[High expression of UBE2S promotes progression of hepatocellular carcinoma by increasing cancer cell stemness].

OBJECTIVE: To investigate the expression of the ubiquitination enzyme UBE2S in different cell types in hepatocellular carcinoma (HCC) microenvironment and its impact on proliferation and stemness of HCC cells. METHODS: TCGA and CPTAC database were used to analyze the transcriptional and promoter methylation levels and protein expressions of UBE2S in HCC. Specific expression patterns of UBE2S, intercellular communication and key transcription factors in different cell types were analyzed based on single-cell sequencing data from TISCH website. We further examined UBE2S expressions in clinical samples of HCC tissues, HCC cells and T cells using immunohistochemistry and immunofluorescence staining. We also tested the effects of UBE2S knockdown on stemness of HCC-LM3 and HepG2 cells using clone formation experiments and sphere formation assay. RESULTS: Analysis based on TCGA database suggested significant overexpression of UBE2S in both paired and non-paired tumor tissues (P < 0.001), and its transcriptional level increased with tumor grades. The methylation level of UBE2S promoter was significantly decreased in HCC (P < 0.001), and its transcription level increased obviously in HCC with TP53 mutation (P < 0.001). Analysis of CPTAC database also demonstrated overexpression of UBE2S protein in HCC tissues (P < 0.001). Three prognostic models suggested that HCC patients with high UBE2S expression had poorer prognosis (P < 0.001). Single-cell sequencing data analysis revealed high expressions of UBE2S in T cells and high intensities of interaction between endothelial cells, epithelial cells and fibroblasts in HCC microenvironment. Immunohistochemistry and immunofluorescence staining demonstrated high UBE2S expressions in clinical samples of HCC tissues, HCC cells and T cells. In HCC-LM3 and HepG2 cells, UBE2S knockdown significantly inhibited cell clone formation and tumor sphere formation (P < 0.05). CONCLUSION: UBE2S is highly expressed in T cells in HCC microenvironment in close correlation with a poor prognosis. High UBE2S expression promotes the stemness of HCC cells.

[Feasibility and efficacy of pre-management of superior laryngeal artery in endoscopic surgery for hypopharyngeal cancer].

Objective: To explore the feasibility and efficacy for the dissection and ligation of the superior laryngeal artery in endoscopic surgery for hypopharyngeal cancer. Methods: Eight cadaveric heads were selected, and the laryngopharynxes were harvested. The positions of the superior laryngeal arteries entering the larynxes were dissected and observed under endoscopic vision, and their anatomical characteristics were summarized. Twenty-nine patients (all were male, aged 39-74 years old) with hypopharyngeal cancer who underwent transoral endoscopic surgery at the Department of Otorhinolaryngology Head and Neck Surgery of the Second Xiangya Hospital, Central South University from January 2018 to December 2019 were selected, and the patients were randomly divided into two groups by drawing lots, namely, the superior laryngeal artery was actively dissected and occluded during surgery in observation group (n=15) or not in control group (n=14). The differences in surgical time, bleeding volume, postoperative complications, and postoperative disease-free survival rate were compared between the two groups. Statistical analysis was conducted using SPSS 25.0 software. Results: The entry point of the superior laryngeal artery into the larynx was approximately at the level of the superior edge of the thyroid cartilage, and entered the larynx at the posterior one-third of the lateral wall of the pyriform fossa. The superior laryngeal artery might be determined through endoscopic exploration in all patients of observation group. The endoscopic surgery time [(40.00±7.56) minutes] and intraoperative bleeding volume [(24.00±8.28) ml] in the observation group were respectively less than those [(48.57±14.06) minutes and (42.86±15.41) ml] in the control group, and the differences were statistically significant (t=-2.064, P=0.049; t=-4.064, P=0.001). There was no case with postoperative bleeding in the observation group, but with one case of postoperative bleeding in the control group. Total disease free survival rate was 86.2% and there was no significant difference in disease free survival rates between the two groups during a follow-up period of at least 36 months (P=0.986). Conclusion: Dissection of the superior laryngeal artery during endoscopic surgery for hypopharyngeal cancer is feasible, and pre-management and occlusion of the superior laryngeal artery can effectively reduce intraoperative bleeding.

[Early efficacy and safety of mini open (air/water medium) endoscopy assisted anterior cervical discectomy and fusion in the treatment of cervical spondylotic myelopathy].

