Integrative analyses of bulk and single-cell transcriptomics reveals the infiltration and crosstalk of cancer-associated fibroblasts as a novel predictor for prognosis and microenvironment remodeling in intrahepatic cholangiocarcinoma.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a highly malignant neoplasm and characterized by desmoplastic matrix. The heterogeneity and crosstalk of tumor microenvironment remain incompletely understood. METHODS: To address this gap, we performed Weighted Gene Co-expression Network Analysis (WGCNA) to identify and construct a cancer associated fibroblasts (CAFs) infiltration biomarker. We also depicted the intercellular communication network and important receptor-ligand complexes using the single-cell transcriptomics analysis of tumor and Adjacent normal tissue. RESULTS: Through the intersection of TCGA DEGs and WGCNA module genes, 784 differential genes related to CAFs infiltration were obtained. After a series of regression analyses, the CAFs score was generated by integrating the expressions of EVA1A, APBA2, LRRTM4, GOLGA8M, BPIFB2, and their corresponding coefficients. In the TCGA-CHOL, GSE89748, and 107,943 cohorts, the high CAFs score group showed unfavorable survival prognosis (p < 0.001, p = 0.0074, p = 0.028, respectively). Additionally, a series of drugs have been predicted to be more sensitive to the high-risk group (p < 0.05). Subsequent to dimension reduction and clustering, thirteen clusters were identified to construct the single-cell atlas. Cell-cell interaction analysis unveiled significant enhancement of signal transduction in tumor tissues, particularly from fibroblasts to malignant cells via diverse pathways. Moreover, SCENIC analysis indicated that HOXA5, WT1, and LHX2 are fibroblast specific motifs. CONCLUSIONS: This study reveals the key role of fibroblasts - oncocytes interaction in the remodeling of the immunosuppressive microenvironment in intrahepatic cholangiocarcinoma. Subsequently, it may trigger cascade activation of downstream signaling pathways such as PI3K-AKT and Notch in tumor, thus initiating tumorigenesis. Targeted drugs aimed at disrupting fibroblasts-tumor cell interaction, along with associated enrichment pathways, show potential in mitigating the immunosuppressive microenvironment that facilitates tumor progression.

The use of intramedullary reduction techniques in the treatment of irreducible intertrochanteric femoral fractures with negative medial cortical support.

Objective: To explore the clinical efficacy of intramedullary reduction techniques for irreducible intertrochanteric femoral fractures with negative medial cortical support. Methods: A retrospective analysis was conducted on 69 patients with irreducible intertrochanteric femoral fractures with negative medial cortical support treated in the Department of Orthopedics at Jiangsu Province Hospital (The First Affiliated Hospital of Nanjing Medical University) from July 2019 to December 2021. Patients were divided into Group A and Group B. Group A (experimental group) consisted of 36 cases with an average age of 76.2 ± 5.9 years, while Group B (control group) comprised 33 cases with an average age of 76.6 ± 6.3 years. Group A received treatment using intramedullary reduction techniques, while Group B received treatment using traditional extramedullary reduction techniques. Both groups achieved anatomic reduction of the medial cortex or slight positive support. Surgical duration, intraoperative fracture reduction time, intraoperative bleeding, intraoperative fluoroscopy time, fracture reduction quality, fracture healing, postoperative neck-shaft angle loss, femoral neck shortening, and hip joint functional recovery score (FRS) were compared between the two groups. Results: All patients were followed up for an average of 13.8 months. Group A showed superior outcomes compared to Group B in surgical duration, intraoperative fracture reduction time, intraoperative bleeding, intraoperative fluoroscopy time, fracture reduction quality, fracture healing, postoperative neck-shaft angle loss, and femoral neck shortening (P < 0.05). Hip joint function assessed by functional recovery score was better in Group A than Group B at 1 and 3 months postoperatively (P < 0.05), with no significant statistical difference at other time points (P > 0.05). Conclusion: For irreducible intertrochanteric femoral fractures with negative medial cortical support, intramedullary reduction techniques used during surgery demonstrated simplicity, significant reduction in surgical duration, decreased intraoperative bleeding, fewer amounts of intraoperative fluoroscopy, improved fracture reduction quality, and reduced surgical complexity. Further clinical research and application are warranted.

The effectiveness of combined extra-hepatic bile duct resection in radically-resected cases with intrahepatic cholangiocarcinoma: a SEER-based retrospective cohort study and an external validation.

