ObjectiveThis paper aims to investigate the intervention effect and molecular mechanism of Gancao Fuzitang （GCFZT） in knee osteoarthritis （KOA）. MethodsNetwork pharmacology was employed to predict the key targets and signaling pathways of GCFZT. Fifty SD rats were randomly divided into a sham group， a model group （KOA）， a low-dose GCFZT group （GCFZT-L， 2.8 g·kg^-1）， a high-dose GCFZT group （GCFZT-H， 5.6 g·kg^-1）， and a positive drug celecoxib group （Celecoxib， 20 mg·kg^-1）， with 10 rats in each group. The rats in the sham group and the model group were given an equal volume of distilled water. Except for the sham group， the other four groups underwent anterior cruciate ligament transection to establish the KOA rat model. After successful modeling， the rats in each group received intragastric administration once a day for eight consecutive weeks. The structural changes of cartilage and subchondral bone were assessed via micro-computed tomography （micro-CT） and histological staining. The levels of inflammatory factors in the serum， such as interleukin-1β （IL-1β）， IL-6， and tumor necrosis factor-α （TNF-α） were measured using an enzyme linked immunosorbent assay （ELISA） kit. Real-time quantitative polymerase chain reaction （Real-time PCR）， Western blot， and immunohistochemistry were used to detect changes in the expression of autophagy-related proteins such as microtubule-associated protein 1 light chain 3B （LC3B）， selective autophagy junction protein 62 （p62）， and autophagy key molecule yeast Atg6 homolog （Beclin-1） in articular cartilage， as well as key molecules of the phosphatidylinositol 3 kinase （PI3K）/protein kinase B （Akt）/mammalian target of rapamycin （mTOR） signaling pathway. ResultsNetwork pharmacology analysis suggests that GCFZT may exert anti-osteoarthritic effects through regulating the PI3K/Akt/mTOR pathway. In vivo experiment shows that GCFZT can significantly improve cartilage degeneration and attenuate subchondral bone destruction in KOA rats. Detection results of inflammatory factors in the serum reveal that， compared with those in the sham group， the levels of IL-6， IL-1β， and TNF-α in the serum of rats in the KOA group are significantly increased （P<0.05）. Compared with those in the KOA group， the levels of these three inflammatory factors in the GCFZT-L， GCFZT-H， and Celecoxib groups were significantly decreased （P<0.05）. However， there was no statistically significant difference in these three inflammatory factor levels between the GCFZT-H group and the celecoxib group. These findings suggest that GCFZT can effectively inhibit the systemic inflammatory response in KOA rats. Mechanism research indicates that GCFZT inhibits activation of the PI3K/Akt/mTOR pathway， thereby enhancing autophagic activity and improving chondrocyte function and matrix degeneration. ConclusionGCFZT improves cartilage and subchondral bone damage in KOA rats by inhibiting the PI3K/Akt/mTOR signaling pathway and promoting autophagy. These findings provide theoretical evidence for the application of GCFZT in the prevention and treatment of osteoarthritis.

Neoadjuvant therapy for pancreatic cancer is undergoing a paradigm shift from conventional chemotherapy to precision medicine. This expert forum discussed cutting-edge issues in pancreatic cancer neoadjuvant therapy from an evidence-based perspective, incorporating the latest clinical research advances. We focused on innovative directions including immunotherapy combination strategies, liquid biopsy applications, artificial intelligence (AI)-assisted decision making, and individualized precision medicine. We proposed forward-looking concepts such as molecular subtyping-guided individualized treatment strategies, multi-omics integrated efficacy prediction models, and standardized multidisciplinary collaborative care systems. These innovative concepts will drive pancreatic cancer neoadjuvant therapy toward more precise and effective directions.