Objective: To investigate the efficacy and safety of mini open (air/water medium) endoscopy assisted anterior cervical discectomy and fusion (MOEA-ACDF) for the treatment of cervical spondylotic myelopathy (CSM). Methods: A follow-up study. The clinical data of 30 patients with CSM treated by MOEA-ACDF from January to December in 2021 in the Henan NO.3 Provincial People's Hospital were retrospectively analyzed. Of the patients, 20 were male and 10 were female, the mean age was (49.8±9.3) years (ranged 28-70 years). The CSM occurred at C3-4 level in 2 cases, at C4-5 level in 3 cases, at C5-6 level in 22 cases and at C6-7 level in 3 cases. Each case was compared at the moment of pre-operation and final follow-up by the Japanese Orthopedic Association (JOA) score, C2-7 Cobb angle, and anterior column height of surgical segment. The postoperative complications were recorded. Prevertebral soft tissue edema and hydrops were assessed. The fusion rate was evaluated. The JOA improvement rate was computed at the final follow-up. Results: All the operations were successfully completed and all the patients received follow-up for (12.7±2.7) months (ranged 9-20 months). The mean operation time was (85.3±11.0) min (ranged 65-110 min). The postoperative drainage volume was (16.7±7.4) ml (ranged 5-35 ml). The JOA score and the C2-7 Cobb angle both improved at the final follow-up when compared with those before the operation (15.3±1.3 vs 12.2±2.3, 15.5°±6.1° vs 12.3°±6.0°, both P<0.001). The anterior column height of surgical segment at the final follow-up was (35.6±2.5) mm, and it was higher than that before the operation [(34.1±2.4) mm](P<0.001). No postoperative complications such as dysphagia, hoarseness, cerebrospinal fluid leakage, nerve injury, hematoma occurred. Postoperative review of cervical MRI revealed 3 cases of prevertebral soft tissue edema and hydrops without obvious symptoms. At the final follow-up, cervical spine X-ray or CT showed that all fusion segments met the criteria for osseous fusion, and the fusion rate was 100%. No complications such as neurological aggravation, internal fixation failure, fusion cage sinking, and adjacent segment degeneration was recorded at the final follow-up. At the final follow-up, the comprehensive efficacy evaluated by JOA improvement rate indicated the excellent and good rate was 90.0%(27/30): 19 cases got an excellent outcome, 8 cases got good and 3 cases got medium outcome. Conclusion: MOEA-ACDF combines the endoscopic system with ACDF technology in the treatment of CSM can achieve satisfactory clinical efficacy with high safety, and effectively restore the cervical intervertebral height and physiological curvature.

[Efficacy, prognosis and influencing factors of transcatheter arterial embolization in the treatment of neuroendocrine neoplasm liver metastases].

Objective: To evaluate the efficacy of transcatheter arterial embolization (TAE) in the treatment of neuroendocrine neoplasm liver metastases (NENLM), analyze the prognosis and related factors. Methods: Clinical data of NENLM patients treated with TAE in the First Affiliated Hospital of Nanjing Medical University from January 2018 to March 2022 were retrospectively analyzed. Objective response rate (ORR), disease control rate (DCR), and adverse event rate after TAE were evaluated according to the Response Evaluation Criteria In Solid Tumors and the Common Terminology Criteria for Adverse Events. The prognosis was evaluated by median overall survival (mOS) and median progression-free survival (mPFS). The survival curve was plotted by Kaplan-Meier method. Multivariate Cox regression was used to analyze prognostic factors. Results: A total of 39 NENLM patients were included in this study, aged (53.3±10.3) (23-74) years old, including 23 males and 16 females. Among them, 9 cases had functional neuroendocrine neoplasms. There were 31 cases with primary sites locating in the digestive system, 32 cases with WHO G1 and G2 primary sites, 27 cases with abundant blood supply for liver metastases and 13 cases with liver tumor load >50%. Thirty patients received treatment of long-acting somatostatin analogue(SSA). A total of 123 TAE were performed in 39 cases, with an ORR of 38.5% (15/39) and a DCR of 76.9% (30/39). There were no serious adverse events of level 4-5 during the perioperative period. The median follow-up was 38.7 (95%CI: 31.3-46.1) months, with mOS of 37.3(95%CI: 27.0-47.5) months and mPFS of 12.6 (95%CI: 7.1-18.1) months. Multivariate Cox regression analysis found that the combination of long-term SSA treatment was an influencing factor for overall survival of patients (HR=0.207, 95%CI: 0.076-0.567, P=0.002). Conclusions: TAE can effectively reduce the load of liver metastases in patients with NENLM, and the combination of long-term SSA treatment can improve the ovreall survival of patients.

[Relationship between blood uric acid levels and body composition in patients with polycystic ovary syndrome].

