Clinical evidence for efficacy of pembrolizumab in MSI-H and TMB-H advanced solid tumor: results from three cancer centers in China.

BACKGROUND: Pembrolizumab has been indicated in the treatment of solid tumors with high frequency microsatellite instability (MSI-H) or high tumor mutational burden (TMB-H); however, real-world data on the effectiveness of pembrolizumab with or without chemotherapy in this molecular subset remain limited. Our retrospective study evaluated the clinical efficacy and safety of pembrolizumab in treating advanced solid tumors with either MSI-H or TMB-H. METHODS: This retrospective study analyzed data from 116 patients with MSI-H or TMB-H advanced solid cancers who received pembrolizumab with or without chemotherapy regardless of treatment setting. We analyzed objective response rate (ORR) and progression-free survival (PFS). RESULTS: The top three cancer types were colorectal (48.6% MSI-H, 6.5% TMB-H), lung (15.4% MSI-H, 84.4% TMB-H), and gastric (15.4% MSI-H, 5.1% TMB-H). The ORR with pembrolizumab was 52.6%, including complete response (CR) observed in 8.6% (n = 10) of cases and partial responses (PR) in 43.9% (n = 51). Of the 93 patients who received first-line pembrolizumab, 52 patients achieved objective response (10 CR, 42 PR), with a median PFS of 14.0 months (95% confidence intervals [CI] 6.6-21.4). Of the 23 who received subsequent-line pembrolizumab, the ORR was 39.1%, disease control rate was 91.3%, and median PFS was 5.7 months (95% CI 3.9-7.5). Treatment-related adverse events were observed in 32 patients (27.6%), with no reported treatment-related fatal adverse events. CONCLUSION: Our study provides real-world evidence on the clinical effectiveness of pembrolizumab with or without chemotherapy in the treatment of patients with MSI-H and TMB-H advanced solid cancers.

First-in-human phase I study of BEBT-109 in previously treated EGFR exon 20 insertion-mutated advanced non-small cell lung cancer.

BACKGROUND: BEBT-109 is an oral pan-mutant-selective inhibitor of epidermal growth factor receptor (EGFR) that demonstrated promising antitumor potency in preclinical models. METHODS: This first-in-human study was a single-arm, open-label, two-stage study. Phase Ia dose-escalation study evaluated the safety and pharmacokinetics of BEBT-109 in 11 patients with EGFR T790M-mutated advanced non-small cell lung cancer (aNSCLC). Phase Ib dose-expansion study evaluated the safety and efficacy of BEBT-109 in 18 patients with EGFR exon 20 insertion (ex20ins)-mutated treatment-refractory aNSCLC. The primary outcomes were adverse events and antitumor activity. Clinical trial registration number CTR20192575. FINDINGS: The phase Ia study demonstrated no dose-limiting toxicity, no observation of the maximum tolerated dose, and no new safety signals with BEBT-109 in the dose range of 20-180 mg/d, suggesting that BEBT-109 had an acceptable safety profile among patients with EGFR T790M-mutated aNSCLC. Plasma pharmacokinetics of BEBT-109 showed a dose-proportional increase in the area under the curve and maximal concentration, with no significant drug accumulation. The dose-expansion study demonstrated that BEBT-109 treatment was tolerable across the three dose levels. The three most common treatment-related adverse events were diarrhea (100%; 22.2% ≥Grade 3), rash (66.7%; 5.6% ≥Grade 3), and anemia (61.1%; 0% ≥Grade 3). The objective response rate was 44.4% (8 of 18). Median progression-free survival was 8.0 months (95% confidence intervals, 1.33-14.67). CONCLUSION: Preliminary findings showed that BEBT-109 had an acceptable safety profile and favorable antitumor activity in patients with refractory EGFR ex20ins-mutated aNSCLC. FUNDING: National Natural Science Foundation of China.

A case report of the treatment and care of decubitus ulcers in macaques with spinal cord injury.

