Spotlight on the treatment of non-small cell lung cancer with rare genetic alterations and brain metastasis: Current status and future perspectives.

In patients with non-small cell lung cancer (NSCLC), oncogenic variants present in <5% of cases are considered rare, the predominant of which include human epidermal growth factor receptor 2 (HER2) mutations, mesenchymal-epithelial transition (MET) alterations, c-ros oncogene 1 (ROS1) rearrangements, rearrangement during transfection (RET) fusions, v-raf mouse sarcoma virus oncogene homolog B1 (BRAF) mutations, and neurotrophic troponin receptor kinase (NTRK) fusions. Brain metastases (BMs) occur in approximately 10%-50% of patients with NSCLC harboring rare genetic variants. The recent advent of small-molecule tyrosine kinase inhibitors and macromolecular antibody-drug conjugates (ADCs) has conferred marked survival benefits to patients with NSCLC harboring rare driver alterations. Despite effective brain lesion control for most targeted agents and promising reports of intracranial remission associated with novel ADCs, BM continues to be a major therapeutic challenge. This review discusses the recent advances in the treatment of NSCLC with rare genetic variants and BM, with a particular focus on intracranial efficacy, and explores future perspectives on how best to treat these patients.

Extensive-stage small-cell lung cancer: Current management and future directions.

Extensive-stage small-cell lung cancer (ES-SCLC) is regarded as a refractory carcinoma associated with extremely rapid disease progression. After more than three decades without clinical advances, research on immune checkpoint inhibitors (ICIs) combined with platinum-based chemotherapy has led to the first treatment breakthrough, establishing a new standard for the first-line treatment of ES-SCLC. Further studies have extensively evaluated small-molecule antiangiogenic drugs, PARP inhibitors, as well as lurbinectedin in SCLC and have demonstrated some benefit, although no breakthroughs have been made. In addition, newer therapeutic strategies with targeted agents, novel chemotherapeutics and immunotherapies are evolving as they are being actively explored and hold promise for patients with this disease. Notably, the preliminary identification of SCLC molecular subtypes driven by the expression of dominant transcription factors with RNA sequencing profiles has made it possible to identify molecularly tailored therapeutic approaches, which increases the potential for individualized precision treatment of SCLC. In this review, we summarize recent research advances in ES-SCLC, outline the current management of this disease and reflect on directions for future development.

Magnetic vagus nerve stimulation alleviates myocardial ischemia-reperfusion injury by the inhibition of pyroptosis through the M2AChR/OGDHL/ROS axis in rats.

BACKGROUND: Myocardial ischemia-reperfusion (I/R) injury is accompanied by an imbalance in the cardiac autonomic nervous system, characterized by over-activated sympathetic tone and reduced vagal nerve activity. In our preceding study, we pioneered the development of the magnetic vagus nerve stimulation (mVNS) system. This system showcased precise vagus nerve stimulation, demonstrating remarkable effectiveness and safety in treating myocardial infarction. However, it remains uncertain whether mVNS can mitigate myocardial I/R injury and its specific underlying mechanisms. In this study, we utilized a rat model of myocardial I/R injury to delve into the therapeutic potential of mVNS against this type of injury. RESULTS: Our findings revealed that mVNS treatment led to a reduction in myocardial infarct size, a decrease in ventricular fibrillation (VF) incidence and a curbing of inflammatory cytokine release. Mechanistically, mVNS demonstrated beneficial effects on myocardial I/R injury by inhibiting NLRP3-mediated pyroptosis through the M2AChR/OGDHL/ROS axis. CONCLUSIONS: Collectively, these outcomes highlight the promising potential of mVNS as a treatment strategy for myocardial I/R injury.

Human resource management research in healthcare: a big data bibliometric study.

Human resource management (HRM) in healthcare is an important component in relation to the quality and efficiency of healthcare delivery. However, a comprehensive overview is lacking to assess and track the current status and trends of HRM research in healthcare. This study aims to describe the current situation and global trends in HRM research in healthcare as well as to indicate the frontiers and future directions of research. The research methodology is based on bibliometric mapping using scientific visualization software (VOSviewer). The data were collected from the Web of Science(WoS) core citation database. After applying the search criteria, we retrieved 833 publications, which have steadily increased over the last 30 years. In addition, 93 countries and regions have published relevant research. The United States and Australia have made significant contributions in this area. Current research articles focus on topics clustered into performance, hospital/COVID-19, job satisfaction, human resource management, occupational/mental health, and quality of care. The most frequently co-occurring keywords are human resource management, job satisfaction, nurses, hospitals, health services, quality of care, COVID-19, and nursing. There is limited research on compensation management and employee relations management, so the current HRM research field still has not been able to present a complete and systematic roadmap. We propose that our colleagues should consider focusing on these research gaps in the future.

