Randomized, open-label, phase 2 study of nivolumab plus ipilimumab or nivolumab monotherapy in patients with advanced or metastatic solid tumors of high tumor mutational burden.

BACKGROUND: Checkpoint inhibitor therapy has demonstrated overall survival benefit in multiple tumor types. Tumor mutational burden (TMB) is a predictive biomarker for response to immunotherapies. This study evaluated the efficacy of nivolumab+ipilimumab in multiple tumor types based on TMB status evaluated using either tumor tissue (tTMB) or circulating tumor DNA in the blood (bTMB). PATIENTS AND METHODS: Patients with metastatic or unresectable solid tumors with high (≥10 mutations per megabase) tTMB (tTMB-H) and/or bTMB (bTMB-H) who were refractory to standard therapies were randomized 2:1 to receive nivolumab+ipilimumab or nivolumab monotherapy in an open-label, phase 2 study (CheckMate 848; NCT03668119). tTMB and bTMB were determined by the Foundation Medicine FoundationOne® CDx test and bTMB Clinical Trial Assay, respectively. The dual primary endpoints were objective response rate (ORR) in patients with tTMB-H and/or bTMB-H tumors treated with nivolumab+ipilimumab. RESULTS: In total, 201 patients refractory to standard therapies were randomized: 135 had tTMB-H and 125 had bTMB-H; 82 patients had dual tTMB-H/bTMB-H. In patients with tTMB-H, ORR was 38.6% (95% CI 28.4% to 49.6%) with nivolumab+ipilimumab and 29.8% (95% CI 17.3% to 44.9%) with nivolumab monotherapy. In patients with bTMB-H, ORR was 22.5% (95% CI 13.9% to 33.2%) with nivolumab+ipilimumab and 15.6% (95% CI 6.5% to 29.5%) with nivolumab monotherapy. Early and durable responses to treatment with nivolumab+ipilimumab were seen in patients with tTMB-H or bTMB-H. The safety profile of nivolumab+ipilimumab was manageable, with no new safety signals. CONCLUSIONS: Patients with metastatic or unresectable solid tumors with TMB-H, as determined by tissue biopsy or by blood sample when tissue biopsy is unavailable, who have no other treatment options, may benefit from nivolumab+ipilimumab. TRIAL REGISTRATION NUMBER: NCT03668119.

Immunogenomic profiles and therapeutic options of the pan-programmed cell death-related lncRNA signature for patients with bladder cancer.

Programmed cell death (PCD) is a process that eliminates infected, damaged, or possibly neoplastic cells to sustain homeostatic multicellular organisms. Although long noncoding RNAs (lncRNAs) are involved in various types of PCD and regulate tumor growth, invasion, and migration, the role of PCD-related lncRNAs in bladder cancer still lacks systematic exploration. In this research, we integrated multiple types of PCD as pan-PCD and identified eight pan-PCD-related lncRNAs (LINC00174, HCP5, HCG27, UCA1, SNHG15, GHRLOS, CYB561D2, and AGAP11). Then, we generated a pan-PCD-related lncRNA prognostic signature (PPlncPS) with excellent predictive power and reliability, which performed equally well in the E-MTAB-4321 cohort. In comparison with the low-PPlncPS score group, the high-PPlncPS score group had remarkably higher levels of angiogenesis, matrix, cancer-associated fibroblasts, myeloid cell traffic, and protumor cytokine signatures. In addition, the low-PPlncPS score group was positively correlated with relatively abundant immune cell infiltration, upregulated expression levels of immune checkpoints, and high tumor mutation burden (TMB). Immunogenomic profiles revealed that patients with both low PPlncPS scores and high TMB had the best prognosis and may benefit from immune checkpoint inhibitors. Furthermore, for patients with high PPlncPS scores, docetaxel, staurosporine, and luminespib were screened as potential therapeutic candidates. In conclusion, we generated a pan-PCD-related lncRNA signature, providing precise and individualized prediction for clinical prognosis and some new insights into chemotherapy and immune checkpoint inhibitor therapy for bladder cancer.