OBJECTIVE: To evaluate the effectiveness of the combined extra-hepatic bile duct resection (EHBDR) in cases with intrahepatic cholangiocarcinoma (IHCC) in terms of clinicopathological features and long-term survival. METHODS: Radically resected cases with IHCC from 2000 to 2020 were identified from Surveillance, Epidemiology, and End Results (SEER) database. Comparative analyses were performed between resected IHCC patients who received EHBDR and those without EHBDR. Moreover, an external validation was further performed based on a single-center cohort. RESULTS: A total of 1521 radically resected cases with IHCC (EHBDR: 189) were identified from SEER database. Comparable age, sex, race, marital status, liver cirrhosis, differentiation status, and adjuvant chemotherapy were acquired between two groups. EHBDR was associated with a higher incidence of adequate lymphadenectomy (P<0.001). The incidence of cases with T3-4 or N+ disease was significantly higher in EHBDR group (P<0.001). Adjuvant radiotherapy was more frequently performed in cases with EHBDR (P<0.001). EHBDR failed to brought any survival benefit and was associated with a worse prognosis even after matching. Similar findings have also been revealed in the external validation cohort (n=522, EHBDR: 117). EHBDR was associated with more extended resections, more aggressive tumor biological features, and worse prognosis. In the matched validation cohort, EHBDR was still associated with a higher incidence of early recurrence. CONCLUSION: EHBDR was an indicator of advanced stage and failed to brought any survival benefit. It is the tumor stage which really determines the prognosis. More in-depth analyses focusing on different situations of EHBDR with more detailed clinical data are required.

A meta-analysis between robotic hepatectomy and conventional open hepatectomy.

Current meta-analysis was performed to compare robotic hepatectomy (RH) with conventional open hepatectomy (OH) in terms of peri-operative and postoperative outcomes. PubMed, EMBASE, and the Cochrane Library were all searched up for comparative studies between RH and OH. RevMan5.3 software and Stata 13.0 software were used for statistical analysis. Nineteen studies with 1747 patients who received RH and 23,633 patients who received OH were included. Pooled results indicated that patients who received RH were generally younger than those received OH (P < 0.00001). Moreover, RH was associated with longer operative time (P = 0.0002), less intraoperative hemorrhage (P < 0.0001), lower incidence of intraoperative transfusion (P = 0.003), lower incidence of postoperative any morbidity (P < 0.00001), postoperative major morbidity (P = 0.0001), mortalities with 90 days after surgery (P < 0.0001), and shorter length of postoperative hospital stay (P < 0.00001). Comparable total hospital costs were acquired between RH and OH groups (P = 0.46). However, even at the premise of comparable R0 rate (P = 0.86), RH was associated with smaller resected tumor size (P < 0.00001). Major hepatectomy (P = 0.02) and right posterior hepatectomy (P = 0.0003) were less frequently performed in RH group. Finally, we concluded that RH was superior to OH in terms of peri-operative and postoperative outcomes. RH could lead to less intraoperative hemorrhage, less postoperative complications and an enhanced postoperative recovery. However, major hepatectomy and right posterior hepatectomy were still less frequently performed via robotic approach. Future more powerful well-designed studies are required for further exploration.

Prognostic factors for resected cases with gallbladder carcinoma: A systematic review and meta-analysis.

OBJECTIVE: Current meta-analysis was performed to systematically evaluate the potential prognostic factors for overall survival (OS) among resected cases with gallbladder carcinoma (GBC). METHODS: PubMed, EMBASE, and the Cochrane Library were systematically retrieved and hazard ratio (HR) and its 95% confidence interval (CI) were directly extracted from the original study or roughly estimated via Tierney's method. Standard Parmar modifications were used to determine pooled HRs. RESULTS: A total of 36 studies with 11502 cases were identified. Pooled results of univariate analyses indicated that advanced age (HR=1.02, P =0.00020), concurrent gallstone disease (HR=1.22, P =0.00200), elevated preoperative CA199 level (HR=1.93, P <0.00001), advanced T stage (HR=3.09, P <0.00001), lymph node metastasis (HR=2.78, P <0.00001), peri-neural invasion (HR=2.20, P <0.00001), lymph-vascular invasion (HR=2.37, P <0.00001), vascular invasion (HR=2.28, P <0.00001), poorly differentiated tumor (HR=3.22, P <0.00001), hepatic side tumor (HR=1.85, P <0.00001), proximal tumor (neck/cystic duct) (HR=1.78, P <0.00001), combined bile duct resection (HR=1.45, P <0.00001), and positive surgical margin (HR=2.90, P <0.00001) were well-established prognostic factors. Pathological subtypes ( P =0.53000) and postoperative adjuvant chemotherapy ( P =0.70000) were not prognostic factors. Pooled results of multi-variate analyses indicated that age, gallstone disease, preoperative CA199, T stage, lymph node metastasis, peri-neural invasion, lymph-vascular invasion, tumor differentiation status, tumor location (peritoneal side vs hepatic side), surgical margin, combined bile duct resection, and postoperative adjuvant chemotherapy were independent prognostic factors. CONCLUSION: Various prognostic factors have been identified beyond the 8th AJCC staging system. By incorporating these factors into a prognostic model, a more individualized prognostication and treatment regime would be developed. Upcoming multinational studies are required for the further refine and validation.