Development of a serum miRNA panel for detection of early stage non-small cell lung cancer.

Minimally invasive testing for early detection of lung cancer to improve patient survival is a major unmet clinical need. This study aimed to develop and validate a serum multi-microRNA (multimiR) panel as a minimally invasive test for early detection of nonsmall cell lung cancer (NSCLC) regardless of smoking status, gender, and ethnicity. Our study included 744 NSCLC cases and 944 matched controls, including smokers and nonsmokers, male and female, with Asian and Caucasian subjects. Using RT-qPCR and a tightly controlled workflow, we quantified the absolute expression of 520 circulating microRNAs (miRNAs) in a Chinese cohort of 180 early stage NSCLC cases and 216 healthy controls (male smokers). Candidate biomarkers were verified in two case-control cohorts of 432 Chinese and 218 Caucasians, respectively (including females and nonsmokers). A multimiR panel for NSCLC detection was developed using a twofold cross-validation and validated in three additional Asian cohorts comprising 642 subjects. We discovered 35 candidate miRNA biomarkers, verified 22 of them, and developed a five-miR panel that detected NSCLC with area under curve (AUC) of 0.936-0.984 in the discovery and verification cohorts. The panel was validated in three independent cohorts with AUCs of 0.973, 0.916, and 0.917. The sensitivity of five-miR test was 81.3% for all stages, 82.9% for stages I and II, and 83.0% for stage I NSCLC, when the specificity is at 90.7%. We developed a minimally invasive five-miR serum test for detecting early stage NSCLC and validated its performance in multiple patient cohorts independent of smoking status, gender, and ethnicity.

A molecular approach integrating genomic and DNA methylation profiling for tissue of origin identification in lung-specific cancer of unknown primary.

BACKGROUND: Determining the tissue of origin (TOO) is essential for managing cancer of unknown primary (CUP). In this study, we evaluated the concordance between genome profiling and DNA methylation analysis in determining TOO for lung-specific CUP and assessed their performance by comparing the clinical responses and survival outcomes of patients predicted with multiple primary or with metastatic cancer. METHODS: We started by retrospectively screening for CUP patients who presented with both intra- and extrathoracic tumors. Tumor samples from included patients were analyzed with targeted sequencing with a 520-gene panel and targeted bisulfite sequencing. TOO inferences were made in parallel via an algorithm using genome profiles and time interval between tumors and via machine learning-based classification of DNA methylation profiles. RESULTS: Four hundred patients were screened retrospectively. Excluding patients definitively diagnosed with conventional diagnostic work-up or without available samples, 16 CUP patients were included. Both molecular approaches alone enabled inference of clonality for all analyzed patients. Genome profile enabled TOO inference for 43.8% (7/16) patients, and the percentage rose to 68.8% (11/16) after considering inter-tumor time lag. On the other hand, DNA methylation analysis was conclusive for TOO prediction for 100% (14/14) patients with available samples. The two approaches gave 100% (9/9) concordant inferences regarding clonality and TOO identity. Moreover, patients predicted with metastatic disease showed significantly shorter overall survival than those with multiple primary tumors. CONCLUSIONS: Genome and DNA methylation profiling have shown promise as individual analysis for TOO identification. This study demonstrated the feasibility of incorporating the two methods and proposes an integrative scheme to facilitate diagnosing and treating lung-specific CUPs.

Apatinib in patients with extensive-stage small-cell lung cancer after second-line or third-line chemotherapy: a phase II, single-arm, multicentre, prospective study.

