Cerebral 18F-FDG PET/CT Metabolism as Diagnostic Signature for Central Nervous System Toxicity After Immune Checkpoint Blockade Cancer Treatment.

Our aim was to investigate probable biomarkers specific to immune-related central nervous system toxicity (CNST) in cancer patients treated with immune checkpoint inhibitors (ICI) by analysis of 18F-FDG PET/CT images. Methods: Cancer patients receiving ICI treatment were enrolled in a multicenter observational study that analyzed regional metabolic changes before and during CNST onset from January 2020 to February 2022. In 1:1 propensity score-matched pairs, the regional SUVmean of each bilateral brain lobe of CNST patients (CNST+) was compared with that of patients who had central nervous system infections (CNSIs) and patients without CNST or CNSI (CNST-). In a validation cohort, patients were recruited from February 2022 to July 2023 and followed up for 24 wk after the start of ICI. Early changes in regional SUVmean at 5-6 wk after therapy initiation were evaluated for ability to predict later CNST onset. Results: Of 6,395 ICI-treated patients, 2,387 underwent prognostic 18F-FDG PET/CT and 125 of the scanned patients had CNST (median time from ICI treatment to onset, 9 wk; quartile range, 2-23 wk). Regional 18F-FDG PET/CT SUVmean changes were higher in CNST+ than in CNST- patients (117 patient pairs) but were lower than in CNSI patients (50 pairs). Differentiating analysis reached an area under the curve (AUC) of 0.83 (95% CI, 0.78-0.88) for CNST+ versus CNST- and of 0.80 (95% CI, 0.72-0.89) for CNST+ versus CNSI. Changes in SUVmean were also higher before CNST onset than for CNST- (60 pairs; AUC, 0.74; 95% CI, 0.66-0.83). In a validation cohort of 2,878 patients, preonset changes in SUVmean reached an AUC of 0.86 (95% CI, 0.79-0.94) in predicting later CNST incidence. Conclusion: Brain regional hypermetabolism could be detected during and before CNST clinical onset. CNST may be a distinct pathologic entity versus brain infections defined by 18F-FDG PET/CT brain scans. Regional SUV differences may be translated into early diagnostic tools based on moderate differentiating accuracy in our study.

Predictive value of NLR and PLR for immune-related adverse events: a systematic review and meta-analysis.

BACKGROUND: Currently, there is a lack of affordable and accessible indicators that can accurately predict immune-related adverse events (irAEs) resulting from the use of immune checkpoint inhibitors (ICIs). In order to address this knowledge gap, our study explore the potential predictive value of two ratios, namely the neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR), for irAEs in cancer patients. METHODS: A systematic search was performed in PubMed, Embase, and the Cochrane library. Studies involving NLR or PLR with irAEs were included. Quality and risk of bias of the selected studies were assessed. Forest plots were created based on Cox model analysis. Random effects meta-analyses were conducted to estimate odds ratio (OR) and its 95% confidence interval (CI). RESULTS: After screening 594 studies, a total of 7 eligible studies with 1068 cancer patients were included. Analysis based on Cox regression showed that low neutrophil-lymphocyte ratio (L-NLR) (OR = 3.02, 95% CI 1.51 to 6.05, P = 0.002) and low platelet-lymphocyte ratio (L-PLR) (OR = 1.83, 95% CI 1.21 to 2.76, P = 0.004) were associated with irAEs. In the subgroup analysis of cut-off value, when the NLR cut-off value was 3, irAEs was significantly correlated with NLR (OR = 2.63, 95% CI 1.63 to 4.26, P < 0.001). CONCLUSIONS: Both L-NLR and L-PLR have been found to be significantly associated with irAEs. Consequently, patients identified as being at a higher risk for irAEs should be subjected to more diligent monitoring and close observation.

κ-Opioid receptor activation attenuates osteoarthritis synovitis by regulating macrophage polarization through the NF-κB pathway.

Osteoarthritis (OA) is a prevalent and chronic joint disease that affects the aging population, causing pain and disability. Macrophages in synovium are important mediators of synovial inflammatory activity and pathological joint pain. Previous studies have demonstrated the significant involvement of κ-opioid receptor (KOR) in the regulation of pain and inflammation. Our study reveals a significant reduction in synovial KOR expression among patients and mice with OA. Here, we find that KOR activation effectively inhibits the expressions of the LPS-induced-inflammatory cytokines TNF-α and IL-6 by inhibiting macrophage M1 phenotype. Mechanistically, KOR activation effectively suppresses the proinflammatory factor secretion of macrophages by inhibiting the translocation of NF-κB into the nucleus. Our animal experiments reveal that activation of KOR effectively alleviates knee pain and prevents synovitis progression in OA mice. Consistently, KOR administration suppresses the expressions of M1 macrophage markers and the NF-κB pathway in the synovium of the knee. Collectively, our study suggests that targeting KOR may be a viable strategy for treating OA by inhibiting synovitis and improving joint pain in affected patients.