Exosomal long non-coding RNA TRPM2-AS promotes angiogenesis in gallbladder cancer through interacting with PABPC1 to activate NOTCH1 signaling pathway.

BACKGROUND: Abnormal angiogenesis is crucial for gallbladder cancer (GBC) tumor growth and invasion, highlighting the importance of elucidating the mechanisms underlying this process. LncRNA (long non-coding RNA) is widely involved in the malignancy of GBC. However, conclusive evidence confirming the correlation between lncRNAs and angiogenesis in GBC is lacking. METHODS: LncRNA sequencing was performed to identify the differentially expressed lncRNAs. RT-qPCR, western blot, FISH, and immunofluorescence were used to measure TRPM2-AS and NOTCH1 signaling pathway expression in vitro. Mouse xenograft and lung metastasis models were used to evaluate the biological function of TRPM2-AS during angiogenesis in vivo. EDU, transwell, and tube formation assays were used to detect the angiogenic ability of HUVECs. RIP, RAP, RNA pull-down, dual-luciferase reporter system, and mass spectrometry were used to confirm the interaction between TRPM2-AS, IGF2BP2, NUMB, and PABPC1. RESULTS: TRPM2-AS was upregulated in GBC tissues and was closely related to angiogenesis and poor prognosis in patients with GBC. The high expression level and stability of TRPM2-AS benefited from m6A modification, which is recognized by IGF2BP2. In terms of exerting pro-angiogenic effects, TRPM2-AS loaded with exosomes transported from GBC cells to HUVECs enhanced PABPC1-mediated NUMB expression inhibition, ultimately promoting the activation of the NOTCH1 signaling pathway. PABPC1 inhibited NUMB mRNA expression through interacting with AGO2 and promoted miR-31-5p and miR-146a-5p-mediated the degradation of NUMB mRNA. The NOTCH signaling pathway inhibitor DAPT inhibited GBC tumor angiogenesis, and TRPM2-AS knockdown enhanced this effect. CONCLUSIONS: TRPM2-AS is a novel and promising biomarker for GBC angiogenesis that promotes angiogenesis by facilitating the activation of the NOTCH1 signaling pathway. Targeting TRPM2-AS opens further opportunities for future GBC treatments.

The prognostic value of combined preoperative PLR and CA19-9 in patients with resectable gallbladder cancer.

