Association of TP53 Mutation Status and Sex with Clinical Outcome in NSCLC Treated with Immune Checkpoint Inhibitors: A Retrospective Cohort Study.

Purpose: Some studies suggest that TP53 mutations are associated with the response to immune checkpoint inhibitors (ICI) in patients with non-small cell lung cancer (NSCLC) and also contribute to sex disparities in several cancers. Thus, we hypothesized that TP53 mutations might serve as sex-dependent genomic biomarkers of ICI treatment response in patients with NSCLC. Materials and Methods: Clinical data of 100 patients with metastatic NSCLC treated with ICI monotherapy at Seoul National University Bundang Hospital (SNUBH) were retrospectively reviewed. Genomic and clinical datasets of TCGA and an ICI-treated lung cancer cohort (cBioPortal) were also analyzed. Results: In SNUBH cohort, no statistically significant difference was observed in disease control rate per the TP53 mutation status (p=0.503); however, female patients with TP53 mutated (MT) had a significantly prolonged median progression-free survival (PFS) compared to wild-type (WT) (6.1 months in TP53 MT vs. 2.6 months in TP53 WT; p=0.021). PD-L1 high (≥50%) expression was significantly enriched in female patients with TP53 MT (p=0.001). The analysis from publicly available dataset also revealed that females with NSCLC with TP53 MT showed significantly longer PFS than those with TP53 WT (p<0.001). In TCGA analysis, expression of immune-related genes, and TMB score in TP53 MT females were higher than in males without TP53 MT. Conclusion: Female patients with NSCLC with TP53 mutations had high PD-L1 expression and showed favorable clinical outcomes following ICI therapy, suggesting a need for further research to explore the role of TP53 mutations for sex disparities in response to ICI therapy.

Genetic Analysis of Melanoma Types Using Japanese Genomic Database.

OBJECTIVES: The purpose of this study is to compare genetic mutations, tumor mutation burden (TMB), and the effects of molecular targeted drugs and immune checkpoint inhibitors (ICIs) in head and neck mucosal melanoma (HNMUM) with those in skin melanoma (SKM) and ocular melanoma (OM). METHODS: Data were analyzed for 72 consecutive patients with HNMUM, including 366 with SKM and 31 with OM, registered at the Japan National Cancer Center, Center for Cancer Genomics and Advanced Therapeutics (C-CAT) between June 2019 and October 2023. Genetic alterations and TMB were determined by FoundationOne CDx next-generation sequencing. RESULTS: The top 10 mutations in HNMUM were RAD21 (47.2%), NBN (45.8%), MYC (40.3%), LYN (31.9%), NRAS (29.1%), IRF4 (23.6%), DAXX (22.2%), KIT (22.2%), NOTCH3 (20.8%), and DDR1 (19.4%), with 16.6 ± 0.8 (mean ± SEM) mutations/individual. In SKM, BRAF (p = 0.04) mutation was associated with a significantly better prognosis. The TMB values were 5.7 ± 2.1 (mean ± SEM) in HNMUM, 4.1 ± 0.2 in SKM, and 3.4 ± 0.9 in OM, with no significant differences among the three groups. The median survival time for patients with distant metastases was 803 (95% confidence interval: 539-NA) days for HNMUM, 1413 (831-2172) days for SKM, and 1138 (438-NA) days for OM. CONCLUSIONS: The top 10 mutations in HNMUM are closer to those in OM than those in SKM. There was no significant difference in TMB values or survival rates with regard to the therapeutic effect of ICIs among the diseases, which suggests that current treatment of HNMUM with ICIs is appropriate. LEVEL OF EVIDENCE: 3 Laryngoscope, 2024.

Mutations in Ras homolog family member A in patients with peripheral T-cell lymphoma and implications for personalized medicine.

