Adipose-derived mesenchymal stromal cells alleviate intestinal fibrosis: The role of tumor necrosis factor-stimulated gene 6 protein.

BACKGROUND: The therapeutic potential of adipose-derived mesenchymal stromal cells (AMSCs) in the treatment of intestinal fibrosis occured in patients with Crohn's disease (CD) remains unclear. Tumor necrosis factor-stimulated gene 6 (TSG6) protein plays a critical role in inflammation regulation and tissue repair. This study aimed to determine if AMSCs attenuate intestinal fibrosis by secreting paracrine TSG6 protein and explore the underlying mechanisms. METHODS: Two murine models for intestinal fibrosis were established using 2,4,6-trinitrobenzene sulfonic acid in BALB/c mice and dextran sulfate sodium in C57BL/6 mice. Primary human fibroblasts and CCD-18co cells were incubated with transforming growth factor (TGF)-ß1 to build two fibrosis cell models in vitro. RESULTS: Intraperitoneally administered AMSCs attenuated intestinal fibrosis in the two murine models, as evidenced by significant alleviation of colon shortening, collagen protein deposits, and submucosal thickening, and also decrease in the endoscopic and fibrosis scores (P < 0.001). Although intraperitoneally injected AMSCs did not migrate to the colon lesions, high levels of TSG6 expression and secretion were noticed both in vivo and in vitro. Similar to the role of AMSCs, injection of recombinant human TSG6 attenuated intestinal fibrosis in the mouse models, which was not observed with the administration of AMSCs with TSG6 knockdown or TSG6 neutralizing antibody. Mechanistically, TSG6 alleviates TGF-ß1-stimulated upregulation of α-smooth muscle actin (αSMA) and collagen I by inhibiting Smad2 phosphorylation. Furthermore, the expression of TSG6 is lower in intestinal fibrosis tissue of patients with Crohn's disease and can reduce pro-fibrotic protein (αSMA) secretion from primary ileal fibrotic tissue. CONCLUSIONS: AMSCs attenuate intestinal fibrosis by secreting paracrine TSG6 protein, which inhibits Smad2 phosphorylation. TSG6, a novel anti-fibrotic factor, could potentially improve intestinal fibrosis treatments.

Optimizing Paclitaxel Oral Absorption and Bioavailability: TPGS Co-Coating via Supercritical Anti-Solvent Fluidized Bed Technology.

Supercritical anti-solvent fluidized bed (SAS-FB) coating technology has the advantages of reducing particle size, preventing high surface energy particle aggregation, improving the dissolution performance and bioavailability of insoluble drugs. The poor solubility of Biopharmaceutics Classification System (BCS) class IV drugs poses challenges in achieving optimal bioavailability. Numerous anti-cancer drugs including paclitaxel (PTX) belong to the BCS class IV, hindering their therapeutic efficacy. To address this concern, our study explored SAS-FB technology to coat PTX with D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) onto lactose. Under our optimized conditions, we achieved a PTX coating efficiency of 96.8%. Further characterization confirmed the crystalline state of PTX in the lactose surface coating by scanning electron microscopy and X-ray powder diffraction. Dissolution studies indicated that SAS-FB processed samples release over 95% of the drug within 1 min. Moreover, cell transmembrane transport assays demonstrated that SAS-FB processed PTX samples co-coated with TPGS had an enhanced PTX internalization into cells and a higher permeability coefficient compared to those without TPGS. Finally, compared to unprocessed PTX, SAS-FB (TPGS) and SAS-FB processed samples showed a 2.66- and 1.49-fold increase in oral bioavailability in vivo, respectively. Our study highlights the efficacy of SAS-FB co-coating for PTX and TPGS as a promising strategy to overcome bioavailability challenges inherent in BCS class IV drugs. Our approach holds broader implications for enhancing the performance of similarly classified medications.

Risk Factors of Chylothorax After Congenital Heart Surgery in Infants: A Single-Centre Retrospective Study.

