibiting TBK1 phosphorylation and thereby suppressing cGAS-Sting signalling. In addition, we found a negative correlation between MVK expression and CD8+ T-cell infiltration via a public database analysis. In summary, our study demonstrates the importance of the nonmetabolic function of MVK in modifying the immunological milieu and provides new targets for lung adenocarcinoma therapy. [ABSTRACT FROM AUTHOR]

Pancreatic intraepithelial neoplasia (PanIN) is the most common precursor lesion of pancreatic ductal adenocarcinoma (PDAC), which has poor prognosis with a short median overall survival of 6-12 months and a low 5-year survival rate of approximately 3%. It is crucial to remove PanIN lesions to prevent the development of invasive PDAC, as PDAC spreads rapidly outside the pancreas. This review aims to provide the latest knowledge on PanIN risk, pathology, cellular origin, genetic susceptibility, and diagnosis, while identifying research gaps that require further investigation in this understudied area of precancerous lesions. PanINs are classified into PanIN 1, PanIN 2, and PanIN 3, with PanIN 3 having the highest likelihood of developing into invasive PDAC. Differentiating between PanIN 2 and PanIN 3 is clinically significant. Genetic alterations found in PDAC are also present in PanIN and increase with the grade of PanIN. Imaging methods alone are insufficient for distinguishing PanIN, necessitating the use of genetic and molecular tests for identification. In addition, metabolomics technologies and miRNAs are playing an increasingly important role in the field of cancer diagnosis, offering more possibilities for efficient identification of PanIN. Although detecting and stratifying the risk of PanIN poses challenges, the combined utilization of imaging, genetics, and metabolomics holds promise for improving patient survival in this field. [ABSTRACT FROM AUTHOR]

Background/Objective: Studies have shown an association between colorectal cancer (CRC) sidedness and gene mutations that may affect CRC clinical behavior. This study examined the association between specific KRAS, NRAS, and BRAF hot-spot mutations and primary CRC sidedness. Methods: We performed a retrospective cohort analysis of 722 patients diagnosed with primary CRC and tested for KRAS, NRAS, and BRAF hot-spot mutations at the University of Texas Medical Branch (UTMB) from January 2016 through July 2023. Multivariable logistic regressions analyses were conducted. Results:KRAS, NRAS, and BRAF hot-spot mutations rates were 37.8%, 4.6%, and 6.1%, respectively. Right-sided primary CRC had the highest prevalence of mutated tumors (64%). KRAS and BRAF hot-spot mutations were significantly different according to tumor sidedness. KRAS p.Gly12Asp, p.Gly12Val, and p.Gly13Asp showed a significantly increased likelihood of right-sided primary CRC compared to KRAS wildtype, 128%, 134%, and 221% higher, respectively. Conversely, KRAS p.Gly12Val and p.Gly13Asp mutations were associated with decreased likelihood of rectal cancer (53% lower) and left-sided tumors (56% lower), respectively. BRAF p.Val600Glu mutation, as opposed to BRAF wildtype, was associated with a 278% higher likelihood of right-sided CRC. No significant associations were observed between NRAS mutations and primary CRC sidedness. Conclusions: In primary CRC, specific mutations in KRAS (p.Gly12Asp, p.Gly12Val, and p.Gly13Asp) and BRAF p.Val600Glu were associated with increased likelihood of right-sided tumors. KRAS p.Gly12Val and p.Gly13Asp mutations were associated with decreased likelihood of rectal cancer and left-sided tumors, respectively. These findings suggest that tumorigenesis and mutational processes differ based on tumor sidedness. Further studies are needed to substantiate these findings. [ABSTRACT FROM AUTHOR]

Simple Summary: This review presents an overview of recent findings on various epigenetic and post-transcriptional modifications of the epidermal growth factor receptor (EGFR), which activates the oncogenes RAS and MYC. Alterations in EGFR, RAS, and MYC play a crucial role in dysregulated processes that contribute to oncogenesis. Focused, targeted research aimed at understanding the distinct effects of these oncogenes and their carcinogenic modifications has facilitated the successful treatment of various malignancies using inhibitors of EGFR tyrosine kinase activity and other therapeutic agents. The epidermal growth factor receptor (EGFR) regulates gene expression through two primary mechanisms: as a growth factor in the nucleus, where it translocates upon binding its ligand, or via its intrinsic tyrosine kinase activity in the cytosol, where it modulates key signaling pathways such as RAS/MYC, PI3K, PLCγ, and STAT3. During tumorigenesis, these pathways become deregulated, leading to uncontrolled proliferation, enhanced migratory and metastatic capabilities, evasion of programmed cell death, and resistance to chemotherapy or radiotherapy. The RAS and MYC oncogenes are pivotal in tumorigenesis, driving processes such as resistance to apoptosis, replicative immortality, cellular invasion and metastasis, and metabolic reprogramming. These oncogenes are subject to regulation by a range of epigenetic and post-transcriptional modifications. This review focuses on the deregulation of EGFR, RAS, and MYC expression caused by (epi)genetic alterations and post-translational modifications. It also explores the therapeutic potential of targeting these regulatory proteins, emphasizing the importance of phenotyping neoplastic tissues to inform the treatment of cancer. [ABSTRACT FROM AUTHOR]