Genome sequencing has revealed frequent mutations in Ras homolog family member A (RHOA) among various cancers with unique aberrant profiles and pathogenic effects, especially in peripheral T-cell lymphoma (PTCL). The discrete positional distribution and types of RHOA amino acid substitutions vary according to the tumor type, thereby leading to different functional and biological properties, which provide new insight into the molecular pathogenesis and potential targeted therapies for various tumors. However, the similarities and discrepancies in characteristics of RHOA mutations among various histologic subtypes of PTCL have not been fully elucidated. Herein we highlight the inconsistencies and complexities of the type and location of RHOA mutations and demonstrate the contribution of RHOA variants to the pathogenesis of PTCL by combining epigenetic abnormalities and activating multiple downstream pathways. The promising potential of targeting RHOA as a therapeutic modality is also outlined. This review provides new insight in the field of personalized medicine to improve the clinical outcomes for patients.

Combination approach for CDC73-related parathyroid carcinoma in an adolescent female patient: a case report and literature review.

Parathyroid carcinoma (PC) is extremely rare in children and adolescent. PC is more often sporadic, but also it could be associated with germline mutations. The clinical features of primary hyperparathyroidism (PHPT) are nonspecific in children and adolescent, which delays the diagnosis for years. This case of PC in a pediatric patient, caused by germline heterozygous pathogenic variant in exon 1 of the CDC73 gene (c.70 G > T, p. Glu24Ter) is the first to be reported in Russia. Due to the rarity of pediatric parathyroid malignancy, the diagnosis of this endocrine neoplasm remains a challenge. The main difficulties that we faced in the management of the patient were the morphological confirmation of diagnosis, multiple surgical interventions, and disseminated PC metastases. We describe a 13-year-old girl with delayed diagnosis of PC and subsequent local recurrence after several surgeries, who underwent specific radiation therapy that allowed controlling hypercalcemia.

Nemaline Myopathy With a Compound Heterozygous Mutation: A Case Report.

A class of genetically based congenital myopathies known as nemaline myopathies is defined by the development of nemaline rods within muscle fibers. We present a case involving an eight-year-old boy who presented with a history of delayed motor development, proximal muscle weakness, and neck flexor weakness. Muscle enzymes were normal, and electrophysiological studies revealed a myopathic pattern. Nemaline myopathy (NM) was diagnosed with the help of clinical exome sequencing, which showed a compound heterozygous mutation with a novel variant in the nebulin (NEB) gene.

Glioma Grade and Molecular Markers: Comparing Machine-Learning Approaches Using VASARI (Visually AcceSAble Rembrandt Images) Radiological Assessment.

OBJECTIVES: This study aimed to leverage Visually AcceSAble Rembrandt Images (VASARI) radiological features, extracted from magnetic resonance imaging (MRI) scans, and machine-learning techniques to predict glioma grade, isocitrate dehydrogenase (IDH) mutation status, and O6-methylguanine-DNA methyltransferase (MGMT) methylation. METHODOLOGY: A retrospective evaluation was undertaken, analyzing MRI and molecular data from 107 glioma patients treated at a tertiary hospital. Patients underwent MRI scans using established protocols and were evaluated based on VASARI criteria. Tissue samples were assessed for glioma grade and underwent molecular testing for IDH mutations and MGMT methylation. Four machine learning models, namely, Random Forest, Elastic-Net, multivariate adaptive regression spline (MARS), and eXtreme Gradient Boosting (XGBoost), were trained on 27 VASARI features using fivefold internal cross-validation. The models' predictive performances were assessed using the area under the curve (AUC), sensitivity, and specificity. RESULTS: For glioma grade prediction, XGBoost exhibited the highest AUC (0.978), sensitivity (0.879), and specificity (0.964), with f6 (proportion of non-enhancing) and f12 (definition of enhancing margin) as the most important predictors. In predicting IDH mutation status, XGBoost achieved an AUC of 0.806, sensitivity of 0.364, and specificity of 0.880, with f1 (tumor location), f12, and f30 (perpendicular diameter to f29) as primary predictors. For MGMT methylation, XGBoost displayed an AUC of 0.580, sensitivity of 0.372, and specificity of 0.759, highlighting f29 (longest diameter) as the key predictor. CONCLUSIONS: This study underscores the robust potential of combining VASARI radiological features with machine learning models in predicting glioma grade, IDH mutation status, and MGMT methylation. The best and most balanced performance was achieved using the XGBoost model. While the prediction of glioma grade showed promising results, the sensitivity in discerning IDH mutations and MGMT methylation still leaves room for improvement. Follow-up studies with larger datasets and more advanced artificial intelligence techniques can further refine our understanding and management of gliomas.

