Oral squamous cell carcinoma (OSCC) is a common head and neck malignancy. Approximately 50% to 60% of patients with OSCC are diagnosed at a locally advanced stage (clinical staging III-IVa). Even with comprehensive and sequential treatment primarily based on surgery, the 5-year overall survival rate remains below 50%, and patients often suffer from postoperative functional impairments such as difficulties with speaking and swallowing. Programmed death receptor-1 (PD-1) inhibitors are increasingly used in the neoadjuvant treatment of locally advanced OSCC and have shown encouraging efficacy. However, clinical practice still faces key challenges, including the definition of indications, optimization of combination regimens, and standards for efficacy evaluation. Based on the latest research advances worldwide and the clinical experience of the expert group, this expert consensus systematically evaluates the application of PD-1 inhibitors in the neoadjuvant treatment of locally advanced OSCC, covering combination strategies, treatment cycles and surgical timing, efficacy assessment, use of biomarkers, management of special populations and immune related adverse events, principles for immunotherapy rechallenge, and function preservation strategies. After multiple rounds of panel discussion and through anonymous voting using the Delphi method, the following consensus statements have been formulated: 1) Neoadjuvant therapy with PD-1 inhibitors can be used preoperatively in patients with locally advanced OSCC. The preferred regimen is a PD-1 inhibitor combined with platinum based chemotherapy, administered for 2-3 cycles. 2) During the efficacy evaluation of neoadjuvant therapy, radiographic assessment should follow the dual criteria of Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and immune RECIST (iRECIST). After surgery, systematic pathological evaluation of both the primary lesion and regional lymph nodes is required. For combination chemotherapy regimens, PD-L1 expression and combined positive score need not be used as mandatory inclusion or exclusion criteria. 3) For special populations such as the elderly (≥ 70 years), individuals with stable HIV viral load, and carriers of chronic HBV/HCV, PD-1 inhibitors may be used cautiously under the guidance of a multidisciplinary team (MDT), with close monitoring for adverse events. 4) For patients with a poor response to neoadjuvant therapy, continuation of the original treatment regimen is not recommended; the subsequent treatment plan should be adjusted promptly after MDT assessment. Organ transplant recipients and patients with active autoimmune diseases are not recommended to receive neoadjuvant PD-1 inhibitor therapy due to the high risk of immune related activation. Rechallenge is generally not advised for patients who have experienced high risk immune related adverse events such as immune mediated myocarditis, neurotoxicity, or pneumonitis. 5) For patients with a good pathological response, individualized de escalation surgery and function preservation strategies can be explored. This consensus aims to promote the standardized, safe, and precise application of neoadjuvant PD-1 inhibitor strategies in the management of locally advanced OSCC patients.

Tumor drug resistance is an important problem in the failure of chemotherapy and targeted drug therapy, which is a complex process involving chromatin remodeling. SWI/SNF is one of the most studied ATP-dependent chromatin remodeling complexes in tumorigenesis, which plays an important role in the coordination of chromatin structural stability, gene expression, and post-translation modification. However, its mechanism in tumor drug resistance has not been systematically combed. SWI/SNF can be divided into 3 types according to its subunit composition: BAF, PBAF, and ncBAF. These 3 subtypes all contain two mutually exclusive ATPase catalytic subunits (SMARCA2 or SMARCA4), core subunits (SMARCC1 and SMARCD1), and regulatory subunits (ARID1A, PBRM1, and ACTB, etc.), which can control gene expression by regulating chromatin structure. The change of SWI/SNF complex subunits is one of the important factors of tumor drug resistance and progress. SMARCA4 and ARID1A are the most widely studied subunits in tumor drug resistance. Low expression of SMARCA4 can lead to the deletion of the transcription inhibitor of the BCL2L1 gene in mantle cell lymphoma, which will result in transcription up-regulation and significant resistance to the combination therapy of ibrutinib and venetoclax. Low expression of SMARCA4 and high expression of SMARCA2 can activate the FGFR1-pERK1/2 signaling pathway in ovarian high-grade serous carcinoma cells, which induces the overexpression of anti-apoptosis gene BCL2 and results in carboplatin resistance. SMARCA4 deletion can up-regulate epithelial-mesenchymal transition (EMT) by activating YAP1 gene expression in triple-negative breast cancer. It can also reduce the expression of Ca²⁺ channel IP3R3 in ovarian and lung cancer, resulting in the transfer of Ca²⁺ needed to induce apoptosis from endoplasmic reticulum to mitochondria damage. Thus, these two tumors are resistant to cisplatin. It has been found that verteporfin can overcome the drug resistance induced by SMARCA4 deletion. However, this inhibitor has not been applied in clinical practice. Therefore, it is a promising research direction to develop SWI/SNF ATPase targeted drugs with high oral bioavailability to treat patients with tumor resistance induced by low expression or deletion of SMARCA4. ARID1A deletion can activate the expression of ANXA1 protein in HER2+ breast cancer cells or down-regulate the expression of progesterone receptor B protein in endometrial cancer cells. The drug resistance of these two tumor cells to trastuzumab or progesterone is induced by activating AKT pathway. ARID1A deletion in ovarian cancer can increase the expression of MRP2 protein and make it resistant to carboplatin and paclitaxel. ARID1A deletion also can up-regulate the phosphorylation levels of EGFR, ErbB2, and RAF1 oncogene proteins.The ErbB and VEGF pathway are activated and EMT is increased. As a result, lung adenocarcinoma is resistant to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Although great progress has been made in the research on the mechanism of SWI/SNF complex inducing tumor drug resistance, most of the research is still at the protein level. It is necessary to comprehensively and deeply explore the detailed mechanism of drug resistance from gene, transcription, protein, and metabolite levels by using multi-omics techniques, which can provide sufficient theoretical basis for the diagnosis and treatment of poor tumor prognosis caused by mutation or abnormal expression of SWI/SNF subunits in clinical practice.