Objective:To investigate the safety and efficacy of the artery-first approach pancreaticoduo-denectomy (PD) combined with portal vein/superior mesenteric vein (PV/SMV) resection and reconstruction for pancreatic head malignancies.Methods:A retrospective analysis was conducted on 322 patients who underwent PD with PV/SMV resection and reconstruction at the Hepatobiliary Pancreatic Surgery Department of the First Hospital Affiliated to Naval Medical University between January 2016 and December 2022. Patients were divided into the artery-first approach PD group (AFA-PD group, n=165) and standard PD group (SPD group, n=157) based on surgical approach. Baseline characteristics, surgical outcomes, postoperative outcomes, pathological results and survival data were compared between two groups. Results:Compared to the SPD group, the AFA-PD group exhibited significantly reduced intraoperative blood loss (500 ml vs 600 ml), lower rates of obvious intraoperative blood loss (≥1 000 ml: 25.45% vs 40.13%), and decreased transfusion requirements (26.67% vs 52.87%). Postoperatively, the AFA-PD group demonstrated lower incidence of grade B/C pancreatic fistula (10.30% vs 19.75%) and higher textbook outcome achievement (78.79% vs 66.24%). Pathologically, the AFA-PD group achieved superior lymph node yield (20 nodes vs 18 nodes) and higher R 0 resection rates (79.39% vs 64.33%), particularly at the posterior pancreatic margin (96.97% vs 91.72%, P=0.040), SMA margin (92.07% vs 82.17%), and SMV margin (88.48% vs 78.98%). Multivariate logistic regression identified arterial invasion >180°, venous invasion >180°, lymph node metastasis, and the artery-first approach as independent predictors of R 0 resection. The AFA-PD group showed prolonged median survival (19.17 month vs 15.73 month). All aforementioned differences were statistically significant (all P value <0.05). Conclusions:The artery-first approach PD combined with PV/SMV resection and reconstruction is safe and effective for pancreatic head malignancies, significantly improving R 0 resection rates and patients' survival outcomes.

Objective:To investigate the safety and efficacy of the artery-first approach pancreaticoduo-denectomy (PD) combined with portal vein/superior mesenteric vein (PV/SMV) resection and reconstruction for pancreatic head malignancies.Methods:A retrospective analysis was conducted on 322 patients who underwent PD with PV/SMV resection and reconstruction at the Hepatobiliary Pancreatic Surgery Department of the First Hospital Affiliated to Naval Medical University between January 2016 and December 2022. Patients were divided into the artery-first approach PD group (AFA-PD group, n=165) and standard PD group (SPD group, n=157) based on surgical approach. Baseline characteristics, surgical outcomes, postoperative outcomes, pathological results and survival data were compared between two groups. Results:Compared to the SPD group, the AFA-PD group exhibited significantly reduced intraoperative blood loss (500 ml vs 600 ml), lower rates of obvious intraoperative blood loss (≥1 000 ml: 25.45% vs 40.13%), and decreased transfusion requirements (26.67% vs 52.87%). Postoperatively, the AFA-PD group demonstrated lower incidence of grade B/C pancreatic fistula (10.30% vs 19.75%) and higher textbook outcome achievement (78.79% vs 66.24%). Pathologically, the AFA-PD group achieved superior lymph node yield (20 nodes vs 18 nodes) and higher R 0 resection rates (79.39% vs 64.33%), particularly at the posterior pancreatic margin (96.97% vs 91.72%, P=0.040), SMA margin (92.07% vs 82.17%), and SMV margin (88.48% vs 78.98%). Multivariate logistic regression identified arterial invasion >180°, venous invasion >180°, lymph node metastasis, and the artery-first approach as independent predictors of R 0 resection. The AFA-PD group showed prolonged median survival (19.17 month vs 15.73 month). All aforementioned differences were statistically significant (all P value <0.05). Conclusions:The artery-first approach PD combined with PV/SMV resection and reconstruction is safe and effective for pancreatic head malignancies, significantly improving R 0 resection rates and patients' survival outcomes.