Pan-cancer analysis of COL15A1: an immunological and prognostic biomarker.

Collagen, type XV, alpha 1 (COL15A1) belongs to the collagen superfamily, which can influence disease progression by modulating immune pathways. Although the growing number of investigations demonstrating the indispensable role of COL15A1 in the progression of certain tumors, no pan-cancer assessment of COL15A1 is accessible to date. Therefore, the available data was used to explore the role of COL15A1 in 33 types of tumors and to investigate their potential immune function. Numerous bioinformatics approaches were used to research the potential oncogenic role of COL15A1, including analysis of tumor prognosis, microsatellite instability (MSI), tumor mutational burden (TMB), single nucleotide polymorphism (SNP), drug sensitivity, immune cell infiltration, and the correlation between cancer stem cells (CSCs) and COL15A1 expression. The outcome implies that most tumors had a high expression of COL15A1, and COL15A1 manifested different relationships with prognosis in different tumors, including both positive and negative correlations. COL15A1 was also found to have a significant correlation with MSI, TMB, and immune infiltrating cells. Our study suggests that COL15A1 may serve as a prognostic marker for malignancy because of its differential expression in tissues and their function in tumor immunity.

Differential impact of intratumor heterogeneity (ITH) on survival outcomes in early-stage lung squamous and adenocarcinoma based on tumor mutational burden (TMB).

Background: Molecular biomarkers are reshaping patient stratification and treatment decisions, yet their precise use and best implementation remain uncertain. Intratumor heterogeneity (ITH), an area of increasing research interest with prognostic value across various conditions, lacks defined clinical relevance in certain non-small cell lung cancer (NSCLC) subtypes. Exploring the relationship between ITH and tumor mutational burden (TMB) is crucial, as their interplay might reveal distinct patient subgroups. This study evaluates how the ITH-TMB dynamic affects prognosis across the two main histological subtypes of NSCLC, squamous cell and adenocarcinoma, with a specific focus on early-stage cases to address their highly unmet clinical needs. Methods: We stratify a cohort of 741 early-stage NSCLC patients from The Cancer Genome Atlas (TCGA) based on ITH and TMB and evaluate differences in clinical outcomes. Additionally, we compare driver mutations and the tumor microenvironment (TME) between high and low ITH groups. Results: In lung squamous cell carcinoma (LUSC), high ITH predicts an extended progression-free survival (PFS) (median: 21 vs. 14 months, P=0.01), while in lung adenocarcinoma (LUAD), high ITH predicts a reduced PFS (median: 15 vs. 20 months, P=0.04). This relationship is driven by the low TMB subset of patients. Additionally, we found that CD8 T cells were enriched in better-performing subgroups, regardless of histologic subtype or ITH status. Conclusions: There are significant differences in clinical outcomes, driver mutations, and the TME between high and low ITH groups among early-stage NSCLC patients. These differences may have treatment implications, necessitating further validation in other NSCLC datasets.

Target-Driven Tissue-Agnostic Drug Approvals-A New Path of Drug Development.

The regulatory approvals of tumor-agnostic therapies have led to the re-evaluation of the drug development process. The conventional models of drug development are histology-based. On the other hand, the tumor-agnostic drug development of a new drug (or combination) focuses on targeting a common genomic biomarker in multiple cancers, regardless of histology. The basket-like clinical trials with multiple cohorts allow clinicians to evaluate pan-cancer efficacy and toxicity. There are currently eight tumor agnostic approvals granted by the Food and Drug Administration (FDA). This includes two immune checkpoint inhibitors, and five targeted therapy agents. Pembrolizumab is an anti-programmed cell death protein-1 (PD-1) antibody that was the first FDA-approved tumor-agnostic treatment for unresectable or metastatic microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) solid tumors in 2017. It was later approved for tumor mutational burden-high (TMB-H) solid tumors, although the TMB cut-off used is still debated. Subsequently, in 2021, another anti-PD-1 antibody, dostarlimab, was also approved for dMMR solid tumors in the refractory setting. Patients with fusion-positive cancers are typically difficult to treat due to their rare prevalence and distribution. Gene rearrangements or fusions are present in a variety of tumors. Neurotrophic tyrosine kinase (NTRK) fusions are present in a range of pediatric and adult solid tumors in varying frequency. Larotrectinib and entrectinib were approved for neurotrophic tyrosine kinase (NTRK) fusion-positive cancers. Similarly, selpercatinib was approved for rearranged during transfection (RET) fusion-positive solid tumors. The FDA approved the first combination therapy of dabrafenib, a B-Raf proto-oncogene serine/threonine kinase (BRAF) inhibitor, plus trametinib, a mitogen-activated protein kinase (MEK) inhibitor for patients 6 months or older with unresectable or metastatic tumors (except colorectal cancer) carrying a BRAFV600E mutation. The most recent FDA tumor-agnostic approval is of fam-trastuzumab deruxtecan-nxki (T-Dxd) for HER2-positive solid tumors. It is important to identify and expeditiously develop drugs that have the potential to provide clinical benefit across tumor types.