Objective: To analyze the difference in blood uric acid levels between patients with polycystic ovary syndrome (PCOS) and healthy women of childbearing age, and to investigate the correlation between body composition and blood uric acid levels. Methods: A total of 153 eligible childbearing age patients with PCOS treated at Tianjin Medical University General Hospital from January 2018 to March 2022 were selected, and 153 healthy women with normal menstruation were selected as the control group. Fasting blood uric acid levels were measured by venous blood test, and body composition was measured by a body composition analyzer. Group comparisons were made to analyze the correlation between body composition and blood uric acid levels. Results: The incidence of hyperuricemia was higher in patients with PCOS than that in the control group [30.1% (46/153) vs 2.0% (3/153)], with a statistically significant difference (χ2=44.429, P<0.001). Blood uric acid level was also significantly higher in patients with PCOS than that in the control group [(371±98) vs (265±67) µmol/L; t=11.170, P<0.001]. Among PCOS patients, there were statistically significant differences in weight, body mass index (BMI), body fat mass, skeletal muscle mass, percent body fat, lean body weight, fat mass/lean body weight, percent skeletal muscle, and visceral fat level between the hyperuricemia group and the normal blood uric acid group (all P<0.001), but no significant difference was observed in waist-hip ratio (P=0.348). The following body composition indicators: weight, BMI, waist-hip ratio, body fat mass, skeletal muscle mass, percent body fat, visceral fat level, lean body weight, and fat mass/lean body weight in all subjects, the PCOS patients and the control group, were positively correlated with blood uric acid levels (all P<0.01). The blood uric acid level in PCOS obese patients was higher than that in non-obese PCOS patients, and the difference was statistically significant [(425±83) vs (336±91) µmol/L; t=6.133, P<0.001]. The blood uric acid level in central obesity PCOS patients was also higher than that in non-central obesity PCOS patients [(385±95) vs (299±79) µmol/L], the difference was statistically significant (t=4.261, P<0.001). The blood uric acid level in normal-weight obese PCOS patients was higher than that in normal-weight non-obese PCOS patients [(333±73) vs (277±54) µmol/L], and the difference was statistically significant (t=2.848, P=0.006). Blood uric acid levels in normal-weight [(315±74) vs (255±67) µmol/L], overweight [(362±102) vs (276±57) µmol/L], and obese PCOS patients [(425±83) vs (303±74) µmol/L] were all higher than those in the corresponding control groups, with statistically significant differences (all P<0.001). Conclusions: PCOS patients have a higher incidence of hyperuricemia than healthy women of childbearing age. Blood uric acid levels are closely correlated with body composition indicators, such as weight, BMI, waist-hip ratio, body fat mass, skeletal muscle mass, percent body fat, and visceral fat level. Body composition analysis of women with PCOS could help identify potentially obese people more accurately and carry out individualized treatment, thereby reducing the risk of metabolic abnormalities.

[Application of supraclavicular fasciocutaneous island flap for reconstruction after removal of tumors in parotid and auricle area].

Objective: To evaluate the efficacy of supraclavicular fasciocutaneous island flap (SIF) for repairing the defect of parotid or auricle regions after tumor resection. Methods: From February 2019 to June 2021, 12 patients (11 males and 1 female, aged 54-77 years old), of whom 4 with parotid adenoid cystic carcinoma and 8 with auricular basal cell carcinoma underwent reconstruction surgery for postoperative defects in the parotid gland area and auricular area with SIF in the Department of Otorhinolaryngology Head and Neck Surgery, the Second Xiangya Hospital of Central South University and their clinical data were retrospectively analyzed. Size of the SIF, time for harvesting SIF, neck lymph node dissection and postoperative complications were recorded. Results: The flap areas were (6-9) cm × (8-13) cm, and the harvesting time for SIF ranged from 40 to 80 min, averaging 51.7 min. The donor sites were directly closed. All patients underwent ipsilateral levels Ⅰ-Ⅲ neck dissection, with 4 cases undergoing additional level Ⅳ neck dissection and 2 cases undergoing level Ⅳ-Ⅴ neck dissection. Of the 12 SIF, 10 were completely survival and 2 had flap arterial crisis with partial flap necrosis, in addition, 1 had donor site wound dehiscence. With follow-up of 10-42 months, there were no tumor recurrences in 10 patients, 1 patient was lost to follow-up at 10 months postoperatively, and 1 patient experienced local tumor recurrence at 11 months after surgery and died 15 months later. Conclusion: SIF is an easily harvested flap with good skin features matching the skin in parotid and auricle regions and less damage to donor site, and this flap has no need for microvascular anastomosis technique. SIF is feasible and effective for repairing defects in parotid and auricle area.

Efficacy and safety of video-assisted thoracoscopic surgery for pulmonary TB.

OBJECTIVE: Compared with thoracotomy, video-assisted thoracoscopic surgery (VATS) has the advantage of post-operative recovery for patients undergoing surgery. However, studies comparing the efficacy of VATS with conventional traditional thoracotomy for treating patients with pulmonary TB (PTB) are inconsistent.METHODS: Five electronic databases were used to search studies on VATS and conventional thoracotomy for PTB up to 15 March 2022. Standardised mean differences (SMDs) and odds ratios (ORs) were calculated for comparison.RESULTS: A total of 14 were included. Compared with traditional thoracotomy, patients with drug-resistant TB treated using VATS had shorter operative time, less intra-operative bleeding, faster post-operative recovery and fewer post-operative complications (operation time: SMD -0.87, 95% CI -1.29 to -0.45; blood loss: SMD -1.31, 95% CI -1.71 to -0.92; duration of hospital stay: SMD -1.68, 95% CI -2.46 to -0.90; catheterisation time: SMD -1.56, 95% CI -2.39 to -0.73; post-operative complication: OR 0.40, 95% CI 0.27 to 0.60).CONCLUSION: Compared with conventional thoracotomy, VATS for patients with multidrug-resistant PTB undergoing lobectomy and wedge resection has the advantages of minor bleeding, shorter operative time, shorter hospital stay and post-operative pleural cavity drainage duration, and fewer post-operative complications, which can accelerate the post-operative recovery of patients.