What do osteoporosis and osteoarthritis have in common? An integrated study of overlapping differentially expressed genes in bone mesenchymal stem cells of osteoporosis and osteoarthritis.

OBJECTIVE: For identification of aberrantly expressed genes in mesenchymal stem cells of osteoporosis (OP) and osteoarthritis (OA), Gene Expression Omnibus (GEO) datasets were integrated to investigate the intersection point. METHODS: GSE35958 (osteoporosis) and GSE19664 (osteoarthritis) datasets were obtained from GEO database. The abnormally expressed genes were analyzed by GEO2R. Functional enrichment was explored by Metascape database and R software. The String database and Cytoscape software were used to build the protein-protein interaction network and identify hub genes. GSE35957 and GSE116925 were used as verification datasets. Single-cell analysis and pseudotime analysis were undertaken. CTDbase, Network Analyst, HPA database, HERB database and MIRW database were used to research the information, tissue and cell distribution, regulation, interaction and ingredients targeting the hub genes. Additionally, in vitro experiments such as RT-PCR, ALP staining and immunofluorescence were undertaken as verification tests. RESULTS: Ten hub genes were identified in this study. All these genes play an important role in bone or cartilage generation. They have diagnostic values and therapeutic potential for OA and OP. Single-cell analysis visualized the cell distribution and pseudotime distribution of these genes. Some potential therapeutic ingredients of these genes were identified, such as curcumin, wogonin and glycerin. In vitro experiments, RT-PCR results showed that COL9A3 and MMP3 were downregulated and PTH1R was upregulated during osteogenic induction of BMSC. Immunohistochemical results showed the expression trend of MMP3 and COL2A1. CONCLUSION: Ten abnormal hub genes of osteoporosis and osteoarthritis were identified successfully by this study. They were important regulatory genes for healthy bone and cartilage. These genes could be the common connections between osteoporosis and osteoarthritis as well as treatment targets. Further study of the regulatory mechanism and treatment effects of these genes would be valuable. The results of this study could contribute to further research.

Development of a prognostic model for glioblastoma multiforme based on the expression levels of efferocytosis-related genes.

Glioblastoma multiforme (GBM) is one of the most common and aggressive brain tumors. The microenvironment of GBM is characterized by its highly immunosuppressive nature with infiltration of immunosuppressive cells and the expression levels of cytokines. Efferocytosis is a biological process in which phagocytes remove apoptotic cells and vesicles from tissues. Efferocytosis plays a noticeable function in the formation of immunosuppressive environment. This study aimed to develop an efferocytosis-related prognostic model for GBM. The bioinformatic methods were utilized to analyze the transcriptomic data of GBM and normal samples. Clinical and RNA-seq data were sourced from TCGA database comprising 167 tumor samples and 5 normal samples, and 167 tumor samples for which survival information was available. Transcriptomic data of 1034 normal samples were collected from the Genotype-Tissue Expression (GTEx) database as a control sample supplement to the TCGA database. In the end, 167 tumor samples and 1039 normal samples were obtained for transcriptome analysis. Efferocytosis-related differentially expressed genes (ERDEGs) were obtained by intersecting 7487 differentially expressed genes (DEGs) between GBM and normal samples along with 1189 hub genes. Functional enrichment analyses revealed that ERDEGs were mainly involved in cytokine-mediated immune responses. Moreover, 9 prognosis-related genes (PRGs) were identified by the least absolute shrinkage and selection operator (LASSO) regression analysis, and a prognostic model was therefore developed. The nomogram combining age and risk score could effectively predict GBM patients' prognosis. GBM patients in the high-risk group had higher immune infiltration, invasion, epithelial-mesenchymal transition, angiogenesis scores and poorer tumor purity. In addition, the high-risk group exhibited higher half maximal inhibitory concentration (IC50) values for temozolomide, carmustine, and vincristine. Expression analysis indicated that PRGs were overexpressed in GBM cells. PDIA4 knockdown reduced efferocytosis in vitro. In summary, the proposed prognostic model for GBM based on efferocytosis-related genes exhibited a robust performance.