The platelet to lymphocyte ratio (PLR) is the marker of host inflammation and it is a potential significant prognostic indicator in various different tumors. The serum carbohydrate antigen 19-9 (CA19-9) is a tumor-associated antigen and it is associated with poor prognosis of gallbladder cancer (GBC). We aimed to analyze the prognostic value of the combination of preoperative PLR and CA19-9 in patients with GBC. A total of 287 GBC patients who underwent curative surgery in our institution was included. To analyze the relationship between PLR and CA19-9 and clinicopathological features. A receiver operating characteristic (ROC) curve was used to identify the optimal cutoff value for PLR and CA19-9. The Kaplan-Meier method was used to estimate the overall survival (OS). Meanwhile, the univariate and multivariate Cox regression models were used to assess the risk factors for OS. The cutoff values of 146.82 and 36.32U/ml defined as high PLR and high CA19-9, respectively. Furthermore, survival analysis showed that patients with PLR > 146.82 and CA19-9 > 36.32 U/ml had a worse prognosis than patients with PLR ≤ 146.82 and CA19-9 ≤ 36.32 U/ml, respectively. The multivariate analysis demonstrated that PLR (hazard ratio (HR) = 1.863, 95% CI: 1.366-2.542, P < 0.001) and CA19-9 (HR = 1.412, 95% CI: 1.021-1.952, P = 0.037) were independent prognostic factors in the GBC patients. When we combined these two parameters, the area under the ROC curve increased from 0.624 (PLR) and 0.661 (CA19-9) to 0.711. In addition, the 1-, 3-, and 5-year OS of group A (patients with PLR ≤ 146.82 and CA19-9 ≤ 36.32 U/ml), group B (patients with either of PLR > 146.82 or CA19-9 > 36.32 U/ml) and group C (patients with PLR > 146.82 and CA19-9 > 36.32 U/ml) were 83.6%, 58.6%, 22.5%, 52.4%, 19.5%, 11.5%, and 42.3%, 11.9%, 0%, respectively. The preoperative PLR and serum CA19-9 are associated with prognosis of patients with GBC. The combination of PLR and CA19-9 may serve as a significant prognostic biomarker for GBC patients superior to either PLR or CA19-9 alone.

PP4R1 promotes glycolysis and gallbladder cancer progression through facilitating ERK1/2 mediated PKM2 nuclear translocation.

Gallbladder cancer (GBC) is a common solid tumor of the biliary tract with a high mortality rate and limited curative benefits from surgical resection. Here, we aimed to elucidate the pathogenesis of GBC from the perspective of molecular mechanisms and determined that protein phosphatase 4 regulator subunit 1 (PP4R1) is overexpressed in GBC tissues and contributes to poor prognosis. Through a series of in vitro and in vivo experiments, we demonstrated that PP4R1 overexpression improved tumorigenesis in GBC cells. Further mechanistic exploration revealed that PP4R1 directly interacts with pyruvate kinase-M2 (PKM2), a key regulator of glycolysis. PP4R1 promotes the extracellular signal-related kinase 1 and 2 (ERK1/2)-mediated PKM2 nuclear translocation, thereby participating in the regulation of tumor glycolysis. Interestingly, we determined that PP4R1 strengthens the interaction between ERK1/2 and PKM2. Furthermore, PP4R1 enhanced the suppressive effects of the ERK inhibitor SCH772984 on GBC. In conclusion, our data showed that PP4R1 is a promising biomarker associated with GBC and confirmed that PP4R1 regulates PKM2-mediated tumor glycolysis, which provides a metabolic growth advantage to GBC cells, thereby promoting GBC tumor growth and metastasis1.

Tailored Polypyrrole Nanofibers as Ion-to-Electron Transduction Membranes for Wearable K+ Sensors.

Conductive polymers are recognized as ideal candidates for the development of noninvasive and wearable sensors for real-time monitoring of potassium ions (K+ ) in sweat to ensure the health of life. However, the low ion-to-electron transduction efficiency and limited active surface area hamper the development of high-performance sensors for low-concentration K+ detection in the sweat. Herein, a wearable K+ sensor is developed by tailoring the nanostructure of polypyrrole (PPy), serving as an ion-to-electron transduction layer, for accurately and stably tracing the K+ fluctuation in human sweat. The PPy nanostructures can be tailored from nanospheres to nanofibers by controlling the supramolecular assembly process during PPy polymerization. Resultantly, the ion-to-electron transduction efficiency (17-fold increase in conductivity) and active surface area (1.3-fold enhancement) are significantly enhanced, accompanied by minimized water layer formation. The optimal PPy nanofibers-based K+ sensor achieved a high sensitivity of 62 mV decade-1 , good selectivity, and solid stability. After being integrated with a temperature sensor, the manufactured wearable sensor realized accurate monitoring of K+ fluctuation in the human sweat.

The significance of peri-neural invasion in patients with resected hilar cholangiocarcinoma: A single-center experience in China.