Case report: Immunotherapy guided by molecular profiling of tumors: illustrative cases and literature review.

Predictive biomarkers are necessary for the identification of immunotherapy-responsive patients. Tumor mutation burden (TMB), as determined by next-generation sequencing (NGS), and PD-L1 expression, as evaluated by Immunohistochemistry (IHC), are the biomarkers most frequently employed in clinical practice. In addition, microsatellite instability (MSI) was the first biomarker to demonstrate immunotherapy efficacy irrespective of the type of tumor and possesses a high predictive value. However, its limited use across most tumor types limits its therapeutic potential. This report describes two cancer patients with positive TMB and PD-L1 expression. The molecular profile of the tumor indicated that the first patient was responsive to Immune checkpoint inhibitors (ICI), while the second patient was resistant. These case studies demonstrate that tumor molecular analysis in combination with immunotherapy predictive biomarkers, such as PD-L1 expression and TMB, can enhance the prediction of response to ICI for specific patients. This methodology enables an individualized and improved approach to the treatment and management of the disease.

Higher tumor mutational burden is associated with inferior outcomes among pediatric patients with neuroblastoma.

INTRODUCTION: Neuroblastoma is a pediatric malignancy with heterogeneous clinical outcomes. Our aim was to identify prognostic genetic markers for patients with neuroblastoma, who were treated with the Taiwan Pediatric Oncology Group (TPOG) neuroblastoma N2002 protocol, to improve risk stratification and inform treatment. METHODS: Our analysis was based on 53 primary neuroblastoma specimens, diagnosed pre-chemotherapy, and 11 paired tumor relapse specimens. Deep sequencing of 113 target genes was performed using a custom panel. Multiplex ligation-dependent probe amplification was performed to identify clinical outcomes related to copy-number variations. RESULTS: We identified 128 variations associated with survival, with the number of variations being higher in the relapse than that in the diagnostic specimen (p = .03). The risk of event and mortality was higher among patients with a tumor mutational burden ≥10 than that in patients with a lower burden (p < .0001). Multivariate analysis identified tumor mutational burden, MYCN amplification, and chromosome 3p deletion as significant prognostic factors, independent of age at diagnosis, sex, and tumor stage. The 5-year event-free survival and overall survival rate was lower among patients with high tumor burden than in patients with low tumor burden. Furthermore, there was no survival of patients with an ALK F1147L variation at 5 years after diagnosis. CONCLUSIONS: Genome sequencing to determine the tumor mutational burden and ALK variations can improve the risk classification of neuroblastoma and inform treatment.

Case report: Precision guided reactive cancer management: molecular complete response in heavily pretreated metastatic CRC by dual immunotherapy and sorafenib.