BACKGROUND: Small-cell lung cancer (SCLC) remains an aggressive cancer with short-term survival due to limited therapeutic options. Apatinib is a small-molecule tyrosine kinase inhibitor that selectively inhibits vascular endothelial growth factor receptor-2. This study aimed to investigate the efficacy and safety of apatinib in patients with extensive-stage (EC) SCLC who had progressed after two or three previous therapies. METHODS: Eligible patients were histologically confirmed ES-SCLC after two or three previous treatments, including a platinum-based regimen. Patients received apatinib at an initial dose of 500 mg once daily. The primary endpoint was the objective response rate. RESULTS: Forty patients were enrolled. At the data cut-off time (November 15, 2018), the median follow-up was 7.4 months; no patients remained on treatment, and five were still in follow-up. An objective response was achieved in 7 of 40 patients (17.5%) in the intention-to-treat population, and 7 of 38 patients (18.4%) in the per-protocol population. The median progression-free survival and overall survival were 3.0 months and 5·8 months, respectively. The most commonly observed grade 3 or greater treatment-related adverse events were hypertension, hand-foot syndrome, increased L-gamma-glutamyltransferase. CONCLUSIONS: Apatinib exhibited efficacy and an acceptable safety profile in previously heavily-treated ES-SCLC patients. Further exploration of apatinib in phase III trials is warranted. TRIAL REGISTRATION: NCT02945852.

A Nomogram to Predict the Pathologic Complete Response of Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer Based on Simple Laboratory Indicators.

BACKGROUND: Triple-negative breast cancer (TNBC) patients who achieve a pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) have better prognoses. OBJECTIVE: This study aimed to develop an intuitive nomogram based on simple laboratory indexes to predict the pCR of standard NAC in TNBC patients. METHODS: A total of 80 TNBC patients who received eight cycles of thrice-weekly standard NAC (anthracycline and cyclophosphamide followed by taxane) and subsequently underwent surgery in Zhejiang Cancer Hospital were retrospectively enrolled, and data on their pretreatment clinical features and multiple simple laboratory indexes were collected. The optimal cut-off values of the laboratory indexes were determined by the Youden index using receiver operating characteristic (ROC) curve analyses. Forward stepwise logistic regression (likelihood ratio) analysis was applied to identify predictive factors for a pCR of NAC. A nomogram was then developed according to the logistic model, and internally validated using the bootstrap resampling method. RESULTS: pCR was achieved in 39 (48.8%) patients after NAC. Multivariate analysis identified four independent indicators: clinical tumor stage, lymphocyte to monocyte ratio, fibrinogen level, and D-dimer level. The nomogram established based on these factors showed its discriminatory ability, with an area under the curve (AUC) of 0.803 (95% confidence interval 0.706-0.899) and a bias-corrected AUC of 0.771. The calibration curve and Hosmer-Lemeshow test showed that the predictive ability of the nomogram was a good fit to actual observation. CONCLUSIONS: The nomogram proposed in the present study exhibited a sufficient discriminatory ability for predicting pCR of NAC in TNBC patients.

GAP43, a novel metastasis promoter in non-small cell lung cancer.

BACKGROUND: Brain metastasis is an extremely serious sequela with a dismal prognosis in non-small cell lung cancer (NSCLC). The present study aimed to identify novel biomarkers and potential therapeutic targets for brain metastases of NSCLC. METHODS: We performed high-throughput Luminex assays to profile the transcriptional levels of 36 genes in 70 operable NSCLC patients, among whom 37 developed brain metastases as the first relapse within 3 years after surgery. The Cox proportional hazards regression model was used to evaluate the association between genes and brain metastases. Wound healing assay and transwell assay was carried out to estimate the function of target gene in vitro. And left ventricular injection on nude mice was used to evaluate the effect of target gene in vivo. RESULTS: Growth-associated protein 43 (GAP43) was found to be related to brain metastasis. Multivariate Cox regression analysis showed that NSCLC patients with elevated GAP43 had a 3.29-fold increase in the risk for brain metastasis compared with those with low levels (95% confidence interval: 1.55-7.00; P = 0.002). Kaplan-Meier survival curves revealed that GAP43 was also associated with overall survival. Analysis of a cohort of 1926 NSCLC patients showed similar results: patients with high levels of GAP43 had worse progression-free and overall survival rates. Furthermore, in vitro experiments showed that GAP43 facilitated cell migration. Animal studies demonstrated that GAP43-silenced NSCLC cells were less likely to metastasize to the brain and bone than control cells. Immunofluorescence and F-actin/G-actin in vivo assays indicated that GAP43 knockdown triggered depolymerization of the F-actin cytoskeleton. Rho GTPase activation assays showed that Rac1 was deactivated after GAP43 was silenced. CONCLUSIONS: Our findings suggest that GAP43 is an independent predictor of NSCLC brain metastasis and that it may facilitate metastasis by regulating the Rac1/F-actin pathway.