The Emerging Role of the Mitochondrial Respiratory Chain in Skeletal Aging.

Maintenance of mitochondrial homeostasis is crucial for ensuring healthy mitochondria and normal cellular function. This process is primarily responsible for regulating processes that include mitochondrial OXPHOS, which generates ATP, as well as mitochondrial oxidative stress, apoptosis, calcium homeostasis, and mitophagy. Bone mesenchymal stem cells express factors that aid in bone formation and vascular growth. Positive regulation of hematopoietic stem cells in the bone marrow affects the differentiation of osteoclasts. Furthermore, the metabolic regulation of cells that play fundamental roles in various regions of the bone, as well as interactions within the bone microenvironment, actively participates in regulating bone integrity and aging. The maintenance of cellular homeostasis is dependent on the regulation of intracellular organelles, thus understanding the impact of mitochondrial functional changes on overall bone metabolism is crucially important. Recent studies have revealed that mitochondrial homeostasis can lead to morphological and functional abnormalities in senescent cells, particularly in the context of bone diseases. Mitochondrial dysfunction in skeletal diseases results in abnormal metabolism of bone-associated cells and a secondary dysregulated microenvironment within bone tissue. This imbalance in the oxidative system and immune disruption in the bone microenvironment ultimately leads to bone dysplasia. In this review, we examine the latest developments in mitochondrial respiratory chain regulation and its impacts on maintenance of bone health. Specifically, we explored whether enhancing mitochondrial function can reduce the occurrence of bone cell deterioration and improve bone metabolism. These findings offer prospects for developing bone remodeling biology strategies to treat age-related degenerative diseases.

Third-line treatment options in metastatic pancreatic cancer patients: a real-world study.

Background: There are currently no standard therapy regimens for the third-line treatment of metastatic pancreatic cancer (mPC) patients. The aim of the present study was to compare the efficacy and safety of different third-line therapy regimens for mPC in the real-world. Methods: This study retrospectively analyzed mPC patients admitted to Zhejiang Provincial People's Hospital between June 2013 and January 2023. All patients' diagnoses were pathologically confirmed and their treatment was continued after the second-line therapy failed. The primary study endpoints included median overall survival (mOS), median progression-free survival (mPFS), and disease control rate (DCR). Results: A total of 72 patients were enrolled in the study. Of these, 36 patients received chemotherapy alone, 16 received chemotherapy combined with targeted therapy or immunotherapy, 14 received chemotherapy-free antitumor therapy, and six received palliative care. The mPFS value for these groups was 4.40 months, 5.20 months, 2.33 months, and 0.80 months, respectively. The mOS value was 6.90 months, 5.90 months, 3.33 months, and 0.80 months, respectively. The DCR was 33.4%, 31.3%, 21.4%, and 0.0%, respectively. Overall, there were significant differences in prognosis between the palliative care group and the other treatment groups (mOS, P < 0.001; mPFS P < 0.001; DCR, P < 0.001). The differences among the mPFS, mOS, and DCR for different antitumor therapy regimens were not statistically significant. Compared to the chemotherapy alone group, the chemotherapy combined with targeted therapy or immunotherapy group experienced more adverse events (100% vs. 75.0%; P = 0.002). Chemotherapy combined with targeted therapy or immunotherapy was associated with a higher risk of grade 3/4 hyperaminotransferemia compared to chemotherapy alone (31.3% vs. 0.0%; P = 0.020) and chemotherapy-free antitumor therapy (31.3% vs. 0.0%; P = 0.020). Conclusions: Third-line antitumor therapy can prolong the survival time of patients with mPC. Targeted therapy or immunotherapy failed to further improve survival benefits based on chemotherapy results. Patients who underwent the third-line treatment with good physical status and family history of cancer were independent prognostic factors for longer mOS. The sequencing of fluorouracil and gemcitabine in the front-line therapy did not affect third-line mOS.

Light controlled self-escape capability of non-cationic carbon nitride-based nanosheets in lysosomes for hepatocellular carcinoma targeting stimulus-responsive gene delivery.