Decubitus ulcers are a common spinal cord injury (SCI) complication that puts patients' lives in danger and has emerged as a more prevalent issue in modern clinical rehabilitation and care. Decubitus ulcers in humans can currently be treated in a number of different ways, but there are fewer studies on how to treat and care for decubitus ulcers in macaques. To treat a 20-year-old adult male macaque monkey with SCI and decubitus ulcers after a quarter transection of the thoracic spinal cord, a number of scientific care procedures and pharmaceutical treatments, such as dietary changes and topical or intravenous administration of medication, were carried out and continuously monitored in real-time. In comparison to the untreated group, we observed a significant improvement in decubitus wound healing in the macaques. In this article, we provide a good protocol for decubitus ulcer care after SCI and suggest that future experimental animal modeling needs to focus on issues such as care for postoperative complications.

Development of an innovative minimally invasive primate spinal cord injury model: A case report.

Spinal cord injury (SCI) animal models have been widely created and utilized for repair therapy research, but more suitable experimental animals and accurate modeling methodologies are required to achieve the desired results. In this experiment, we constructed an innovative dorsal 1/4 spinal cord transection macaque model that had fewer severe problems, facilitating postoperative care and recovery. In essence, given that monkeys and humans share similar genetics and physiology, the efficacy of this strategy in a nonhuman primate SCI model basically serves as a good basis for its prospective therapeutic use in human SCI.

Stratification of patients with KRAS-mutated advanced non-small cell lung cancer: improving prognostics.

INTRODUCTION: KRAS is the most frequently mutated oncogene in cancer and encodes a key signaling protein in tumors. Due to its high affinity for GTP and the lack of a large binding pocket that allosteric inhibitors can occupy, KRAS has long been considered 'non-druggable.' Finding effective treatment measures for patients with KRAS mutations is our top priority. AREAS COVERED: In this article, we will provide an overview of the KRAS pathway and review the current state of therapeutic strategies for targeting oncogenic KRAS, as well as their potential to improve outcomes in patients with KRAS-mutant malignancies. We will also discuss the development of these strategies and gave an outlook on prospects. EXPERT OPINION: KRAS mutations have posed a significant challenge in the treatment of advanced non-small cell lung cancer (NSCLC) over the past few decades. However, the emergence of immunotherapy and KRAS inhibitors, such as Sotorasib (AMG 510) and Adagrasib (MRTX849), has marked a new era in cancer therapy. As more research and clinical trials continue, we anticipate the development of more effective treatment strategies and better options for lung cancer patients.

Dynamic cytokines signature predicts survival outcome from severe Immune-related hepatitis with PD-1/PD-L1 blockade in lung cancer.

BACKGROUND: Immune-related adverse events (irAEs), particularly immune-related hepatitis (IRH) is a potentially serious complication of immune checkpoint inhibitor (ICI) therapy. This retrospective cohort study investigated potential prognostic and predictive biomarkers for IRH. METHOD: This study included 37 patients with advanced lung cancer who received ICIs and were divided into two groups: ≥Grade 3 (G3)-IRH group (n = 17) and without irAE (no-irAE) group (n = 20). Blood samples collected at three different time points and pre-treatment tumor biopsy samples were analyzed using multi-omics assays. RESULTS: The IL-1B RNA expression was significantly increased (limma, fold = 1.94) in the ≥ G3-IRH group than the no-irAE group. Compared with no-irAE group, ≥G3-IRH group had higher monocyte and eosinophil infiltration and lower macrophage infiltration, particularly macrophage M2. Transcriptomics analyses of pre-treatment tumor samples revealed significant upregulation of various inflammation-related genes in the ≥ G3-IRH group (False discovery rate < 0.05). Moreover, various proinflammatory cytokines and chemokines were significantly lower in the plasma of the ≥ G3-IRH group than in the no-irAE group. Subgroup analyses of the ≥ G3-IRH group revealed that plasma IL-1A was significantly higher among those whose IRH resolved than those who had IRH-related death. Patients who died had a greater increase in immune score and Euclidean distance from the baseline to the seventh day of IRH onset, with a dramatic increase in Euclidean distance after immunosuppression, suggesting overstimulated immune status. CONCLUSION: Our study demonstrated the association between IL-1B overexpression and IRH susceptibility. Immune score and Euclidean distance of inflammatory cytokines may provide predictive value on the survival outcome from ≥ G3 IRH.