Low Serum Levels of Pre-Surgical Total Cholesterol are Associated with Unfavorable Overall Survival in Patients with Operable Non-Small Cell Lung Cancer.

BACKGROUND: Cholesterol is an essential building block of the cell membrane and an important molecule for cell signaling and function. The dysregulation of cholesterol metabolism has been linked to several diseases, including cancer. The aim of this study is to investigate whether serum cholesterol is associated with the survival outcomes of patients with non-small cell lung cancer (NSCLC). METHODS: The concentration of total cholesterol (TC) was measured in pre-operative serum samples of 637 NSCLC patients. The associations of TC with recurrence and overall survival were analyzed using a Cox proportional hazard regression model. Kaplan-Meier survival curves were calculated for overall survival analysis. RESULTS: Our analyses showed that low serum levels of TC were associated with an increased risk of death. The association between TC and overall survival remained significant after patient age at diagnosis, gender, disease stage, histotype, tumor grade, body mass index (BMI), and smoking status were adjusted in the analysis. The patients with low serum TC had a 61% (95% confidence interval: 1.18 - 2.19) higher risk of death compared to those with normal TC. A Kaplan-Meier survival analysis showed similar results. No association was found between TC and recurrence in NSCLC. CONCLUSIONS: Our study suggests that the pre-surgical serum level of TC may be an independent prognostic indicator for NSCLC overall survival.

Regenerating Family Member 4 (Reg4) Enhances 5-Fluorouracil Resistance of Gastric Cancer Through Activating MAPK/Erk/Bim Signaling Pathway.

BACKGROUND Reg4, a member of the Reg multigene family, is highly upregulated in many gastrointestinal cancers including gastric cancer (GC). The enhanced expression of Reg4 is associated with the resistance of GC to 5-fluorouracil (5-FU), while the underlying mechanism is not clear. The aim of the present study was to explore the resistant mechanism underlying 5-FU resistance. MATERIAL AND METHODS Reg4 expression was assessed by Western blot analysis for SGC-7901, BGC-823, AGS, MKN28, and MKN45. Synthetic short single strand RNA oligonucleotides and Flag-Reg4 plasmid were used to investigate the biological function of Reg4 in vitro. The cell viability assay was performed by MTT. Flow cytometry was carried out to measure the apoptosis caused by 5-FU. Reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR) was used to examine the expression of 5-FU metabolism related enzymes. The effect of Reg4 on intracellular signaling was evaluated by Western blot. RESULTS Western blot analysis of 5 GC cells showed that Reg4 was low or null in SGC-7901 and BGC-823, while high in AGS, MKN28, and MKN45. Over-expression of flag-Reg4 in SGC-7901 led to an increase in cell viability and lower apoptosis with 5-FU treatment. In contrast, siRNA knockdown of Reg4 enhanced 5-FU induced apoptosis. However, over-expression or knockdown of Reg4 had no significant influence on the expression of 5-FU metabolic enzymes. Further investigation revealed that Reg4 could activate Erk1/2-Bim-caspase3 cascade. CONCLUSIONS Reg4 inhibited apoptosis through regulating MAPK/Erk/Bim signaling pathway and thereby enhanced the resistance of GC to 5-FU.

Tumor-Infiltrating CD4+ Lymphocytes Predict a Favorable Survival in Patients with Operable Esophageal Squamous Cell Carcinoma.

BACKGROUND The immune status within the tumor microenvironment has not been well determined in esophageal squamous cell carcinoma (ESCC). The aim of this study was to investigate the distributions of tumor-infiltrating T lymphocytes (TILs), and analyze their associations with clinical characteristics and prognosis; as well as investigate the expression of programmed death-ligand 1 (PD-L1) which has been identified as a favorable indicator of prognosis in our previous study on ESCC. MATERIAL AND METHODS Five hundred and thirty-six patients who underwent radical surgery for ESCC between January 2008 and April 2012 in Department of Thoracic Surgery at Zhejiang Cancer Hospital were included in the study. Immunohistochemistry was used to investigate the infiltration of various TILs (CD3+, CD4+, CD8+ T lymphocytes) in ESCC tissues. Chi-square test and Cox proportional hazards regression were used to explore the correlations between TILs abundance and clinicopathological variables and survival. RESULTS The infiltration of intraepithelial CD4+ (iCD4+) lymphocytes was markedly higher than it in the stromal region (44.2% for intraepithelial versus 28.9% for stromal, p<0.001). Moreover, increased iCD4+ lymphocytes were significantly associated with longer overall survival (OS, p=0.001) in univariate analysis and were identified as an independent predictor for improved OS in multivariate analysis (hazard ratio [HR]=0.67, 95% confidence interval [CI]: 0.51-0.88, p=0.040). Neither the infiltration of CD3+ nor CD8+ lymphocytes showed the prognostic value in ESCC (p>0.05). Unexpectedly, combined with our previous study results, the TILs infiltration in ESCC showed an inverse association with the expression of PD-L1 (p=0.027). CONCLUSIONS Our results suggested that iCD4+ lymphocytes infiltration could be a favorable indicator for prognosis in ESCC.