High positive charge-induced toxicity, easy lysosomal degradation of nucleic acid drugs, and poor lesion sites targeting are major problems faced in the development of gene carriers. Herein, we proposed the concept of self-escape non-cationic gene carriers for targeted delivery and treatment of photocontrolled hepatocellular carcinoma (HCC) with sufficient lysosome escape and multiple response capacities. Functional DNA was bound to the surface of biotin-PEG2000-modified graphitic carbon nitride (Bio-PEG-CN) nanosheets to form non-cationic nanocomplexes Bio-PEG-CN/DNA. These nanocomposites could actively target HCC tissue. Once these nanocomplexes were taken up by tumor cells, the accumulated reactive oxygen species (ROS) generated by Bio-PEG-CN under LED irradiation would disrupt the lysosome structure, thereby facilitating nanocomposites escape. Due to the acidic microenvironment and lipase in the HCC tissue, the reversible release of DNA could be promoted to complete the transfection process. Meanwhile, the fluorescence signal of Bio-PEG-CN could be monitored in real time by fluorescence imaging technology to investigate the transfection process and mechanism. In vitro and in vivo results further demonstrated that these nanocomplexes could remarkably upregulate the expression of tumor suppressor protein P53, increased tumor sensitivity to ROS generated by nanocarriers, and realized effective gene therapy for HCC via loading P53 gene.

Effects and action mechanisms of individual cytokines contained in PRP on osteoarthritis.

Osteoarthritis (OA) is defined as a degenerative joint disease that can affect all tissues of the joint, including the articular cartilage, subchondral bone, ligaments capsule, and synovial membrane. The conventional nonoperative treatments are ineffective for cartilage repair and induce only symptomatic relief. Platelet-rich plasma (PRP) is a platelet concentrate derived from autologous whole blood with a high concentration of platelets, which can exert anti-inflammatory and regenerative effects by releasing multiple growth factors and cytokines. Recent studies have shown that PRP exhibits clinical benefits in patients with OA. However, high operational and equipment requirements greatly limit the application of PRP to OA treatment. Past studies have indicated that high-concentration PRP growth factors and cytokines may be applied as a commercial replacement for PRP. We reviewed the relevant articles to summarize the feasibility and mechanisms of PRP-based growth factors in OA. The available evidence suggests that transforming growth factor-α and ß, platelet-derived growth factors, epidermal growth factor, insulin-like growth factor-1, and connective tissue growth factors might benefit OA, while vascular endothelial growth factor, tumor necrosis factor-α, angiopoietin-1, and stromal cell derived factor-1α might induce negative effects on OA. The effects of fibroblast growth factor, hepatocyte growth factor, platelet factor 4, and keratinocyte growth factor on OA remain uncertain. Thus, it can be concluded that not all cytokines released by PRP are beneficial, although the therapeutic action of PRP has a valuable potential to improve.

Reducedhumoral response against variants of concern in childhood solid cancer patients compared to adult patients and healthy children after SARS-CoV-2 vaccination.

Introduction: Although there is extended research on the response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in adult cancer patients (ACP), the immunogenicity to the variants of concern (VOCs) in childhood cancer patients (CCP) and safety profiles are now little known. Methods: A prospective, multi-center cohort study was performed by recruiting children with a solid cancer diagnosis and childhood healthy control (CHC) to receive standard two-dose SARS-CoV-2 vaccines. An independent ACP group was included to match CCP in treatment history. Humoral response to six variants was performed and adverse events were followed up 3 months after vaccination. Responses to variants were compared with ACP and CHC by means of propensity score-matched (PSM) analysis. Results: The analysis included 111 CCP (27.2%, median age of 8, quartile 5.5-15 years), 134 CHC (32.8%), and 163 ACP (40.0%), for a total 408 patients. Pathology included carcinoma, neural tumors, sarcoma, and germ cell tumors. Median chemotherapy time was 7 (quartile, 5-11) months. In PSM sample pairs, the humoral response of CCP against variants was significantly decreased, and serology titers (281.8 ± 315.5 U/ml) were reduced, as compared to ACP (p< 0.01 for the rate of neutralization rate against each variant) and CHC (p< 0.01 for the rate of neutralization against each variant) groups. Chemotherapy time and age (Pearson r ≥ 0.8 for all variants) were associated with the humoral response against VOCs of the CHC group. In the CCP group, less than grade II adverse events were observed, including 32 patients with local reactions, and 29 patients had systemic adverse events, including fever (n = 9), rash (n = 20), headache (n = 3), fatigue (n = 11), and myalgia (n = 15). All reactions were well-managed medically. Conclusions: The humoral response against VOCs after the CoronaVac vaccination in CCP was moderately impaired although the vaccine was safe. Age and chemotherapy time seem to be the primary reason for poor response and low serology levels.