Functional determination of site-mutations in rdxA involved in metronidazole resistance of Helicobacter pylori.

Background: Metronidazole (MTZ) is among the first-line drugs against the human gastric pathogen Helicobacter pylori (H. pylori). MTZ is used as a prodrug that is activated by an oxygen-insensitive enzyme NADPH nitroreductase (RdxA). Loss-of-function mutations in rdxA make H. pylori MTZ resistant; however, experimental proof is lacking. Methods: We collected 139 gastric biopsy samples from patients suspected of H. pylori infection in Shanghai, and amplified Hp-specific rdxA gene from 134 samples. All these rdxA genes were sequenced and phylogenetically compared. The effect of mutations on RdxA function was measured by expressing them in Escherichia coli DH5α by using the MTZ sensitivity test. Results: In total, 134 gastric biopsy samples were identified as H. pylori positive. Of the 134 samples, 74 and 6 had point mutations at the various sites or promoter region of rdxA, generating truncated and extended fused proteins, respectively. The remaining 54 were full-length with single nucleotide variation (SNV) compared with the wild-type RdxA from H. pylori, with 49 clustering with hpEastAsia, 3 with hpEurope, and 2 with hpNEAfrica. All 134 rdxA were expressed in E. coli DH5α; 22 and 112 resultant strains showed MTZ-sensitive and MTZ-resistant phenotypes, respectively. Comparative analysis of single nucleotide polymorphisms (SNPs) in the functional and inactivated RdxA revealed 14 novel mutations in RdxA, 5 of which conferred MTZ resistance: S18F, D59S, L62I, S79N, and A187V. Conclusion: The occurrence of MTZ resistance induced by site-mutation of RdxA in patients with H. pylori infection was 83.6% (112/134) in the Shanghai region. The major form of loss-of-function mutation was truncation of RdxA translation at a rate of 58/112 (51.8%). Molecular detection reliably determined the resistance of H. pylori to MTZ. Thus, the functional mutants involved in MTZ resistance facilitate clinical diagnosis and medication based on sequence analysis.

CHNet: A multi-task global-local Collaborative Hybrid Network for KRAS mutation status prediction in colorectal cancer.

Accurate prediction of Kirsten rat sarcoma (KRAS) mutation status is crucial for personalized treatment of advanced colorectal cancer patients. However, despite the excellent performance of deep learning models in certain aspects, they often overlook the synergistic promotion among multiple tasks and the consideration of both global and local information, which can significantly reduce prediction accuracy. To address these issues, this paper proposes an innovative method called the Multi-task Global-Local Collaborative Hybrid Network (CHNet) aimed at more accurately predicting patients' KRAS mutation status. CHNet consists of two branches that can extract global and local features from segmentation and classification tasks, respectively, and exchange complementary information to collaborate in executing these tasks. Within the two branches, we have designed a Channel-wise Hybrid Transformer (CHT) and a Spatial-wise Hybrid Transformer (SHT). These transformers integrate the advantages of both Transformer and CNN, employing cascaded hybrid attention and convolution to capture global and local information from the two tasks. Additionally, we have created an Adaptive Collaborative Attention (ACA) module to facilitate the collaborative fusion of segmentation and classification features through guidance. Furthermore, we introduce a novel Class Activation Map (CAM) loss to encourage CHNet to learn complementary information between the two tasks. We evaluate CHNet on the T2-weighted MRI dataset, and achieve an accuracy of 88.93% in KRAS mutation status prediction, which outperforms the performance of representative KRAS mutation status prediction methods. The results suggest that our CHNet can more accurately predict KRAS mutation status in patients via a multi-task collaborative facilitation and considering global-local information way, which can assist doctors in formulating more personalized treatment strategies for patients.