Background: Metastatic colon adenocarcinoma presents significant challenges in treatment, particularly when resistant to standard therapies. Precision oncology, guided by multidisciplinary tumor boards (MTBs), offers a promising way for individualized therapeutic approaches. Integration of comprehensive genomic profiling (CGP) and minimal residual disease (MRD) testing strengthens treatment decision-making, yet challenges persist in identifying and overcoming resistance mechanisms. FLT3 amplification can be one of those resistance/escape mechanisms that needs to be targeted. Case presentation: This case report presents a 58-year-old male diagnosed with metastatic colon adenocarcinoma with liver metastasis, resistant to conventional treatments. Utilizing CGP and MRD testing, our multidisciplinary MTB identified a complex mutational profile, including APC, DAXX, TP53 mutations, and CDK8 and FLT3 amplifications. With a tumor mutational burden of 10 muts/mb and TPS, CPS scores of 0, immunotherapy was considered, employing dual immune checkpoint inhibitors alongside mebendazole and Lenvatinib targeting the WNT and VEGF/angiogenesis pathways. MRD testing revealed early treatment failure. Re-evaluation identified high copied FLT3 amplification (62 copies) as a resistance mechanism, prompting modification to incorporate sorafenib and dual immunotherapy with mebendazole. Subsequent MRD assessments and radiological scans demonstrated a remarkable therapeutic response, with sustained efficacy and absence of detectable residual disease. Conclusion: This case highlights the successful application of precision oncology principles, facilitated by dynamic MTB-guided treatment strategies. Integration of MRD testing provided early detection of treatment inefficacy, allowing for timely intervention and adaptation of the treatment plan. Additionally, the case highlights the educational value of rare molecular alterations, emphasizing continual learning and refinement of treatment approaches in precision oncology.

Synthesis, Structural Analysis, and Peroxidase-Mimicking Activity of AuPt Branched Nanoparticles.

Bimetallic nanomaterials have generated significant interest across diverse scientific disciplines, due to their unique and tunable properties arising from the synergistic combination of two distinct metallic elements. This study presents a novel approach for synthesizing branched gold-platinum nanoparticles by utilizing poly(allylamine hydrochloride) (PAH)-stabilized branched gold nanoparticles, with a localized surface plasmon resonance (LSPR) response of around 1000 nm, as a template for platinum deposition. This approach allows precise control over nanoparticle size, the LSPR band, and the branching degree at an ambient temperature, without the need for high temperatures or organic solvents. The resulting AuPt branched nanoparticles not only demonstrate optical activity but also enhanced catalytic properties. To evaluate their catalytic potential, we compared the enzymatic capabilities of gold and gold-platinum nanoparticles by examining their peroxidase-like activity in the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB). Our findings revealed that the incorporation of platinum onto the gold surface substantially enhanced the catalytic efficiency, highlighting the potential of these bimetallic nanoparticles in catalytic applications.

Modular probe-based colorimetric miRNA detection via polymerase/endonuclease assisted chain displacement.

Methods for sequence-specific microRNA (miRNA) analysis are crucial for miRNA research and guiding nursing strategies. We have devised a colorimetric technique for detecting miRNA using a dumbbell probe-based polymerase/endonuclease assisted chain displacement, along with silver ions (Ag+) aptamer assisted color reaction. The suggested approach enables precise measurement of miRNA-21 within the concentration range of 100 fM-5 nM, with a low detection limit of 45.32 fM. Additionally, it exhibits exceptional capability in distinguishing variations at the level of individual nucleotides. Furthermore, the detection technique may be utilized to precisely measure the amount of miRNA-21 in serum samples, demonstrating a high level of concordance with the findings obtained from a commercially available miRNA detection kit.

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Frameshift Mutations in Leukemia-Associated Genes Correlate With Superior Outcomes in Patients Undergoing Allogeneic Stem Cell Transplant for De Novo Acute Myeloid Leukemia.