Objective:To investigate the clinical value of adjuvant therapy after conversion resection for pancreatic cancer.Methods:The retrospective cohort study was conducted. The clinicopathological data of 173 patients with pancreatic cancer who underwent surgical resection after neoadjuvant and/or induction therapy in The First Affiliated Hospital of Naval Medical University from January 2019 to December 2021 were collected. There were 107 males and 66 females, aged (59±9)years. Observation indicators: (1) comparison of clinicopathological data between patients with and without adjuvant therapy after conversion resection for pancreatic cancer; (2) analysis of influencing factors for prognosis of pancreatic cancer after conversion resection; (3) follow-up and prognosis; (4) survival benefit of adjuvant therapy in subgroup populations. Measurement data with normal distribution were represented as Mean± SD, and comparison between groups was conducted using the t test. Measurement data with skewed distribution were represented as M( Q1, Q3), and comparison between groups was conducted using the Mann-Whitney U test. Count data were expressed as absolute numbers or percentages, and comparison between groups was conducted using the chi-square test. Comparison of ordinal data was conducted using the non-parameter rank sum test. The Graphpad prism 8 software was used to draw survival curves, the Kaplan-Meier method was used to calculate survival time and survival rates, and the Log-Rank test was used for survival analysis. The COX proportional hazards regression model was used for univariate and multivariate analyses. Interaction analysis was used to determine the benefit of adjuvant therapy in subgroup populations. Results:(1) Comparison of clinicopathological data between patients with and without adjuvant therapy after conversion resection for pancreatic cancer. Of the 173 pancreatic cancer patients, there were 108 cases with adjuvant therapy after conversion resection and 65 cases without adjuvant therapy after conversion resection, respectively. Age and body mass index were (58±9)years and (23.2±2.8)kg/m 2 in patients with adjuvant therapy, versus (61±8)years and (22.2±2.8)kg/m 2 in patients without adjuvant therapy, showing significant differences in the above indicators between them ( t=-2.036, 2.200, P<0.05). (2) Analysis of influencing factors for prognosis of pancreatic cancer after conversion resection. Results of multivariate analysis showed that CA19-9 normalization, pathological N staging, degree of tumor differentiation and postoperative adjuvant therapy were independent factors influencing overall survival time in pancreatic cancer patients receiving conversion resection ( hazard ratio=1.598, 1.541, 2.004, 2.571, 95% confidence interval as 1.041-2.453, 1.021-2.327, 1.288-3.118, 1.721-3.843, P<0.05). (3) Follow-up and prognosis. All 173 patients were followed up for 24.5(5.0,52.0)months. The postoperative median overall survival time of 173 patients was 28.9(5.7,51.9)months, and the 1-, 2-, 3-year overall survival rates were 90%, 59%, 40%, respectively. Of 2019, 2020, 2021, the proportions of patients receiving adjuvant therapy after conversion resection were 62.8%(27/43), 57.7%(30/52) and 65.4%(51/78) respectively. The postoperative median overall survival time was 42.2(8.8,49.7)months in patients with adjuvant therapy after conversion resection, versus 20.4(5.7,51.9)months in patients without adjuvant therapy after conversion resection, showing a significant difference between them ( χ2=29.893, P<0.05). (4) Survival benefit of adjuvant therapy in subgroup populations. Results of interaction analysis showed that in subgroup populations with CA19-9 normalization, pathological stage N0, pathological stage N1-2, moderate to well differentiated tumors, adjuvant therapy after conversion resection can bring a better survival benefit for patients with pancreatic cancer ( adjustment hazard ratio=0.220, 0.300, 0.410, 0.340, 95% confidence interval as 0.120-0.400, 0.170-0.560, 0.240-0.690, 0.210-0.690). Conclusions:Postoperative adjuvant therapy is an independent factor influencing overall survival time in pancreatic cancer patients receiving conversion resection. Adjuvant therapy after conversion resection can bring additional survival benefits for pancreatic cancer, particularly for patients who respond favorably to neoadjuvant and/or induction therapy.

Paxlovid is a nirmatrelvir (NMV) and ritonavir (RTV) co-packaged medication used for the treatment of coronavirus disease 2019 (COVID-19). The active component of Paxlovid is NMV and RTV is a pharmacokinetic booster. Our work aimed to investigate the drug/herb-drug interactions associated with Paxlovid and provide mechanism-based guidance for the clinical use of Paxlovid. By using recombinant human cytochrome P450s (CYPs), we confirmed that CYP3A4 and 3A5 are the major enzymes responsible for NMV metabolism. The role of CYP3A in Paxlovid metabolism were further verified in Cyp3a-null mice, which showed that the deficiency of CYP3A significantly suppressed the metabolism of NMV and RTV. Pregnane X receptor (PXR) is a ligand-dependent transcription factor that upregulates CYP3A4/5 expression. We next explored the impact of drug- and herb-mediated PXR activation on Paxlovid metabolism in a transgenic mouse model expressing human PXR and CYP3A4/5. We found that PXR activation increased CYP3A4/5 expression, accelerated NMV metabolism, and reduced the systemic exposure of NMV. In summary, our work demonstrated that PXR activation can cause drug interactions with Paxlovid, suggesting that PXR-activating drugs and herbs should be used cautiously in COVID-19 patients receiving Paxlovid.