BACKGROUND: The significance of peri-neural invasion (PNI) in resected patients with hilar cholangiocarcinoma (HCCA) has been rarely explored. Our study was performed to evaluate the significance of PNI in resected HCCA patients in terms of tumor biological features and long-term survival. METHODS: We retrospectively reviewed surgically-treated HCCA patients between June, 2000 and June 2018. SPSS 25.0 software was used for statistical analysis. RESULTS: A total of 239 resected HCCA patients were included (No. PNI: 138). PNI indicated more aggressive tumor biological features. Major vascular reconstruction was more frequently performed in patients with PNI (34.8% vs 24.8%, P = 0.064). Patients with PNI shared a significantly higher percentage of surgical margin width <5 mm (29.0% vs 16.8%, P = 0.02). The proportion of patients with T1-2 disease (31.2% vs 40.6%, P = 0.085) or I-II disease (21% vs 34.7%, P = 0.014) was significantly lower in patients with PNI. The overall morbidity rate was significantly higher in patients with PNI (P = 0.042). A much worse overall survival (OS) (P = 0.0003) or disease-free survival (DFS) (P = 0.0011) in patients with PNI. Even after matching vital prognostic factors, a significantly worse OS (P = 0.0003) or DFS (P = 0.0002) was still observed in patients with PNI. PNI was an independent prognostic factor in both OS (P = 0.011) and DFS (P = 0.024). CONCLUSION: PNI indicated more aggressive tumor biological features and more advanced tumor stage in patients with resected HCCA. PNI can be an independent prognostic factor in both OS and DFS. Future multi-center studies covering various races or populations are required for further validation.

Meta-analysis of prognostic factors for overall survival and disease-free survival among resected patients with combined hepatocellular carcinoma and cholangiocarcinoma.

BACKGROUND: Combined hepatocellular carcinoma and cholangiocarcinoma (CHCC-CC) is a rare subtype of primary liver malignancy and has been treated equally as intra-hepatic cholangiocarcinoma (IHCC) according to the 8th AJCC staging system. Owing to its rarity, its prognostic factors have been rarely explored and defined. METHODS: PubMed, EMBASE, the Cochrane Library and Web of Science were searched up till January 1st, 2023 and eligible studies were restricted to studies reported prognostic factors of resected CHCC-CC. Standard Parmar modifications were used to determine pooled univariable hazard ratios (HRs). RESULTS: A total of eleven studies with 1286 patients with resected classical CHCC-CC were finally included. Pooled results indicated that serum tumor biomarkers, including AFP, CA199, and CEA, were prognostic factors for postoperative overall survival (OS) and disease-free survival (DFS). Moreover, liver cirrhosis (P = 0.010), HBV infection (P = 0.030), and HCV infection (P < 0.001) were prognostic factors for OS. Age (HR = 1.03, P = 0.005) was a prognostic factor for DFS. Tumor size (OS: HR = 2, P < 0.001, DFS: HR = 2.15, P < 0.001), tumor number (OS: HR = 2.05, P < 0.001; DFS: HR = 1.96, P = 0.006), surgical margin (OS: HR = 2.33, <0.001001; DFS: HR = 2.35, P < 0.001), node metastasis (OS: HR = 2.96, P < 0.001; DFS: HR = 2.1, P < 0.001), vascular invasion (OS: HR = 2.17, P < 0.001; DFS: HR = 2.64, P < 0.001), and postoperative prophylactic trans-arterial chemotherapy embolization (PPTACE) (OS: HR = 1.67, P = 0.04; DFS: HR = 2.31, P < 0.001) were common prognostic factors for OS and DFS. CONCLUSION: Various risk factors unmentioned in the 8th AJCC staging system were identified. These promising findings would facilitate a more personalized predictive model and help clinicians to stratify patients with different survival outcomes.

Prognostic Significance of Tumor Necrosis in Patients with Gallbladder Carcinoma Undergoing Curative-Intent Resection.

BACKGROUND: Tumor necrosis has been indicated to correlate with dismal survival outcomes of a variety of solid tumors. However, the significance and prognostic value of tumor necrosis remain unclear in gallbladder carcinoma. The aim of this research is to explore the relationships between necrosis with long-term survival and tumor-related biological characteristics of patients with gallbladder carcinoma. PATIENTS AND METHODS: Patients with gallbladder carcinoma who accepted curative-intent resection in West China Hospital of Sichuan University (China) between January 2010 and December 2021 were retrospectively analyzed. Tumor necrosis was determined by staining the patient's original tissue sections with hematoxylin and eosin. Based on the presence of tumor necrosis, the pathologic features and survival outcomes were compared. RESULTS: This study enrolled 213 patients with gallbladder carcinoma who underwent curative-intent surgery, of whom 89 had tumor necrosis. Comparative analyses indicated that patients with tumor necrosis had more aggressive clinicopathological features, such as larger tumor size (p = 0.002), poorer tumor differentiation (p = 0.029), more frequent vascular invasion (p < 0.001), presence of lymph node metastasis (p = 0.014), and higher tumor status (p = 0.01), and experienced poorer survival. Univariate and multivariate analyses revealed that tumor necrosis was an independent prognostic factor for overall survival (multivariate: HR 1.651, p = 0.026) and disease-free survival (multivariate: HR 1.589, p = 0.040). CONCLUSIONS: Tumor necrosis can be considered as an independent predictive factor for overall survival and disease-free survival among individuals with gallbladder carcinoma, which was a valuable pathologic parameter.