Background: Studies of chylothorax after congenital heart disease in infants are rare. Chylothorax has a higher incidence in infancy, but its risk factors are not well understood. Objective: The purpose of this study is to investigate the risk factors of chylothorax after congenital heart surgery in infants. Methods: This retrospective study included 176 infants who underwent congenital heart disease surgery at the Guangdong Cardiovascular Institute, China, between 2016 and 2020. According to the occurrence of chylothorax, the patients were divided into a control group (n = 88) and a case group (n = 88). Univariate and multivariate logistic regression were performed to analyse the incidence and influencing factors of chylothorax after congenital heart surgery in infants. Results: Between 2016 and 2020, the annual incidence rate fluctuated between 1.55% and 3.17%, and the total incidence of chylothorax was 2.02%. Multivariate logistic regression analysis showed that postoperative albumin (p = 0.041; odds ratio [OR] = 0.095), preoperative mechanical ventilation (p = 0.001; OR = 1.053) and preterm birth (p = 0.002; OR = 5.783) were risk factors for postoperative chylothorax in infants with congenital heart disease. Conclusion: The total incidence of chylothorax was 2.02% and the annual incidence rate fluctuated between 1.55% and 3.17% between 2016 and 2020. Premature infants, longer preoperative mechanical ventilation and lower albumin after congenital heart surgery may be risk factors for chylothorax. In addition, infants with chylothorax are inclined to be infected, need more respiratory support, use a chest drainage tube for longer and remain longer in hospital.

Prognostic value of hyperthermic intraperitoneal chemotherapy in gastric cancer with synchronous peritoneal metastases: a real-world retrospective study.

PURPOSE: Peritoneal metastasis in gastric cancer (GC) is a late-stage condition with a poor prognosis. Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is a popular treatment for peritoneal metastases. Here, we aim to investigate the real-world application and efficacy of HIPEC alone for GC patients with synchronous peritoneal metastases. METHODS: We conducted a retrospective analysis on GC patients with synchronous peritoneal metastasis at the Sixth Affiliated Hospital of Sun Yat-sen University between January 2011 and December 2022. Survival analyses and Cox regression models were performed based on overall survival (OS) and cancer-specific survival (CSS), and subgroup analysis was used to determine the prognostic value of HIPEC across different treatment. RESULTS: We enrolled 250 patients, of whom 120 (48%) received HIPEC while 130 (52%) did not. HIPEC showed no survival benefit for GC patients (P = 0.220 for OS and P = 0.370 for CSS). However, subgroup analysis found that HIPEC can only improve OS and CSS when combined with primary tumor resection (P = 0.034 for OS and P = 0.036 for CSS). Moreover, survival analyses also demonstrated that HIPEC independently improved OS (HR for OS = 0.58, 95% CI 0.37-0.92, P = 0.020) and CSS (HR for CSS = 0.58, 95% CI 0.37-0.93, P = 0.024) for patients who underwent primary site resection, but not for those who did not. CONCLUSION: HIPEC can improve survival in GC patients with synchronous peritoneal metastases who have primary tumor resection, but not in those without primary tumor resection.

Implication of perineural invasion in patients with stage II gastric cancer.

BACKGROUND: Perineural invasion (PNI) is regarded as a prognostic factor for patients with GC. However, the significance of PNI in patients with stage II GC remains unclear. This study aimed to investigate the clinical implication of PNI in patients with stage II GC undergoing curative resection. METHODS: Patients with stage II GC who underwent curative resection were retrospectively evaluated from January 2010 to July 2019. According to PNI status, all patients were divided into two groups: with or without PNI. The prognostic value of PNI was analyzed by univariate and multivariate Cox proportional hazards regression models. RESULTS: A total of 233 patients were included in this study. There were 100 patients with PNI (42.92%) and 133 patients without PNI (57.08%). The overall survival (OS) and disease-free survival (DFS) rates for patients with PNI were significantly lower than that for patients without PNI (p = 0.019 and p = 0.032, respectively). Multivariate analysis indicated that the presence of PNI was an independent risk factor for OS (hazard ratio (HR): 1.76, 95% confidence interval (CI) 1.02-3.06, p = 0.044) and DFS (HR: 1.70, 95% CI 1.04-2.80, p = 0.035), while adjuvant chemotherapy (AC) was an independent protective factor for OS (HR: 0.51, 95% CI 0.30-0.88, p = 0.016) and DFS (HR: 0.52, 95% CI 0.31-0.86, p = 0.011). Furthermore, among patients with PNI, those who received AC had better OS (p = 0.022) and DFS (p = 0.027) than their counterparts. When patients with PNI received AC, the OS (p = 0.603) and DFS (p = 0.745) appeared to be similar to those without PNI and no AC. CONCLUSION: In patients with stage II GC undergoing curative resection, the presence of PNI was associated with worse survival, which appeared to improve with the treatment of AC, indicating a potential need for more intensive AC.

