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In the context of structural investigation and optimization of various potential EGFR inhibitors, a novel series of asymmetrical piperazine-tethered trisubstituted thiophene-3-carboxamide selenide derivatives were synthesized and evaluated for their antiproliferative potential against selected human cancer cell lines. These derivatives, built based on a previously identified hit molecule, were synthesized via multiple-step reactions, including optimization of the C-Se cross-coupling reaction. Two compounds, 17i and 18i, displayed significant cytotoxicity (IC50 value: 4.82 ± 0.80 µM and 1.43 ± 0.08 µM) against HCT116 and A549 cancer cell lines, respectively. Quantitative analysis of apoptotic stages using Annexin V-FITC/PI double staining validated their apoptotic potential. Further, compound 18i demonstrated a remarkable inhibition of EGFR kinase, with an IC50 concentration of 42.3 nM. The lead compound 18i, with remarkable in vitro cytotoxicity, apoptosis induction capability, and EGFR inhibition, emerges as a promising candidate for anticancer therapy.
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BACKGROUND: In the initial analysis of a pivotal phase 2 single-arm study (NCT03861156), befotertinib (D-0316) showed clinical benefit with a manageable safety profile in pretreated patients with EGFR T790M mutated non-small cell lung cancer (NSCLC), including those with brain metastases. METHODS: Eligible patients received oral befotertinib of 50 mg (cohort A) or 75-100 mg (cohort B) once daily until disease progression, withdrawal of informed consent, or death. The primary endpoint for the initial analysis was objective response rate (ORR) assessed by an independent review committee. OS and safety were secondary endpoints. Herein, we present the final OS and safety data. RESULTS: A total of 176 patients in cohort A and 290 patients in cohort B were finally enrolled. At data cutoff (May 31, 2023), the median duration of follow-up was 47.9 months (95 % CI: 47.1-48.3) in cohort A and 36.7 months (35.9-37.9) in cohort B. The median OS was 23.9 months (95 % CI: 21.1-27.2) in cohort A and 31.5 months (26.8-35.3) in cohort B. The median OS for patients with and without brain metastasis in cohort A was 18.6 months (95 % CI: 14.9-26.3) and 26.4 months (95 % CI: 23.0-29.0), respectively. In cohort B, these data was 23.0 months (95 % CI: 18.6-29.1) and 35.5 months (95 % CI: 29.3-NE), respectively. The safety profile of befotertinib remained consistent with previous data. Grade 3 or higher treatment-emergent adverse events were 38.1 % in the cohort A and 50.3 % in the cohort B, and 22.2 % and 31.7 % were related to the study drug. CONCLUSION: Befotertinib demonstrated a more profound OS benefit compared to other 3rd-generation EGFR TKI, despite that cross trial data comparison should be interpreted with caution. The safety profile was manageable and consistent with previously report data in pretreated patients with confirmed T790M mutation-positive NSCLC.
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OBJECTIVES: Blood cell-free DNA (cfDNA) can be a new reliable tool for detecting epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) patients. However, the currently reported cfDNA assays have a limited role in detecting drug-resistant mutations due to their deficiencies in sensitivity, stability, or mutation detection rate. METHODS: We developed an Archaeoglobus fulgidus-derived flap endonuclease (Afu FEN)-based DNA-enhanced amplification system of mutated cfDNA by designing a pair of hairpin probes to anneal with wild-type cfDNA to form two 5'-flaps, allowing for the specific cleavage of wild-type cfDNA by Afu FEN. When the dominant wild-type somatic cfDNA fragments were cleaved by structure-recognition-specific Afu FEN, the proportion of mutated cfDNA in the reaction system was greatly enriched. As the amount of mutated cfDNA in the system was further increased by PCR amplification, the mutation status could be easily detected through first-generation sequencing. RESULTS: In a mixture of synthetic wild-type and T790M EGFR DNA fragments, our new assay still could detect T790M mutation at the fg level with remarkably high sensitivity. We also tested its performance in detecting low variant allele frequency (VAF) mutations in clinical samples from NSCLC patients. The plasma cfDNA samples with low VAF (0.1 and 0.5â¯%) could be easily detected by DNA-enhanced amplification. CONCLUSIONS: This system with enhanced amplification of mutated cfDNA is an effective tool used for the early screening and individualized targeted therapy of NSCLC by providing a rapid, sensitive, and economical way for the detection of drug-resistant mutations in tumors.
