Objective:To assess the clinicopathological characteristics of non-muscle-invasive bladder cancers (NMIBC) with high expression of human epidermal growth factor receptor 2 (HER2) and to examine the prognostic values of HER2 expression in NMIBC patients with intravesical anthracycline instillation.Methods:A total of 221 NMIBC samples diagnosed between January 1, 2017 and April 15, 2024 were collected. Their clinical, diagnostic and treatment features were analyzed. The expression of HER2 protein and the Ki-67 proliferation index were assessed using immunohistochemistry (IHC). For the patients with HER2 high-expression (IHC 3+), the clinical pathological features (age, gender, tumor grade, Ki-67 expression level, tumor size, and tumor number) were compared with those without (i.e., HER2 IHC 0/1+/2+). The impact of HER2 expression on the recurrence-free survival (RFS) of patients with intravesical anthracycline (epirubicin or pirarubicin) instillation after transurethral resection of bladder tumor (TURBT) was evaluated.Results:Among the 221 NMIBC patients, 30 (13.6%) were HER2 IHC 3+, 142 (64.3%) HER 2+, 46 (20.8%) HER2 1+, and 3 (1.4%) HER2 IHC 0. The proportion of high-grade tumors in patients with HER2 high-expression was higher than that in patients without (83.3% versus 44.5%, P<0.001). Additionally, a high Ki-67 index (≥20%) was more commonly noted in HER2 high-expression tumors ( P=0.003). In the patients treated with intravesical anthracycline instillation, HER2 high-expression was associated with a shorter RFS ( P<0.001). Conclusion:HER2 high-expression seems to be not only associated with worse clinicopathological features of NMIBC but also a poor RFS in NMIBC patients treated with anthracycline instillation after TURBT.

Objective:To assess the clinicopathological characteristics of non-muscle-invasive bladder cancers (NMIBC) with high expression of human epidermal growth factor receptor 2 (HER2) and to examine the prognostic values of HER2 expression in NMIBC patients with intravesical anthracycline instillation.Methods:A total of 221 NMIBC samples diagnosed between January 1, 2017 and April 15, 2024 were collected. Their clinical, diagnostic and treatment features were analyzed. The expression of HER2 protein and the Ki-67 proliferation index were assessed using immunohistochemistry (IHC). For the patients with HER2 high-expression (IHC 3+), the clinical pathological features (age, gender, tumor grade, Ki-67 expression level, tumor size, and tumor number) were compared with those without (i.e., HER2 IHC 0/1+/2+). The impact of HER2 expression on the recurrence-free survival (RFS) of patients with intravesical anthracycline (epirubicin or pirarubicin) instillation after transurethral resection of bladder tumor (TURBT) was evaluated.Results:Among the 221 NMIBC patients, 30 (13.6%) were HER2 IHC 3+, 142 (64.3%) HER 2+, 46 (20.8%) HER2 1+, and 3 (1.4%) HER2 IHC 0. The proportion of high-grade tumors in patients with HER2 high-expression was higher than that in patients without (83.3% versus 44.5%, P<0.001). Additionally, a high Ki-67 index (≥20%) was more commonly noted in HER2 high-expression tumors ( P=0.003). In the patients treated with intravesical anthracycline instillation, HER2 high-expression was associated with a shorter RFS ( P<0.001). Conclusion:HER2 high-expression seems to be not only associated with worse clinicopathological features of NMIBC but also a poor RFS in NMIBC patients treated with anthracycline instillation after TURBT.