Cognitive adverse events in patients with lung cancer treated with checkpoint inhibitor monotherapy: a propensity score-matched analysis.

Background: Cancer-related cognitive decline is a serious problem in long-term survival but no pivotal study has investigated whether checkpoint inhibitors (ICI) may be associated with cognitive adverse events. Methods: This propensity score-matched analysis recruited non-small cell lung cancer (NSCLC) patients prescribed with or without ICI monotherapy from three Chinese tertiary hospitals. Patients were excluded from study who developed brain metastasis or had disorders severely affecting cognitive abilities. Primary outcomes were changes in neuropsychological battery test (NBT) at baseline, 6- and 12-month sessions, and any NBT score changes that exceeded 3∗SD of baseline scores would be marked as objective cognitive adverse events (CoAE). Secondary endpoint was the 20-item Perceived Cognitive Impairment (PCI) sub-scale score change in Functional Assessment of Cancer Therapy-Cognitive Function questionnaire, administered at baseline, 3-, 6-, 9-, 12-, and 15-month follow-up session. Per-protocol ICI and control arms were matched with propensity scores that incorporated baseline variables to compare both NBT and PCI assessment results. Patients participating in PCI assessments were analysed in intention-to-treat analysis. Kaplan-Meier survival curves with log-rank tests were adopted to analyse incidence of perceived cognitive decline events (PCDE). Findings: Between March 12, 2020, and March 28, 2021, 908 participants were enrolled. Compared to control, 3 of 4 subtest of NBT scores in ICI arm showed significant cognitive decline in 6- and 12-month sessions, in which Trail Making Test score change (13.56 ± 11.73) reached threshold of cognitive deficit diagnosis in the 12-month session. In 1:1 matched 292 pairs from 908 patients, PCI score changes in ICI arms were -4.26 ± 8.54 (3rd month), -4.72 ± 11.83 (6th month), -6.16 ± 15.41 (9th month), -6.07 ± 15.71 (12th month), and -7.96 ± 13.97 (15th month). The scores were significantly lower than control arm in 3-, 6-, and 12-session follow-up. The result was validated after adjusting quality of life scores and in intention-to-treat analysis. Mean PCI change exceeded 1/2 SD of baseline PCI score (5.81) in 9-, 12-, and 15-month sessions in ICI arm, but not in control arm. PCDE incidence/prevalence was significantly higher in ICI arm (incidence 26.4% vs. 5.1%, and prevalence 16.2% vs. 1.7%). Immune-related adverse events related to incidence of PCDE after adjusting for baseline variables. Interpretation: ICI monotherapy seemed to relate to higher cognitive decline represented by score changes and incidence/prevalence rates. The decline deteriorated as treatment progressed, and immune-related adverse events seemed to be associated with higher cognitive adverse events incidence in the ICI treatment. Funding: The Fellowship of China Postdoctoral Science Foundation and National Natural Science Foundation of China Youth Science Fund Project.

Apatinib combined with SOX regimen for conversion therapy in advanced gastric cancer patients: a retrospective cohort study.

BACKGROUND: Recently, many studies have shown that the progress of conversion therapy can provide surgical opportunities for patients with advanced gastric cancer (GC) and bring survival benefits. However, the results of the current study show that the regimen used in conversion therapy is still controversial. Apatinib, as the standard third-line treatment for GC, has an inconclusive status in conversion therapy. METHODS: This study retrospectively analyzed GC patients admitted to Zhejiang Provincial People's Hospital from June 2016 to November 2019. All patients were pathologically diagnosed, had unresectable factors, and received SOX regimen with or without apatinib as conversion therapy. RESULTS: A total of 50 patients were enrolled in the study. Altogether 33 patients (66%) received conversion surgery and 17 patients (34%) received conversion therapy without surgery. The median progression-free survival (PFS) between surgery group and non-surgery group were 21.0 versus 4.0 months (p < 0.0001), and the median overall survival (OS) were 29.0 versus 14.0 months (p < 0.0001). In conversion surgery group, 16 patients (16/33) were treated with SOX plus apatinib, and the R0 resection rate was 81.3%; 17 patients (17/33) were treated with SOX regimen along, and the R0 resection rate was 41.2% (p = 0.032). The PFS in the SOX combined with apatinib group was significantly longer than that of SOX group (25.5 versus 16 months, p = 0.045), and the median OS were 34.0 versus 23.0 months (p = 0.048). The addition of apatinib did not increase the incidence of serious adverse reactions throughout the preoperative therapy period. CONCLUSIONS: Patients with advanced inoperable gastric cancer could benefit probably from conversion chemotherapy and subsequence conversion surgery. Apatinib-targeted therapy combined with SOX chemotherapy may be a safe and feasible option for conversion therapy.