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INTRODUCTION: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR) are linked with side effects involving skin and mucosa. Herein, we present a unique case of oral lichenoid drug eruption (LDE) in a patient treated with osimertinib. CASE REPORT: A 75-year-old woman was diagnosed with metastatic EGFR-mutated lung adenocarcinoma, and started on osimertinib 80â mg PO daily. At 24 months of therapy, the patient developed a painful, red, and white striated oral lesion involving the left buccal mucosa and the adjacent buccal aspect of gingivae. Biopsy showed oral LDE. Causality assessment between osimertinib and the oral LDE via Naranjo Adverse Drug Reaction probability scale revealed a score of 5. MANAGEMENT AND OUTCOME: Osimetinib discontinuation was not felt to be in the best interest of the patient. Therefore, diphenhydramine HCL mouthwash every 6â h PRN (before meals) was started. Spicy and hot foods were discontinued. At a four-week follow-up visit, the patient reported moderate improvement in her symptoms. CONCLUSION: Oral LDEs are considered premalignant lesions as they can transform into squamous cell carcinoma; therefore, regular follow-up is needed. Awareness of this potential side effect of osimertinib would also prevent unnecessary (and potentially costly) work-up and lead to its prompt diagnosis and treatment.
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The truancy of representation of the estrogen, progesterone, and human epidermal growth factor receptors occurs during TNBC. TNBC is recognized for the upper reappearance and has a poorer diagnosis compared with rest breast cancer (BC) types. Presently, as such, no targeted therapy is approved for TNBC and treatment options are subjected to chemotherapy and surgery, which have high mortality rates. Hence, the current article focuses on the scenario of TNBC vital pathways and discusses the latest advances in TNBC treatment, including immune checkpoint inhibitors (ICIs), PARP suppressors, and cancer vaccines. Immunotherapy and ICIs, like PD 1 and PD L1 suppressors, displayed potential in clinical trials (CTs). These suppressors obstruct the mechanisms which allow tumor cells to evade the system thereby boosting the body's defense against TNBC. Immunotherapy, either alone or combined with chemotherapy has demonstrated patient outcomes such as increased survival rates and reduced treatment-related side effects. Additionally, targeted therapy approaches include BRCA/2 mutation poly ribose polymerase inhibitors, Vascular Endothelial Growth Factor Receptor (VEGFR) inhibitors, Epidermal growth factor receptor inhibitors, Fibroblast growth factor inhibitors, Androgen Receptor inhibitors, PIK3/AKT/mTOR pathway inhibitors, Cyclin-dependent kinase (CDK) inhibitors, Notch signaling pathway inhibitors, Signal transducer and activator of transcription 3 (STAT3) signaling pathway inhibitors, Chimeric antigen receptor T (CAR-T) cell therapy, Transforming growth factor (TGF) -ß inhibitors, Epigenetic modifications (EPM), Aurora Kinase inhibitors and antibody-drug conjugates. We also highlight ongoing clinical trials and potential future directions for TNBC therapy. Despite the challenges in treating TNBC, recent developments in understanding the molecular and immune characteristics of TNBC have opened up new opportunities for targeted therapies, which hold promise for improving outcomes in this aggressive disease.