Radioiodine-refractory thyroid cancer(RAIR-TC)refers to thyroid cancer that is unable to or difficult to benefit from 131I treatment.The type of RAIR-TC we commonly encounter is differentiated thyroid cancer(DTC),which is originally well-differentiated but gradually loses its ability to take up iodine during disease progression or after 131I treatment.Compared to DTC that can still take up 131I,RAIR-TC is more malignant,progresses more rapidly,and carries a higher risk of death.Therefore,the subsequent treatment of RAIR-TC has become a hotspot and a challenge in the field of international thyroid cancer research.The treatment of RAIR-TC has evolved through several stages,from initial radioactive iodine therapy to the introduction of targeted drugs in recent years,followed by attempts at immunotherapy,diversifying treatment options.Molecular targeted therapy,especially tyrosine kinase inhibitors(TKIs),has provided new treatment choices for RAIR-TC patients.However,resistance to single-agent targeted therapy has quickly emerged as a bottleneck in treatment efficacy.Studies have shown that the activation of the phosphoinositide3-kinase(PI3K)/protein kinase(AKT)/mammalian target of rapamycin(mTOR)pathway and epidermal growth factor receptor(EGFR)pathway is the main mechanism by which tumors evade targeted therapy.As a result,combination therapy strategies have emerged,aiming to target multiple signaling pathways and optimize the use of combined drugs to overcome single-drug resistance.Additionally,designing personalized treatment plans based on patients'molecular features(such as BRAF mutations and tumor immune phenotypes)has become a research focus.Immunotherapy,especially immune checkpoint inhibitors(ICIs)such as pembrolizumab,has shown some clinical effect in RAIR-TC patients with high level of programmed death ligand-1(PD-L1)expression.However,due to the low immunogenicity of RAIR-TC,the overall response rate to immunotherapy remains relatively low,typically ranging from 10%to 15%.In recent years,combination strategies involving targeted therapy and immunotherapy,such as the triplet therapy of BRAF inhibitors,vascular endothelial growth factor receptor(VEGFR)inhibitors,and programmed death-1(PD-1)inhibitors,have shown significant efficacy in some patients,even achieving complete remission.This offers new directions for improving the efficacy of immunotherapy,however optimizing combination therapy,overcoming resistance,and managing side effects remain key challenges for future research.Moreover,epigenetics and metabolism studies have provided new insights into the treatment of RAIR-TC.Research has shown that epigenetic mechanisms,such as DNA methylation and histone deacetylation,play important roles in the progression and resistance of RAIR-TC.Inhibitors targeting these mechanisms may restore the ability of tumor to take up radioactive iodine,thus enhancing sensitivity to 131I therapy.Although progress has been made in epigenetic research,clinical trials are still in the early stages,and further verification of their potential is needed.Tumor metabolic abnormalities,particularly changes in lactate and glutamine metabolism,play crucial roles in tumor growth and resistance.Studies have found that glutamine synthetase(GLS)inhibitors and lactate dehydrogenase A(LDHA)inhibitors can effectively suppress tumor growth and potentially reverse resistance.Thus,the development of innovative drugs targeting these metabolic pathways is becoming an important direction for future RAIR-TC treatments.Although current therapies have improved the survival of RAIR-TC patients to some extent,challenges such as resistance,toxic reactions and tumor heterogeneity remain.Future research should focus on optimizing combination treatment strategies,developing new targeted drugs,and improving the adaptability of immunotherapy in clinical trials.With the advancement of multidisciplinary collaboration and technological innovation,breakthroughs in RAIR-TC treatment are expected in the future,ultimately improving patient prognosis and quality of life.

Radioiodine-refractory thyroid cancer(RAIR-TC)refers to thyroid cancer that is unable to or difficult to benefit from 131I treatment.The type of RAIR-TC we commonly encounter is differentiated thyroid cancer(DTC),which is originally well-differentiated but gradually loses its ability to take up iodine during disease progression or after 131I treatment.Compared to DTC that can still take up 131I,RAIR-TC is more malignant,progresses more rapidly,and carries a higher risk of death.Therefore,the subsequent treatment of RAIR-TC has become a hotspot and a challenge in the field of international thyroid cancer research.The treatment of RAIR-TC has evolved through several stages,from initial radioactive iodine therapy to the introduction of targeted drugs in recent years,followed by attempts at immunotherapy,diversifying treatment options.Molecular targeted therapy,especially tyrosine kinase inhibitors(TKIs),has provided new treatment choices for RAIR-TC patients.However,resistance to single-agent targeted therapy has quickly emerged as a bottleneck in treatment efficacy.Studies have shown that the activation of the phosphoinositide3-kinase(PI3K)/protein kinase(AKT)/mammalian target of rapamycin(mTOR)pathway and epidermal growth factor receptor(EGFR)pathway is the main mechanism by which tumors evade targeted therapy.As a result,combination therapy strategies have emerged,aiming to