IGSF6 is a novel biomarker to evaluate immune infiltration in mismatch repair-proficient colorectal cancer.

Immunotherapy has dramatically changed the landscape of treatment for colorectal cancer (CRC), but currently lack of effective predictive biomarker, especially for tumors with mismatch repair (MMR) proficiency. The response of immunotherapy is associated with the cell-cell interactions in tumor microenvironment, encompassing processes such as cell-cell recognition, binding, and adhesion. However, the function of immunoglobulin superfamily (IGSF) genes in tumor immune microenvironment remains uncharacterized. This study quantified the immune landscape by leveraging a gene expression matrix from publicly accessible databases. The associations between IGSF6 gene expression and immune cell infiltration were assessed. The expression levels of IGSF6, CD8+ T cells, CD4+ T cells and CD68+ macrophage cells in cancer tissues from CRC patients and CRC cell lines were evaluated. IGSF6 was more highly expressed in CRC tumor tissues than adjacent normal tissues. And IGSF6 was significantly correlated with immune cell infiltration in MMR-proficient patients. Remarkably, MMR-proficient patients with high IGSF6 expression showed more sensitive to immunotherapy and chemotherapy than those with low IGSF6 expression. In summary, IGSF6 could be a novel biomarker to evaluate immune infiltration and predict therapeutic effect for MMR-proficient CRC.

Elderly patients with stage II gastric cancer do not benefit from adjuvant chemotherapy.

BACKGROUND: With the aging of the population, the burden of elderly gastric cancer (EGC) increases worldwide. However, there is no consensus on the definition of EGC and the efficacy of adjuvant chemotherapy in patients with stage II EGC. Here, we investigated the effectiveness of adjuvant chemotherapy in defined EGC patients. METHODS: We enrolled 5762 gastric cancer patients of three independent cohorts from the Sixth Affiliated Hospital of Sun Yat-sen University (local), the Surveillance, Epidemiology, and End Results (SEER), and the Asian Cancer Research Group (ACRG). The optimal age cutoff for EGC was determined using the K-adaptive partitioning algorithm. The defined EGC group and the efficacy of adjuvant chemotherapy for them were confirmed by Cox regression and Kaplan-Meier survival analyses. Furthermore, gene set variation analyses (GSVA) were performed to reveal pathway enrichment between groups. RESULTS: The optimal age partition value for EGC patients was 75. In the local, SEER, and ACRG cohorts, the EGC group exhibited significantly worse overall survival and cancer-specific survival than the non-EGC group (P < 0.05) and was an independent risk factor. Stratified analyses based on chemotherapy showed that EGC patients derived little benefit from adjuvant chemotherapy. Furthermore, GSVA analysis revealed the activation of DNA repair-related pathways and downregulation of the p53 pathway, which may partially contribute to the observed findings. CONCLUSION: In this retrospective, international multi-center study, 75 years old was identified as the optimal age cutoff for EGC definition, and adjuvant chemotherapy proved to be unbeneficial for stage II EGC patients.

Advanced lung cancer inflammation index predicts the outcomes of patients with non-metastatic gastric cancer after radical surgical resection.

