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Small bowel adenocarcinoma (SBA) is a rare and aggressive malignancy with limited treatment options and poor prognosis. The molecular landscape and immunological characteristics of SBA are poorly understood. Here, we performed comprehensive mutation profiling of tissue and plasma biopsies from 143 and 42 patients with SBA. Analysis showed that SBA had a distinct mutation spectrum from left- and right-sided colorectal carcinoma. Plasma biopsy had high concordance with tissue biopsy for single nucleotide variants and structural variants, but low concordance for copy number variations, which showed that plasma biopsy can be an alternative to tissue biopsy. Moreover, we analyzed the association of TMB with clinical and molecular features, and found that TMB was significantly higher in tumors with DNA damage response alterations. Our findings provide valuable insights into the molecular and immunological features of SBA and demonstrate the potential of plasma biopsy as a non-invasive method for SBA diagnosis and treatment.
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Adenocarcinoma , Variaciones en el Número de Copia de ADN , Humanos , Intestino Delgado , Adenocarcinoma/genética , Biopsia , Genómica , Mutación , Secuenciación de Nucleótidos de Alto Rendimiento/métodosRESUMEN
The increase in the detection rate of synchronous multiple primary lung cancer (MPLC) has posed remarkable clinical challenges due to the limited understanding of its pathogenesis and molecular features. Here, comprehensive comparisons of genomic and immunologic features between MPLC and solitary lung cancer nodule (SN), as well as different lesions of the same patient, were performed. Compared with SN, MPLC displayed a lower rate of EGFR mutation but higher rates of BRAF, MAP2K1, and MTOR mutation, which function exactly in the upstream and downstream of the same signaling pathway. Considerable heterogeneity in T cell receptor (TCR) repertoire exists among not only different patients but also among different lesions of the same patient. Invasive lesions of MPLC exhibited significantly higher TCR diversity and lower TCR expansion than those of SN. Intriguingly, different lesions of the same patient always shared a certain proportion of TCR clonotypes. Significant clonal expansion could be observed in shared TCR clonotypes, particularly in those existing in all lesions of the same patient. In conclusion, this study provided evidences of the distinctive mutational landscape, activation of oncogenic signaling pathways, and TCR repertoire in MPLC as compared with SN. The significant clonal expansion of shared TCR clonotypes demonstrated the existence of immune commonality among different lesions of the same patient and shed new light on the individually tailored precision therapy for MPLC.
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Neoplasias Pulmonares , Mutación , Neoplasias Primarias Múltiples , Receptores de Antígenos de Linfocitos T , Humanos , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Neoplasias Primarias Múltiples/inmunología , Neoplasias Primarias Múltiples/genética , Neoplasias Primarias Múltiples/patología , Masculino , Femenino , Persona de Mediana Edad , AncianoRESUMEN
BACKGROUND: The precise identification of the underlying causes of infectious diseases, such as severe pneumonia, is essential, and the development of next-generation sequencing (NGS) has enhanced the effectiveness of pathogen detection. However, there is limited information on the systematic assessment of the clinical use of targeted next-generation sequencing (tNGS) in cases of severe pneumonia. METHODS: A retrospective analysis was conducted on 130 patients with severe pneumonia treated in the ICU from June 2022 to June 2023. The consistency of the results of tNGS, metagenomics next-generation sequencing (mNGS), and culture with the clinical diagnosis was evaluated. Additionally, the results for pathogens detected by tNGS were compared with those of culture, mNGS, and quantitative reverse transcription PCR (RT-qPCR). To evaluate the efficacy of monitoring severe pneumonia, five patients with complicated infections were selected for tNGS microbiological surveillance. The tNGS and culture drug sensitisation results were then compared. RESULTS: The tNGS results for the analysis of the 130 patients showed a concordance rate of over 70% with clinical diagnostic results. The detection of pathogenic microorganisms using tNGS was in agreement with the results of culture, mNGS, and RT-qPCR. Furthermore, the tNGS results for pathogens in the five patients monitored for complicated infections of severe pneumonia were consistent with the culture and imaging test results during treatment. The tNGS drug resistance results were in line with the drug sensitivity results in approximately 65% of the cases. CONCLUSIONS: The application of tNGS highlights its promise and significance in assessing the effectiveness of clinical interventions and providing guidance for anti-infection therapies for severe pneumonia.