Clinical activity of pembrolizumab with or without chemotherapy in advanced pulmonary large-cell and large-cell neuroendocrine carcinomas: a multicenter retrospective cohort study.

BACKGROUND: Immune checkpoint inhibitors (ICI)-based combination strategies have improved the survival outcomes in advanced non-small cell lung cancers; however, data regarding their efficacy remains limited for uncommon histological types, including large-cell carcinoma (LCC) and large-cell neuroendocrine carcinoma (LCNEC). METHODS: We retrospectively analyzed a total of 60 patients with advanced LCC and LCNEC - 37 treatment-naïve and 23 pre-treated - who received pembrolizumab with or without chemotherapy. Treatment and survival outcomes were analyzed. RESULTS: Of the 37 treatment-naïve patients who received first-line pembrolizumab combined with chemotherapy, the 27 patients with LCC had an overall response rate (ORR) of 44.4% (12/27) and a disease control rate (DCR) of 88.9% (24/27); whereas 10 patients with LCNEC had an ORR of 70% (7/10) and DCR of 90% (9/10). The median progression-free survival (mPFS) was 7.0 months (95% confidence intervals [CI]: 2.2-11.8) and median overall survival (mOS) was 24.0 months (95%CI: 0.0-50.1) for first-line pembrolizumab plus chemotherapy of LCC (n = 27), whereas mPFS was 5.5 months (95%CI: 2.3-8.7) and mOS was 13.0 months (95%CI: 11.0-15.0) for first-line pembrolizumab plus chemotherapy of LCNEC (n = 10). Of the 23 pre-treated patients who received subsequent-line pembrolizumab with or without chemotherapy, mPFS was 2.0 months (95% CI: 0.6-3.4) and mOS was 4.5 months (95% CI: 0.0-9.0) for LCC and mPFS was 3.8 months (95% CI: 0.0-7.6) and mOS was not reached for LCNEC. CONCLUSION: Our study provides real-world clinical evidence of the anti-tumor activity of pembrolizumab plus chemotherapy in advanced LCC and LCNEC, indicating that this regimen could serve as a treatment option, particularly as first-line therapy, for improving the survival outcomes of patients with these rare histological subtypes of lung cancer. TRIAL REGISTRATION: NCT05023837(ESPORTA, 27/08/2021).

Efficacy of Immune Checkpoint Inhibitor Plus Chemotherapy in Patients With ROS1-Rearranged Advanced Lung Adenocarcinoma: A Multicenter, Retrospective Cohort Study.