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Background: Li-Fraumeni syndrome (LFS) is a rare hereditary disorder caused by mutations in the tumor protein p53 (TP53). It causes a predisposition for the development of multiple malignancies, primarily including breast cancers, sarcomas, and central nervous system tumors. There are a few cases reported in the literature of patients with LFS presenting with an epidermal growth factor receptor (EGFR) mutated lung cancer. Still, it has been suggested that there may be an association between the TP53 pathogenic variant and lung cancer with EGFR mutation in somatic cells. Case Description: A 47-year-old non-smoker woman with LFS with a history of multiple tumors, including bilateral breast cancer, pecoma, and sarcoma. In one of her computed tomography, a lesion in the lingula of the lung was detected. It was biopsied, which diagnosed lung adenocarcinoma, and genetic studies detected an EGFR exon 19 deletion. She was treated with a left inferior lobectomy, followed by pemetrexed and cisplatin. Conclusions: The association between TP53 and lung cancer with EGFR mutation has been suggested in case reports. Studies in lung cancer cell lines have shown a link between TP53 mutation and EGFR overexpression. Nonetheless, as more cases are reported, further research is needed to comprehend the interrelation between these two pathologies and the risk posed by LFS to the emergence of EGFR-mutated lung cancer.
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Various driver mutations and the corresponding molecular-targeted drugs have been detected and developed in non-small cell lung cancer. There were many cases in which surgical specimens had happened to find double primary cancers. However, to our knowledge, our case was the first report of synchronous double primary lung adenocarcinomas harboring epidermal growth factor receptor (EGFR) L858R and mesenchymal-to-epithelial transition (MET) exon 14 skipping mutations. A 75-year-old Japanese woman with chronic heart and renal failures was referred to our department because of a growing nodule in the right upper lung field on chest X-ray films. Chest computed tomography (CT) detected a nodule in the right S1 and another nodule in the left S1+2. Bronchoscopic biopsy diagnosed the right S1 nodule as moderately differentiated adenocarcinoma. Oncomine Dx Target Test Multi-CDx system of the right S1 adenocarcinoma detected EGFR L858R mutation. The 18F-fluorodeoxyglucose positron emission tomography/CT showed abnormal uptakes both in the right S1 and the left S1+2 nodules, and in the bilateral inferior paratracheal lymph nodes. We made a diagnosis of c-stage IIIA (cT1bN2M0) of adenocarcinoma in the right S1 and suspected another primary lung cancer in the left S1+2. Considering her general conditions, comorbidities and wishes, we started osimertinib. The right S1 cancer achieved partial response (PR), while the left S1+2 nodule and lymph nodes enlarged. Aspiration cytology from the left supraclavicular lymph node showed adenocarcinoma. The FoundationOne® Liquid CDx tumor profiling test detected not only EGFR L858R, but also MET exon 14 skipping mutation. We made a diagnosis of another primary adenocarcinoma from the left S1+2 nodule (cT1bN3M0, c-stage IIIB) with MET mutation, and changed osimertinib to capmatinib. Although the left S1+2 cancer achieved and maintained PR by capmatinib, the right S1 cancer increased, and several new metastases appeared. The subsequent switch from capmatinib to osimertinib could not control cancers. In this case, we tried to switch monotherapies from osimertinib to capmatinib for double primary adenocarcinomas harboring different two driver mutations, according to each cancer progression. The temporal and spatial heterogeneity reinforces the need for primary tissue biopsy if dual primaries are suspected. Temporally distinct liquid biopsies, not standard at present, may be considered.
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We aimed to investigate the clinical value of allograft biopsy performed long after renal transplantation. We retrospectively evaluated 99 allograft biopsies in recipients with transplantation vintages of 10 years or longer. Mixed-effects model showed that 1-year estimated glomerular filtration rate (eGFR) slopes after biopsy were significantly greater than those before biopsy [-3.13, -4.42 mL/min/1.73 m2/year, p = 0.01]. Renal biopsy changed the treatment strategies in more than half of the patients. Improvement in eGFR slopes was pronounced in 51 patients with treatment modification based on the biopsy results [2.27 (95% confidence interval (CI): 0.66, 3.89) mL/min/1.73 m2/year], whereas no improvement was observed in those without [0.33 (95% CI: -1.05, 1.71) mL/min/1.73 m2/year, Pinteraction = 0.001]. Among the treatment modifications, enhancement of immunosuppression (IS) led to the most remarkable improvement in eGFR slope. Patients with g scores ≥2 were more likely to receive IS enhancement than those with g scores = 0 [odds ratio; 15.0 (95% CI: 1.65, 136)]. Patients with active glomerulitis (g ≥ 1) without chronicity (cg ≤ 1) showed the most significant improvement in eGFR slope. Given the prevalence of active glomerulitis (g ≥ 1, 21%), which is responsive to treatment even long after transplantation, and the observed magnitude of eGFR slope improvement, renal biopsy can indeed improve allograft prognosis.