Background: Allogeneic stem cell transplant (allo-SCT) is a mainstay of treatment for acute myeloid leukemia (AML). Its success depends largely on response of donor T lymphocytes against leukemia cells, known as graft-vs-leukemia (GvL) effect. A key potential driver of GvL is immune response to mutation-derived neoantigens. Previous studies in solid tumors have demonstrated enhanced immunogenicity of frameshift (FS)-derived peptides vs. those from non-synonymous single nucleotide variants (SNVs). We therefore hypothesized that AML cases bearing FS mutations in leukemia-associated genes would be more immunogenic than those with only other types of mutations (non-FS), and thus benefit more from allo-SCT via more robust GvL. Methods: We identified AML patients who had undergone allo-SCT between 2010 and 2022 and had next-generation sequencing data available on diagnostic specimens using a 42-gene hot spot panel. We compared the impact of tumor mutations present at diagnosis on overall survival and relapse-free survival based on FS versus non-FS status. Results: Ninety-five AML allo-SCT patients were identified. We observed superior relapse-free survival (P = 0.038, hazard ratio (HR): 0.24) and borderline superior overall survival (P = 0.058, HR: 0.55) post-transplant in de novo AML patients, who had at least one FS mutation (other than NPM1) in one of the 42 assessed genes versus those with only non-FS mutations. Conclusions: Our findings suggest that FS-mutated AML cases may benefit more from allo-SCT than those with only non-FS mutations, possibly due to increased generation of immunogenic neoepitopes. If validated in an expanded study, incorporation of somatic FS mutation status in AML could improve patient selection algorithms for bone marrow transplant and thereby lead to superior outcomes.

MYBL2 is a Novel Independent Prognostic Biomarker and Correlated with TMB in pancreatic cancer.

Background: Pancreatic cancer continues to pose a significant threat due to its high mortality rate. While MYB family genes have been identified as oncogenes in certain cancer types, their role in pancreatic cancer remains largely unexplored. Methods: The mRNA and protein expression of MYB family genes in pancreatic cancer samples was analyzed using TNMplot, HPA, and TISBID online bioinformatics tools, sourced from the TCGA and GETx databases. The relationship between MYB family gene expression and survival time was assessed through Kaplan-Meier analysis, while the prognostic impact of MYB family gene expression was evaluated using the Cox proportional hazards model. Additionally, Spearman's correlation analysis was employed to investigate the correlation between MYB family genes and TMB/MSI. Results: The integration of data from various databases demonstrated that all MYB family genes exhibited dysregulated expression in pancreatic cancer. However, only the expression of the MYBL2 gene displayed a notable association with the grade and stage of pancreatic cancer. Furthermore, the MYBL2 gene exhibited significant variations in both univariate and multivariate factor analyses.Subsequent functional analyses revealed a significant correlation between MYBL2 expression in pancreatic cancers and various biological processes, such as DNA replication, tumor proliferation, G2M checkpoint regulation, pyrimidine metabolism, and the P53 pathway. Additionally, a notable positive association was observed between MYBL2 expression and tumor mutational burden (TMB), a predictive indicator for response to PD1 antibody treatment. Conclusion: MYBL2 may be a double marker for independent diagnosis and PD1 antibody response prediction of pancreatic cancer patients.

Tumor mutation burden and FAT3 mutation influence long-term survival in surgically resected small cell lung cancer.

Background: Small cell lung cancer (SCLC) is highly malignant and has a higher risk of recurrence even in patients who undergo early surgery. However, a subgroup of patients survived for many years. So far, the factors that determine the long-term survivorship remain largely unknown. To determine the genetic characteristics of long-term survival (LTS) after surgery in SCLC, we performed comprehensive comparative genomic profiling and tumor mutation burden (TMB) analysis of resected tumor tissues from patients with LTS and short-term survival (STS) after surgery. Methods: The present study screened 11 patients from 52 patients with SCLC who underwent surgery at Zhejiang Cancer Hospital from April 2008 to December 2017. A total of six LTS patients (≥4 years) with stage IIB or IIIA SCLC and five STS patients (<2 years) with stage IA or IB SCLC were included in the study. The STS patients were used as a control. All the patients underwent resection without neoadjuvant therapy. We assessed the genomic profiles of the resected tumor tissues and calculated the TMB using next-generation sequencing. We then analyzed and compared the molecular characteristics between the LTS and STS groups. Results: Our data indicated that tumor tissues from patients with LTS harbor a high TMB. The median TMB for LTS patients was high (approximately 16.4 mutations/Mb), while that for STS patients was low (approximately 8.5 mutations/Mb). The median TMB of patients with LTS and STS showed a trend of significant difference (P=0.08). Gene alterations characterized the survival differences between the two groups. The FAT3 mutation was only found in the LTS group, and the P value determined by Fisher's exact test was 0.06. Conclusions: A high non-synonymous TMB and the FAT3 mutation could potentially influence LTS after SCLC resection. This study provides valuable information about the molecular differences between LTS and STS patients. Studies with larger sample sizes need to be conducted to confirm our findings in the future.