PURPOSE: Immune checkpoint inhibitors (ICIs) exert robust antitumor activity in non-small-cell lung cancer (NSCLC) without actionable mutations. Apart from isolated case reports, the efficacy of PD-1 blockade in ROS1-rearranged NSCLC is currently unknown. METHODS: This retrospective cohort study included 23 patients with ROS1-rearranged advanced lung adenocarcinoma who received ICI plus chemotherapy regardless of the treatment setting. ICI plus chemotherapy was received as a later-line regimen by 14 patients, as the first-line regimen by six patients, and after chemoradiotherapy by three patients. RESULTS: All three patients who received chemoradiotherapy followed by ICI plus chemotherapy achieved partial response (PR) and had a progression-free survival (PFS) of >17.9 months. Of the six patients who received first-line ICI plus chemotherapy, five patients achieved PR and one had stable disease (SD), with a median PFS of 24.3 months (95% CI, 4.9 to 43.7). Of the 14 previously treated patients who received later-line ICI plus chemotherapy, the Objective Response Rate (ORR) was 28.6%, the Disease Control Rate (DCR) was 92.9%, and the median PFS was 5.8 months (95% CI, 0.2 to 9.4). The median time on ICI therapy was 10.0 months (95% CI, 1.5 to 32.5). The duration of response was 24.3 months (95% CI, 5.4 to 43.2) and 4.8 months (95% CI, 2.3 to 12.7) for first-line (n = 5) and subsequent-line (n = 4) ICI plus chemotherapy, respectively. Of the 10 patients with brain metastasis before receiving ICI plus chemotherapy, four patients achieved intracranial PR and five patients achieved intracranial SD, achieving an intracranial ORR of 40.0% and an intracranial DCR of 90.0%. CONCLUSION: Our retrospective study provides real-world clinical evidence that ROS1-rearranged NSCLCs benefit from ICI plus chemotherapy in any treatment setting, including patients who present with brain metastasis.

DNA methylation: The epigenetic mechanism of Alzheimer's disease.

Nowadays, with the development of the social health care system, there is an increasing trend towards an aging society. The incidence of Alzheimer's disease (AD) is also on the rise. AD is a kind of neurodegenerative disease that can be found in any age group. For years, scientists have been committing to discovering the cause of AD. DNA methylation is one of the most common epigenetic mechanisms in mammals and plays a vital role in the pathogenesis of several diseases, including tumors. Studying chemical changes in the epigenome, or DNA methylation can help us understand the effects of our environment and life on diseases, such as smoking, depression, and menopause, which may affect people's chances of developing Alzheimer's or other diseases. Recent studies have identified some crucial genes like ANK1, RHBDF2, ABCA7, and BIN1, linking DNA methylation to AD. This review focuses on elucidating the relationship between DNA methylation and the pathogenesis of AD and provides an outlook on possible targeted therapeutic modalities.

Advances in the study of the relationship between Alzheimer's disease and the gastrointestinal microbiome.

There are many trillions of bacteria in the gastrointestinal microbiome (GM). Their ecological dysregulation can contribute to the development of certain neurodegenerative diseases, including Alzheimer's disease (AD). AD is common dementia and its incidence is increasing year by year. However, the relationship between GM and AD is unclear. Therefore, this review discusses the relationship between GM and AD, elaborates on the possible factors that can affect this relationship through the inflammation of the brain induced by blood-brain damage and accumulation of amyloid deposit, and proposes feasible ways to treat AD through GM-related substances, such as probiotics, Mega-3, and gut hormones, including their shortcomings as well.

Protective effect of isoflurane preconditioning on neurological function in rats with HIE.

Hypoxic-ischemic encephalopathy (HIE) is an important cause of neonatal death and disability, which can lead to long-term neurological and motor dysfunction. Currently, inhalation anesthetics are widely used in surgery, and some studies have found that isoflurane (ISO) may have a positive effect on neuroprotection. In this paper, we investigated whether ISO pretreatment has a neuroprotective effect on the neurological function of HIE rats. Here, 7-day-old neonatal rats were randomly divided into a sham group, a hypoxic-ischemic (HI) group, and an ISO pretreatment (pretreatment) group. The pretreatment group was pretreated with 2% ISO for 1 h, followed by the HI group to establish an HI animal model. The HI­induced neurological injury was evaluated by Zea­Longa scores and triphenyltetrazolium (TTC) staining. Neuronal number and histomorphological changes were observed with Nissl staining and Hematoxylin-eosin (HE) staining. In addition, motor learning memory function was evaluated by the Morris water maze (MWM), the Y-maze, and the rotarod tests. HI induced severe neurological dysfunction, brain infarction, and cell apoptosis as well as obvious neuron loss in neonatal rats. In the MWM, the rats in the pretreatment group showed a decrease in escape latency (p = 0.042), indicating that pretreatment with ISO could improve the learning ability of HI rats. The results of Nissl staining showed that in the HI group, there was an irregular arrangement of neurons and nuclear fixation; however, the cell damage was significantly reduced and the total number of neurons was increased after ISO pretreatment (p < 0.001). In conclusion, ISO pretreatment improved cognitive function and attenuated HI-induced reduction of Nissl-positive cells and spatial memory impairment, suggesting that pretreatment with ISO before HI modeling could reduce neuronal cell death in the hippocampus after HI.