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Secuenciación de Nucleótidos de Alto Rendimiento , Neumonía , Humanos , Estudios Retrospectivos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Neumonía/diagnóstico , Neumonía/tratamiento farmacológico , Neumonía/microbiología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Unidades de Cuidados Intensivos/organización & administración , Unidades de Cuidados Intensivos/estadística & datos numéricosRESUMEN
The nanopore sensor as a high-throughput and low-cost technology can detect a single molecule in a solution. In the present study, relatively large silicon nitride (Si3N4) nanopores with diameters of â¼28 and â¼88 nm were fabricated successfully using a focused Ga ion beam. We have used solid-state nanopores with various sizes to detect the single horseradish peroxidase (HRP) molecule and for the first time analyzed single HRP molecular translocation events. In addition, a real-time monitored single enzyme molecular biochemical reaction and a translocation of the product of enzyme catalysis substrates were investigated by using a Si3N4 nanopore. Our nanopore system showed a high sensitivity in detecting single enzyme molecules and a real-time monitored single enzyme molecular biochemical reaction. This method could also be significant for studying gene expression or enzyme dynamics at the single-molecule level.
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Técnicas Biosensibles/métodos , Peroxidasa de Rábano Silvestre/análisis , Nanoporos , Técnicas Biosensibles/instrumentación , Peroxidasa de Rábano Silvestre/aislamiento & purificación , Límite de Detección , Modelos Moleculares , Compuestos de Silicona/químicaRESUMEN
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare autosomal dominant syndrome caused by a germline mutation in the fumarate hydratase (FH) gene that manifests with cutaneous leiomyomas, uterine fibroids, and renal cell cancer (RCC). Patients with HLRCC-associated RCC (HLRCC-RCC) have aggressive clinical courses, but there is no standardized therapy for advanced HLRCC-RCC. In this study, we described a case of aggressive HLRCC in a 33-year-old female who exhibited a novel heterozygous germline insertion mutation in exon 8 of the FH gene (c.1126 C > T; p.Q376*). The patient underwent laparoscopic resection of the right kidney, but metastases appeared within 3 months after surgery. Histological staining of the resected tumor revealed high expression levels of programmed cell death-ligand 1 (PD-L1). Therefore, the patient was treated with immunotherapy. The patient achieved a partial response to immunotherapy, and the treatment of metastatic lesions has continued to improve. A thorough literature review pinpointed 76 historical cases of HLRCC-RCC that had undergone immunotherapy. From this pool, 46 patients were selected for this study to scrutinize the association between mutations in the FH gene and the effectiveness of immunotherapy. Our results indicate that immunotherapy could significantly improve the overall survival (OS) of patients with HLRCC-RCC. However, no influence of different mutations in the FH germline gene on the therapeutic efficacy of immunotherapy was observed. Therefore, our study suggested that immunotherapy was an effective therapeutic option for patients with HLRCC regardless of the type of FH germline mutation.