BACKGROUND:In recent years,numerous studies have shown that autophagy and mitophagy play an important role in the regulation of bone metabolism.Under non-physiological conditions,mitophagy breaks the balance of bone metabolism and triggers metabolism disorders,which affect osteoblasts,osteoclasts,osteocytes,chondrocytes,bone marrow mesenchymal stem cells,etc. OBJECTIVE:To summarize the mechanism of mitophagy in regulating bone metabolic diseases and its application in clinical treatment. METHODS:PubMed,Web of Science,CNKI,WanFang and VIP databases were searched by computer using the keywords of"mitophagy,bone metabolism,osteoblasts,osteoclasts,osteocytes,chondrocytes,bone marrow mesenchymal stem cells"in English and Chinese.The search time was from 2008 to 2023.According to the inclusion criteria,90 articles were finally included for review and analysis. RESULTS AND CONCLUSION:Mitophagy promotes the generation of osteoblasts through SIRT1,PINK1/Parkin,FOXO3 and PI3K signaling pathways,while inhibiting osteoclast function through PINK1/Parkin and SIRT1 signaling pathways.Mitophagy leads to bone loss by increasing calcium phosphate particles and tissue protein kinase K in bone tissue.Mitophagy improves the function of chondrocytes through PINK1/Parkin,PI3K/AKT/mTOR and AMPK signaling pathways.Modulation of mitophagy shows great potential in the treatment of bone diseases,but there are still some issues to be further explored,such as different stages of drug-activated mitophagy,and the regulatory mechanisms of different signaling pathways.

Background: s/Aims: Sarcomatoid hepatocellular carcinoma (HCC) is a rare histological subtype of HCC characterized by extremely poor prognosis; however, its molecular characterization has not been elucidated. Methods: In this study, we conducted an integrated multiomics study of whole-exome sequencing, RNA-seq, spatial transcriptome, and immunohistochemical analyses of 28 paired sarcomatoid tumor components and conventional HCC components from 10 patients with sarcomatoid HCC, in order to identify frequently altered genes, infer the tumor subclonal architectures, track the genomic evolution, and delineate the transcriptional characteristics of sarcomatoid HCCs. Results: Our results showed that the sarcomatoid HCCs had poor prognosis. The sarcomatoid tumor components and the conventional HCC components were derived from common ancestors, mostly accessing similar mutational processes. Clonal phylogenies demonstrated branched tumor evolution during sarcomatoid HCC development and progression. TP53 mutation commonly occurred at tumor initiation, whereas ARID2 mutation often occurred later. Transcriptome analyses revealed the epithelial–mesenchymal transition (EMT) and hypoxic phenotype in sarcomatoid tumor components, which were confirmed by immunohistochemical staining. Moreover, we identified ARID2 mutations in 70% (7/10) of patients with sarcomatoid HCC but only 1–5% of patients with non-sarcomatoid HCC. Biofunctional investigations revealed that inactivating mutation of ARID2 contributes to HCC growth and metastasis and induces EMT in a hypoxic microenvironment. Conclusions We offer a comprehensive description of the molecular basis for sarcomatoid HCC, and identify genomic alteration (ARID2 mutation) together with the tumor microenvironment (hypoxic microenvironment), that may contribute to the formation of the sarcomatoid tumor component through EMT, leading to sarcomatoid HCC development and progression.