target multiple signaling pathways and optimize the use of combined drugs to overcome single-drug resistance.Additionally,designing personalized treatment plans based on patients'molecular features(such as BRAF mutations and tumor immune phenotypes)has become a research focus.Immunotherapy,especially immune checkpoint inhibitors(ICIs)such as pembrolizumab,has shown some clinical effect in RAIR-TC patients with high level of programmed death ligand-1(PD-L1)expression.However,due to the low immunogenicity of RAIR-TC,the overall response rate to immunotherapy remains relatively low,typically ranging from 10%to 15%.In recent years,combination strategies involving targeted therapy and immunotherapy,such as the triplet therapy of BRAF inhibitors,vascular endothelial growth factor receptor(VEGFR)inhibitors,and programmed death-1(PD-1)inhibitors,have shown significant efficacy in some patients,even achieving complete remission.This offers new directions for improving the efficacy of immunotherapy,however optimizing combination therapy,overcoming resistance,and managing side effects remain key challenges for future research.Moreover,epigenetics and metabolism studies have provided new insights into the treatment of RAIR-TC.Research has shown that epigenetic mechanisms,such as DNA methylation and histone deacetylation,play important roles in the progression and resistance of RAIR-TC.Inhibitors targeting these mechanisms may restore the ability of tumor to take up radioactive iodine,thus enhancing sensitivity to 131I therapy.Although progress has been made in epigenetic research,clinical trials are still in the early stages,and further verification of their potential is needed.Tumor metabolic abnormalities,particularly changes in lactate and glutamine metabolism,play crucial roles in tumor growth and resistance.Studies have found that glutamine synthetase(GLS)inhibitors and lactate dehydrogenase A(LDHA)inhibitors can effectively suppress tumor growth and potentially reverse resistance.Thus,the development of innovative drugs targeting these metabolic pathways is becoming an important direction for future RAIR-TC treatments.Although current therapies have improved the survival of RAIR-TC patients to some extent,challenges such as resistance,toxic reactions and tumor heterogeneity remain.Future research should focus on optimizing combination treatment strategies,developing new targeted drugs,and improving the adaptability of immunotherapy in clinical trials.With the advancement of multidisciplinary collaboration and technological innovation,breakthroughs in RAIR-TC treatment are expected in the future,ultimately improving patient prognosis and quality of life.

OBJECTIVES: Spinal cord ischemia-reperfusion injury (SCIRI) remains a major challenge in the field of organ protection due to the lack of effective prevention and therapeutic strategies. Hyperglycemia, a common perioperative condition, contributes to neurological injury via multiple mechanisms. However, its role and underlying mechanism in SCIRI are still unclear. This study aims to investigate the involvement of the precursor of brain-derived neurotrophic factor (proBDNF) in hyperglycemia-induced SCIRI in mice. METHODS: Eight-week-old male C57BL/6 mice were randomly assigned to a control group (Vehicle) or a diabetes mellitus (DM) group. The DM group was established using intraperitoneal injection of streptozotocin (STZ) combined with 10% sucrose water. The Vehicle group received an equal volume of 50 mmol/L sodium citrate buffer (pH 4.5). Fasting blood-glucose levels ≥11.1 mmol/L were considered successful DM modeling. Both Vehicle and DM groups underwent SCIRI modeling via descending aortic clamping, while the Sham group underwent a sham procedure without aortic occlusion. Lower limb motor function was assessed using the Basso Mouse Scale (BMS) and its subscale (sub-BMS). Locomotor activity was evaluated using an open field test. Immunohistochemistry was performed to detect changes in neuronal nuclear protein (NeuN) and proBDNF expression in spinal cord tissues. Real-time reverse transcription polymerase chain reaction (RT-PCR) was used to measure mRNA expression of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). To explore the effect of proBDNF inhibition, diabetic mice were divided into groups: A DM+SCIRI+monoclonal anti-proBDNF antibody (McAb-proB) group received an intraperitoneal injection of 100 μg of McAb-proB 30 minutes before SCIRI modeling, and a DM+SCIRI+Vehicle group received an equal amount of isotype immunoglobulin G. BMS and sub-BMS scores were recorded, and the gene expression of inflammatory cytokines mentioned above were evaluated. RESULTS: Compared with the Vehicle+SCIRI group, the DM+SCIRI group showed significantly reduced BMS and sub-BMS scores, decreased NeuN expression, shorter total movement distance, slower locomotion, increased proBDNF expression, and elevated IL-1β, IL-6, and TNF-α mRNA levels (all P<0.05 or P<0.01). Compared with the DM+SCIRI+Vehicle group, the DM+SCIRI+McAb-proB group exhibited significantly improved BMS and sub-BMS scores and decreased mRNA expression of IL-1β, IL-6, and TNF-α (all P<0.05 or P<0.01). CONCLUSIONS Hyperglycemia exacerbates neural injury and inflammatory response in SCIRI through upregulation of proBDNF expression, delaying motor functional recovery. Antagonizing proBDNF expression can alleviate neurological damage and promote functional recovery in diabetic mice after SCIRI.