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Fumarato Hidratasa , Inmunoterapia , Leiomiomatosis , Síndromes Neoplásicos Hereditarios , Neoplasias Cutáneas , Neoplasias Uterinas , Humanos , Femenino , Leiomiomatosis/genética , Leiomiomatosis/patología , Leiomiomatosis/terapia , Fumarato Hidratasa/genética , Adulto , Síndromes Neoplásicos Hereditarios/genética , Síndromes Neoplásicos Hereditarios/terapia , Síndromes Neoplásicos Hereditarios/complicaciones , Síndromes Neoplásicos Hereditarios/patología , Neoplasias Uterinas/genética , Neoplasias Uterinas/patología , Neoplasias Uterinas/terapia , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/terapia , Mutación de Línea Germinal , Neoplasias Renales/genética , Neoplasias Renales/patología , Neoplasias Renales/terapia , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/terapiaRESUMEN
As sequencing technology transitions from research to clinical settings, due to technological maturity and cost reductions, metagenomic nextgeneration sequencing (mNGS) is increasingly used. This shift underscores the growing need for more costeffective and universally accessible sequencing assays to improve patient care and public health. Therefore, targeted NGS (tNGS) is gaining prominence. tNGS involves enrichment of target pathogens in patient samples based on multiplex PCR amplification or probe capture with excellent sensitivity. It is increasingly used in clinical diagnostics due to its practicality and efficiency. The present review compares the principles of different enrichment methods. The high positivity rate of tNGS in the detection of pathogens was found in respiratory samples with specific instances. tNGS maintains high sensitivity (70.895.0%) in samples with low pathogen loads, including blood and cerebrospinal fluid. Furthermore, tNGS is effective in detecting drugresistant strains of Mycobacterium tuberculosis, allowing identification of resistance genes and guiding clinical treatment decisions, which is difficult to achieve with mNGS. In the present review, the application of tNGS in clinical settings and its current limitations are assessed. The continued development of tNGS has the potential to refine diagnostic accuracy and treatment efficacy and improving infectious disease management. However, further research to overcome technical challenges such as workflow time and cost is required.
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Enfermedades Transmisibles , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Enfermedades Transmisibles/diagnóstico , Enfermedades Transmisibles/microbiología , Enfermedades Transmisibles/genética , Metagenómica/métodos , Técnicas de Diagnóstico Molecular/métodosRESUMEN
Background: Colorectal cancer (CRC) is a heterogeneous cancer. Its treatment depends on its anatomical site and molecular features. Carcinomas of the rectosigmoid junction are frequent; however, specific data on these tumors are sparse, as they are frequently assigned to either the colon or rectum. This study sought to identify the molecular features of rectosigmoid junction cancer to determine whether there should be any difference between the therapeutic management of rectosigmoid junction cancer and that of sigmoid colon or rectum cancer. Methods: The data of 96 CRC patients with carcinomas in the sigmoid colon, rectosigmoid junction, and rectum were retrospectively summarized. The next-generation sequencing (NGS) data of the patients were analyzed to study the molecular characteristics of the carcinomas in different locations of the bowel. Results: In total, there was no difference in the clinicopathologic characteristics of the three groups. TP53, APC, and KRAS genes were the top 3 alteration genes in sigmoid colon, rectosigmoid junction, and rectum cancer. The rates of the KRAS, NRAS, and PIK3CA increased as the location moved distally, while the rates of APC and BRAF decreased. Almost no significant molecular differences were found among the three groups. The prevalence of the FLT3, fms-related tyrosine kinase 1 (FLT1), and phosphoenolpyruvate carboxykinase 1 (PCK1) mutation was lower in the rectosigmoid junction group than the sigmoid colon and rectum groups (P>0.05). The proportion of the transforming growth factor beta pathway was higher in the rectosigmoid junction and rectum groups than the sigmoid colon group (39.3% vs. 34.3% vs. 18.2%, respectively, P=0.121, P=0.067, P=0.682); a higher proportion of MYC pathway was also observed in the rectosigmoid junction than that in rectum and sigmoid colon (28.6% vs. 15.2% vs. 17.1%, P=0.278, P=0.202, P=0.171). Regardless of the clustering method employed, the patients were divided into two clusters, and the composition of clusters revealed no significant differences in terms of the different locations. Conclusions: Rectosigmoid junction cancer has a distinctive molecular profile compared to the molecular profiles of the adjacent bowel segment cancers.