Comparative analyses between radically re-resected incidental gallbladder carcinoma and primary radically resected gallbladder carcinoma: a single-center experience in China.

PURPOSES: The current study was performed to comparatively evaluate the similarities and differences between cases with radically re-resected incidental gallbladder carcinoma (RRIGBC) and those with primary radically resected gallbladder carcinoma (PRGBC). METHODS: Comparative analysis between patients with RRIGBC and those with PRGBC were performed in terms of clinic-pathological features and long-terms survival. RESULTS: A total of 330 surgically treated GBC patients with 110 patients with IGBC were identified. PRGBCs were generally in a more advanced tumor stage, sharing more aggressive tumor biological features and worse prognosis than those with RRIGBC. Subgroup analyses indicated a comparable prognosis among T1-2 patients between RRIGBC and PRGBC groups. However, among T3-4 patients, patients in the PRGBC group shared a much worse prognosis. Moreover, IGBC itself can be regarded as a prognostic factor but cannot be regarded as an independent prognostic factor. It is the tumor stage which really determined the overall prognosis. CONCLUSION: Patients with RRIGBC were generally in a much earlier tumor stage and shared a much better prognosis than those with PRGBC. IGBC itself can be regarded as a prognostic factor but cannot be regarded as the independent prognostic factors. It is the tumor stage which really determine the overall prognosis.

Meta-analysis of Prognostic Factors for Overall Survival Among Resected Patients with Spontaneous Ruptured Hepatocellular Carcinoma.

OBJECTIVE: Our meta-analysis was performed to explore the prognostic factors for overall survival among post-hepatectomy patients with spontaneous ruptured hepatocellular carcinoma (SRHCC). METHODS: PubMed, EMBASE, the Cochrane Library, and Web of Science were all searched up for relevant studies regarding prognostic factors with SRHCC. RevMan5.3 software and Stata 14.0 software were used for statistical analysis. RESULTS: A total of nineteen studies with 1876 resected SRHCC patients were finally identified. Pooled results indicated that preoperative AFP (high vs low) (P = 0.003), concurrent liver cirrhosis (yes vs no) (P = 0.02), preoperative liver function (child A vs non-child A) (P = 0.0007), tumor size (large vs small) (P < 0.00001), tumor number (solitary vs multiple) (P = 0.002), satellite foci (yes vs no) (P = 0.0006), micro-vascular invasion (yes vs no) (P < 0.00001), type of hepatectomy (major or minor) (P = 0.04), surgical margin (R + vs R -) (P < 0.00001), and type of hepatectomy (emergency hepatectomy vs staged hepatectomy) (P = 0.005) were prognostic factors for overall survival among post-hepatectomy SRHCC patients. CONCLUSION: Apart from some conventional prognostic factors identified in resected patients with SRHCC, numerous prognostic factors have also been unmasked, which might provide clinical reference to stratify patients with different therapeutic regimes.

DNA damage repair mutations in pancreatic cancer- prognostic or predictive?

Objective: The efficacy of platinum-based chemotherapy (PtCh) for pancreatic cancer (PC) patients with DNA damage repair gene mutations (DDRm) compared to those without DDRm remains uncertain. Methods: After a thorough database searching in PubMed, Embase, and Web of Science, a total of 19 studies that met all the inclusion criteria were identified. The primary outcomes were overall survival (OS) and progression-free survival (PFS) for PC patients with DDRm versus those without DDRm after PtCh. Results: Patients with advanced-stage PC who have DDRm tend to have longer OS compared to patients without DDRm, regardless of their exposure to PtCh (HR=0.63; I2 = 66%). Further analyses indicated that the effectiveness of PtCh for OS was modified by DDRm (HR=0.48; I2 = 59%). After the first- line PtCh (1L-PtCh), the PFS of advanced-stage PC with DDRm was also significantly improved (HR=0.41; I2 = 0%). For patients with resected PC, regardless of their exposure to PtCh, the OS for patients with DDRm was comparable to those without DDRm (HR=0.82; I2 = 71%). Specifically, for patients with resected PC harboring DDRm who received PtCh (HR=0.85; I2 = 65%) and for those after non-PtCh (HR=0.87; I2 = 0%), the presence of DDRm did not show a significant association with longer OS. Conclusion: 1L-PtCh treatment is correlated with favorable survival for advanced-stage PC patients with DDRm. For resected-stage PC harboring DDRm, adjuvant PtCh had limited effectiveness. The prognostic value of DDRm needs to be further verified by prospective randomized controlled trials. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022302275.