Mesothelioma: molecular pathology and biomarkers.

Diffuse mesotheliomas are characterized by recurrent genomic alterations involving tumor suppressors and epigenetic regulators such as BAP1, CDKN2A, MTAP, and NF2. Depending on the differential diagnosis as informed by histologic assessment, one can apply the appropriate immunohistochemical and/or molecular panels to reach the correct pathologic diagnosis, sometimes even in cases with limited tissues. Biomarkers aid in the diagnosis of mesothelioma in the following scenarios: 1) For a tumor that is overtly malignant, how can one distinguish mesothelioma from other tumors? 2) For a mesothelial proliferation, how can one distinguish mesothelioma from a reactive process? To distinguish mesotheliomas from carcinomas, at least two positive and two negative markers are currently recommended. To distinguish sarcomatoid mesothelioma from pleomorphic carcinoma, even more markers-and sometimes molecular testing-are needed. To distinguish mesothelioma from reactive mesothelial conditions, useful immunohistochemical biomarkers include BAP1, MTAP, and merlin, which serve as surrogates for the corresponding gene mutation status. In patients with unusual clinical history, for tumors with a peculiar microscopic appearance, and/or in cases with an equivocal immunophenotypic profile, molecular testing can help to exclude mimics and to confirm the pathologic diagnosis.

Vitreoretinal large B- cell lymphoma (VR- LBCL): Clinical and pathological features and treatment outcomes.

CONTEXT: Vitreoretinal large B- cell lymphoma (VR- LBCL) is a type of non- Hodgkin lymphoma confined to the eye and central nervous system (CNS). The clinical manifestations of intraocular lymphoma can precede, occur simultaneously with, or follow disease at CNS sites. It differs from other forms of extra-nodal lymphoma; in that it does not involve systemic sites other than CNS. OBJECTIVES: To analyse the clinical and pathological features, and treatment outcomes of a cohort of patients diagnosed with vitreoretinal lymphoma (VRL) in Royal Victoria Eye and Ear Hospital, Ireland between 2010 and 2024. METHOD: Retrospective review of medical records and pathology specimens of patients with ocular involvement in VR- LBCL over 14-year period and a review of the literature. RESULTS: Eight patients were included. All of them underwent pars plana vitrectomy and were confirmed to have VR- LBCL. The median age at diagnosis was 71 years. Three were men and five were women. Six had bilateral disease and two unilateral. Four of four patients had MYD88 L265P mutation present. Four patients showed a high interleukin-10 (IL-10) to interleukins-6 (IL-6) ratio in keeping with the diagnosis of VRL. Three patients had primary CNS lymphoma with subsequent eye involvement, despite systemic chemotherapy treatment. Of the five patients who presented with ocular lymphoma, two patients had CNS involvement after primary vitreoretinal lymphoma was diagnosed. Of those, one was initially treated with local intravitreal chemotherapy. Three patients had no CNS recurrence. At the time of this study, seven patients of eight are alive, four are disease free and two are on a first- line local chemotherapy treatment. One underwent treatment for CNS relapse. One patient died of the disease before commencing targeted therapy. CONCLUSION: This case series demonstrated excellent treatment outcomes for seven patients, alive at the time of the study. Both local radiotherapy and intravitreal chemotherapy achieved good ocular control with acceptable side effects and no significant difference in visual outcome. VRL is a difficult diagnosis and vitreous cytology should be prioritised in cases of vitritis unresponsive to treatment. Analysis of MYD88 L265P mutation and IL- 10: IL- 6 ratio >1 are useful adjuncts in the diagnosis of VR- LBCL, particularly in cases where limited vitreous material makes cytological evaluation challenging.