Effectiveness of high-dose third-generation EGFR-tyrosine kinase inhibitors in treating EGFR-mutated non-small cell lung cancer patients with leptomeningeal metastasis.

BACKGROUND: Leptomeningeal metastasis (LM) is associated with an extremely poor prognosis in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). The third-generation EGFR-tyrosine kinase inhibitors (TKIs), currently the preferred drug of choice, have significantly improved treatment outcomes in these patients. However, the optimal dose of third-generation EGFR-TKIs for clinical use remains undetermined in NSCLC patients with LM. METHODS: We retrospectively analyzed the clinical characteristics and treatment outcomes of 105 patients with EGFR-mutated NSCLC and cytologically confirmed LM who had received third-generation EGFR-TKI treatment after LM diagnosis. Patients were stratified into high- and standard-dose groups based on the treatment dose of third-generation EGFR-TKI. Subsequent treatments for LM were collected, particularly the efficacy of different doses of third-generation EGFR-targeted drugs. RESULTS: The median follow-up period was 28.7 months (range 0.6-40.2) at the cut-off date of August 27, 2023. The 105 included patients who received third-generation EGFR-TKI treatment had a clinical response rate (CRR) of 54.3 % (57/105), and the median overall survival (OS) from LM diagnosis was 12.3 months (95 % confidence interval [CI] = 10.0-15.0). Among them, 46 (43.8 %) patients received a high-dose regimen, and the remaining 59 (56.2 %) patients were treated with standard-dose drugs. Patients treated with high-dose third-generation EGFR-TKIs showed a higher CRR and longer OS than those treated with standard-dose therapy (65.2 % vs. 45.8 %, p = 0.047; 15.0 vs. 10.2 months, p = 0.014). Importantly, high-dose third-generation EGFR-TKI showed superior OS than standard-dose treatment in all subgroups (prior first-/second-generation EGFR-TKI resistance group, 19.5 vs. 9.8 months, p = 0.047; third-generation EGFR-TKI resistance group, 10.0 vs. 4.3 months, p = 0.045; EGFR-TKI naive group, not reach vs. 15.6 months, p = 0.031). Multivariate analysis revealed that high-dose third-generation EGFR-TKIs, intrathecal chemotherapy, previous TKI treatment history, and Karnofsky Performance Status score were independent predictors of OS (all p < 0.05). CONCLUSIONS: High-dose third-generation EGFR-TKIs are effective treatments for NSCLC patients with EGFR mutations and LM, regardless of previous EGFR-TKI exposure.

Uterine giant cell tumor of soft tissue: A case report.

INTRODUCTION: Giant cell tumor of soft tissue (GCT-ST) is a rare primary soft tissue tumor. GCT-ST mainly occurs in the trunk and extremities. There is no standard treatment for GCT-ST. This paper reports a rare case of primary uterine GCT-ST. CASE PRESENTATION: A 48-year-old female patient underwent a transabdominal subhysterectomy for uterine leiomyoma. Postoperative pathological examination showed GCT-ST with unclear tissue boundary (10.0 × 6.0 × 5.0 cm). A small amount of GCT-ST tissue could be seen on the local edge of the leiomyoma. Residual tumor tissue was found around the uterine cavity. The patient reported persistent lower abdominal distension pain 3 months after the operation. Pelvic and abdominal imaging showed a huge tumor and multiple pelvic and abdominal organ metastasis. No pulmonary metastasis was found. Exploratory surgery revealed widespread metastases in the abdominal and peritoneal cavities, involving both ovaries, right tubal serous membrane, appendix serous membrane, bladder, pelvic peritoneum, and abdominal wall incision. After surgery, the patient had 6 cycles of docetaxel and carboplatin but stopped treatments due to economic reasons. The patient died 3 months later because of multiple organs failure. CONCLUSION: GCT-ST is generally benign but has unpredictable behavior. A massive recurrence with wide invasion is possible after subtotal resection.