Objective:To explore the indications and effect of surgical treatment of autoimmune pancreatitis.Methods:Clinical data of these 15 patients with autoimmune pancreatitis diagnosed and treated at the Department of General Surgery, the First Hospital of Peking University from 2010 to 2021 were retrospectively analyzed.Results:The main clinical symptoms were obstructive jaundice, abdominal pain, distension and weight loss. The diagnosis of AIP was confirmed by EUS-FNA in 6 patients,among them, 4 did not relapse after oral hormone treatment, 2 did not receive relevant treatment, and 1 developed gastric cancer one year later. Under a suspicion of malignancy, 9 patients underwent surgical laparotomy ,and the diagnosis was established by pathology. There was no recurrence after oral hormone therapy in 1 patient who underwent laparotomy and pancreatic biopsy. One out of the 3 patients with choledochojejunostomy relapsed after 3 years. Of the 5 patients who underwent pancreatectomy, 4 had no obvious recurrence, and 1 had recurrence after 3 years.Conclusions:Untypical autoimmune pancreatitis is likely to be misdiagnosed as pancreatic cancer. For patients with suspicious malignancy, operational management and biopsy may benefit.

Objective:To investigate the clinical imaging features and prognosis of von Hippel-Lindau (VHL) syndrome associated with pancreatic lesions.Method:The retrospective case-control study was conducted. The clinicopathological data of 161 patients with VHL syndrome who were admitted to Peking University First Hospital from September 2010 to August 2022 were collected. There were 83 males and 78 females, with age of onset as 27.0(range, 8.0-66.0)years. Observation indicators: (1) imaging results of VHL syndrome associated with pancreatic lesions; (2) clinical characteristics of VHL syndrome associated with pancreatic lesions; (3) comparison of clinicopathological factors in patients with VHL syndrome associated with pancreatic cystic lesions; (4) comparison of clinicopathological factors in patients with VHL syndrome associated with pancreatic neuroendocrine neoplasms (pNENs). (5) Treatment and prognosis of patients with VHL syndrome associated with pancreatic lesions. Measurement data with normal distribution were represented as Mean± SD, and comparison between groups was conducted using the independent sample t test. Measurement data with skewed distribution were represented as M(range), and comparison between groups was conducted using the non-parameter test. Count data were described as absolute numbers, and comparison between groups was conducted using the chi-square test. Results:(1) Imaging results of VHL syndrome associated with pancreatic lesions. Of the 161 patients with VHL syndrome, there were 151 patients associated with pancreatic lesions and 10 patients not associated with pancreatic lesions. Of the 151 patients with VHL syndrome associated with pancreatic lesions, there were 136 patient with pancreatic cystic lesions and 34 patients with pNENs, 22 patients with both pNENs and pancreatic cystic lesions, and the type of pancreatic lesions could not be accurately determined in 3 cases. (2) Clinical characteristics of VHL syndrome associated with pancreatic lesions. The age of onset in 151 patients with VHL syndrome associated with pancreatic lesions was 33.0(range, 14.0-68.0)years. Cases with gene site mutation of exon 1, exon 2, exon 3 and other types of gene site was 51, 16, 43 and 41, respectively. There were 116 patients of VHL type 1 and 35 patients of VHL type 2. There were 92 patients with family history of VHL syndrome and 59 patients without family history of VHL syndrome. There were 127 patients combined with renal cell carcinoma, 112 patients combined with central nervous system lesions, 46 patients combined with retinal hemangioblastoma. Patients may combined with multiple lesions. (3) Comparison of clinicopathological factors