The significance of countable and treatable metastatic liver disease in patients with gallbladder carcinoma after curative-intent surgery: A 10-year experience in China.

OBJECTIVE: Our study was performed to evaluate the significance of countable and treatable metastatic liver disease (CTMLD) in patients with gallbladder carcinoma (GBC) after curative-intent surgery. METHODS: Resected GBC patients between September 2010 and January 2021 were reviewed. Comparative analyses between patients with CTMLD and those without it were performed. A propensity score matching analysis was conducted for further validation. RESULTS: A total of 326 resected GBC patients were identified (33 with CTMLD). A significantly higher preoperative CA199 level was detected in those with CTMLD (p = 0.0160). Significantly higher incidences of major hepatectomy (p = 0.0010), lymph node metastasis (p < 0.0001), direct liver invasion (p < 0.0001), moderate to poor differentiation status (p < 0.0001), and T3-4 disease (p < 0.0001) were detected in patients with CTMLD. Even sharing comparable surgical margin status, patients with CTMLD still shared a significantly higher recurrence rate (93.9% vs. 57.3%, p < 0.0001) as well as a significantly higher recurrence rate within 6 months after surgery (63.6% vs. 14.7%, p < 0.0001). A significantly worse overall survival (median survival time: 12 vs. 33 months, p < 0.0001) or disease-free survival (median recurrence-free time: 6 vs. 30 months, p < 0.0001) was acquired in patients with CTMLD. After matching, a significantly higher early recurrence rate was still detected. Adjuvant chemotherapy seemed to have survival benefit for patients with CTMLD. CONCLUSION: CTMLD was an indicator of advanced disease and served as an independent predictor of early recurrence among resected GBC patients. Whether curative-intent surgery is superior to nonsurgical treatment among GBC patients with CTMLD remains to be explored in future prospective studies.

Neuroendocrine Component in Extrahepatic Cholangiocarcinoma is Associated with Better Survival: Data from the SEER Study.

INTRODUCTION: This study was performed to evaluate the prognostic value of the neuroendocrine component in patients with extrahepatic cholangiocarcinoma (EHCC). METHODS: Cases with EHCC derived from the SEER database were retrospectively reviewed and analyzed. The clinicopathological features and long-term survival were compared between patients with neuroendocrine carcinoma (NECA) and those with pure adenocarcinoma (AC). RESULTS: A total of 3277 patients with EHCC were included (62 patients with NECA and 3215 patients with AC). T stage (P = 0.531) and M stage (P = 0.269) were comparable between the two groups. However, lymph node metastasis was more frequently detected in NECA (P = 0.022). NECA was correlated with more advanced tumor stage than pure AC (P < 0.0001). Inconsistent differentiation status was also observed between the two groups (P = 0.001). The proportion of patients who received surgery was significantly higher in the NECA group (80.6% vs 62.0%, P = 0.003) while chemotherapy was more frequently performed among patients with pure AC (45.7% vs 25.8%, P = 0.002). Comparable incidence of radiotherapy was acquired (P = 0.117). Patients with NECA shared a better overall survival than those with pure AC (P = 0.0141), even after matching (P = 0.0366). The results of univariate and multivariate analyses indicated that the neuroendocrine component was a protective factor as well as an independent prognostic factor for overall survival (HR < 1, P < 0.05). CONCLUSION: Patients with EHCC with a neuroendocrine component shared a better prognosis than those with pure AC, and NECA could serve as a favorable prognostic factor for overall survival. Considering various unprovided but potentially confounding factors, future more well-conducted research is required.

Bibliometric and visual analysis of microglia-related neuropathic pain from 2000 to 2021.