Animals ; Male ; Hyperglycemia/metabolism* ; Brain-Derived Neurotrophic Factor/genetics* ; Mice, Inbred C57BL ; Reperfusion Injury/metabolism* ; Mice ; Diabetes Mellitus, Experimental/metabolism* ; Inflammation/metabolism* ; Disease Models, Animal ; Spinal Cord/metabolism* ; Tumor Necrosis Factor-alpha/metabolism* ; Protein Precursors/genetics* ; Spinal Cord Ischemia/metabolism* ; Interleukin-6/metabolism* ; Interleukin-1beta/metabolism*

Objective::The purpose of this study was to determine the relationship between remnant-like particle cholesterol (RLP-C) and major adverse cardiovascular events (MACEs) in patients with different levels of proprotein convertase subtilisin/kexin 9 (PCSK9).Methods::From September 2007 to January 2009, 1,859 subjects in Pingguoyuan communities in Beijing were initially screened. After excluding those with bedridden status, mental illness, severe systemic diseases, and missing data, 1,680 subjects were recruited for follow up. All recruited subjects were followed up from February 2013 to September 2013 (181 subjects were lost to follow-up) and from June 2017 to September 2018 (174 subjects were lost to follow up). Finally, 1,325 subjects were included in the study. General demographic characteristics, lifestyle and behaviors, disease history and use of medication was collected. Levels of total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, fast blood glucose, RLP-C, low-density lipoprotein triglycerides and PCSK9 were measured. The levels of RLP-C (low: RLP-C ≤ 157 mg/L; high: RLP-C > 157 mg/L) and PCSK9 (low: PCSK9 ≤ 135.87 μg/L; high: PCSK9 > 135.87 μg/L) were represented using quartiles. Subjects were categorized into 4 groups according to their RLP-C and PCSK9 levels: Q4, high levels of RLP-C with high levels of PCSK9; Q3, high levels of RLP-C with low levels of PCSK9; Q2, low levels of RLP-C with high levels of PCSK9; and Q1, low levels of RLP-C with low levels of PCSK9. The association of RLP-C with MACEs in subjects with different PCSK9 levels was evaluated.Results::After a median follow-up of 9.5 years, 1,325 subjects were included in the study and a total of 191 MACEs had occurred. The incidence of MACEs was higher in the RLP-C > 157 mg/L group than the RLP-C ≤ 157 mg/L group (18.40% vs. 10.42%). Cox proportional hazards regression model analysis showed that increased RLP-C levels were associated with an increased risk of MACEs (hazard ratio: 1.405; 95% confidence interval: 1.005-1.964; P < 0.005). The incidence of MACEs was higher in the high RLP-C/PCSK9 group vs. the low RLP-C/PCSK9 group (20.68% vs. 8.76%). Cox proportional hazards regression model analysis showed that RLP-C was associated with an increased risk of MACEs in subjects with high PCSK9 levels independent of traditional risk factors (hazard ratio: 1.791; 95% confidence interval: 1.168-2.825; P = 0.001), but not in those with low PCSK9 levels. Conclusions::RLP-C was identified as a risk factor for MACEs, particularly in subjects with high PCSK9 levels. Lowering PCSK9 levels may reduce residual risk in subjects with elevated plasma RLP-C levels.