Background: s/Aims: Sarcomatoid hepatocellular carcinoma (HCC) is a rare histological subtype of HCC characterized by extremely poor prognosis; however, its molecular characterization has not been elucidated. Methods: In this study, we conducted an integrated multiomics study of whole-exome sequencing, RNA-seq, spatial transcriptome, and immunohistochemical analyses of 28 paired sarcomatoid tumor components and conventional HCC components from 10 patients with sarcomatoid HCC, in order to identify frequently altered genes, infer the tumor subclonal architectures, track the genomic evolution, and delineate the transcriptional characteristics of sarcomatoid HCCs. Results: Our results showed that the sarcomatoid HCCs had poor prognosis. The sarcomatoid tumor components and the conventional HCC components were derived from common ancestors, mostly accessing similar mutational processes. Clonal phylogenies demonstrated branched tumor evolution during sarcomatoid HCC development and progression. TP53 mutation commonly occurred at tumor initiation, whereas ARID2 mutation often occurred later. Transcriptome analyses revealed the epithelial–mesenchymal transition (EMT) and hypoxic phenotype in sarcomatoid tumor components, which were confirmed by immunohistochemical staining. Moreover, we identified ARID2 mutations in 70% (7/10) of patients with sarcomatoid HCC but only 1–5% of patients with non-sarcomatoid HCC. Biofunctional investigations revealed that inactivating mutation of ARID2 contributes to HCC growth and metastasis and induces EMT in a hypoxic microenvironment. Conclusions We offer a comprehensive description of the molecular basis for sarcomatoid HCC, and identify genomic alteration (ARID2 mutation) together with the tumor microenvironment (hypoxic microenvironment), that may contribute to the formation of the sarcomatoid tumor component through EMT, leading to sarcomatoid HCC development and progression.

Background: s/Aims: Sarcomatoid hepatocellular carcinoma (HCC) is a rare histological subtype of HCC characterized by extremely poor prognosis; however, its molecular characterization has not been elucidated. Methods: In this study, we conducted an integrated multiomics study of whole-exome sequencing, RNA-seq, spatial transcriptome, and immunohistochemical analyses of 28 paired sarcomatoid tumor components and conventional HCC components from 10 patients with sarcomatoid HCC, in order to identify frequently altered genes, infer the tumor subclonal architectures, track the genomic evolution, and delineate the transcriptional characteristics of sarcomatoid HCCs. Results: Our results showed that the sarcomatoid HCCs had poor prognosis. The sarcomatoid tumor components and the conventional HCC components were derived from common ancestors, mostly accessing similar mutational processes. Clonal phylogenies demonstrated branched tumor evolution during sarcomatoid HCC development and progression. TP53 mutation commonly occurred at tumor initiation, whereas ARID2 mutation often occurred later. Transcriptome analyses revealed the epithelial–mesenchymal transition (EMT) and hypoxic phenotype in sarcomatoid tumor components, which were confirmed by immunohistochemical staining. Moreover, we identified ARID2 mutations in 70% (7/10) of patients with sarcomatoid HCC but only 1–5% of patients with non-sarcomatoid HCC. Biofunctional investigations revealed that inactivating mutation of ARID2 contributes to HCC growth and metastasis and induces EMT in a hypoxic microenvironment. Conclusions We offer a comprehensive description of the molecular basis for sarcomatoid HCC, and identify genomic alteration (ARID2 mutation) together with the tumor microenvironment (hypoxic microenvironment), that may contribute to the formation of the sarcomatoid tumor component through EMT, leading to sarcomatoid HCC development and progression.