KRAS is one of the most mutated genes, driving alternations in metabolic pathways that include enhanced nutrient uptaking, increased glycolysis, elevated glutaminolysis, and heightened synthesis of fatty acids and nucleotides. However, the beyond mechanisms of KRAS-modulated cancer metabolisms remain incompletely understood. In this review, we aim to summarize current knowledge on KRAS-related metabolic alterations in cancer cells and explore the prevalence and significance of KRAS mutation in shaping the tumor microenvironment and influencing epigenetic modification via various molecular activities. Given that cancer cells rely on these metabolic changes to sustain cell growth and survival, targeting these processes may represent a promising therapeutic strategy for KRAS-driven cancers. [ABSTRACT FROM AUTHOR]

Background: Cholesteatoma is a proliferative disease that affects the tympanic cavity and temporal bone. Despite many studies and various theories, the etiopathogenesis of cholesteatoma has not been fully elucidated. Features such as invasion, migration, uncontrolled proliferation, and lack of differentiation are observed in both cholesteatoma and neoplasia. Aims/Objectives: The aim of this study is to investigate somatic genetic alterations in known proto-oncogenes and tumor suppressor genes in cholesteatoma. Material and Methods: 60 different known proto-oncogenes and tumor suppressor genes were comparatively analyzed in cholesteatoma and peripheric blood samples from 15 middle ear cholesteatoma patients using next-generation sequencing. Results: JAK3 c.2164G > A, TP53 c.284delC, and KRAS c.377A > T alterations were observed in cholesteatoma tissue but not in normal tissue. In addition, 12 different germline variants were also identified in 8 patients. Conclusions and Significance: In this study, the presence of changes in cancer-related genes in cholesteatoma was determined and these changes were discussed in terms of possible clinical applications. We hope that the genetic alterations that emerged in this study, will be beneficial in guiding future research in this field. [ABSTRACT FROM AUTHOR]

Background: Lung cancer is a globally pervasive and deadly disease, claiming more than 1 million lives annually. Therefore, the identification of mutations in crucial cancer-related genes is paramount for guiding optimal chemotherapy strategies. The distribution of EGFR, KRAS, ALK, and ROS1 mutations varies across diverse ethnic populations. Nonetheless, there is limited data available on the prevalence of these mutations and their correlation with PD-L1 expression among Iranian lung cancer patients. Aim: This study involved an analysis of EGFR, KRAS, ALK, and ROS1 gene mutations in lung cancer patients, followed by an assessment of the correlation between PD-L1 expression and clinicopathological variables. Methods: Mutational profiling was conducted by examining EGFR (exons 18–21) and KRAS (exon 2) through pyrosequencing. Detection of ALK and ROS1 rearrangements, alongside PD-L1 expression, was carried out using immunohistochemistry techniques. Results: EGFR mutations were identified in 23.4% of cases, exhibiting a notably higher occurrence in females (p = 0.001). KRAS mutations were present in 7.1% of cases, with no significant association found between KRAS mutations and sex (p = 0.229). ALK rearrangements were found in 4.9% of cases, while ROS1 rearrangements were present in 0.6% of patients. The overall prevalence of PD-L1 protein expression was 36.85%. Notably, PD-L1 expression was detected in 24.8% of cases with EGFR mutations, 20% of cases with KRAS mutations, 64.7% of cases with ALK rearrangements, and in 100% of cases with ROS1 rearrangements. Conclusion: Although no correlation was found between PD-L1 expression and EGFR, KRAS mutations, and ROS1 rearrangements, a noteworthy association was identified between ALK rearrangements and elevated PD-L1 expression. [ABSTRACT FROM AUTHOR]

Background: Radioactive iodine (RAI) therapy is a core part of differentiated thyroid cancer (DTC) treatment. To predict patients' response to RAI is a contributing factor in improving their prognosis and extending their survival. We aimed to investigate the clinical significance of EGFR exon 20, BRAF V600e, and KRAS G13V variants in DTC patients and their predictive role in patients' responses to RAI. Methods: 117 DTC patients receiving radioactive iodine (I-131) therapy were included; from each, 5 ml of venous blood samples was obtained before RAI treatment, and 3 ml of venous blood samples was obtained after 3 months of treatment. Polymerase chain reaction (PCR) was used to detect the forementioned mutations, and TgAb and TSH were assessed to evaluate DTC patients' response to RAI therapy. Results: Data showed that EGFR exon 20, BRAF V600e and KRAS G13V mutations were significantly associated with higher TgAbs levels, advanced clinical stage, and positive vascular invasion. EGFR exon 20 and BRAF V600e are associated with larger tumor size. Patients with BRAF V600e and KRAS G13V required higher I-131 doses during RAI and only KRAS was associated with distant metastasis. The co-existence of all three mutations was correlated with higher TgAbs, clinical stage, vascular invasion, larger tumor size, and higher I-131 dose. Conclusions: EGFR exon 20/BRAF V600e/KRAS G13V mutations are associated with advanced clinical stage and higher radioiodine dose requirements for DTC patients' treatment indicating a significant role in the disease progression of DTC patients and its impact on predicting their response to RAI therapy. [ABSTRACT FROM AUTHOR]