Objective::The purpose of this study was to determine the relationship between remnant-like particle cholesterol (RLP-C) and major adverse cardiovascular events (MACEs) in patients with different levels of proprotein convertase subtilisin/kexin 9 (PCSK9).Methods::From September 2007 to January 2009, 1,859 subjects in Pingguoyuan communities in Beijing were initially screened. After excluding those with bedridden status, mental illness, severe systemic diseases, and missing data, 1,680 subjects were recruited for follow up. All recruited subjects were followed up from February 2013 to September 2013 (181 subjects were lost to follow-up) and from June 2017 to September 2018 (174 subjects were lost to follow up). Finally, 1,325 subjects were included in the study. General demographic characteristics, lifestyle and behaviors, disease history and use of medication was collected. Levels of total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, fast blood glucose, RLP-C, low-density lipoprotein triglycerides and PCSK9 were measured. The levels of RLP-C (low: RLP-C ≤ 157 mg/L; high: RLP-C > 157 mg/L) and PCSK9 (low: PCSK9 ≤ 135.87 μg/L; high: PCSK9 > 135.87 μg/L) were represented using quartiles. Subjects were categorized into 4 groups according to their RLP-C and PCSK9 levels: Q4, high levels of RLP-C with high levels of PCSK9; Q3, high levels of RLP-C with low levels of PCSK9; Q2, low levels of RLP-C with high levels of PCSK9; and Q1, low levels of RLP-C with low levels of PCSK9. The association of RLP-C with MACEs in subjects with different PCSK9 levels was evaluated.Results::After a median follow-up of 9.5 years, 1,325 subjects were included in the study and a total of 191 MACEs had occurred. The incidence of MACEs was higher in the RLP-C > 157 mg/L group than the RLP-C ≤ 157 mg/L group (18.40% vs. 10.42%). Cox proportional hazards regression model analysis showed that increased RLP-C levels were associated with an increased risk of MACEs (hazard ratio: 1.405; 95% confidence interval: 1.005-1.964; P < 0.005). The incidence of MACEs was higher in the high RLP-C/PCSK9 group vs. the low RLP-C/PCSK9 group (20.68% vs. 8.76%). Cox proportional hazards regression model analysis showed that RLP-C was associated with an increased risk of MACEs in subjects with high PCSK9 levels independent of traditional risk factors (hazard ratio: 1.791; 95% confidence interval: 1.168-2.825; P = 0.001), but not in those with low PCSK9 levels. Conclusions::RLP-C was identified as a risk factor for MACEs, particularly in subjects with high PCSK9 levels. Lowering PCSK9 levels may reduce residual risk in subjects with elevated plasma RLP-C levels.

Objective:To evaluate the kinetic metrics changes of FDG in key organs after chemo-immunotherapy in patients with locally advanced non-small cell lung cancer (NSCLC) identified by total-body PET/CT dynamic imaging, and explore its potential biological significance.Methods:From August 2020 to March 2021, 16 patients (13 males, 3 females; age: 43-67 years) with locally advanced NSCLC who underwent total-body 18F-FDG PET/CT dynamic imaging in Sun Yat-sen University Cancer Center were retrospectively analyzed. ROIs of key organs were drawn at baseline and after chemo-immunotherapy to obtain the time-activity curves (TACs). The kinetic metrics, including K1, k2, k3 and metabolic rate of FDG (MR FDG), were fitted by the two-tissue compartment model. Paired t test or Wilcoxon signed rank test was used to compare the differences of FDG kinetic parameters in each organ before and after treatment. Results:Compared with baseline, SUV max of colon (3.23±1.29 vs 4.81±2.73), MR FDG ((2.77±1.96) vs 3.56(1.07, 9.89) μmol·100 g -1·min -1) of lungs, SUV max (2.16±0.27 vs 2.33±0.41), k3 ((0.008±0.002) vs (0.012±0.004) min -1) and MR FDG ((2.65±0.81) vs (3.76±1.59) μmol·100 g -1·min -1) of spleen, and SUV max (2.59±0.45 vs 4.49±2.73), k2 ((0.76±0.37) vs (1.27±0.66) min -1), k3 ((0.032±0.007) vs (0.066±0.029) min -1) and MR FDG ((5.14±1.44) vs (8.39±2.67) μmol·100 g -1·min -1) of bone marrow were increased after chemo-immunotherapy with significant differences ( t values: from -5.40 to 3.47, z=-2.02, all P<0.05). There were no significant differences of SUV max, k values and MR FDG in other organs ( t values: from -2.00 to 2.35, z values: from -1.45 to -0.05, all P>0.05). Conclusions:After chemo-immunotherapy, the activation of immune system may be manifested as the increase of FDG kinetic rate constants in spleen and bone marrow. The lung and colon may be target organs for immune-related adverse effects.