Oxidized 3,3',5,5'-tetramethylbenzidine nanobelts enhance colorimetric sensing of H2O2.

Herein, oxidized 3,3',5,5'-tetramethylbenzidine (oxTMB) nanobelts were developed to enhance the colorimetric and paper-based sensing of H2O2. It was found that the minor component of Fe2+ in Na2SO4 reagent could catalyze the oxidization of TMB by H2O2 into positively charged oxTMB, which was further assembled into dark blue oxTMB nanobelts via electrostatic interaction with SO42-. The extinction originating from the absorption and scattering of oxTMB nanobelts was utilized to quantitatively detect H2O2 with a wide linear detection range (1.0-300 µM) and a low limit of detection (0.48 µM). In addition, no coffee-ring effect was observed in the test zone of the paper-based colorimetric array, which was beneficial to judge the color by naked eye. Finally, the colorimetric method was applied to detect H2O2 in contact lens care solution. This work not only proposed a new colorimetric sensing platform for H2O2, but also highlighted the minor component in the reagent might influence the experimental result.

Fabrication of Highly Sensitive and Selective Nitrite Colorimetric Sensor Based on the Enhanced Peroxidase Mimetic Activity of Using Acetic Acid Capped Zinc Oxide Nanosheets.

Nitrite ions (NO2-), as one of the leading type-A inorganic-anion, showing significant-effects in the aquatic environment and also to humans health. Whereas, the higher uptake causes detrimental threat to human health leading to various chronic diseases, thus demanding efficient, reliable and convenient method for its monitoring. For this purpose, in the present research study we have fabricated the mimetic nonozyme like catalyst based colorimetric nitrite sensor. The acetic acid capped Zinc Oxide (ZnO) nanosheets (NSs) were introduce as per-oxidase mimetic like catalyst which shows high efficiency towards the oxidative catalysis of colorless tetramethylbenzidine (TMB) to oxidized-TMB (blue color) in the presence of Hydrogen-peroxide (H2O2). The present nitrite ions will stimulate the as formed oxidized-TMB (TMBox), and will caused diazotization reaction (diazotized-TMBox), which will not only decreases the peak intensity of UV-visible peak of TMBox at 652 nm but will also produces another peak at 446 nm called as diazotized-TMBox peak, proving the catalytic reaction between the nitrite ions and TMBox. Further, the prepared colorimetric sensor exhibits better sensitivity with a wider range of concentration (1 × 10-3-4.50 × 10-1 µM), lowest limit of detection (LOD) of 0.22 ± 0.05 nM and small limit of quantification (LOQ) 0.78 ± 0.05 nM having R2 value of 0.998. Further, the colorimetric sensor also manifest strong selectivity towards NO2- as compared to other interference in drinking water system. Resultantly, the prepared sensor with outstanding repeatability, stability, reproducibility, re-usability and its practicability in real water samples also exploit its diverse applications in food safety supervision and environmental monitoring.

Intrapatient variation in PD-L1 expression and tumor mutational burden and the impact on outcomes to immune checkpoint inhibitor therapy in patients with non-small-cell lung cancer.