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Aloinjertos , Tasa de Filtración Glomerular , Trasplante de Riñón , Riñón , Humanos , Trasplante de Riñón/efectos adversos , Masculino , Femenino , Biopsia , Estudios Retrospectivos , Persona de Mediana Edad , Adulto , Riñón/patología , Factores de Tiempo , Inmunosupresores/uso terapéutico , Rechazo de Injerto , Terapia de Inmunosupresión , AncianoRESUMEN
To overcome C797S mutation, the latest and most common resistance mechanism in the clinical treatment of third-generation EGFR inhibitor, a novel series of substituted 6-(2-aminopyrimidine)-indole derivatives were designed and synthesized. Through the structure-activity relationship (SAR) study, compound 11eg was identified as a novel and potent EGFR L858R/T790M/C797S inhibitor (IC50 = 0.053 µM) but had a weak effect on EGFRWT (IC50 = 1.05 µM). 11eg significantly inhibited the proliferation of the non-small cell lung cancer (NSCLC) cells harboring EGFRL858R/T790M/C797S with an IC50 of 0.052 µM. 11eg also showed potent inhibitory activity against other NSCLC cell lines harboring main EGFR mutants. Furthermore, 11eg exhibited much superior activity in arresting cell cycle and inducing apoptosis of NSCLC cells with mutant EGFRC797S. It blocked cellular EGFR signaling. Importantly, 11eg markedly suppressed the tumor growth in in vivo xenograft mouse model with good safety. Additionally, 11eg displayed good microsomal stability. These results demonstrated the potential of 11eg with novel scaffold as a promising lead compound targeting EGFRC797S to guide in-depth structural optimization.
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PURPOSE: MET amplification is a common resistance mechanism to EGFR inhibition in EGFR-mutant non-small cell lung cancer (NSCLC). Several trials showed encouraging results with combined EGFR and MET inhibition (EGFRi/METi). However, MET amplification has been inconsistently defined and frequently included both polysomy and true amplification. METHODS: This is a multicenter, real-world analysis in patients with disease progression on EGFR inhibition and MET copy number gain (CNG), defined as either true amplification (MET to centromere of chromosome 7 ratio [MET-CEP7] ≥ 2) or polysomy (gene copy number ≥ 5, MET-CEP7 < 2). RESULTS: A total of 43 patients with MET CNG were included, 42 of whom were detected by FISH. Twenty-three, 7, and 14 received EGFRi/METi, METi, and SoC, respectively. Patients in the EGFRi/METi cohort exhibited a superior real-world clinical benefit rate, defined as stable disease or better, of 82% (95% confidence interval [CI], 60-95) compared to METi (29%, 4-71) and SoC (50%, 23-77). Median real-world progression-free survival was longer with EGFRi/METi with 9.8 vs. 4.3 months with METi (hazard ratio [HR], 0.19, 95% CI, 0.06-0.57) and 3.7 months with SoC (0.41, 0.18-0.91), respectively. Overall survival was numerically improved. Interaction analysis with treatment and type of CNG (amplification vs. polysomy) suggests that differences were exclusively driven by MET-amplified patients receiving EGFRi/METi (HR for OS, 0.09, 0.01-0.54). CONCLUSION: In this real-world study, EGFRi/METi showed clinical benefit over METi and SoC. Future studies should focus on the differential impact of the type of MET CNG with a focus on true MET amplification as predictor of response.