Baicalin alleviates silica-induced lung inflammation and fibrosis by inhibiting TLR4/NF-?B pathway in rats.

Silicosis is an occupational lung disease caused by inhaling silica dust. The disease is characterized by early lung inflammation and late irreversible pulmonary fibrosis. Here we report the effect of Baicalin, a main flavonoid compound from the roots of Chinese herbal medicine Huang Qin on silicosis in a rat model. Results showed Baicalin (50 or 100 mg/kg/day) can mitigate the silica-induced lung inflammation and reduce the harm of alveolar structure and the blue region of collagen fibers in rat lung at 28 days after administration. At the same time, Baicalin also diminished the level of interleukin-1beta (IL-1beta, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta1 (TGF-beta1) in lung tissues. The protein expression of collagen I (Col-1), alpha-smooth muscle actin (alpha-SMA) and vimentin were down-regulated while E-cadherin (E-cad) was increased in Baicalin-treated rats. In addition, the Toll Like Receptor 4 (TLR4)/ nuclear factor kappaB (NF-kappaB) pathway was enabled at 28 days after silica infusion, and the treatment of Baicalin diminished the expression of TLR4 and NF-?B in the lungs of rat with silicosis. These results suggested that Baicalin inhibited the pulmonary inflammatory and fibrosis in a rat model of silicosis, which could be attributed to inhibition of the TLR4/NF-kappaB pathway.

[Surgical treatment for perihilar cholangiocarcinoma:a single-center experience].

Objective: To investigate surgical strategies and the corresponding benefits for patients with perihilar cholangiocarcinoma(pCCA). Methods: A total of 81 patients with pCCA who underwent radical excision in the Department of Biliary and Pancreatic Surgery of Sun Yat-Sen Memorial Hospital between January 2014 and December 2021 were retrospectively collected.The cohort consisted of 50 male and 31 female patients,with an age of (62.5±11.5)years(range:26 to 83 years).Seventy-five cases were diagnosed with jaundice,60 of whom received preoperative biliary drainage,while 20 patients received portal vein embolization.Their serum bilirubin level within one week before the operation(M(IQR)) was 44.3 (41.9) µmol/L(range:8.0 to 344.2 µmol/L).Preoperative imaging examinations were performed to evaluate the Bismuth-Corlette type of pCCA,showing 3,6,21,27,and 24 cases of Bismuth-Corlette type Ⅰ,Ⅱ,Ⅲa,Ⅲb,and Ⅳ,respectively.The primary outcome was overall survival (OS),and the secondary outcomes were relapse-free survival (RFS),90-day postoperative morbidity and 90-day postoperative mortality.OS and RFS were estimated using the Kaplan-Meier method and compared by the Log-rank test.Significant prognostic factors were determined using univariate and multivariable Cox proportional hazard regression analyses. Results: In the cohort of 81 pCCA patients,67 cases(82.7%) underwent major hepatectomy while 3 cases received major hepatectomy combined with pancreaticoduodenectomy.Thirty-four patients underwent hepatectomy combined with vascular resection and reconstruction(18 cases of portal vein resection and reconstruction alone;9 cases of hepatic artery resection and reconstruction alone;7 cases of combination of portal vein and hepatic artery resection and reconstruction).Margin negative(R0 excision) were achieved in 53.1%(43/81) of these patients.The operation duration was (627±136)minutes(range:565 to 940 minutes),and the intraoperative blood loss was 400(455)ml(range:200 to 2 800 ml).The 90-day postoperative mortality was 3.7%(3/81).Grade 3-4 postoperative morbidity was 23.4% (19/81) according to the Clavien-Dindo classification of surgical complications.Up to the last follow-up at September 2022,the follow-up time was 34.0(24.2)months (range:0.4 to 103.6 months).Three patients who died within 90 days after surgery were excluded from the survival analysis.The median OS was 36.10 months (95%CI:18.23 to 42.97 months) and the 1-,3-and 5-year OS rates were 85.3%,46.8% and 27.3%,respectively.The median OS of 41 patients with negative margins was 47.83 months(95%CI:36.90 to 58.80 months) and that of 37 patients with positive margins was 20.47 months(95%CI:10.52 to 30.58 months).The median RFS of 70 patients with R0 and R1 resection was 24.50 months(95%CI:12.15 to 31.85 months)and the 1-,3-and 5-year RFS rates were 65.2%,45.7% and 29.9%,respectively.The median RFS of 41 patients with R0 resection was 38.57 months(95%CI:21.50 to 55.63 months) and that of 29 patients with R1 resection was 10.83 months(95%CI:2.82 to 19.86 months). Conclusions: The primary therapy for pCCA is radical surgical resection.A precise preoperative evaluation and sufficient preparation can reduce postoperative morbidity.Surgical treatment can achieve a better survival outcome by increasing the radical resection rate.

[Prognosis and risk factors for mortality in cirrhotic patients with probable spontaneous bacterial peritonitis].