Excitation/emission-enhanced heterostructure photonic crystal array synergizing with "DD-A" FRET entropy-driven circuit for high-resolution and ultrasensitive analysis of ctDNA.

Circulating tumor DNA (ctDNA) is an emerging biomarker of liquid biopsy for cancer. But it remains a challenge to achieve simple, sensitive and specific detection of ctDNA because of low abundance and single-base mutation. In this work, an excitation/emission-enhanced heterostructure photonic crystal (PC) array synergizing with entropy-driven circuit (EDC) was developed for high-resolution and ultrasensitive analysis of ctDNA. The donor donor-acceptor FÖrster resonance energy transfer ("DD-A" FRET) was integrated in EDC based on the introduction of simple auxiliary strand, which exhibited higher sensitivity than that of traditional EDC. The heterostructure PC array was constructed with the bilayer periodic nanostructures of nanospheres. Because the heterostructure PC has the adjustable dual photonic band gaps (PBGs) by changing nanosphere sizes, and the "DD-A" FRET can offer the excitation and emission peak with enough distance, it helps the successful matches between the dual PBGs of heterostructure PC and the excitation/emission peaks of "DD-A" FRET; thus, the fluorescence from EDC can be enhanced effectively from both of excitation and emission processes on heterostructure PC array. Besides, high-resolution of single-base mutation was obtained through the strict recognition of EDC. Benefiting from the specific spectrum-matched and synergetic amplification of heterostructure PC and EDC with "DD-A" FRET, the proposed array obtained ultrasensitive detection of ctDNA with LOD of 12.9 fM, and achieved the analysis of mutation frequency as low as 0.01%. Therefore, the proposed strategy has the advantages of simple operation, mild conditions (enzyme-free and isothermal), high-sensitivity, high-resolution and high-throughput analysis, showing potential in bioassay and clinical application.

Evaluation of homeobox protein B13 (HOXB13) gene G84E mutation in patients with prostate cancer.

OBJECTIVES: To comprehensively investigate the potential association between prostate cancer (PCa) and the G84E mutation within the Homeobox Protein B13 (HOXB13) gene among individuals of Turkish descent, our study aims to undertake a prospective examination. METHODS: We evaluated 300 patients (150 diagnosed with prostate cancer, 150 controls) who presented in our clinic. Data collected were prospectively examined. DNA isolation was performed using an isolation kit. The HOXB13-G84E mutation (rs138213197) was analyzed in the obtained samples. Data encoding and statistical analysis were performed. RESULTS: The pathological allele for the G84E mutation was T. According to the findings, no mutations were detected in the control group, while the G84E mutation was detected in 17 patients in the patient group, all of whom had the TC genotype. The analysis showed that having the CC genotype reduced the risk of prostate cancer by 0.47 times (OR=0.47, CI=0.415-0.532). Our results did not support a trend toward family history or earlier-onset disease in comparisons between carriers and non-carriers of HOXB13 G84E mutation. Individuals with a positive family history exhibited a higher frequency of the G84E mutation. CONCLUSIONS: We concluded that HOXB13 gene mutation is indeed linked to PCa in Turkish men. However, we did not find a relationship between the HOXB13 gene G84E mutation carrier status and either early-onset PCa or familial PCa in Turkish men.