Sintilimab plus anlotinib as second- or third-line therapy in metastatic non-small cell lung cancer with uncommon epidermal growth factor receptor mutations: A prospective, single-arm, phase II trial.

BACKGROUND: Patients with non-small-cell lung cancer (NSCLC) and uncommon EGFR alterations typically have worse treatment outcomes than patients with classically EGFR-mutated NSCLC. This study aimed to investigate the efficacy and safety of PD-1 blockade with sintilimab plus anti-angiogenic treatment with anlotinib in patients with NSCLC harboring uncommon EGFR mutations. METHODS: Patients with metastatic NSCLC harboring uncommon EGFR mutations after two previous treatments, including a platinum-based chemotherapy regimen and a targeted treatment (or chemotherapy only for patients harboring EGFR ex20ins), received sintilimab combined with anlotinib. The primary endpoint was objective response rate (ORR). RESULTS: At data cutoff (September 27, 2022), median follow-up was 22.3 months (range, 1.2-37.6). Among 21 enrolled patients, 12 had EGFR ex20ins and nine had other uncommon EGFR mutations such as L861Q, G719A, and G709X. Overall, eight patients (38.1%) achieved an objective response, and 18 (85.7%) achieved disease control. Median (95% CI) progression-free survival (PFS) was 7.0 (5.4-8.6) months, and median overall survival (OS) was 20.0 (15.6-24.4) months. The 12-month PFS rate (95% CI) was 22.2% (7.4-42.0), and the 12-month OS rate was 66.7% (42.5-82.5). Patients harboring EGFR ex20ins had similar ORR and PFS to those with other mutations. Six patients (28.6%) experienced grade 3 treatment-related adverse events (TRAEs); hand-foot syndrome was the most common grade 3 TRAE (2 patients; 9.5%). No grade ≥4 TRAEs were observed. CONCLUSIONS: The combination of sintilimab and anlotinib demonstrated durable efficacy and was generally well tolerated in patients with NSCLC and uncommon EGFR mutations who had received prior standard-of-care treatments. (ClinicalTrials.gov identifier: NCT04790409).

A first-in-human, open-label, dose-escalation and dose-expansion phase I study to evaluate the safety, tolerability, pharmacokinetics/pharmacodynamics, and antitumor activity of QL1604, a humanized anti-PD-1 mAb, in patients with advanced or metastatic solid tumors.

Background: QL1604 is a humanized immunoglobulin G4 monoclonal antibody against programmed cell death protein 1. This first-in-human, open-label phase I study aimed to investigate the safety and tolerability and to identify the recommended doses of QL1604 for future studies. Pharmacokinetics/pharmacodynamics (PK/PD) and preliminary antitumor activity were also assessed. Methods: Patients with advanced or metastatic solid tumors who failed or had no standard therapies available were recruited. In the dose-escalation phase, patients were treated with QL1604 at 0.3 mg/kg, 1 mg/kg, 3 mg/kg, and 10 mg/kg intravenously once every 2 weeks (Q2W) in an accelerated titration with a traditional 3 + 3 design, followed by a dose-expansion phase at 3 mg/kg Q2W, 3 mg/kg once every 3 weeks (Q3W), 10 mg/kg Q2W and a fixed dose of 200 mg Q3W. Dose-limiting toxicities (DLTs) were assessed during the first 28 days after the first dose of study drug. Adverse events (AEs) were graded per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0, and antitumor activity of QL1604 was evaluated by investigators on the basis of Response Evaluation Criteria in Solid Tumors version 1.1. Results: A total of 35 patients with advanced or metastatic solid tumors were enrolled. DLTs were reported in one patient at the dose level of 3 mg/kg Q2W (grade 3 immune-mediated myositis and myasthenia gravis), and maximum tolerated dose was not reached. The most frequent treatment-related AEs (≥10%) were fatigue (37.1%), anemia (22.9%), increased blood thyroid-stimulating hormone (17.1%), increased aspartate aminotransferase (AST) (17.1%), increased alanine aminotransferase (ALT) (14.3%), decreased white blood cell (WBC) count (11.4%), rash (14.3%), and pruritus (14.3%). AEs leading to discontinuation of QL1604 occurred in three of the 35 patients (8.6%). Partial responses (PRs) occurred in seven patients, resulting in an objective response rate of 20.0% (7/35). Single dose of QL1604 exhibited a dose-dependent increase in the exposure ranging from 0.3 mg/kg to 10 mg/kg. Mean receptor occupancy (RO) for QL1604 at the dose of 3 mg/kg (Q2W and Q3W) and 200 mg (Q3W) was greater than 80% during cycle 1 after one infusion. Conclusion: QL1604 monotherapy exhibited favorable safety, PK, and signal of antitumor activity in patients with advanced or metastatic solid tumors, and the results supported further clinical studies of QL1604. On the basis of the safety, PK, and RO data, the recommended dosage for further clinical trials is 3 mg/kg or a fixed dose of 200 mg given every 3 weeks. Clinical Trial Registration: https://classic.clinicaltrials.gov/ct2/show/NCT05649761?term=QL1604&draw=2&rank=1, identifier NCT05649761.