TEDC2 correlated with prognosis and immune microenvironment in lung adenocarcinoma.

Tubulin epsilon and delta complex 2 (TEDC2) is a protein coding gene whose functions are poorly identified yet. This study aimed to identify the role of TEDC2 in prognosis and immune microenvironment of lung adenocarcinoma (LUAD). Through The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, the mRNA expression of TEDC2 was upregulated in LUAD tissues compared to normal tissues. The protein level of TEDC2 was also higher in LUAD in the Human Protein Atlas. The receiver operating characteristic (ROC) curve showed that high TEDC2 level could distinguish LUAD patients from normal subjects. In addition, the impact of TEDC2 expression on prognosis was evaluated by Kaplan-Meier and Cox regression analyses, and the results suggested that high TEDC2 expression was significantly associated with poor prognosis and was the independent prognostic factor in LUAD. GO and KEGG pathway analyses indicated the co-expressed genes of TEDC2 were mainly related to mitotic cell cycle processes. Importantly, high expression of TEDC2 indicated low infiltration of immune cells, especially dendritic cells and B cells. TEDC2 was also positively correlated with immune checkpoints such as PDCD1, LAG3 and CD276. Taken together, this study preliminarily revealed the clinical significance of TEDC2 in LUAD and provided novel insights into the role of TEDC2 in immune microenvironment.

Comparison of the efficacy and safety of fruquintinib and regorafenib in the treatment of metastatic colorectal cancer: A real-world study.

Background: Fruquintinib and regorafenib have been approved for the third-line therapy of metastatic colorectal cancer (mCRC) in China. However, at present, there is a lack of head-to-head clinical trials on the comparison of efficacy and safety between the two drugs. Materials and methods: The data of patients with mCRC who were treated with fruquintinib or regorafenib after the standard chemotherapy in Zhejiang Provincial People's Hospital from October 2018 to November 2021 were collected and analyzed. The primary endpoints were overall survival (OS), progression-free survival (PFS) and adverse events. The secondary endpoints were the appropriate sequence, objective remission rate (ORR) and disease control rate (DCR) of fruquintinib and regorafenib. Results: A total of 105 patients were enrolled in this study. The ORR of fruquintinib group (n=55) and regorafenib group (n=50) were 6.1% and 2.0%; the DCR were 65.3% and 54.2%, respectively. There was no significant difference in median OS (mOS) and PFS (mPFS) between the two groups (mOS:14.2 vs12.0 months, p=0.057; mPFS:4.4 vs 3.5 months, p=0.150). Combined immunotherapy showed a synergistic effect. The mPFS and mOS of fruquintinib combined with anti-PD-1 therapy were longer than those of fruquintinib monotherapy (mPFS:5.9 vs 3.0 months, p=0.009; mOS:17.5 vs 11.3 months, p=0.008). The mOS of patients treated with regorafenib combined with anti-PD-1 therapy was 14.8 months higher than that of regorafenib monotherapy (p=0.045). When combined with anti-PD-1 therapy, the mPFS and mOS of fruquintinib was significantly longer than regorafenib (mPFS:5.9 vs 3.8 months, p=0.018; mOS:17.5 vs 14.8 months, p=0.044). In the treatment sequence, the OS of patients treated with regorafenib and then fruquintinib was significantly longer than that of the reverse treatment sequence (15.0 vs 8.3 months, p=0.019). The adverse reactions were generally similar, but the incidence of hand-foot syndrome of regorafenib was higher than that of fruquintinib, while fruquintinib was more prone to grade 3 hypertension. Conclusion: Fruquintinib monotherapy showed better disease control rate and objective remission rate in the post-line therapy of metastasis colorectal cancer. Notably, the combination of PD-1 immunotherapy brought the additional effect, especially in the fruquintinib combined with anti-PD-1 therapy. Patients treated with regorafenib and then fruquintinib was significantly longer than that of the reverse treatment sequence. The toxicity of fruquintinib and regorafenib are similar.

The Role of Nomogram Based on the Combination of Ultrasound Parameters and Clinical Indicators in the Degree of Pathological Remission of Breast Cancer.