OBJECTIVE: To investigate the survival outcomes and risk factors for mortality in cirrhotic patients with probable spontaneous bacterial peritonitis (SBP). METHODS: We retrospectively analyzed the clinical data of 323 cirrhotic patients with ascites admitted from June 2021 to May 2022, including 115 patients with SBP [ascites polymorphonuclear leucocyte (PMN) count ≥250/mm3], 52 patients with bacterascites (PMN count < 250/mm3 with positive microbiological finding in ascites), 67 patients with probable SBP (PMN count < 250/mm3 with negative microbiological finding in ascites but clinical symptoms of SBP) and 89 patients without infection (PMN count < 250/mm3 with negative microbiological finding without clinical symptoms of SBP). The clinical characteristics, laboratory data and 90-day mortality of the patients were compared among the 4 groups. Cox proportional hazard model and propensity score matching (PSM) in a 1∶1 ratio were used to analyze the risk factors for mortality in patients with probable SBP. RESULTS: The patients with probable SBP had a 90-day mortality rate of 43.28%, similar to those of patients with SBP (46.95%, P=0.121) and bacterascites (48.07%, P=0.805) but significantly higher than that of non-infected patients (11.23%, P < 0.001). In the 46 pairs of patients matched using PSM, the 90-day mortality rates were higher in probable SBP group than in non-infected group both before (43.28% vs 11.23%, P < 0.001) and after PSM (34.78% vs 15.21%, P=0.038). Cox regression analysis indicated that probable SBP was an independent predictor of 90-day mortality in cirrhotic patients with ascites (HR=1.539, 95% CI: 1.048-2.261, P=0.028). A Model for End-Stage Liver Disease (MELD) score > 15 (HR=1.943, 95% CI: 1.118-3.377, P=0.018) and procalcitonin level > 0.48 ng/mL (HR=1.989, 95% CI: 1.111-3.560, P=0.021) at diagnostic paracentesis were both independent risk factors for 90-day mortality in patients with probable SBP. CONCLUSION: Cirrhotic patients with probable SBP have poor survival outcomes, and their management should be further optimized based on their MELD score and procalcitonin level.

[Correlation between daily fluid intake behavioral habits and pathological characteristics of upper tract urothelial carcinoma].

OBJECTIVE: To investigate the correlation between drinking habits and pathological characteristics of patients with upper tract urothelial carcinoma (UTUC). METHODS: A preoperative questionnaire survey was conducted to understand the drinking habits of UTUC patients who were admitted to the Department of Urology, Peking University First Hospital for radical nephroureterectomy within one year from August 2020 to July 2021, and statistical analysis was performed in combination with their postoperative pathological characteristics. The statistical procedure was performed using SPSS 22.0 software, and firstly, the preliminary analysis was performed one by one using the columnar χ2 test on the pathological characteristics of UTUC tumors as the dependent variable and the factors related to patients' general information, past history and drinking habits as the independent variables, and the independent variables that met P < 0.2 between the case and control groups for each dependent variable were specified for screening. The screened variables were included in the binary Logistic regression analysis. A difference of P < 0.05 was used to indicate a statistically significant difference. RESULTS: A total of 239 patients, 134 males and 105 females, with a mean age of (68.1±9.98)years and a median disease duration of 4.8 months, were included in this study. Multifactorial Logistic regression results suggested that after adjusting for the effects of other variables, UTUC patients who had the habit of drinking at least once every hour during the daytime had a significantly increased risk of high grade (G3) tumors(OR=1.941, 95%CI: 0.352-1.029, P < 0.01); these patients also had a significantly decreased risk of multifocal UTUC tumors (OR=0.344, 95% CI: 1.18-5.582, P=0.004). The patients who had the habit of drinking over 100 mL water each time had a significantly decreased risk of mutifocal UTUC incidence (OR=0.477, 95%CI: 0.225-1.012, P=0.046). Patients who pay attention to daily water intakes had a significantly increased risk of renipelvic carcinoma (OR=2.530, 95%CI: 1.434-4.463, P=0.001) and a significantly decreased risk of ureteral carcinoma (OR=0.314, 95%CI: 0.172-0.573, P < 0.01). Other variables included in the regression model did not differ significantly in their effects on the occurrence of tumor pathological characteristics. CONCLUSION: Having the awareness of drinking water every 1 h during the day, drinking over 100 mL water each time, having the awareness of daily drinking habits correlated significantly with pathological characteristics of UTUC such as the presence of G3 tumor, multifocal tumors and location of the tumor. This conclusion still needs to be verified by subsequent trials with higher levels of evidence.

[Clinical features of immune checkpoint inhibitor-related myositis in patients with urological cancer].