Design of Growth Trend Map of Children and Adolescents Based on Bone Age.

Accurate height prediction has important reference significance for the development of children and adolescents and the selection of athletes. The current mainstream height prediction methods include the B-P (Bayley-Pinneau) method and the TW2 (Tanner-Whitehouse) method. A large number of documents show that the B-P method and the TW2 method have relatively large deviations in the lifelong height prediction results of Chinese children and adolescents. Based on the data collected by the Chinese Adolescent Students' Physical Fitness and Growth and Development Health Project in Zhejiang's primary and secondary schools, this paper proposes a graph of height growth trends based on bone age. The height map of age has more reference value. Aiming at the feasibility of the height data in the statistical results, the interpolation prediction method is used to verify the data, and the height growth trend graph is drawn through the method of fitting. Validation results with actual data show that the average error of the lifetime height prediction of the height growth trend map proposed in this paper is 2.1 cm, which is 1.4 cm lower than the 3.5 cm error predicted by the B-P method and 0.4 cm lower than the 2.5 cm error predicted by the TW2 method.

Real-world utilization of PD-1/PD-L1 inhibitors with palliative radiotherapy in patients with metastatic non-small cell lung cancer.

BACKGROUND: Programmed cell death protein 1 (PD-1) blockade plus radiotherapy may be a promising strategy to improve the prognosis of patients with metastatic non-small cell lung cancer (NSCLC). However, the optimum combined scheme, treatment time of radiotherapy, and irradiated lesion have not been fully determined. METHODS: A total of 321 metastatic NSCLC patients treated with immunotherapy were identified. Among them, 107 patients received PD-1/PD-ligand 1 (PD-L1) inhibitors with radiotherapy, while the remaining cases did not receive radiotherapy. Data on overall survival (OS), progression-free survival (PFS), treatment response and adverse events were collected. Comparisons based on type of radiation, timing of radiotherapy and number of irradiated lesions were performed. RESULTS: The median OS in PD-1/PD-L1 inhibitors plus radiotherapy was longer than in nonradiotherapy (22.8 vs. 16.6 months, p = 0.022). The median PFS showed a similar trend in this study (9.4 vs. 6.2 months, p = 0.042). Moreover, the combined strategy demonstrated a superior disease control rate and abscopal control rate versus without radiotherapy (both p ≤ 0.001). Further multivariate analysis in the immunotherapy and radiotherapy groups revealed that age below 65 (p = 0.004), Eastern Cooperative Oncology Group performance scores of 0-1 (p = 0.001), oligometastasis (p = 0.006), concurrent combination (p = 0.002), and treated with SRT (p = 0.013) were associated with longer OS. There was a similar incidence of adverse events between the two groups (both p ≥ 0.05). CONCLUSIONS: The combination of PD-1/PD-L1 inhibitors plus palliative radiotherapy demonstrated favorable survival and good tolerability in metastatic NSCLC patients.

Exosomal thioredoxin-1 from hypoxic human umbilical cord mesenchymal stem cells inhibits ferroptosis in doxorubicin-induced cardiotoxicity via mTORC1 signaling.