Background: The mortality rate of breast cancer (BC) ranks first among female tumors worldwide and presents a trend of younger age, which poses a great threat to women's health and life. Neoadjuvant chemotherapy (NAC) for breast cancer is defined as the first step of treatment for breast cancer patients without distant metastasis before planned surgical treatment or local treatment with surgery and radiotherapy. According to the current NCCN guidelines, patients with different molecular types of BC should receive neoadjuvant chemotherapy (NAC), which can not only achieve tumor downstaging, increase the chance of surgery, and improve the breast-conserving rate. In addition, it can identify new genetic pathways and drugs related to cancer, improve patient survival rate, and make new progress in breast cancer management. Objective: To explore the role of the nomogram established by the combination of ultrasound parameters and clinical indicators in the degree of pathological remission of breast cancer. Methods: A total of 147 breast cancer patients who received neoadjuvant chemotherapy and elective surgery in the Department of Ultrasound, Nantong Cancer Hospital, from May 2014 to August 2021 were retrospectively included. Postoperative pathological remission was divided into two groups according to Miller-Payne classification: no significant remission group (NMHR group, n = 93) and significant remission group (MHR group, n = 54). Clinical characteristics of patients were recorded and collected. The multivariate logistic regression model was used to screen the information features related to the MHR group, and then, a nomogram model was constructed; ROC curve area, consistency index (C-index, CI), calibration curve, and H-L test were used to evaluate the model. And the decision curve is used to compare the net income of the single model and composite model. Results: Among 147 breast cancer patients, 54 (36.7%) had pathological remission. Multivariate logistic regression showed that ER, reduction/disappearance of strong echo halo, Adler classification after NAC, PR + CR, and morphological changes were independent risk factors for pathological remission (P < 0.05). Based on these factors, the nomogram was constructed and verified. The area under the curve (AUC) and CI were 0.966, the sensitivity and specificity were 96.15% and 92.31%, and the positive predictive value (PPV) and negative predictive value (NPV) were 87.72% and 97.15%, respectively. The mean absolute error of the agreement between the predicted value and the real value is 0.026, and the predicted risk is close to the actual risk. In the range of HRT of about 0.0∼0.9, the net benefit of the composite evaluation model is higher than that of the single model. H-L test results showed that χ 2 = 8.430, P=0.393 > 0.05. Conclusion: The nomogram model established by combining the changes of ultrasound parameters and clinical indicators is a practical and convenient prediction model, which has a certain value in predicting the degree of pathological remission after neoadjuvant chemotherapy.

Acute aortic dissection caused by fruquintinib for metastatic colorectal cancer-a case report and literature review.

Background: Fruquintinib is a highly selective tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR). At present, it has been approved for third-line therapy for advanced metastatic colorectal cancer in China. Like other small-molecule tyrosine kinase inhibitors, adverse reactions such as hand-foot syndrome, hypertension and cardiotoxicity may be seen. However, acute aortic dissection caused by fruquintinib has not been reported so far. Case Description: Here, we report a case of aortic dissection. The patient, a 61-year-old man with advanced metastatic colorectal cancer, without history of hypertension or other risk factors for aortic dissection, received fruquintinib as the third line of treatment. Six weeks after oral fruquintinib treatment, the patient developed acute aortic dissection, and the occurrence of the adverse effect was determined to be probably related to the use of fruquintinib. This article focuses on the potential pathogenesis of fruquintinib-induced active dissection. Conclusions: We reported the first case of fruquintinib-associated aortic dissection, and discussed the possible mechanism of vascular endothelial growth factor (VEGF)-VEGFR signal pathway (VSP) inhibitors leading to aortic dissection. As a new drug, fruquintinib brings not only clinical benefits, but also brings some adverse reactions. Clinicians must be vigilant to the cardiovascular toxicity caused by small molecular tyrosine kinase inhibitors, especially the severe cardiovascular toxicity, and strengthen monitoring and management.

Targeted mechanical forces enhance the effects of tumor immunotherapy by regulating immune cells in the tumor microenvironment.

Mechanical forces in the tumor microenvironment (TME) are associated with tumor growth, proliferation, and drug resistance. Strong mechanical forces in tumors alter the metabolism and behavior of cancer cells, thus promoting tumor progression and metastasis. Mechanical signals are transformed into biochemical signals, which activate tumorigenic signaling pathways through mechanical transduction. Cancer immunotherapy has recently made exciting progress, ushering in a new era of "chemo-free" treatments. However, immunotherapy has not achieved satisfactory results in a variety of tumors, because of the complex tumor microenvironment. Herein, we discuss the effects of mechanical forces on the tumor immune microenvironment and highlight emerging therapeutic strategies for targeting mechanical forces in immunotherapy.