BACKGROUND: Programmed death receptor ligand 1 (PD-L1) tumor proportion score (TPS) and tumor mutational burden (TMB) are key predictive biomarkers for immune checkpoint inhibitor (ICI) efficacy in non-small-cell lung cancer (NSCLC). Data on their variation across multiple samples are limited. PATIENTS AND METHODS: Patients with NSCLC and multiple PD-L1 TPS and/or TMB assessments were included. Clinicopathologic and genomic data were analyzed according to PD-L1 and TMB variation. RESULTS: In total, 402 PD-L1 sample pairs and 413 TMB sample pairs were included. Concordance between pairs was moderate for PD-L1 (ρ = 0.53, P < 0.0001) and high for TMB (ρ = 0.80, P < 0.0001). Shorter time between biopsies correlated with higher concordance in PD-L1, but not in TMB. Major increases (ΔTPS ≥ +50%) and decreases (ΔTPS ≤ -50%) in PD-L1 were observed in 9.7% and 8.0% of cases, respectively. PD-L1, but not TMB, decreased with intervening ICI (P = 0.02). Acquired copy number loss of CD274, PDCD1LG2, and JAK2 were associated with major decrease in PD-L1 (q < 0.05). Among patients with multiple PD-L1 assessments before ICI, cases where all samples had a PD-L1 ≥1%, compared to cases with at least one sample with PD-L1 <1% and another with PD-L1 ≥1%, achieved improved objective response rate and progression-free survival (PFS). Among patients with at least one PD-L1 <1% and one ≥1% before ICI, cases where the most proximal sample was PD-L1 ≥1% had longer median PFS compared to cases where the most proximal PD-L1 was <1%. Among patients with multiple TMB assessments before ICI, patients with a TMB ≥10 mut/Mb based on the most recent assessment, as compared to those with a TMB <10 mut/Mb, achieved improved PFS and overall survival to ICI; instead, no differences were observed when patients were categorized using the oldest TMB assessment. CONCLUSIONS: Despite intrapatient concordance in PD-L1 and TMB, variation in these biomarkers can influence ICI outcomes, warranting consideration for reassessment before ICI initiation when feasible.

Pembrolizumab with external radiation therapy effectively controlled TMB-high unresectable recurrent parathyroid cancer: a case report with review of literature.

Parathyroid cancer (PC) is extremely resistant to chemotherapy and radiotherapy (RT), but hormonally functional by producing excessive parathyroid hormone (PTH), causing remarkable hypercalcemia even in biochemical disease recurrence. Accordingly, management of hypercalcemia by calcimimetics and bisphosphonates has been main treatment for unresectable PC. Here, we report a case of unresectable tumor mutational burden (TMB)-high recurrent PC that has been effectively controlled by pembrolizumab (PEM) with RT. A 48-year-old male patient, with previous history of left single parathyroidectomy for primary hyperparathyroidism, underwent surgeries for recurrent hyperparathyroidism at 47 and 48 years of age, and was pathologically diagnosed with PC. He was referred to our hospital due to persistent hypercalcemia and elevated PTH. The recurrent tumors were identified in the superior mediastinum and radically resected, then the hyperparathyroidism was improved. A FoundationOne® CDx of the specimen called TMB-high. He demonstrated recurrent hyperparathyroidism at 49 years of age, and underwent a gross curative resection. However, hyperparathyroidism achieved only insufficient improvement, indicating biochemical residual cancer cells. PEM treatment was initiated in combination with RT to the left central-lateral neck and superior mediastinum. He successfully achieved evocalcet and zoledronate withdrawal, and the PTH level improvement was continuously observed for 8 months at present, with only grade 2 subclinical hypothyroidism. Interestingly, leukocyte fraction ratios were reversed corresponding to disease improvement. A combination of PEM and RT is a promising treatment of unresectable TMB-high PC. Recent evidence on the immunomodulatory effect of RT provides the rationale for the combination of RT and PEM.

Somatic CpG hypermutation is associated with mismatch repair deficiency in cancer.