Inborn errors of immunity and its clinical significance in children with lymphoma in China: a single-center study

Abstract Objective: To investigate the incidence, clinical and genetic characteristics of pediatric lymphoma patients of China with inborn errors of immunity (IEI)-related gene mutations, which have not been fully studied. Method: From Jan. 2020 to Mar. 2023, IEI-related genetic mutations were retrospectively explored in 108 children with lymphomas admitted to Beijing Children's Hospital by NGS. Genetic rule and clinical characteristics as well as treatment outcomes were compared between patients with or without IEI-related gene mutations. Results: A total of 17 patients (15.7 %) harbored IEI-associated mutations, including 4 cases with X-linked lymphoproliferative syndrome (XLP), 3 cases had mutations in tumor necrosis factor receptor superfamily 13B (TNFRSF13B), 2 cases with Activated p110 syndrome (APDS). Patients with IEI all had alteration of immunocompetence with decreased levels of immunoglobulin and lymphocyte subsets. Recurrent infection existed in 41.2 % of patients. The 18-month event-free survival (EFS) and the overall response rate (ORR) of patients with IEI are significantly lower than those without IEI (33.86% vs. 73.26 %, p = 0.011; 52.94% vs. 87.91 %, p = 0.002, respectively). In addition, patients with IEI had a higher progression disease (PD) rate of 23.5 % than those without IEI of 4.4% (p = 0.006). Conclusion: The present study demonstrated that IEI-associated lymphomas were much more common than originally appreciated in pediatric lymphomas, and those were insensitive to treatment and more likely to progress or relapse. The genomic analysis and a thorough review of the medical history of IEI can be used to distinguish them from pediatric lymphomas without IEI, which are beneficial for the early diagnosis and direct intervention.

An Overview on Prevalence and Detection Approaches of BRAF V600E Mutation in Anaplastic Thyroid Carcinoma: A Systematic Review and Meta-Analysis.

Background: BRAF V600E mutation is proved critical in the progression and invasion of thyroid cancer, and as a prognostic biomarker. As anaplastic thyroid cancer (ATC) is a rare and aggressive form of thyroid cancer, this study was conducted to provide a view on prevalence of BRAF V600E as well as the best molecular diagnostic method in ATC patients. Methods: A comprehensive literature search was performed from their inception to Oct 2022 in PubMed, Scopus, Google Scholar, and Web of Science (WoS). The data of the prevalence of ATC were extracted. Moreover, the diagnostic feature of the available diagnostic tools was extracted to measure the sensitivity and specificity. To pool the prevalence data, we used meta-proportion analysis and diagnostic meta-analysis was conducted to determine the specificity and sensitivity of the immunohistochemistry method in detecting BRAF V600E mutation among patients with ATC. Results: Overall, 34 studies were included in this meta-analysis. The incidence of BRAF V600E was shown 33% in the 978 patients. The sensitivity and specificity of IHC in detecting BRAF V600E were detected 78.9% (95%CI: 60.1-97.2), and 69.7% (95%CI: 41.2-98.1), respectively. Conclusion: IHC had an acceptable prognostic profile for detecting BRAF V600E in ATC patients. The diagnosis of BRAF mutation is critical in clinical trials and may be helpful for choosing proper-targeted therapy strategies in ATC patients.

A Novel NR5A1 Mutation in a Thai Boy with 46, XY DSD.

Disorders of sex development (DSD) can be classified as 46,XX DSD, 46,XY DSD, and sex chromosome DSD. Several underlying causes including associated genes have been reported. Steroidogenic factor-1 is encoded by the NR5A1 gene, a crucial regulator of steroidogenesis in the growth of the adrenal and gonadal tissues. It has been discovered to be responsible for 10 to 20% of 46, XY DSD cases. Here, we described a 2-month-old infant who had ambiguous genitalia and 46, XY. Using whole exome sequencing followed by polymerase chain reaction-Sanger sequencing, a novel heterozygous nonsense c.1249C > T (p.Gln417Ter) variant in the NR5A1 gene was identified. It is present in his mother but absent in his father and maternal aunt and uncle. At the age of 7 months, the patient received a monthly intramuscular injection of low-dose testosterone for 3 months in a row. His penile length and diameter increased from 1.8 to 3 cm and from 0.8 to 1.3 cm, respectively. The patient also had normal adrenal reserve function by adrenocorticotropic hormone stimulation test. This study identified a novel causative p.Q417X (c.1249C > T) variant in NR5A1 causing 46,XY DSD in a Thai boy which is inherited from his unaffected mother.