in patients with VHL syndrome associated with pancreatic cystic lesions. The age of onset, VHL syndrome type (VHL1 type, VHL2 type) and cases combined with renal cell carcinoma were 32.5(range, 14.0-68.0)years, 110, 26 and 115 in 136 patients with VHL syndrome associated with pancreatic cystic lesions, versus 22.0(range, 8.0-64.0)years, 13, 12 and 14 in 25 patients with VHL syndrome not associated with pancreatic cystic lesions, showing significant differences in the above indicators between them ( Z=-3.384, χ2=9.770, 10.815, P<0.05). (4) Comparison of clinicopathological factors in patients with VHL syndrome associated with pNENs. The age of onset, gene mutation sites (exon 1, exon 2, exon 3, other types of gene site) and VHL syndrome type (VHL1 type, VHL2 type) were 33.5(range, 14.0-64.0)years, 12, 5, 14, 3 and 18, 16 in 34 patients with VHL syndrome associated with pNENs, versus 27.0(range, 9.0-66.0)years, 41, 12, 32, 42 and 105, 22 in 127 patients with VHL syndrome not associated with pNENs, showing significant differences in the above indicators between them ( Z=-4.030, χ2=8.814, 13.152, P<0.05). (5) Treatment and prognosis of patients with VHL syndrome associated with pancreatic lesions. Of the 161 patients with VHL syndrome, 3 patients underwent surgical treatment, and the remaining patients were followed up. All 161 patients with VHL syndrome were followed up for 6 (range, 1-12)years, in which 15 patients died and 146 patients alive during the follow-up. The follow-up time of 3 patients undergoing surgical treatment was 4, 14, 9 years, respectively, and all of them were alive. Conclusions:The clinical imaging features of pancreatic lesions related to VHL syndrome are cystic lesions and pNENs, which with the characteristics of multiple lesions and benign tumors. Such patients usually do not requiring surgical treatment and have good prognosis.

Objective:To evaluate the risk factors of acute kidney injury (AKI) in patients with multiple wasp stings.Methods:Patients with multiple wasp stings were retrospectively enrolled in Hanzhong Central Hospital from September 2010 to November 2020. Based on whether the patients developed AKI, the patients were divided into AKI group and non-AKI group. The general characteristics and laboratory examinations between the two groups were compared. The logistic regression model was used to analyze the risk factors of AKI.Results:A total of 356 patients with multiple wasp stings were recruited in this study, with 196 males (55.1%). The age was 56.0(45.0, 64.0) years old. There were 59 patients (16.6%) with hypertension and 13 patients (3.6%) with diabetes. There were 51 patients (14.3%) in the AKI group and 305 patients (85.7%) in the non-AKI group. Baseline data and biochemical examinations indicated that the two groups showed significant differences in gender, age, sting sites (systemic or local), sting needles, proportions of gross hematuria, leukocyte count, hemoglobin, creatine kinase, alanine transaminase, aspartate aminotransferase, total bilirubin, proportions of urinary protein, and proportions of urine occult blood (all P<0.05). The multivariate logistic regression analysis results showed that the increasing number of sting needles (every 10 needles increase, OR=1.866, 95% CI 1.289-2.071, P=0.001), gross hematuria ( OR=9.770, 95% CI 2.586-36.910, P=0.001), decreasing hemoglobin (every 1 g/L increase, OR=0.016, 95% CI 0.001-0.355, P=0.009), increasing aspartate aminotransferase (every 100 U/L increase, OR=1.311, 95% CI 1.144-1.502, P<0.001), and increasing total bilirubin (every 10 μmol/L increase, OR=1.200, 95% CI 1.008-1.430, P=0.041) were independent influencing factors of AKI. Conclusions:The increasing number of sting needles, gross hematuria, decreasing hemoglobin, increasing aspartate aminotransferase, and increasing total bilirubin are independent risk factors of AKI in patients with multiple wasp stings.