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BACKGROUND: Targeted therapy has revolutionized the treatment of patients with malignancies harboring mutations in driver genes and has brought a favorable survival benefit to the population with actionable oncogenic mutations. In recent years, the MET exon14 skipping mutation has been recognized as a potentially promising therapeutic target in non-small cell lung cancer (NSCLC). These changes are mutually exclusive with molecular drivers such as EGFR, KRAS, HER-2, BRAF, ALK and ROS1. The prevalence rate of coexisting MET exon 14 mutations and EGFR sensitive mutations (L858R, exon 19 deletions) in Chinese population was reported to be 0.2% (3/1590). However, the coexistence of MET exon 14 mutations with EGFR exon 20 insertion mutations has never been reported and the management of this subtype is not identified. CASE PRESENTATION: A 69-year-old male with a right lung adenocarcinoma (T4N2M0, IIIB) was confirmed to be positive for MET exon 14 skipping (c.3028_3028+1delGGinsTT, 44.4%), MET amplification (copy number 4.4), and EGFR exon 20 insertion (p. N771_H773dup, 22.1%) mutations. After the progression of one cycle of chemotherapy (Pemetrexed 0.8 g d1), the patient was subsequently accepted treatment with Crizotinib (250 mg twice a day) and achieved an important clinical remission for six months until the development of brain metastases. Then, he was submitted to a cycle of anti-programmed cell death-1 (PD-1) therapy after failure of Crizotinib and eventually acquired resistance despite of the high expression of programmed death ligand-1 (PD-L1) and tumor mutational burden (TMB) status. CONCLUSION: This case report provides treatment strategies for epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs)-untreated lung adenocarcinoma patients simultaneously carrying MET alterations and EGFR exon 20 insertion mutations. In addition, the signatures of PD-L1 or TMB expression were not the candidate for predicting the efficacy of immunotherapy in this context.
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Adenocarcinoma del Pulmón , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/genética , Anciano , Quinasa de Linfoma Anaplásico/genética , Antígeno B7-H1/genética , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Crizotinib/farmacología , Crizotinib/uso terapéutico , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Mutación , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas , Proteínas Proto-Oncogénicas/genéticaRESUMEN
Mutations in the B-Raf proto-oncogene, serine/threonine kinase (BRAF), have been linked to a variety of solid tumors such as papillary thyroid carcinoma. The purpose of this study was to compare the DP-TOF, a DNA mass spectroscopy (MS) platform, and next-generation sequencing (NGS) methods for detecting multiple-gene mutations (including BRAFV600E) in thyroid nodule fine-needle aspiration fluid. In this study, we collected samples from 93 patients who had previously undergone NGS detection and had sufficient DNA samples remaining. The MS method was used to detect multiple-gene mutations (including BRAFV600E) in DNA remaining samples. NGS detection method was used as the standard. The MS method's overall sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 95.8%, 100%, 100%, and 88%, respectively in BRAFV600E gene mutation detection. With a kappa-value of 0.92 (95%CI 0.82-0.99), the level of agreement between these methods was incredibly high. Furthermore, when compared to NGS in multiple-gene detection, the MS method demonstrated higher sensitivity and specificity, 82.9% and 100%, respectively. In addition, we collected the postoperative pathological findings of 50 patients. When the postoperative pathological findings were used as the standard, the MS method demonstrated higher sensitivity and specificity, at 80% and 80%, respectively. Our findings show that the MS method can be used as an inexpensive, accurate, and dependable initial screening method to detect genes mutations and as an adjunct to clinical diagnosis.