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BACKGROUND: Treatment of advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) has a higher response rate than with conventional chemotherapy in patients positive for EGFR mutations. However, the efficacy of EGFR-TKI therapy may be reduced in patients positive for the EGFR exon 21 L858R point mutation. OBJECTIVE: To determine the clinical characteristics of patients with EGFR exon 21 L858R point mutation-positive NSCLC who are non-responders to EGFR-TKI therapy and the factors that predict response to EGFR-TKI therapy. METHODS: Patients with NSCLC treated with EGFR-TKIs were evaluated for response after treatment, and those who responded were compared with those who did not respond. RESULTS: Of 31 patients, 21 (67.7%) responded to EGFR-TKI therapy (the response group). There were significantly more programmed death ligand 1 (PDL1)-negative patients in the response group than in the non-response group. A significantly higher number of patients in the PDL1-positive group developed interstitial lung disease (ILD) after EGFR-TKI therapy than those in the PDL1-negative group. CONCLUSION: EGFR-TKI therapy is likely to be non-responsive in PDL1-positive patients with EGFR exon 21 L858R point mutation-positive NSCLC. The PDL1-positive group is at a high risk of developing ILD.
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Background: Chronic kidney disease (CKD) is a major public health burden and is often undiagnosed in the primary care setting. Untested and untreated, this often leads to renal failure and dialysis. Materials and Methods: This was a cross-sectional study of adults aged 20 years and over, diagnosed with type 2 diabetes mellitus and/or hypertension, with no previous history or record of CKD, and attending three chronic disease clinics in the Eastern Regional Health Authority (ERHA). Patients were screened for risk of CKD by using the albumin creatinine ratio. The eGFR was calculated based on serum creatinine by using the CKD Epidemiology Collaboration (EPI) 2009 equation. Results: In total, 430 patients agreed to participate with 61.2% of response rate. Of the 385 with complete data, 357 (92%) were detected as having a high risk for CKD; older patients (>66 years) and those with both diabetes and hypertension had high proportions of risk for CKD. There were significant associations between age, systolic hypertension, and the severity of risk for CKD. Conclusion: CKD is common at the primary care level among adults with NCDs in Trinidad, with many patients having been left out without being tested for CKD. Primary care physicians must take this into consideration in caring for NCD patients.
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Introduction: Characteristics of long-term survivors in EGFR-mutant (EGFRm) NSCLC are not fully understood. This retrospective analysis evaluated a multi-institution cohort of patients with EGFRm NSCLC treated in the pre-osimertinib era and sought to describe characteristics of long-term survivors. Methods: Clinical characteristics and outcomes were abstracted from the electronic medical records of patients with EGFRm metastatic NSCLC who started first-line therapy before 2015. Demographics and comutations were compared between greater than or equal to 5-year survivors and less than 5-year survivors. Multivariable Cox proportional hazard and logistic regression models were used to evaluate factors associated with survival and the odds of death within 5 years, respectively. Results: Overall, 133 patients were greater than or equal to 5-year survivors; 127 were less than 5-year survivors. Burden of pathogenic comutations including TP53 and PIK3CA was similar between greater than or equal to 5-year survivors and less than 5-year survivors. Receipt of first-line chemotherapy rather than EGFR tyrosine kinase inhibitor was similar between the groups (22% of <5-y versus 31% of ≥5-y). Baseline brain metastasis and history of smoking were associated with higher odds of death within 5 years (odds ratio = 2.16, p = 0.029 and odds ratio = 1.90, p = 0.046, respectively). Among patients without baseline brain metastases, cumulative incidence of brain metastases at 5 years was 42.3%. Both baseline and post-baseline brain metastasis were associated with worse overall survival compared with no brain metastasis (hazard ratio = 3.26, p < 0.001 and hazard ratio = 4.99, p < 0.001, respectively). Conclusions: Within patients treated for EGFRm metastatic NSCLC before 2015, absence of brain metastasis and nonsmoking status were predictive of 5-year survival. Our findings help to define a subset of patients with EGFRm NSCLC with excellent survival outcomes who may not require intensification of initial therapy.