OBJECTIVE: Immune checkpoint inhibitors (ICI) have significantly improved the treatment efficacy of a variety of malignant tumors. However, patients may experience a series of special side effects during treatments with ICI. Immune-related myositis after ICI treatment is characterized by autoimmune rheumatic and musculoskeletal damage, which is relatively rare. To analyze the clinical characteristics and outcomes of ICI-associated myositis in urological tumors, we summarized the clinical manifestations, electrophysiological and pathological characteristics, treatments and outcomes in 8 patients. METHODS: The clinical data of the 8 patients with immune-related myositis after ICI treatment for urological tumors treated in the Department of Urology, Peking University First Hospital from March 2018 to March 2022 were retrospectively analyzed for demographic characteristics, drug regimen, clinical symptoms, laboratory indices, electromyography examination, pathological manifestations and outcomes. RESULTS: The eight patients included 2 females and 6 males with a median age of 68 years, all treated with ICI for urological neoplasms, including 2 upper tract urothelial carcinoma (UTUC), 3 renal cell carcinoma (RCC), and 3 bladder cancer (BCa). The median time between the first ICI treatment and the detection of immune-related myositis was 39.5 days, and the median duration of treatment was 2 sessions. The main symptoms were muscle pain and weakness, 5 cases with ptosis, 3 cases with secondary rhabdomyolysis, 5 cases with myocarditis, 1 case with myasthenia gravis, and 1 case with enterocolitis. Among them, patients with immune-related myocarditis had a shorter interval from the first anti-programmed cell death protein-1 (PD-1) therapy to the onset of immune-related myositis (P=0.042) compared with patients without myocarditis. The 8 patients had significant elevation of transaminases and muscle enzyme profile indexes, and 5 patients showed positive auto-antibodies. 3 patients had perfected muscle biopsies and showed typical skeletal muscle inflammatory myopathy-like pathological changes with CD3+, CD4+, CD8+, CD20+ lymphocytes and CD68+ macrophage infiltration. After the diagnosis of immune-related myositis, all the 8 patients immediately discontinued ICI therapy and improved after intravenous administration of methylprednisolone alone or in combination with gamma-globulin. CONCLUSION: Immune-related myositis after ICI treatment is an immune-related adverse reactions (irAEs) with unique clinical and pathological features, commonly combined with cardiovascular adverse reactions. Immediate discontinuation of ICI and initiation of glucocorticoid therapy may improve the patient's condition in a timely manner.

[Numerical simulation modeling of middle ear-eustachian tube ventilation based on Chinese digital visual human body].

Objective: To establish a three-dimensional model of middle ear-eustachian tube based on Chinese digital visual human dataset, and the deformation and pressure changes of the middle ear-eustachian tube system after eustachian tube opening are simulated by computer numerical simulation. Methods: The first female Chinese Digital Visual Human data was adopted. The images were imported by Amira image processing software, and the images were segmented by Geomagic software to form a three-dimensional model of middle ear-eustachian tube system, including eustachian tube, tympanum, tympanic membrane, auditory ossicles, and mastoid air cells system. The 3D model was imported into Hypermesh software for meshing and analysis. The structural mechanics calculation was carried out by Abaqus, and gas flow was simulated by Xflow. The tissue deformation and middle ear pressure changes during eustachian tube opening were numerically simulated by fluid-solid coupling algorithm. Several pressure monitoring points including tympanum, mastoid, tympanic isthmus, and external auditory canal were set up in the model, and the pressure changes of each monitoring point were recorded and compared. Results: In this study, a three-dimensional model of middle ear-eustachian tube and a numerical simulation model of middle ear ventilation were established, including eustachian tube, tympanum, mastoid air cells, tympanic membrane, and auditory ossicles. The dynamic changes of the model after ventilation could be divided into five stages according to the pressure. In addition, the pressure changes of tympanum and tympanic isthmus were basically synchronous, and the pressure changes of mastoid air cells system were later than that of tympanum and tympanic isthmus, which verified the pressure buffering effect of mastoid. The extracted pressure curve of the external auditory canal was basically consistent with that of tympanometry in terms of value and trend, which verified the effectiveness of the model. Conclusions: The numerical simulation model of middle ear-eustachian tube ventilation established in this paper can simulate the tissue deformation and middle ear pressure changes after eustachian tube opening, and its accuracy and effectiveness are also verified. This not only lays a foundation for further research, but also provides a new research method for the study of middle ear ventilation.

[Focused dilemmas in the diagnosis and treatment of digestive system neuroendocrine neoplasms].

Neuroendocrine neoplasms (NENs) originate from neuroendocrine cells diffusely distributed throughout the body. NENs are liable to be misdiagnosed and missed clinically, which brings great difficulties to clinical diagnosis and treatment, and seriously affects their prognosis. This article will introduce the difficulties and hot spots in the diagnosis and treatment of NENs from the aspects of laboratory and pathological examinations, anatomical and functional imaging examinations, including endoscopy, peptide receptor radionuclide therapy, somatostatin analogue and immune checkpoint inhibitor therapy. It aims to provide more ideas for the early diagnosis and early treatment of NENs, standardized diagnosis and treatment of high-grade NENs in the middle and late stages, and to provide more strategies for clinical multidisciplinary experts towards the management of focused dilemmas in NENs.

[Comparison of clinical features between sporadic pancreatic neuroendocrine tumors and those associated with multiple endocrine neoplasia type 1].