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Neoplasias de la Tiroides , Nódulo Tiroideo , Biopsia con Aguja Fina/métodos , Análisis Mutacional de ADN/métodos , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Espectrometría de Masas , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Nódulo Tiroideo/diagnóstico , Nódulo Tiroideo/genética , Nódulo Tiroideo/patologíaRESUMEN
BACKGROUND: Epidermal growth factor receptor (EGFR) T854A is an uncommon exon 21 mutation in patients with non-small cell lung cancer (NSCLC). It was first reported in samples collected after first generation EGFR tyrosine kinase inhibitor (TKI) treatment as an acquired resistant mutation to first generation EGFR-TKI. The efficacy of osimertinib, a third generation EGFR-TKI, in these patients was not clear. METHODS: In this study, a total of 8932 NSCLC patients with NGS data were retrospectively analyzed to investigate the molecular characteristics and clinical outcomes of patients with EGFR T854A mutation. RESULTS: Eight of 8932 patients (0.09%) had EGFR T854A mutation, and 5 of them (62.5%) were treatment-naïve. Interestingly, all EGFR T854A mutations were co-occurred with EGFR L858R mutation in cis. TP53 was the most common concomitant mutation and no other driver mutation was found. Five of the 8 patients received treatment of osimertinib. Four patients achieved partial response, and one had stable disease, resulting in an overall objective response rate of 80% and disease control rate of 100%. The median progression-free survival of patients who received osimertinib was 10 months. Moreover, EGFR C797S mutation was detected in 1 patient after resistant to osimertinib treatment. CONCLUSION: Presence of EGFR T854A mutation was rare in NSCLC patients and our retrospective study provides clinical evidence that osimertinib may be an effective treatment to improve survival outcomes in patients with EGFR T854A.
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Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas , Receptores ErbB , Neoplasias Pulmonares , Inhibidores de Proteínas Quinasas/uso terapéutico , Acrilamidas , Compuestos de Anilina , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Receptores ErbB/genética , Exones/genética , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Mutación/genética , Estudios RetrospectivosRESUMEN
Background: Breast cancer is a highly heterogeneous disease. Early-stage, non-metastatic breast cancer is considered curable after definitive treatment. Early detection of tumor recurrence and metastasis through sensitive biomarkers is helpful for guiding clinical decision-making and early intervention in second-line treatment, which could improve patient prognosis and survival. Methods: In this real-world study, we retrospectively analyzed 82 patients with stages I to III breast cancer who had been analyzed by molecular residual disease (MRD) assay. A total of 82 tumor tissues and 224 peripheral blood samples were collected and detected by next-generation sequencing (NGS) based on a 1,021-gene panel in this study. Results: MRD positivity was detected in 18 of 82 patients (22.0%). The hormone receptor-/human epidermal growth factor receptor 2+ (HR-/HER2+) subgroup had the highest postoperative MRD detection rate at 30.8% (4/13). The BRCA2 and SLX4 genes were significantly enriched in all patients in the MRD positive group and FGFR1 amplification was significantly enriched in the MRD negative group with HR+/HER2-. The number of single nucleotide variants (SNVs) in tissue samples of MRD-positive patients was higher than that of MRD-negative patients (11.94 vs. 8.50 SNVs/sample). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that there was a similar biological function of the tumor-mutated genes in the 2 MRD status groups. Conclusions: This real-world study confirmed that patient samples of primary tumor tissue with different MRD status and molecular subtypes had differential genetic features, which may be used to predict patients at high risk for recurrence.
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OBJECTIVES: Head and neck cancers are aggressive epithelial tumours that are recognised as being particularly challenging to treat. Here, we report the targeted DNA profiling and the prevalence of neurotrophic-tropomyosin receptor tyrosine kinase gene (NTRK) aberrations in Chinese patients with head and neck cancers. METHODS: Samples of 127 patients with head and neck cancer were retrospectively analysed. Profiling was performed by next-generation sequencing of the 1021-gene panel with tumour tissue and matched peripheral blood control samples. RESULTS: This study was inspired by the outcome benefit of a parotid cancer patient harbouring ETV6-NTRK3 fusion, who received crizotinib treatment and achieved a 2-year progression-free survival. Genomic profiling of 127 patients with head and neck cancers indicated that TP53 is the most frequently mutated gene both in our cohort and in The Cancer Genome Atlas (TCGA) database. A higher prevalence of NTRK genetic aberrations (7.9%, 10/127), including NTRK fusion (3.1%) and mutation, was observed in our population than in TCGA. The most common fusion was the ETV6-NTRK3. Compared to the NTRK-wt group, the NTRK aberration group had more APC and PTPRD aberrations (p < 0.05). NTRK fusion was also associated with lower tumour mutation burden (TMB) (p < 0.05). TP53 and LRP1B mutations were significantly associated with higher TMB (both p < 0.01), which may be potential markers of immunotherapy. CONCLUSIONS: This is the first study to report targeted DNA profiling of Chinese patients with head and neck cancers. As NTRK genetic aberrations are more common in this Chinese population, the efficacy of NTRK inhibitors should be studied further.