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Background: In first/second generation EGFR-TKIs, strong PD-L1 expression contributes to primary resistance, significantly affecting patient prognosis. The relationship between PD-L1 expression levels and third-generation TKIs remains unclear.Methods: This study analyzed advanced NSCLC who received third-generation EGFR-TKIs as first-line systemic therapy from March 2019 to June 2022. The EGFR and PD-L1 status of the patients was also assessed.Results: Overall, 150 patients were included in this study. PD-L1 expression was negative (PD-L1 tumor proportion score <1%) in 89 cases, weak (1-49%) in 42 cases, and strong (≥50%) in 19 cases. mPFS for patients with negative, weak and strong PD-L1 expressions was 23.60, 26.12 and 16.60 months, respectively. The mPFS for strong PD-L1 expression was significantly shorter than that for with weak PD-L1 expression but was not associated with negativity. The same conclusions were shown in subgroup analyses of mutation types and TKI kinds. In addition, Relative to PD-L1-negative patients, resistance to TKIs may be associated with early progression for patients with strong PD-L1 expression.Conclusion: PD-L1 expression in tumor cells influenced the clinical outcomes of patients with advanced NSCLC treated with third-generation EGFR-TKIs. Stronger PD-L1 expression in TKIs-treated patients with advanced first-line EGFR-mutated NSCLC was associated with worse PFS.
[Box: see text].
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Background: Recent evidences showed that resection of lung tumor post-targeted therapy has shown progression-free survival (PFS) benefits in initially unresectable patients. The aim of this study is to evaluate pathologic findings of resected lung tumor samples in patients who have undergone prior epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) treatment, and also to assess the prognostic factors related to outcomes after resection. Methods: The deidentified data of non-small cell lung cancer (NSCLC) patients admitted to seven university hospitals affiliated with the Catholic University of Korea were obtained from the Clinical Data Warehouse (CDW) database. Among screened patients, 40 individuals who had previously undergone targeted therapies and later received surgical resection of a primary lung tumor were evaluated for the study. Results: All 40 patients were diagnosed with adenocarcinoma. Of these, 36 with EGFR mutations received prior EGFR TKI treatment. Only one postoperative complication, atrial fibrillation, was observed. At the time of resection, 19 patients showed primary lung tumor size regressing or unchanged, while 21 patients showed primary lung tumor regrowth or new lesions being developed before the resection. The group with no programmed death-ligand 1 (PD-L1) expression from resected samples showed significantly better post-resection PFS when compared to the other group (P=0.01). In the Model II multivariate analysis for post-resection PFS, PD-L1 detection from the resected sample was significantly associated with PFS [P=0.03; hazard ratio (HR) =5.465; 95% confidence interval (CI): 1.200-24.885]. Furthermore, an increase in PD-L1 expression compared to the baseline value was associated with an increasing lung tumor burden at the time of resection (P=0.03). Conclusions: Resected specimen following targeted therapy can provide valuable clinical information that can be used to predict the prognosis of patients with initially unresectable NSCLC.
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Background: Squamous cell carcinomas are the most common type of oral cancer contributing for around 90%. The overall survival is below 50% for these patients. There is a requirement for a non-invasive marker to predict the prognosis. The epidermal growth factor (EGF) and their receptors (EGFR, ErbB-1) are not only documented to play a critical and an influential role in cell growth and differentiation in normal/healthy tissues, but may also plays an important role in malignant disease progression and tumorigenesis. Objective: This study was done to find the significance of EGF receptor expression on microscopic free tumour margins and lymph nodal margins to predict the survival of the patient in a 2-year follow-up. Materials and Methods: A prospective cohort study of 25 patients was performed in biopsy proven oral squamous cell carcinoma patients who reported to our department from July 2017 to June 2019. The data were collected from their histopathological report, they were- pTNM staging, surgical margins (superior and inferior, anterior, posterior), nodal status and scoring of EGFR expression on wax blocks was done. Total of 125 wax blocks were analysed for the study. Follow-up of 2 years were recorded in the study to evaluate the survival of the patients. Result: The expression of EGFR on microscopic tumour-free surgical margins and lymph nodes was p value 0.023 which was statistically significant. The level of significance between EGFR and status of patients after 2-year follow-up was having p value 0.031. Out of 25 patients, 5 patients were dead at a 2-year follow-up. Out of these 5 patients who were dead, 3 patients had a local recurrence and 2 patients had distant metastasis. Conclusion: This cohort study concludes that EGFR is an important prognostic marker and must be analysed in all microscopic tumour-free margins and lymph nodes in advanced oral squamous cell carcinomas to predict the local recurrences affecting the survival of the patients and the need for addition of anti-EGFR agents in adjuvant treatment. Since the sample size is small, large scale studied must be done to validate the need for adding anti-EGFR agents in adjuvant treatment to improve the survival of patients.