Prediction of Deleterious Single Amino Acid Polymorphisms with a Consensus Holdout Sampler.

Background: Single Amino Acid Polymorphisms (SAPs) or nonsynonymous Single Nucleotide Variants (nsSNVs) are the most common genetic variations. They result from missense mutations where a single base pair substitution changes the genetic code in such a way that the triplet of bases (codon) at a given position is coding a different amino acid. Since genetic mutations sometimes cause genetic diseases, it is important to comprehend and foresee which variations are harmful and which ones are neutral (not causing changes in the phenotype). This can be posed as a classification problem. Methods: Computational methods using machine intelligence are gradually replacing repetitive and exceedingly overpriced mutagenic tests. By and large, uneven quality, deficiencies, and irregularities of nsSNVs datasets debase the convenience of artificial intelligence-based methods. Subsequently, strong and more exact approaches are needed to address these problems. In the present work paper, we show a consensus classifier built on the holdout sampler, which appears strong and precise and outflanks all other popular methods. Results: We produced 100 holdouts to test the structures and diverse classification variables of diverse classifiers during the training phase. The finest performing holdouts were chosen to develop a consensus classifier and tested using a k-fold (1 ≤ k ≤5) cross-validation method. We also examined which protein properties have the biggest impact on the precise prediction of the effects of nsSNVs. Conclusion: Our Consensus Holdout Sampler outflanks other popular algorithms, and gives excellent results, highly accurate with low standard deviation. The advantage of our method emerges from using a tree of holdouts, where diverse LM/AI-based programs are sampled in diverse ways.

Current Trial Report: A Multicenter Phase I/Ib study of Capmatinib Plus Trametinib in Patients With Metastatic Nonsmall Cell Lung Center Harboring MET Exon 14 Skipping Mutations and Other MET-Alterations.

INTRODUCTION: MET tyrosine kinase inhibitor (TKI) therapy is associated with improved outcomes in patients with nonsmall cell lung cancer (NSCLC) harboring a MET alteration, including MET exon 14 (METex14) skipping mutation, MET amplification, or MET fusion. However, primary or acquired resistance to TKI therapy ultimately develops. In preclinical models, hyperactivation of MAPK signaling was shown to promote resistance to MET TKI; resistance was overcome by co-treatment with a MET inhibitor and a MEK inhibitor. This phase I/Ib study offers a potential combination strategy simultaneously targeting MET (with capmatinib) and MEK signaling (with trametinib) to overcome resistance to MET inhibitor monotherapy in METex14 NSCLC. METHODS: In the dose escalation phase, a minimum of 6 and maximum of 18 patients will be enrolled using a conventional 3+3 design with the primary endpoint of identifying a recommended phase 2 dose (RP2D) of capmatinib in combination with trametinib. Once the RP2D is identified, patients will continue to enroll in a dose expansion phase to a total of 15 patients. The primary endpoint of the dose expansion phase is to further characterize the safety profile of the combination. CONCLUSION: This phase I/Ib clinical trial will assess the safety and efficacy of combination capmatinib and trametinib in NSCLC patients whose tumors harbor METex14 skipping mutations, MET amplification, or MET fusion and had developed progressive disease on single agent MET inhibitor therapy.

An ultrasensitive DNA-enhanced amplification method for detecting cfDNA drug-resistant mutations in non-small cell lung cancer with selective FEN-assisted degradation of dominant somatic fragments.

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 0.5 %) 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.

EGFR-mutated lung cancer as a secondary neoplasm in a patient with Li-Fraumeni syndrome: case report.

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.