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Neoplasias de Cabeza y Cuello , Receptor trkA/genética , China/epidemiología , Dermatoglifia del ADN , Neoplasias de Cabeza y Cuello/epidemiología , Neoplasias de Cabeza y Cuello/genética , Humanos , Prevalencia , Estudios RetrospectivosRESUMEN
ROS1 rearrangement, identified in ~2% of non-small cell lung cancer (NSCLC), has defined a distinctive molecular subtype. Patients with ROS1 fusion have been shown to be highly sensitive to treatment with crizotinib. However, the efficacy of crizotinib in NSCLC patients with double ROS1 fusions remains to be elucidated. Here, we report a 40-year-old male diagnosed with stage IIIA lung adenocarcinoma. Two ROS1 fusions [SDC4-ROS1 (EX2:EX32) and ROS1-GK (EX31:EX13)] were detected simultaneously in tumor tissue of this patient by next-generation sequencing. Crizotinib was administered, and the patient showed a partial response in lung lesions. Nevertheless, a brain lesion was found at 8 months after treatment. The slightly short duration of response may be related to the presence of ROS1-GK rearrangement. This case proved that patients with SDC4-ROS1 and ROS1-GK fusions may be sensitive to crizotinib, but short progression-free survival of this case showed that the presence of ROS1-GK rearrangement may affect the efficacy of crizotinib. A large-scale investigation on the efficacy of ROS1 inhibitors in patients with complex ROS1 fusions should be conducted in the future.
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Breast cancer is one of the most commonly diagnosed malignancies. Although endocrine therapy improves the survival of patients with hormone receptor (HR)-positive breast cancer, the post-endocrine therapy strategy for metastatic breast cancer remains challenging. Herein, we report two patients who benefited from antiestrogen agents combined with an immunotherapy regimen to support the notion that an immunotherapy combination regimen may be a potential treatment for patients with HR-positive metastatic breast cancer post-endocrine therapy. Case 1 involved a patient with relapsed breast cancer with ovarian and brain metastases after endocrine therapy. After undergoing surgery for the ovarian lesions, she received three cycles of chemotherapy. Given that the lesions in the brain did not change, chemotherapy was discontinued. A high T cell receptor (TCR) repertoire (high Shannon index and clonality) was observed in the tumor. Considering the patient's preference and safety, and the efficacy of immunotherapy, she was administered with letrozole combined with pembrolizumab. The patient achieved a partial response, and the progression-free survival (PFS) was more than 21 months. Case 2 involved a patient with breast cancer with multiple bone metastases. After failure of combined radiotherapy and chemotherapy, the patient received tamoxifen combined with pembrolizumab based on the patient's preference and clinical biomarkers of a positive differentiation cluster of eight tumor-infiltrating lymphocytes and a high TCR repertoire (high Shannon index and clonality) in the tumor. The patient's bone pain and biomarkers were relieved after the treatment. The patients completed six cycles of pembrolizumab, and the PFS was more than 21 months. In conclusion, our study confirmed that antiestrogen agents combined with an immunotherapy regimen is a promising treatment for patients with HR-positive metastatic breast cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Adulto , Anticuerpos Monoclonales Humanizados/administración & dosificación , Antineoplásicos Hormonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Inmunohistoquímica , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
Lung cancer is the leading cause of cancer-related deaths worldwide, and its occurrence is related to the accumulation of gene mutations and immune escape of the tumor. Sequencing of the T-cell receptor (TCR) repertoire can reveal the immunosurveillance status of the tumor microenvironment, which is related to tumor escape and immunotherapy. This study aimed to determine the characteristics and clinical significance of the TCR repertoire in lung cancer. To comprehensively profile the TCR repertoire, results from high-throughput sequencing of samples from 93 Chinese patients with lung cancer were analyzed. We found that the TCR clonality of tissues was related to smoking, with higher clonality in patients who had quit smoking for less than 1 year. As expected, TCR