Background: The prognostic value of the advanced lung cancer inflammation index (ALI) has been demonstrated in various tumors. However, the prognostic significance of ALI in non-metastatic gastric cancer (GC) remains unclear. This study aimed to identify the prognostic values of ALI in patients with non-metastatic GC who underwent radical surgical resection. Methods: Patients who underwent radical surgery for non-metastatic GC from January 2008 to September 2020 were enrolled in this study. The preoperative ALI was calculated as follows: body mass index × serum albumin/neutrophil to lymphocyte ratio. The primary outcomes were overall survival (OS) and cancer-specific survival (CSS). Cox regression analyses were performed to assess the association between ALI and survival. The potential of ALI was supported by sensitivity testing based on the propensity score matching (PSM) analysis. Results: Low preoperative ALI was significantly correlated with male gender (P=0.037), older age (P=0.004), T3/4 stage (P=0.001), lymph node metastasis (P=0.030), Tumor Node Metastasis (TNM) stage classification progression (P=0.004), and vessel invasion (P=0.001). Patients with low ALI showed worse OS (P<0.001) and CSS (P=0.001) compared to those with high ALI. Multivariable analysis showed that ALI was an independent prognostic factor for both OS [hazard ratio (HR) =1.55; 95% confidence interval (CI), 1.11-2.16]; P=0.010] and CSS (HR =1.46; 95% CI, 1.01-2.10; P=0.043) in non-metastatic GC patients who underwent radical surgical resection. Further PSM analysis confirmed the prognostic value of ALI in the PSM cohort. Conclusions: The preoperative ALI is associated with survival outcomes in patients who have undergone radical surgical resection for non-metastatic GC. Low ALI appears to predict a worse prognosis.

Lymphovascular or perineural invasion is associated with lymph node metastasis and survival outcomes in patients with gastric cancer.

BACKGROUND: Lymphovascular invasion (LVI) and perineural invasion (PNI) are associated with poorer prognosis in several human malignancies, but their significance in gastric cancer (GC) remains to be clearly defined. Our study aimed to investigate the prognostic value of LVI/PNI in patients with curative resected GC. METHODS: Records of 1488 patients with stage I--III GC and 3327 patients with stage I-III colorectal cancer (CRC) were reviewed retrospectively, and difference in the incidence of LVI/PNI between GC and CRC was compared. Univariate and multivariate analyses were used to evaluate whether LVI/PNI was an independent risk factor for lymph node metastasis (LNM) and overall survival (OS) in GC. RESULTS: Patients with stage I-III GC had a significantly higher incidence of LVI/PNI than patients with stage I-III CRC (50.54% vs. 21.91%, p < 0.001). LVI/PNI was significantly associated with higher CEA, higher CA199, deeper tumor invasion, more lymph node metastasis, and advanced TNM stage in GC ( p < 0.05). Multivariate logistic regression analysis identified LVI/PNI (OR = 2.64, 95%CI: 2.05-3.40, p < 0.001) as an independent risk factor for LNM in GC. The OS rate was significantly lower in the LVI/PNI-positive GC group than that in the LVI/PNI-negative GC group ( p < 0.001). On multivariate Cox regression analysis, LVI/PNI (HR = 1.34, 95%CI: 1.04-1.71, p  = 0.023) was an independent prognostic factor for OS in GC. CONCLUSION: GC has a high incidence of LVI/PNI, which was closely associated with disease progression. LVI/PNI could serve as an independent risk factor for LNM and the prognosis of patients with curative resected GC. These findings will be helpful in predicting survival outcomes more accurately and establishing individualized treatment plans.

Characteristics of sublingual microcirculatory changes during the early postoperative period following cardiopulmonary bypass-assisted cardiac surgery-a prospective cohort study.