Objective: To compare the clinical features of multiple endocrine adenoma type 1 (MEN-1) associated pancreatic neuroendocrine neoplasms (pNENs) as well as sporadic pNENs. Methods: The clinical data of 28 sporadic pNENs patients and 10 MEN-1-related pNENs patients admitted to the First Affiliated Hospital of Nanjing Medical University from January 2010 to June 2021 were collected. Meanwhile, by searching PubMed database and reviewing the clinical data of 20 foreign patients with MEN-1-related pNENs which were reported at the same time.Compare and analyze the similarities and differences between MEN1-associated pNENs and sporadic pNENs in clinical features, such as family history, blood tests, pathological diagnostic indicators, tumor grade, stage and metastasis, treatment and prognosis and so on. Results: A total of 58 pNENs patients were included, and there were 30 MEN1-related pNENs patients and 28 sporadic pNENs patients. Eighteen patients (60%) had a family history of MEN1-related pNENs, and the mean age of onset was (35.3±13.0)years. There were no patients (0) with family history of sporadic pNENs, and the mean age of onset was(55.3±13.4)years. In contrast, the differences in family history, age of onset and NSE were statistically significant(all P<0.05).Among the pathological diagnostic indicators, there were 19 patients (63.3%) with Grade G2 of MEN1-related pNENs, and 25 patients (83.3%) with somatostatin receptor 2(SSTR2) negative. In sporadic pNENs, there were 16 patients (57.1%) with Grade G2 and 9 patients (32.1%) with SSTR2 negative. The differences in pathological grade, immunohistochemistry (Chromogranin A, CD56, and somatostatin receptor 2, SSTR2) between the two groups were statistically significant(all P<0.05). In terms of tumor staging and metastasis, 21 patients with MEN-1-related pNENs had metastasis (70%) and 20 patients with stage Ⅰ and Ⅱ AJCC (71%) in all. Eight patients with sporadic pNENs had metastasis (26.7%) and 8 patients were with stage Ⅰ and Ⅱ AJCC (28.6%). By contrast, the differences in total metastasis rate, AJCC stage and distant metastasis between the two groups were statistically significant(all P<0.05). In terms of treatment and prognosis, there was no statistical significance in the differences between surgical treatment and prognosis (P>0.05), and the difference was also not statistically significant in survival rate between them (P>0.05). Conclusions: There are no significant differences between MEN1-related pNENs and sporadic pNENs in terms of treatment, prognosis, and survival rate, but there are significant differences in clinical features, pathological features and the staging and grading of tumors. The rate of tumor grade, stage and metastasis of sporadic pNENs is higher.

[Efficiency and safety of peptide receptor radionuclide therapy in the treatment of metastatic neuroendocrine tumors].

The clinical data of 14 patients with neuroendocrine tumors who received Peptide Receptor Radionuclide Therapy (PRRT) from December 2018 to May 2021 were retrospectively analyzed. Among them, 2 patients demonstrated proprogressive disease, 2 patients had partial response, and 10 patients had stable disease. Grade 1-2 myelosuppression occurred in 5 patients. and 1 patient became grade 3 myelosuppression，which recovered to grade 2 after symptomatic treatment. No grade 2 or higher treatment-related renal toxicity was observed in any of the patients. PRRT is efficacy and no significant side effects for unresectable metastatic neuroendocrine tumors.

BMSC-Derived ApoEVs Promote Craniofacial Bone Repair via ROS/JNK Signaling.

Bone defect caused by trauma, neoplasia, congenital defects, or periodontal disease is a major cause of disability and physical limitation. The transplantation of bone marrow mesenchymal stem cells (BMSCs) promotes bone repair and regeneration. However, it has been shown that most BMSCs die within a short period after transplantation. During apoptosis, BMSCs generate a large number of apoptotic cell-derived extracellular vesicles (ApoEVs). This study aims to understand the potential role of ApoEVs in craniofacial bone defect repair and regeneration. First, we confirmed that BMSCs undergo apoptosis within 2 d after transplantation into the defect of the cranium. Abundant ApoEVs were generated from apoptotic BMSCs. Uptake of ApoEVs efficiently promoted the proliferation, migration, and osteogenic differentiation of recipient BMSCs in vitro. ApoEVs from cells in the middle stage of apoptosis were the most efficient to enhance the regenerative capacity of BMSCs. Moreover, a critical size bone defect model in rats was used to evaluate the osteogenic property of ApoEVs in vivo. Local transplantation of ApoEVs promoted bone regeneration in the calvarial defect. Mechanistically, ApoEVs promoted new bone formation by increasing intracellular reactive oxygen species to activate JNK signaling. This study reveals a previously unknown role of the dying transplanted BMSCs in promoting the viability of endogenous BMSCs and repairing the calvarial defects. Since it could avoid several adverse effects and limits of BMSC cytotherapy, treatment of ApoEVs might be a promising strategy in craniofacial bone repair and regeneration.

Orthodontic Force-Induced BMAL1 in PDLCs Is a Vital Osteoclastic Activator.