clonality was correlated with stages: patients with stage IV disease showed higher clonality than others. The correlation between TCR repertoire and epidermal growth factor receptor (EGFR) status was also investigated. Patients with EGFR non-L858R mutations showed higher clonality and a lower Shannon index than other groups, including patients with EGFR L858R mutation and wild-type EGFR. Furthermore, we analyzed the TCR similarity metrics-that is, the TCR shared between postoperative peripheral blood and tissue of patients with non-distant metastasis of lung cancer. A similar trend was found, in which patients with EGFR L858R mutations had lower overlap index (OLI) and Morisita index (MOI) scores. Moreover, the OLI showed a positive correlation with several clinical characteristics, including the tumor mutational burden of tissues and the maximum somatic allele frequency of blood; OLI showed a negative correlation with the ratio of CD4+CD28+ in CD4+ cells and the ratio of CD8+CD28+ in CD8+ cells. In conclusion, TCR clonality and TCR similarity metrics correlated with clinical characteristics of patients with lung cancer. Differences in TCR clonality, Shannon index, and OLI across EGFR subtypes provide information to improve understanding about varied responses to immunotherapy in patients with different EGFR mutations.
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Immune checkpoint inhibitors have radically changed the landscape of antitumor therapies in several malignancies. Despite the long-term efficacy, severe immune-related adverse events (irAEs) were not uncommon. However, fatal simultaneous multiorgan failure was rare. Here, we described a patient who developed multiorgan failure, including fulminant myocarditis, myasthenia gravis crisis, hepatic dysfunction, and delayed pneumonitis after pembrolizumab therapy for lung large-cell neuroendocrine carcinoma. After failure of high-dose steroid treatment, implantation of cardiac pacemaker combined with high-dose steroids successfully controlled myocarditis caused by immune checkpoint inhibitors (ICIs). Delayed pneumonitis occurred unexpectedly, and it was treated successfully with steroids. With wild adoption of ICIs in clinical practice, investigations for predictive markers of irAEs are warranted, and more successful treatment strategies are worth sharing.
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Comprehensive Genomic Profiling may be informative for novel treatment strategies and to improve outcomes for patients with rare tumors. This study aims to discover opportunities for use of targeted therapies already approved for routine use in patients with rare tumors. Solid tumors with an incidence lower than 2.5/100,000 per year was defined as rare tumors in China after comprehensive analysis based on epidemiological data and current availability of standardized treatment. Genomic data of rare tumors from the public database cBioPortal were compared with that of the Chinese population for targetable genomic alterations (TGAs). TGAs were defined as mutations of ALK, ATM, BRAF, BRCA1, BRCA2, CDKN2A, EGFR, ERBB2, FGFR1,2,3, KIT, MET, NF1, NTRK1,2,3, PIK3CA, PTEN, RET, and ROS1 with level 1 to 4 of evidence according to the OncoKB knowledge database. Genomic data of 4,901 patients covering 63 subtypes of rare tumor from cBioPortal were used as the western cohort. The Chinese cohort was comprised of next generation sequencing (NGS) data of 1,312 patients from across China covering 67 subtypes. Forty-one subtypes were common between the two cohorts. The accumulative prevalence of TGAs was 20.40% (1000/4901) in cBioPortal cohort, and 53.43% (701/1312) in Chinese cohort (p < 0.001). Among those 41 overlapping subtypes, it was still significantly higher in Chinese cohort compared with cBioPortal cohort (54.1%% vs. 26.1%, p < 0.001). Generally, targetable mutations in BRAF, BRCA2, CDKN2A, EGFR, ERBB2, KIT, MET, NF1, ROS1 were ≥3 times more frequent in Chinese cohort compared with that of the cBioPortal cohort. Cancer of unknown primary tumor type, gastrointestinal stromal tumor, gallbladder cancer, intrahepatic cholangiocarcinoma, and sarcomatoid carcinoma of the lung were the top 5 tumor types with the highest number of TGAs per tumor. The incidence of TGAs in rare tumors was substantial worldwide and was even higher in our Chinese rare tumor population. Comprehensive genomic profiling may offer novel treatment paradigms to address the limited options for patients with rare tumors.