Objective To investigate the clinical characteristics and influencing factors of thyroid function abnormality (TFA) in patients with malignant tumors receiving programmed death-1 (PD-1) inhibitor therapy, and its correlation with PD-1 inhibitors. Methods A retrospective analysis was conducted on the clinical data and biochemical indicators of 669 patients with malignant tumors who received PD-1 inhibitor therapy. Of these, 561 patients maintained normal thyroid function (normal group), while 108 developed TFA (TFA group). Baseline characteristics, PD-1 inhibitor type, tumor type, and other indice were compared between the two groups. Univariate and multivariate logistic regression analyses were performed to identify related factors for TFA development. Additionally, the relationship between PD-1 inhibitors and TFA types was further analyzed within the TFA group. Results The rates of patients treated with pembrolizumab and with respiratory tumors were significantly higher in TFA group than those in the normal group (P＜0.01). Multivariate logistic regression analysis revealed that treatment with pembrolizumab and with respiratory tumor increased 5.350 and 1.514 times than tislelizumab and digestive tumor for risk of TFA development, respectively (P＜0.01). Within the TFA group, hypothyroidism was the predominant type (75, 69.4%); treatment with pembrolizumab increased 2.999 times than tislelizumab for development risk of hyperthyroidism (P＝0.042). Conclusions Among patients with malignant tumors treated with PD-1 inhibitors, pembrolizumab is more frequently associated with TFA, and patients with respiratory tumors were at a higher risk of developing TFA. Clinicians should closely monitor thyroid function in patients with respiratory tumors treated with pembrolizumab.

BACKGROUND: The achievement of an optimal return to sport (RTS) has remained a key goal after sports-related injuries, with the ongoing debate on the effectiveness of different surgical approaches for anterior cruciate ligament (ACL) rupture. This study aims to assess clinical outcomes and RTS across various surgical methods, such as anatomical single-bundle reconstruction (ASBR), central-axial single-bundle reconstruction (CASBR), and double-bundle reconstruction (DBR). METHODS: A randomized clinical trial was conducted, comprising 191 patients who underwent ACL rupture. These patients were divided into three groups based on the ACL reconstruction techniques they received (ASBR, CASBR, DBR). Over the 2-year follow-up period, the study assessed RTS through four single-hop tests, isokinetic extension tests, and limb asymmetry indices. Postoperative graft status was determined using the signal-to-noise quotient (SNQ), while knee function was evaluated using the International Knee Documentation Committee 2000 (IKDC-2000) score, Lysholm score, Tegner score, and degree of knee laxity. A binary logistic regression model was developed to forecast the factors influencing ideal RTS. RESULTS: DBR (67.63%) and CASBR (58.00%) exhibited higher RTS passing rates compared to ASBR (30.39%; χ2 = 19.57, P <0.05). Quadriceps strength symmetry in the lower limbs was identified as the key determinant of RTS ( χ2 = 17.08, P <0.05). The RTS rate was influenced by SNQs of the graft's tibial site (odds ratio: 0.544) and quadriceps strength of the reconstructed knee joint at 60°/s (odds ratio: 6.346). Notably, the DBR group showed enhanced knee stability, evidenced by superior results in the Lachman test ( χ2 = 13.49, P <0.01), objective IKDC-2000 ( χ2 = 27.02, P = 0.002), and anterior instability test ( χ2 = 9.46, P <0.01). Furthermore, DBR demonstrated superior clinical outcomes based on the Lysholm score (DBR: 89.57 ± 7.72, CASBR: 83.00 ± 12.71, ASBR: 83.21 ± 11.95; F = 10.452, P <0.01) and IKDC-2000 score (DBR: 90.95 ± 7.00, CASBR: 84.64 ± 12.68, ASBR: 83.63 ± 11.41; F = 11.78, P <0.01). CONCLUSION: For patients with ACL rupture, more ideal RTS rate and clinical outcomes were shown in the DBR group than in the ASBR and CASBR groups. Autograft status and quadriceps strength are postively related to RTS. TRIAL REGISTRATION ClinicalTrials.gov (NCT05400460).
Humans ; Anterior Cruciate Ligament Reconstruction/methods* ; Male ; Female ; Adult ; Anterior Cruciate Ligament Injuries/surgery* ; Young Adult ; Return to Sport ; Adolescent ; Anterior Cruciate Ligament/surgery* ; Treatment Outcome