Background: Microglia has gradually gained researchers' attention in the past few decades and has shown its promising prospect in treating neuropathic pain. Our study was performed to comprehensively evaluate microglia-related neuropathic pain via a bibliometric approach. Methods: We retrospectively reviewed publications focusing on microglia-related neuropathic pain from 2000 to 2021 in WoSCC. VOS viewer software and CiteSpace software were used for statistical analyses. Results: A total of 2,609 articles were finally included. A steady increase in the number of relevant publications was observed in the past two decades. China is the most productive country, while the United States shares the most-cited and highest H-index country. The University of London, Kyushu University, and the University of California are the top 3 institutions with the highest number of publications. Molecular pain and Pain are the most productive and co-cited journals, respectively. Inoue K (Kyushu University) is the most-contributed researcher and Ji RR (Duke University) ranks 1st in both average citations per article and H-index. Keywords analyses revealed that pro-inflammatory cytokines shared the highest burst strength. Sex differences, neuroinflammation, and oxidative stress are the emerging keywords in recent years. Conclusion: In the field of microglia-related neuropathic pain, China is the largest producer and the United States is the most influential country. The signaling communication between microglia and neurons has continued to be vital in this field. Sexual dimorphism, neuroinflammation, and stem-cell therapies might be emerging trends that should be closely monitored.

Comparison of clinicopathological characteristics and long-term survival between patients with gallbladder adenosquamous carcinoma and pure gallbladder adenocarcinoma after curative-intent surgery: a single-center experience in China and a meta-analysis.

Objective: The aim of the study was to evaluate the similarities and differences between gallbladder adenosquamous carcinoma (GBASC) and pure gallbladder adenocarcinoma (GBAC). Methods: Patients with GBASC and GBAC from 2010 to 2020 were analyzed in terms of clinicopathological features and long-term survival. Moreover, a meta-analysis was also performed for further validation. Results: Our experience: A total of 304 patients with resected GBC were identified, including 34 patients with GBASC and 270 patients with GBAC. Patients with GBASC had a significantly higher preoperative CA199 level (P <0.0001), a significantly higher incidence of liver invasion (P <0.0001), a relatively larger tumor size (P = 0.060), and a significantly higher proportion of patients with T3-4 (P <0.0001) or III-IV disease (P = 0.003). A comparable R0 rate was obtained between two groups (P = 0.328). A significantly worse overall survival (OS) (P = 0.0002) or disease-free survival (DFS) (P = 0.0002) was observed in the GBASC. After propensity score matching, comparable OS (P = 0.9093) and DFS (P = 0.1494) were obtained. Clear margin (P = 0.001), node metastasis (P <0.0001), T stage (P <0.0001), and postoperative adjuvant chemoradiotherapy (P <0.0001) were independent prognostic factors for OS for the entire cohort. Adjuvant chemoradiotherapy had a survival benefit for patients with GBAC, while the survival benefit was still being validated in patients with GBASC. Meta-analysis: With our cohort incorporated, a total of seven studies involving 1,434 patients with GBASC/squamous carcinoma (SC) were identified. GBASC/SC shared a worse prognosis (P <0.00001) and more aggressive tumor biological features than GBAC. Conclusion: GBASC/SC shared more aggressive tumor biological features and a much worse prognosis than those with pure GBAC.

Organoids: The current status and biomedical applications.

Organoids are three-dimensional (3D) miniaturized versions of organs or tissues that are derived from cells with stem potential and can self-organize and differentiate into 3D cell masses, recapitulating the morphology and functions of their in vivo counterparts. Organoid culture is an emerging 3D culture technology, and organoids derived from various organs and tissues, such as the brain, lung, heart, liver, and kidney, have been generated. Compared with traditional bidimensional culture, organoid culture systems have the unique advantage of conserving parental gene expression and mutation characteristics, as well as long-term maintenance of the function and biological characteristics of the parental cells in vitro. All these features of organoids open up new opportunities for drug discovery, large-scale drug screening, and precision medicine. Another major application of organoids is disease modeling, and especially various hereditary diseases that are difficult to model in vitro have been modeled with organoids by combining genome editing technologies. Herein, we introduce the development and current advances in the organoid technology field. We focus on the applications of organoids in basic biology and clinical research, and also highlight their limitations and future perspectives. We hope that this review can provide a valuable reference for the developments and applications of organoids.