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This case report examines the effectiveness of osimertinib in a 64-year-old non-smoking female diagnosed with stage IV lung adenocarcinoma and an epidermal growth factor receptor (EGFR) exon 19 mutation, focusing on the treatment's impact on bone metastasis. Despite initial responsiveness to osimertinib, the patient's bone lesions remained largely unresponsive, prompting a comprehensive exploration of alternative treatments and clinical trials. This report highlights the patient's clinical journey, from diagnosis through various treatment phases, culminating in palliative care, and underscores the need for further research into targeted treatments for bone metastasis in lung cancer.
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Kirsten Rat Sarcoma (KRAS) is the most commonly mutated oncogene in colorectal carcinoma (CRC). We have previously reported the interactions between microsatellite instability (MSI), DNA promoter methylation, and gene expression. In this study, we looked for associations between KRAS mutation, gene expression, and methylation that may help with precision medicine. Genome-wide gene expression and DNA methylation were done in paired CRC tumor and surrounding healthy tissues. The results suggested that (a) the magnitude of dysregulation of many major gene pathways in CRC was significantly greater in patients with the KRAS mutation, (b) the up- and down-regulation of these dysregulated gene pathways could be correlated with the corresponding hypo- and hyper-methylation, and (c) the up-regulation of CDKN2A was more pronounced in tumors with the KRAS mutation. A recent cell line study showed that there were higher CDKN2A levels in 5-FU-resistant CRC cells and that these could be down-regulated by Villosol. Our findings suggest the possibility of a better response to anti-CDKN2A therapy with Villosol in KRAS-mutant CRC. Also, the more marked up-regulation of genes in the proteasome pathway in CRC tissue, especially with the KRAS mutation and MSI, may suggest a potential role of a proteasome inhibitor (bortezomib, carfilzomib, or ixazomib) in selected CRC patients if necessary.
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Neoplasias Colorrectales , Metilación de ADN , Regulación Neoplásica de la Expresión Génica , Mutación , Proteínas Proto-Oncogénicas p21(ras) , Transcriptoma , Humanos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Perfilación de la Expresión Génica , Inestabilidad de Microsatélites , Epigenoma , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismoRESUMEN
EGFR mutations are critical oncogenic drivers in lung adenocarcinoma (LUAD). However, the mechanisms by which they impact the tumor microenvironment (TME) and tumor immunity are unclear. Furthermore, the reasons underlying the poor response of EGFR-mutant (EGFR-MU) LUADs to immunotherapy with PD-1/PD-L1 inhibitors are unknown. Utilizing single-cell RNA (sc-RNA) and bulk RNA sequencing datasets, we conducted high-dimensional weighted gene coexpression network analysis to identify key genes and immune-related pathways contributing to the immunosuppressive TME. EGFR-MU cancer cells downregulated MHC class I genes to evade CD8+ cytotoxic T cells, expressed substantial levels of MHC class II molecules, and engaged with CD4+ regulatory T cells (Tregs). EGFR-MU tumors may recruit Tregs primarily through the CCL17/CCL22/CCR4 axis, leading to a Treg-enriched TME. High levels of MHC class II-positive cancer-associated fibroblasts and tumor endothelial cells were found within EGFR-MU tumors. Owing to the absence of costimulatory factors, they may inhibit rather than activate the tumor antigen-specific CD4+ T-cell response, contributing further to immune suppression. Multiplex immunohistochemistry analyses in a LUAD cohort confirmed increased expression of MHC class II molecules in cancer cells and fibroblasts in EGFR-MU tumors. Our research elucidates the highly immunosuppressive TME in EGFR-MU LUAD and suggests potential targets for effective immunotherapy.