Spying on the Polarity Dynamics during Wound Healing of Zebrafish by Using Rationally Designed Carbon Dots.

Wound healing is an essential and complex biological process. Research into its mechanism and factors that influence its effectiveness has led to better treatments. Changes in the microenvironment are demonstrated to affect wound healing. Cell polarity is a significant microenvironment-related parameter that is associated with many physiological and pathological activities. However, dynamic changes in polarity during wound healing have not been investigated. Monitoring cell polarity during wound healing may open up a new avenue for developing better treatments. Here, a method is developed to monitor cell polarity that involved taking advantage of the fascinating optical properties and biocompatibility of carbon dots (CDs). Specifically, near-infrared (NIR) polarity-sensitive N-phenyl-p-phenylenediamine (PPh-CDs) are successfully prepared, which exhibit high sensitivity to polarity, with 509-fold stronger fluorescence in dioxane than in water. The PPh-CDs are successfully applied to monitor the changes of lysosomal polarity during starvation conditions. Using this method, dynamic changes of polarity during wound healing of zebrafish are monitored for the first time. Upon an amputation performed at the zebrafish tail, stronger PPh-CDs fluorescence appeared at the wound sites, and the intensity increased for 25 min and then gradually decreased. This report provides an important experimental basis for investigating wound healing by employing polarity-sensitive CDs.

Rational Design of Far-Red to Near-Infrared Emitting Carbon Dots for Ultrafast Lysosomal Polarity Imaging.

Carbon dots (CDs) have been widely studied for their excellent properties. However, most of the prepared CDs only show strong emission in the blue to green region, which greatly limits the application of CDs in the biomedical field. In this report, a new design strategy of long-wavelength CDs was reported. The orange phenyl-CDs with good optical properties and biocompatibility were successfully prepared by changing the substituted group of the o-phenylenediamine and the main emission band of phenyl-CDs was in the far-red region. With the increase of polarity, the wavelength of phenyl-CDs red-shifts and the fluorescence intensity decreases, demonstrating their sensitive polarity response function. In addition, phenyl-CDs can achieve ultrafast target imaging of lysosome within 40 s through clathrin-mediated endocytosis. Finally, phenyl-CDs were successfully applied for monitoring lysosomal polarity induced by drugs, which is helpful in getting a better understanding of the physiological and pathological processes of lysosomes. This report provides an important theoretical basis for the rational design and precise synthesis of long-wavelength fluorescent CDs.

A wash-free lysosome targeting carbon dots for ultrafast imaging and monitoring cell apoptosis status.

In this work, a novel bright yellow fluorescent carbon dots (CDs) was synthesized from N-methyl-1,2-phenylenediamine hydrochloride in ethanol solvent through the solvothermal method. The obtained carbon dots had no fluorescence in water, but could specifically light up in the cell which makes the staining process without washing. Interestingly, the imaging process can be performed by simply shaking the culture with the cells for only 1 min, indicating ultrafast and easy to operate fluorescence imaging. Moreover, the carbon dots with abundant amino functional groups had good lysosome targeting properties (the Pearson's correlation coefficient is 0.92) and could achieve the ultrafast lysosome imaging in cell and zebrafish and monitoring cell apoptosis status. This is the first lysosome targeting carbon dots that allows the combination of a short incubation at the second-level with wash-free process providing great potential for continuous observation lysosome in vivo.