Somatic hypermutation in cancer has gained momentum with the increased use of tumour mutation burden as a biomarker for immune checkpoint inhibitors. Spontaneous deamination of 5-methylcytosine to thymine at CpG dinucleotides is one of the most ubiquitous endogenous mutational processes in normal and cancer cells. Here, we performed a systematic investigation of somatic CpG hypermutation at a pan-cancer level. We studied 30,191 cancer patients and 103 cancer types and developed an algorithm to identify somatic CpG hypermutation. Across cancer types, we observed the highest prevalence in paediatric leukaemia (3.5%), paediatric high-grade glioma (1.7%), and colorectal cancer (1%). We discovered germline variants and somatic mutations in the mismatch repair complex MutSα (MSH2-MSH6) as genetic drivers of somatic CpG hypermutation in cancer, which frequently converged on CpG sites and TP53 driver mutations. We further observe an association between somatic CpG hypermutation and response to immune checkpoint inhibitors. Overall, our study identified novel cancer types that display somatic CpG hypermutation, strong association with MutSα-deficiency, and potential utility in cancer immunotherapy.

Raspberry-shaped ZIF-8/Au nanozymes with excellent peroxidase-like activity for simple and visual detection of glutathione.

Artificial enzymes with high stability, adjustable catalytic activity, controllable preparation, and good reproducibility have been widely studied. Noble metal nanozymes, particularly gold nanoparticles (Au NPs), exhibit good catalytic activity, but their stability is poor. In this study, zeolitic imidazolate framework-8 (ZIF-8) was used as a carrier for Au NPs, thus improving the utilization efficiency and conservation stability of the nanozymes. A ZIF-8/Au nanocomposite with peroxidase activity and a raspberry-shaped structure was synthesized. In the assay, ZIF-8/Au catalyzed the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) to a blue product oxidized TMB (oxTMB). Glutathione (GSH) selectively inhibited this reaction, with a detection limit of 0.28 µM and linear range of 0.5-60 µM. Using the photo and chromaticity analysis functions, we developed a portable analysis method using a smartphone equipped with a camera module as a detection terminal for a wide range of rapid screening techniques for GSH. Preparation of raspberry-shaped ZIF-8/Au improved the catalytic activity of Au NPs and good results were demonstrated in serum, which suggests their promising application under physiological conditions.

The potent potential of MFAP2 in prognosis and immunotherapy of triple-negative breast cancer.

BACKGROUNDS: Microfibril-associated protein 2 (MFAP2) is a protein presenting in the extracellular matrix that governs the activity of microfibrils through its interaction with fibrillin. While the involvement of MFAP2 in metabolic disorders has been documented, its expression and prognostic significance in triple-negative breast cancer (TNBC) remain unexplored. METHODS: We acquired datasets pertaining to breast cancer (BC) from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Next, a Venn diagram was used to identify the differentially expressed genes (DEGs). The DEGs were used to perform Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), protein-protein interaction (PPI), immune and survival analysis. The expressions of MFAP2, PD-1 and PD-L1 were examined by immunohistochemistry and western blot and their relationship with clinical pathological parameters were analyzed by clinical specimen samples from patients with TNBC. Tumor Immune Estimation Resource (TIMER, https://cistrome.shinyapps.io/timer/ ) was adopted to calculate the immune infiltration level of TNBC. The link between gene expression and tumor mutational burden (TMB) was described using Spearman's correlation analysis. RESULTS: We identified 66 differentially expressed genes (DEGs) that were up-regulated. Among these DEGs, MFAP2 was found to be overexpressed in TNBC and was associated with a lower probability of survival. This finding was confirmed through the use of immunohistochemistry and western blot techniques. Additionally, MFAP2 was found to be related to various pathological parameters in TNBC patients. Mechanistically, gene set enrichment analysis (GSEA) revealed that MFAP2 primarily influenced cellular biological behavior in terms of epithelial mesenchymal transition, glycolysis, and apical junction. Notably, MFAP2 expression was positively correlated with the abundance of macrophages, while a negative correlation was observed with the abundance of B cells, CD4 + T cells, CD8 + T cells, neutrophils and dendritic cells through immune analysis. Furthermore, it was observed that MFAP2 displayed a negative correlation not only with tumor mutational burden (TMB), a recognized biomarker for PD-1/PD-L1 immunotherapy, but also with PD-L1 in samples of TNBC. CONCLUSION: MFAP2 may be an important prognostic biomarker for TNBC, as well as a viable target for immunotherapy in this disease.