Orthodontic tooth movement (OTM) depends on periodontal ligament cells (PDLCs) sensing biomechanical stimuli and subsequently releasing signals to initiate alveolar bone remodeling. However, the mechanisms by which PDLCs sense biomechanical stimuli and affect osteoclastic activities are still unclear. This study demonstrates that the core circadian protein aryl hydrocarbon receptor nuclear translocator-like protein 1 (BMAL1) in PDLCs is highly involved in sensing and delivering biomechanical signals. Orthodontic force upregulates BMAL1 expression in periodontal tissues and cultured PDLCs in manners dependent on ERK (extracellular signal-regulated kinase) and AP1 (activator protein 1). Increased BMAL1 expression can enhance secretion of CCL2 (C-C motif chemokine 2) and RANKL (receptor activator of nuclear factor-κB ligand) in PDLCs, which subsequently promotes the recruitment of monocytes that differentiate into osteoclasts. The mechanistic delineation clarifies that AP1 induced by orthodontic force can directly interact with the BMAL1 promoter and activate gene transcription in PDLCs. Localized administration of the ERK phosphorylation inhibitor U0126 or the BMAL1 inhibitor GSK4112 suppressed ERK/AP1/BMAL1 signaling. These treatments dramatically reduced osteoclastic activity in the compression side of a rat orthodontic model, and the OTM rate was almost nonexistent. In summary, our results suggest that force-induced expression of BMAL1 in PDLCs is closely involved in controlling osteoclastic activities during OTM and plays a vital role in alveolar bone remodeling. It could be a useful therapeutic target for accelerating the OTM rate and controlling pathologic bone-remodeling activities.

[Feasibility and efficacy of preserving internal branch of superior laryngeal nerve in endoscopic surgery for hypopharyngeal squamous cancer: an observational study].

Objective: This study was performed to investigate the feasibility of preservation of internal branch of superior laryngeal nerve(ibSLN) during transoral endoscopic surgery for hypopharyngeal squamous cancer(HSCC) and the influence on patient's swallowing function after operation. Methods: From May 2020 to June 2021, the data of 29 HSCC patients who required for transoral endoscopic surgery in the Department of Otorhinolaryngology Head and Neck Surgery, the Second Xiangya Hospital of Central South University were prospectively included, and the included patients were divided into two groups randomly by lottery. According to whether ibSLN was actively dissected during operation, they were divided into ibSLN preservation group (n=15) and control group (n=14, without ibSLN preservation). Operation time, intraoperative hemorrhage, intraoperative neck dissection, postoperative radiotherapy, postoperative recurrence within 1 year, retention and swallowing function, the recovery of oral soft diet and the quality of life were compared between two groups. SPSS 25.0 software was used for statistical analysis. Results: The study included 29 eligible patients, including 25 males and 4 females.The age ranged from 42 to 67 (56.07±5.93) years. There were no significant differences(P>0.05) between 2 groups in the following data,including age(t=-0.56), gender(χ2=0.01), TNM stage(T stageχ2=0.29, N stage χ2=0.02), pathological diagnosis(χ2=0.03), preoperative swallowing function(χ2=0.00) and M. D. Anderson Dysphagia Inventory(MDADI) score(global t=0.55, emotional t=0.16, functional t=0.60, physical t=0.64), operation time(t=1.62) and intraoperative hemorrhage(t=-1.46), intraoperative neck dissection(χ2=0.01), postoperative radiotherapy(χ2=0.32), postoperative recurrence within 1 year(P>0.050). The swallowing function was evaluated by water swallowing test after operation. The swallowing function of ibSLN preservation group was better than control group, and the difference between two groups was statistically significant on the 1st (χ2=4.44, P=0.035), 5th (χ2=4.24, P=0.039) and 7th (χ2=4.55, P=0.033) day after operation. On the 14th day after operation, the MDADI scores of patients in the ibSLN preservation group were higher than those in the control group in global (t=2.45, P=0.021), functional (t=2.54, P=0.017) and physical (t=2.24, P=0.034) dimensions, except for emotional dimension (t=1.89, P=0.070). The median time of oral soft diet(U=23.00, P<0.001), normal oral diet(U=21.00, P<0.001) and the nasogastric tube removal time (U=18.50, P<0.001) in ibSLN preservation group was 2 days, 5 days and 6 days respectively, earlier than that in control group, which had statistically significant difference. Conclusion: Our results show that it is feasible to preserve the ibSLN during HSCC transoral endoscopic surgery, which can achieve rapid recovery of postoperative swallowing function.

[Precision medicine and renal cell carcinoma: current situation and the future].

The prevalence of renal cell carcinoma is increasing in recent years. With the development of research, we know more about the mechanism and biological characteristics of renal cell carcinoma. Currently, the most used prognosis evaluation methods are clinical factors based prognostic prediction models. New drugs, typified by the checkpoint inhibitors, have achieved great success in the treatment of renal cell carcinoma, on the basis of traditional tyrosine kinase inhibitor. With recognition of more prognosis and treatment related biomarkers, directive role for the prognosis prediction and treatment options could be expected.