Objective:To investigate the clinicopathological characteristics and treatment strategies of undifferentiated carcinoma with osteoclast-like giant cells of pancreas (UCOGCP).Methods:The retrospective and descriptive study was conducted. The clinicopathological data of 5 patients with UCOGCP who were admitted to Peking University First Hospital from January 2004 to January 2019 were collected. There were 1 male and 4 females, aged from 33 to 71 years, with a median age of 56 years. Patients underwent preoperative laboratory test, imaging and histopatho-logical examinations. Patients with pancreatic head tumors underwent pancreaticoduodenectomy, and those with tumors in the body or tail of pancreas underwent distal pancreatectomy combined with splenectomy. All patients underwent standard lymph node dissection. Postoperative adjuvant therapy was individually decided by a multidisciplinary team. Observation indicators: (1) preopera-tive examination and treatment; (2) postoperative histopathological situations; (3) follow-up. Follow-up using outpatient examination and telephone interview was performed to detect tumor recurrence of patients up to January 2020. Measurement data with normal distribution were represented as Mean± SD. Measurement data with skewed distribution were described as M (range). Count data were described as absolute numbers. Results:(1) Preoperative examination and treatment: of the 5 UCOGCP patients, CA19-9 was elevated as 65.43 U/mL in only 1 patient preoperatively, while the CA19-9 was normal in other 4 patients. Four patients showed a solid cystic mass on preoperative contrast-enhanced computed tomography (CT) scan, and 1 patient showed a delayed peripheral enhancement of the solid tumor with central necrosis. The magnetic resonance imaging (MRI) scan showed hypointense signals on T1, T2 and weighted diffusion sequences in all 5 patients. Three of the 5 patients were resectable according to imaging data, 1 patient had locally advanced tumor, infiltrating the transverse colon, stomach, and partial small intestine, with the portal vein thrombus, and 1 patient had pancreatic head tumor with a liver metastatic lesion of 0.4 cm diameter which was detected on position emission tomography CT and was diagnosed as UCOGCP by endoscopic ultrasound-guided fine-needle aspiration biopsy. All patients underwent radical resection. Of the 3 patients with resectable tumors, 2 patients underwent pancreaticoduo-denectomy and 1 patient underwent distal pancreatectomy combined with splenectomy. One patient with locally advanced tumor in the body and tail of pancreas underwent distal pancreatectomy + transverse colostomy + partial gastrectomy + portal vein thrombectomy, and 1 patient with pancreatic head tumor and liver metastasis underwent pancreatoduodenectomy combined with left lateral hepatectomy. Of the 5 patients, 2 received postoperative adjuvant chemotherapy with single-agent gemcitabine, 1 received albumin-paclitaxel+gemcitabine combination chemotherapy, 1 received S1 as single agent chemotherapy, and 1 did not receive adjuvant chemotherapy. (2) Postoperative histopathological situations: of the 5 patients, 4 cases showed a cystic solid appearance of gross specimens, and 1 case had a solid appearance with central hemorrhagic necrosis. The tumor diameter was 5.2 cm(range, 2.0?14.0 cm). All the 5 patients achieved negative margins. Of the 5 patients, there was 1 case with portal vein invasion, 2 cases with vascular invasion, 3 cases with perineural invasion, and 2 cases with regional lymph node metastasis. One patient may had multiple tumor invasion and metastasis. Four of 5 patients had paraffin specimens available for immuno-histochemical staining. Four patients were positive for both CD68 and vimentin stains, while 3 patients were positive for programmed death ligand-1 (PD-L1), including 2 samples with 5% positive cells and 1 sample with 25% positive cells. Postoperative pathological examination showed a large number of spindle histiocytoid sarcoma cells scattered with osteoclast like giant cells and pleomorphic carcinoma giant cells. The tumor mutation burden in the 4 patients was 3.23 Muts/Mb(range, 2.61?21.77 Muts/Mb). Microsatellite status was stable in 4 patients. The next generation sequencing of 4 patients showed that all patients had KRAS mutation which was the most frequently mutation in pancreatic ductal adenocarcinoma. Of the 4 patients, 1 case had germline pathogenic mutation in TP53, 1case had somatic mutation in TP53, 1 case had somatic mutation in TP53, BLM, CDKN2A, and 1 case had somatic mutation in ARID1A. (3) Follow-up: 5 patients were followed up for 14?173 months, with a median follow-up time of 46 months. During the follow-up, 4 patients achieved disease-free survival and 1 patient had local recurrence at postoperative 11 months.Conclusions:UCOGCP is a rare variant of pancreatic tumor that exhibits a cystic solid mass in imaging examinations. High expression of PD-L1 is common in UCOGCP. The prognosis for UCOGCP is favorable following radical surgery. Patients may benefit from extended radical surgery even if the tumor has locally progression or distant metastasis.