Background: Persistent microcirculatory dysfunction associated with increased morbidity and mortality. Interventions in the early resuscitation can be tailored to the changes of microcirculation and patient's need. However, there is usually an uncoupling of macrocirculatory and microcirculatory hemodynamics during resuscitation. Current research on the patterns of microcirculatory changes and recovery after cardiopulmonary bypass (CPB)-assisted cardiac surgery is limited. This study aimed to analyze changes in the microcirculatory parameters after CPB and their correlation with macrocirculation and to explore the characteristics of microcirculatory changes following CPB-assisted cardiac surgery. Methods: Between December 2018 and January 2019, 24 adult patients with indwelling pulmonary artery catheters after elective cardiac surgery using CPB were enrolled in this study. Both microcirculatory and macrocirculatory parameters were collected at 0, 6, 16, and 24 hours after admission to the intensive care unit (ICU). Video images of sublingual microcirculation were analyzed to obtain the microcirculatory parameters, including total vascular density (TVD), perfused small vessel density (PSVD), the proportion of perfused small vessels (PPV), microvascular flow index (MFI), and flow heterogeneity index (HI). The characteristics of microcirculatory parameter change following cardiac surgery and the correlation between microcirculatory parameters and macroscopic hemodynamic indicators, oxygen metabolic indicators, and carbon dioxide partial pressure difference (PCO2gap) were analyzed. Results: There were significant differences in the changes of TVD (P=0.012) and PSVD (P=0.005) during the first 24 hours postoperatively in patients who underwent CPB-assisted cardiac surgery. The microcirculatory density parameters (TVD: r=-0.5059, P=0.0456; PVD: r=-0.5499, P=0.0273) were correlated with oxygen delivery index (DO2I) at 24 hours after surgery. The microcirculatory flow parameters (PPV: r=0.4370, P=0.0327; MFI: r=0.6496, P=0.0006; and HI: r=-0.5350, P=0.0071) had a strong correlation with PCO2gap at 0 hour after surgery. Conclusions: TVD and PSVD might be two most sensitive indicators affected by CPB-assisted cardiac surgery. There was no consistency between microcirculation and macrocirculation until 24 hours following cardiac surgery, meaning the improvement of systemic hemodynamic indicators does not guarantee correspondently improvement in microcirculation. Early controlled oxygen supply after CPB-assisted cardiac surgery may be conducive to the resuscitation of patients to a certain extent.

Long-term effects of total vs. partial pancreatectomy among patients with pancreatic cancer: a population-based study.

Background: Total pancreatectomy (TP) for pancreatic cancer (PC) has been limited historically for fear of elevated perioperative morbidity and mortality. With advances in perioperative care, TP may be an alternative option to partial pancreatectomy (PP). Limited evidence clarified the indication for these two procedures in PC patients, especially in patients with different tumor staging and location. Thus, this study aims to compare the outcomes after TP and PP for PCs of different T stages and locations. Methods: The study identified 14,456 PC patients with potentially curable primary tumor (T1-3) who received TP or PP from the Surveillance, Epidemiology, and End Results (SEER) database during 2000 to 2016. Detailed clinical and tumor covariates were all collected. Overall survival (OS) and cancer-specific survival (CSS) were the primary endpoints of interest in this study. OS and CSS were compared between patients after TP and PP using log-rank analysis. Results: For all patients, except for tumor location, TP group was comparable to the PP group. OS and CSS of the TP group were worse than of the PP group (median OS: 19 vs. 20 months, P=0.0058; median CSS: 24 vs. 26 months, P=0.00098, respectively). In stratifying analyses, TP was significantly related to worse OS and CSS than PP in pancreatic head and neck cancer patients with T2-stage tumors (median OS: 18 vs. 19 months, P=0.0016; median CSS: 22 vs. 24 months, P=0.00055, respectively), whereas for patients with T1- or T3-stage pancreatic head and neck cancer as well as T1- to T3-stage pancreatic body and tail cancer or overlapping location cancer, OS and CSS of the two groups were similar (all P>0.05). Conclusions: Compared with PP, TP offered worse prognosis in pancreatic head and neck cancer patients with T2-stage tumors, furthermore, TP and PP achieved comparable prognosis in patients with T1- or T3-stage pancreatic head and neck cancer as well as T1- to T3-stage pancreatic body and tail cancer or overlapping location cancer.

Mutation of MUC16 Is Associated With Tumor Mutational Burden and Lymph Node Metastasis in Patients With Gastric Cancer.