Anti-inflammatory and Chondroprotective Effects of Platelet-derived Growth Factor-BB on Osteoarthritis Rat Models.

Osteoarthritis (OA) is a common and challenging joint disease that mainly affects the diarthrodial joints. Traditionally, except for surgery for severe cases, treatments for OA mainly focus on relieving pain and improving joint function. However, these treatments are not effective for cartilage repair and induce only symptomatic relief. Platelet-derived growth factor (PDGF)-BB, a member of the PDGF cytokine family, has been proved to have effects on protecting the chondrocytes via multiple mechanisms. In this study, we further focused on the effects of PDGF-BB on OA and found that PDGF-BB could attenuate OA development by inhibiting inflammation and enhancing cell proliferation via JAK2/STAT3, PI3K/AKT, and p38 signaling pathways and PKA-mediated regulation of SOX-9/RunX-2. This article demonstrates the feasibility of PDGF-BB application as a treatment for OA. This is the first article that reports that PDGF-BB attenuates OA development via PKA-mediated regulation of SOX-9 and RunX-2.

Investigation on the Attainment of High-Density 316L Stainless Steel with Selective Laser Sintering.

Due to the low density of the green part produced by selective laser sintering (SLS), previous reports mainly improve the sample's density through the infiltration of low-melting metals or using isostatic pressing technology. In this study, the feasibility of preparing high-density 316L stainless steel using 316L and epoxy resin E-12 as raw materials for SLS combined with debinding and sintering was investigated. The results indicated that in an argon atmosphere, high carbon and oxygen contents, along with the uneven distribution of oxygen, led to the formation of impurity phases such as metal oxides, including Cr2O3 and FeO, preventing the effective densification of the sintered samples. Hydrogen-sintered samples can achieve a high relative density exceeding 98% without losing their original design shape. This can be attributed to hydrogen's strong reducibility (effectively reducing the carbon and oxygen contents in the samples, improving their distribution uniformity, and eliminating impurity phases) and hydrogen's higher thermal conductivity (about 10 times that of argon, reducing temperature gradients in the sintered samples and promoting better sintering). The microstructure of the hydrogen-sintered samples consisted of equiaxed austenite and ferrite phases. The samples exhibited the highest values of tensile strength, yield strength, and elongation at 1440 °C, reaching 513.5 MPa, 187.4 MPa, and 76.1%, respectively.

Parent Acceptance toward Inactivated COVID-19 Vaccination in Children with Acute Lymphoblastic Leukemia: The Power of Oncologist and Alliance.

Objectives: The current study aims to survey the willingness of parents to vaccinate their children, who are childhood acute lymphoblastic leukemia survivors (CALLS), and identify factors associated with vaccine acceptance. Methods: Parents of CALLS on/off treatment, with the general condition of being amendable to vaccination, were recruited for interviews with attending oncologists about COVID-19 vaccination acceptance from July to November 2021 in China. After controlling for socioeconomic factors, the Association of Oncologists' recommendations and parent−oncologist alliance with acceptance status were investigated. For validation, propensity score-matched (PSM) analysis was used. Results: A total of 424 families were included in the study, with CALLS mean remission age of 5.99 ± 3.40 years. Among them, 91 (21.4%) agreed, 168 (39.6%) hesitated, and 165 (38.9%) parents disagreed with the vaccination. The most common reason that kept parents from vaccinating their children was lack of recommendations from professional personnel (84/165, 50.9%), and massive amounts of internet information (78/175, 44.6%) was the main nonhealthcare resource against vaccination. Logistic regression analysis showed that only the recommendation from the oncologist was associated with parents' vaccine acceptance (OR = 3.17, 95% CI = 1.93−5.20), as demonstrated by PSM comparison (42 in recommendation group vs. 18 in nonrecommendation group among 114 pairs, p < 0.001). An exploratory analysis revealed that parents with a better patient−oncologist alliance had a significantly higher level of acceptance (65.6% in alliance group vs. 15.6% in nonalliance group among 32 pairs, p < 0.001). Conclusions: Due to a lack of professional recommendation resources and the potential for serious consequences, parents were generally reluctant to vaccinate their CALLS. The recommendation of oncologists, which was influenced by the parent−oncologist alliance, significantly increased acceptance. This study emphasizes the critical role of oncologists in vaccinating cancer survivors and can be used to promote COVID-19 vaccines among vulnerable populations.