RESUMEN
BACKGROUND: Rearranged during transfection (RET) has been proven to be a tumorigenic target in non-small cell lung cancers (NSCLCs). In RET-rearranged NSCLCs, molecular features and their impact on prognosis were not well illustrated, and the activity of mainstay therapeutics has not currently been well compared. METHODS: Patients diagnosed with NSCLCs with RET rearrangements were analyzed for concomitant mutations, tumor mutation burden (TMB), PD-L1 expression, T cell receptor repertoire and clinical outcomes with chemotherapy, immune checkpoint inhibitors (ICIs), and multikinase inhibitors (MKIs). RESULTS: Among 129 patients with RET-rearranged NSCLC who were analyzed, 41.1% (53/129) had co-occurring genetic alterations by next-generation sequencing, and concomitant TP53 mutation appeared most frequently (20/53, 37.7%). Patients with concurrent TP53 mutation (n = 15) had shorter overall survival than those without (n = 30; median, 18.4 months [95% CI, 8.6-39.1] vs 24.8 months [95% CI, 11.7-52.8]; P < 0.05). Patients with lower peripheral blood TCR diversity (n = 5) had superior overall survival compared with those with higher diversity (n = 6; median, 18.4 months [95% CI, 16.9-19.9] vs 4.8 months [95% CI, 4.5-5.3]; P = 0.035). An association with overall survival was not observed for PD-L1 expression nor for tumor mutation burden level. Median progression-free survival was not significantly different across chemotherapy, ICIs, and MKIs (median, 3.5 vs 2.5 vs 3.8 months). For patients treated with ICIs, the disease control rate was 60% (6/10) and the objective response rate was 20% (2/10). CONCLUSIONS: RET-rearranged lung cancers can be heterogeneous in terms of concomitant genetic alterations. Patients with concurrent TP53 mutation or high peripheral blood TCR repertoire diversity have relatively inferior overall survival in this series. Outcomes with traditional systemic therapies in general are suboptimal.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogénicas c-ret/genética , Adulto , Anciano , Anciano de 80 o más Años , Antígeno B7-H1/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/epidemiología , Femenino , Reordenamiento Génico , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/epidemiología , Masculino , Persona de Mediana Edad , Mutación , Estudios Retrospectivos , Análisis de Supervivencia , Proteína p53 Supresora de Tumor/genética , Adulto JovenRESUMEN
There are many techniques for the detection of molecules. But detection of molecules through solid-state nanopore in a solution is one of the promising, high-throughput, and low-cost technology used these days. In the present investigation, a solid-state nanopore platform was fabricated for the detection of hydrogen peroxide (H2O2), which is not only a label free product but also a significant participant in the redox reaction. We have successfully fabricated silicon nitride (Si3N4) nanopores with diameters of ~50 nm by using a focused Ga ion beam, the inner surface of the nanopore has been modified with horseradish peroxidase (HRP) by employing carbodiimide coupling chemistry. The immobilized HRP enzymes have ability to induce redox reactions in a single nanopore channel. Moreover, a real-time single aggregated ABTSâ¢+ molecular translocation events were monitored and investigated. The designed solid-state nanopore biosensor is reversible and can be applied to detect H2O2 multiple times.