Objective:To analyze the association between thyroglobulin antibody (TgAb) and differentiated thyroid cancer (DTC) metastases detected by post-radioactive iodine (RAI) therapy scan, when stimulated thyroglobulin (sTg) <1 μg/L.Methods:A total of 314 (68 males, 246 females, age (44.5±12.5) years) post-thyroidectomy DTC patients whose sTg <1 μg/L between March 2013 and May 2017 in Henan Cancer Hospital were enrolled retrospectively. Patients underwent 131I whole-body planar imaging ( 131I-WBS) and SPECT/CT imaging 5 d after 131I administration. Iodine avid metastases were compared between TgAb-positive group and TgAb-negative (TgAb<4 kU/L) group. Logistic regression analysis was conducted to assess odds ratio ( OR) for iodine avid metastases in each subgroup (Q1: 4 kU/L≤TgAb≤9.27 kU/L; Q2: 9.27 kU/L101.43 kU/L) of TgAb-positive patients, with the TgAb-negative patients as the reference. χ2 test was used to analyze the data. Results:Iodine avid metastases were found in 16.9% (53/314) of DTC patients and were more frequently in TgAb-positive group with TgAb>26.75 kU/L than TgAb-negative group (26.0%(19/73) vs 13.7%(23/168); χ2=5.382, P=0.02). Most metastases (92.5%, 49/53) occurred in cervical and mediastinal lymph nodes. The OR for iodine avid metastases was obviously high in TgAb-positive patients with 26.75 kU/L

Objective:To investigate the diagnostic efficacy of 99Tc m-MIBI SPECT dual-phase imaging combined with rapid parathyroid hormone detection in thyroid cancer with suspected parathyroid mass. Methods:Data of 76 cases of thyroid cancer with suspected cervical parathyroid gland tumors receiving colorectal ultrasonography or CT examination in Thyroid Surgery Department of the Affiliated Cancer Hospital of Zhengzhou University were retrospectively analyzed. Blood samples were taken before surgery to detect parathyroid hormone. Parathyroid hormone was quickly detected after clamping the tumor blood vessels during surgery. Based on the postoperative pathological results, the sensitivity, specificity, accuracy and consistency of various diagnostic methods were evaluated. The ROC curve was drawn by measuring the value of the parathyroid gland concentration after reduction of the tumor blood vessels by clamping the tumor.Results:The sensitivity and accuracy of the 99Tc m-MIBI SPECT dual-phase imaging combined with the rapid detection of parathyroid hormone in diagnosis of suspected parathyroid tumors were (96.5%, 93.4%) better than the 99Tc m-MIBI SPECT dual-phase imaging methods (77.6%, 78.9%) and intraoperative rapid detection methods (86.2%, 82.8%) , and had a high consistency with the results of pathological examination, Kappa value of 0.81. The combined detection rate of suspected parathyroid tumors was significantly higher than that of 99Tc m-MIBI SPECT dual-phase imaging and rapid intraoperative detection, but there was no significant difference between 99Tc m-MIBI SPECT dual-phase imaging and intraoperative rapid detection. The area under the ROC curve of the reduction ratio a value after clamping the blood vessels of the tumor was 0.774, and the standard error was 0.073. The difference was statistically significant ( P<0.001,95% CI:0.631-0.918) . According to the results obtained by the ROC, the index (sensitivity + specificity-1) was plotted on the ordinate and a was the abscissa. The maximum value of the Jordan index was 0.584. The a value corresponding to this point was 0.52. 0.52 is the DCP value. The corresponding sensitivity, specificity, accuracy was 86.2%,72.2%,and 82.9%. Conclusion:99Tc m-MIBI SPECT dual-phase imaging combined with rapid parathyroid hormone detection during surgery has good diagnostic value for thyroid cancer with suspected parathyroid mass, and is completely consistent with pathological diagnosis.