BACKGROUND: While emotional distress, encompassing anxiety and depression, has been associated with negative clinical outcomes, its impact across various clinical departments and general hospitals has been less explored. Previous studies with limited sample sizes have examined the effectiveness of specific treatments (e.g., antidepressants) rather than a systemic management strategy for outcome improvement in non-psychiatric inpatients. To enhance the understanding of the importance of addressing mental health care needs among non-psychiatric patients in general hospitals, this study retrospectively investigated the impacts of emotional distress and the effects of early detection and management of depression and anxiety on hospital length of stay (LOS) and rate of long LOS (LLOS, i.e., LOS >30 days) in a large sample of non-psychiatric inpatients. METHODS: This retrospective cohort study included 487,871 inpatients from 20 non-psychiatric departments of a general hospital. They were divided, according to whether they underwent a novel strategy to manage emotional distress which deployed the Huaxi Emotional Distress Index (HEI) for brief screening with grading psychological services (BS-GPS), into BS-GPS ( n = 178,883) and non-BS-GPS ( n = 308,988) cohorts. The LOS and rate of LLOS between the BS-GPS and non-BS-GPS cohorts and between subcohorts with and without clinically significant anxiety and/or depression (CSAD, i.e., HEI score ≥11 on admission to the hospital) in the BS-GPS cohort were compared using univariable analyses, multilevel analyses, and/or propensity score-matched analyses, respectively. RESULTS: The detection rate of CSAD in the BS-GPS cohort varied from 2.64% (95% confidence interval [CI]: 2.49%-2.81%) to 20.50% (95% CI: 19.43%-21.62%) across the 20 departments, with a average rate of 5.36%. Significant differences were observed in both the LOS and LLOS rates between the subcohorts with CSAD (12.7 days, 535/9590) and without CSAD (9.5 days, 3800/169,293) and between the BS-GPS (9.6 days, 4335/178,883) and non-BS-GPS (10.8 days, 11,483/308,988) cohorts. These differences remained significant after controlling for confounders using propensity score-matched comparisons. A multilevel analysis indicated that BS-GPS was negatively associated with both LOS and LLOS after controlling for sociodemographics and the departments of patient discharge and remained negatively associated with LLOS after controlling additionally for the year of patient discharge. CONCLUSION Emotional distress significantly prolonged the LOS and increased the LLOS of non-psychiatric inpatients across most departments and general hospitals. These impacts were moderated by the implementation of BS-GPS. Thus, BS-GPS has the potential as an effective, resource-saving strategy for enhancing mental health care and optimizing medical resources in general hospitals.
Humans ; Retrospective Studies ; Male ; Length of Stay/statistics & numerical data* ; Female ; Middle Aged ; Adult ; Psychological Distress ; Inpatients/psychology* ; Aged ; Anxiety/diagnosis* ; Depression/diagnosis*

BACKGROUND: China has made significant progress in medical accessibility and quality over the past decades, and quality improvements in gastroenterology and digestive endoscopy have been consistent. The study aimed to describe the status quo of gastroenterology and digestive endoscopy in the Chinese mainland based on the data from the National Clinical Improvement System (NCIS) and the Hospital Quality Monitoring System (HQMS). METHODS: Data were extracted from the NCIS and the HQMS. Data analysis included general information from the Department of Gastroenterology and Endoscopy centers, management of inpatients and outpatients, and annual volume and quality indicators of digestive endoscopy. Acute pancreatitis, gastrointestinal bleeding, inflammatory bowel disease, and cirrhosis were identified as priority diseases and were subjected to detailed analysis. RESULTS: Data from 4620 and 7074 hospitals were extracted from the NCIS and HQMS, respectively. In 2023, 9.6 gastroenterologists, 6.7 endoscopists, and 37.3 gastroenterology beds per hospital nationwide were observed, achieving 19,252.4 outpatient visits, 1615.2 hospitalizations (97.0 for acute pancreatitis, 146.1 for gastrointestinal bleeding, 40.2 for inflammatory bowel disease, and 111.4 for cirrhosis), and 9432.7 digestive endoscopic procedures per hospital. Overall, the quality of practice improved significantly. The proportion of early cancer among gastrointestinal cancers increased from 11.1% in 2015 to 23.4% in 2023, and the adenoma detection rate during colonoscopy increased from 19.3% in 2019 to 26.9% in 2023. Regarding priority diseases, hospitalizations increased, and 31-day unplanned readmission rates decreased between 2019 and 2023. The median hospitalization costs and median proportion of medication costs decreased for acute pancreatitis, gastrointestinal bleeding, and cirrhosis. However, it increased for inflammatory bowel disease. CONCLUSION This report evaluates the status quo and development of gastroenterology and digestive endoscopy in the Chinese mainland, providing guidance for future quality improvements.
Humans ; China ; Gastroenterology/statistics & numerical data* ; Gastrointestinal Hemorrhage ; Endoscopy, Gastrointestinal/statistics & numerical data* ; Endoscopy, Digestive System/statistics & numerical data*