Doxorubicin (DOX), a clinical chemotherapeutic drug, is often annoyed by its cardiotoxicity which involves ferroptosis in its pathological progress. Human umbilical cord mesenchymal stem cells (HucMSCs)-derived exosomes (HucMSCs-Exo) are proven effective in treating cardiovascular diseases. This study aimed to compare the therapeutic effects between normoxic HucMSCs-Exo (Exo) and hypoxic HucMSCs-Exo (Hypo-Exo) on DOX-induced ferroptosis and explore the underlying mechanisms. An acute cardiotoxicity model was successfully constructed by administrating two doses intraperitoneal injections of DOX (25 mg/kg in total). Exo and Hypo-Exo were extracted by ultracentrifugation and characterized. Compared with Exo, Hypo-Exo and Ferrostatin-1 (Fer-1) exerted superior effects on inhibiting DOX-induced ferroptosis, as evidenced by decreasing malondialdehyde (MDA), iron content and increasing glutathione (GSH) level as well as ferroptosis-related genes expression including prostaglandin-endoperoxide synthase 2 (Ptgs2) mRNA level and glutathione peroxidase 4 (GPX4) protein level. Based on quantitative proteomics analysis, we found that thioredoxin1 (Trx1) was remarkably upregulated in Hypo-Exo and exhibited anti-ferroptosis activity via activating the mechanistic target of rapamycin complex 1 (mTORC1) in neonatal rat cardiomyocytes (NRCMs). Trx1 knockdown and rapamycin (an mTORC1 inhibitor) partially abolished the protective effects of Hypo-Exo. Furthermore, our data indicated that solute carrier family 7 member 11 (SLC7A11) was critical for GPX4 protein synthesis. In conclusion, Hypo-Exo exhibited a better suppression of ferroptosis in DOX-induced cardiotoxicity. Trx1-mediated mTORC1 activation is critical for the Hypo-Exo anti-ferroptosis process, which involves increased GPX4 protein synthesis and decreased iron overload. This study indicated that Hypo-Exo may present a potential strategy against ferroptosis in DOX-induced cardiotoxicity.

Tolerability, safety, and preliminary antitumor activity of fuzuloparib in combination with SHR-1316 in patients with relapsed small cell lung cancer: a multicenter, open-label, two-stage, phase Ib trial.

Background: Second-line treatment options for small cell lung cancer (SCLC) are limited. Preclinical research shows that inhibition of poly (ADP-ribose) polymerase (PARP) could upregulate programmed death-ligand 1 (PD-L1), and thus render cancer cells more sensitive to immune checkpoint inhibitors. This study investigated the tolerability, safety, and preliminary antitumor activity of fuzuloparib (a PARP inhibitor) plus SHR-1316 (a PD-L1 inhibitor) for relapsed SCLC. Methods: Patients with SCLC who failed previous first-line platinum-based therapy were enrolled in this two-stage phase Ib trial. In stage 1, 2 dose levels were designed: fuzuloparib 100 mg or 150 mg twice daily plus SHR-1316 600 mg every 2 weeks, with 6 patients in each dose level. Based on the tolerability during the first 28-day cycle and the preliminary antitumor activity in stage 1, a recommended phase II dose (RP2D) was determined and introduced in the stage 2 expansion phase. The primary endpoints were safety and RP2D in stage 1 and objective response rate (ORR) in stage 2. Results: A total of 23 patients were enrolled, with 16 receiving fuzuloparib 100 mg plus SHR-1316 and 7 receiving fuzuloparib 150 mg plus SHR-1316. At data cutoff on April 23, 2021, the median follow-up duration was 6.4 months (IQR, 3.0-9.7 months). All patients discontinued study treatment. One patient receiving fuzuloparib 150 mg plus SHR-1316 had clinically significant toxicities, and fuzuloparib 100 mg plus SHR-1316 was considered as the RP2D. In the RP2D cohort, the confirmed ORR was 6.3% (95% CI: 0.2-30.2%), and the disease control rate was 37.5% (95% CI: 15.2-64.6%). The median progression-free survival was 1.4 months (95% CI: 1.3-2.8 months), and the median overall survival was 5.6 months (95% CI: 3.0-16.7 months). Grade ≥3 treatment-related adverse events (TRAE) occurred in 8 patients (34.8%). No treatment-related death occurred, and no patients discontinued treatment due to TRAEs. Conclusions: Fuzuloparib combined with SHR-1316 failed to improve the outcomes in unselected patients with relapsed SCLC. Future studies with biomarker analysis are warranted to select patients most likely to benefit from this combination treatment. Fuzuloparib 100 and 150 mg plus SHR-1316 were both tolerable with no new signals observed.