BACKGROUND: Lymph node metastasis (LNM) is a critical factor in determining the prognosis of gastric cancer (GC), but its underlying mechanism remains unclear. The tumor mutational burden (TMB) has recently been recognized as a biomarker for predicting prognosis and response to immune checkpoint inhibitors, while mucin 16, cell surface associated (MUC16) is frequently mutated in GC. This study explored whether MUC16 mutation status is associated with TMB, LNM, and prognosis in patients with GC. METHODS: Somatic mutation data were downloaded from three GC cohorts. TMB values were calculated and associations between the TMB and clinical characteristics were analyzed. The mutational landscapes of these three GC cohorts were individually explored and visualized using waterfall diagrams. Univariate logistic regression and Kaplan-Meier survival analysis were performed to screen for mutated genes associated with LNM and overall survival (OS). Associations between MUC16 mutations and TMB, microsatellite instability (MSI), LNM, and tumor microenvironment signatures were explored. RESULTS: TMB was associated with LNM and OS in patients with GC. Analyzing the three GC cohorts (The Cancer Genome Atlas-Stomach Adenocarcinoma, International Cancer Genome Consortium [ICGC]-China, and ICGC-Japan) revealed that MUC16 was one of the most frequently mutated genes in patients with GC. MUC16 mutations were associated with better prognosis, including lower LNM rates and improved OS rates. In addition, MUC16 mutation status was associated with TMB and MSI statuses. Fifteen upregulated and 222 downregulated genes were identified in patients with MUC16 mutations, compared to in those in patients with wild-type MUC16. An altered tumor microenvironment signature was also identified in GC samples with MUC16 mutations; it was characterized by significantly decreased infiltration regarding stromal cells, CD4+ T cells, and macrophages. CONCLUSION: MUC16 mutation status was associated with TMB, microsatellite status, LNM, and survival in patients with GC. These findings may provide new insights into the mechanism of LNM and could act as a signpost for prognostic predictions and immunotherapy guidance for patients with GC.

Triplet versus doublet neoadjuvant chemotherapy regimens for locally advanced gastric cancer: a propensity score matching analysis.

BACKGROUND: To investigate the differences between doublet and triplet neoadjuvant chemotherapy (NAC) regimens in efficacy and safety profile. METHODS: A total of 227 locally advanced gastric cancer (LAGC) patients who received NAC and sequential radical gastrectomy were reviewed. After propensity score matching (PSM), 140 patients with similar baseline characteristics were selected. Among them, 70 received doublet NAC regimens consisted of platinum and fluorouracil; the other 70 received triplet NAC regimens consisted of docetaxel, platinum, and fluorouracil. RESULTS: The efficacy of doublet and triplet regimens was comparable after propensity score matching in terms of tumor regression (pathological complete response, Doublet 11.4% vs. Triplet 15.7%, p = 0.642), achieving of R0 resection (Doublet 88.6% vs. Triplet 88.6%, p = 1), 1-year disease-free survival (DFS) (Doublet 77.1% vs. Triplet 68.6%, p = 0.178), 3-years overall survival (OS) (Doublet 54.3% vs. Triplet 60.9%, p = 0.941). Post-surgery complications were more common in the triplet cohort (Doublet 5.7% vs. Triplet 27.1%, p = 0.001), especially abdominal infection (Doublet 0% vs. Triplet 11.1%, p = 0.001). CONCLUSIONS: A more intense preoperative triplet NAC regimen does not bring extra downstage effect and survival benefit compared to a doublet regimen. It may even result in a higher risk of post-surgery complications.

Surgical interventions for gastric cancer: a review of systematic reviews.

AIM: To evaluate methodological quality and the extent of concordance among meta-analysis and/or systematic reviews on surgical interventions for gastric cancer (GC). METHODS: A comprehensive search of PubMed, Medline, EMBASE, the Cochrane library and the DARE database was conducted to identify the reviews comparing different surgical interventions for GC prior to April 2014. After applying included criteria, available data were summarized and appraised by the Oxman and Guyatt scale. RESULTS: Fifty six reviews were included. Forty five reviews (80.4%) were well conducted, with scores of adapted Oxman and Guyatt scale ≥ 14. The reviews differed in criteria for avoiding bias and assessing the validity of the primary studies. Many primary studies displayed major methodological flaws, such as randomization, allocation concealment, and dropouts and withdrawals. According to the concordance assessment, laparoscopy-assisted gastrectomy (LAG) was superior to open gastrectomy, and laparoscopy-assisted distal gastrectomy was superior to open distal gastrectomy in short-term outcomes. However, the concordance regarding other surgical interventions, such as D1 vs. D2 lymphadenectomy, and robotic gastrectomy vs. LAG were absent. CONCLUSION: Systematic reviews on surgical interventions for GC displayed relatively high methodological quality. The improvement of methodological quality and reporting was necessary for primary studies. The superiority of laparoscopic over open surgery was demonstrated. But concordance on other surgical interventions was rare, which needed more well-designed RCTs and systematic reviews.