Macrophages as Targets in Hepatocellular Carcinoma Therapy.

Hepatocellular carcinoma (HCC) is a malignant tumor with a complex and diverse immunosuppressive microenvironment. Tumor-associated macrophages (TAM) are an essential component of the tumor immune microenvironment. TAMs typically exist in two primary states: anti-tumor M1 macrophages and protumor M2 macrophages. Remarkably, TAMs possess high plasticity, enabling them to switch between different subtypes or alter their biological functions in response to the tumor microenvironment. Based on research into the biological role of TAMs in the occurrence and development of malignant tumors, including HCC, TAMs are emerging as promising targets for novel tumor treatment strategies. In this review, we provide a detailed introduction to the origin and subtypes of TAMs, elucidate their interactions with other cells in the complex tumor microenvironment of HCC, and describe the biological roles, characteristics, and mechanisms of TAMs in the progression of HCC. Furthermore, we furnish an overview of the latest therapeutic strategies targeting TAMs.

Investigating the day-level associations between affective variability and physical activity using ecological momentary assessment.

BACKGROUND: Understanding affect as a determinant of physical activity has gained increased attention in health behavior research. Fluctuations in affect intensity from moment-to-moment (i.e., affective variability) may interfere with cognitive and regulatory processes, making it difficult to engage in goal-directed behaviors such as physical activity. Preliminary evidence indicates that those with greater trait-level affective variability engage in lower levels of habitual physical activity. However, the extent to which daily fluctuations in affect variability are associated with same-day physical activity levels is unknown. This study used ecological momentary assessment (EMA) to investigate day-level associations between affective variability (i.e., within-subject variance) and physical activity. METHODS: Young adults (N = 231, M = 23.58 ± 3.02 years) provided three months of smartphone-based EMA and smartwatch-based activity data. Every two weeks, participants completed a 4-day EMA measurement burst (M = 5.17 ± 1.28 bursts per participant). Bursts consisted of hourly randomly-prompted EMA surveys assessing momentary positive-activated (happy, energetic), positive-deactivated (relaxed), negative-activated (tense, stressed), and negative-deactivated (sad, fatigued) affect. Participants continuously wore a smartwatch to measure physical activity across the three months. Mixed-effects location scale modeling examined the day-level associations of affective variability (i.e., positive-activated, positive-deactivated, negative-activated, and negative-deactivated) and physical activity, controlling for covariates such as mean levels of affect, between-subject effects of physical activity, time of day, day of week, day in study, and smartwatch wear time. RESULTS: There were 41,546 completed EMA surveys (M = 182.22 ± 69.82 per participant) included in the analyses. Above and beyond mean levels of affect, greater day-level variability in positive-activated affect was associated with greater physical activity on that same day compared to other days (τ = 0.01, p < .001), whereas greater day-level variability in negative-deactivated affect was associated with less physical activity on that same day compared to other days (τ = -0.01, p < .001). Day-level variability in positive-deactivated affect or negative-activated affect were not associated with day-level physical activity (ps > .05) CONCLUSIONS: Individuals were less active on days with greater variability in feeling sad and fatigued but more active on days with greater variability in feeling happy and energetic. Understanding the dynamic relationships of affective variability with day-level physical activity can strengthen physical activity interventions by considering how these processes differ within individuals and unfold within the context of daily life. Future research should examine causal pathways between affective variability and physical activity across the day.

Retraction: Down-regulation of MRPS23 inhibits LPS-induced proliferation and invasion via regulation of the NF-κB signaling pathway in osteosarcoma cells.

[This retracts the article DOI: 10.1039/C8RA08973F.].

Switch/Sucrose Non-Fermentable Complex-Deficient Rhabdoid Carcinoma of Stomach: A Rare Case Report and Literature Review.

Gastric undifferentiated/rhabdoid carcinoma is a rare highly invasive tumor of epithelial origin. Due to mutations in the switch/sucrose non-fermentable (SWI/SNF) complex, these tumor cells are usually dedifferentiated, presenting a characteristic rhabdoid profile. In this report, we present a gastric rhabdoid carcinoma in a 77-year-old man who presented with intermittent epigastric pain. Gastroscopy revealed a giant ulcer in the antrum, which proved to be a malignant tumor in the biopsy. Therefore, he was admitted to our hospital and underwent laparoscopic radical gastrectomy and D2 lymphadenectomy. The resected neoplasm contained a variety of rhabdoid cells that lacked well-differentiated elements. Immunohistochemical staining revealed that SMARCA4/BRG1 expression was absent in tumor cells. Finally, the patient was diagnosed with undifferentiated/rhabdoid carcinoma of the stomach. The patient was treated with tegafur-gimeracil-oteracil potassium capsules postoperatively. There were no signs of imaging changes observed at the 18-month follow-up. We reviewed similar cases in previous reports. These tumors are more likely to affect older male adults and usually lack typical symptoms. Histologically, most tumor cells are poorly cohesive and rhabdoid, and differentiated compositions of various degrees can occasionally be seen. Positive staining for vimentin was seen in all tumor cells. Epithelial markers are positive in the majority of tumors. SWI/SNF mutant tumors tend to be associated with a poor prognosis. In this review, more than half of the patients died within one year after surgery. The treatments for these diseases are still being explored.

Analysis of high risk factors for chronic atrophic gastritis.

Background: Screening for chronic atrophic gastritis (CAG) is crucial for the prevention and early detection of gastric cancer. Endoscopy is the main method of CAG diagnosis, with high training requirements and limited accuracy, making it difficult to popularize. The study attempts to improve the positive rate and accuracy of CAG screening through non-invasive testing. Methods: A total of 2564 patients who underwent gastroscopy were included in this study. The results of gastroscopic evaluation, histological biopsy results (including H. pylori biopsy), urea breath test (UBT) results, serum pepsinogen, and testosterone were statistically analyzed. Results: We found significant differences in the diagnosis of CAG between endoscopy and histological biopsy. Pepsinogen II and pepsinogen I/II ratio were more useful for the diagnosis of CAG compared with pepsinogen I. The risk of CAG was increased when pepsinogen II exceeded 11.05 µg/L, and the pepsinogen I/II ratio was less than 3.75. CAG positivity was higher in patients with positive H. pylori infection on UBT screening. In addition, higher levels of testosterone, SHBG and HSD17B2, and lower level of GNRH1 were found in CAG mucosa. Patients with high serum testosterone had a higher risk of CAG. Conclusion: CAG screening should be combined with endoscopic evaluation, biopsy, and other non-invasive tests. Non-invasive tests include the combination of serum pepsinogen II protein and pepsinogen I/II ratio and high level of serum testosterone. UBT combined with serum pepsinogen testing may improve the positive rate of CAG and reduce gastric mucosal damage from multiple biopsies.

Pemigatinib in previously treated Chinese patients with locally advanced or metastatic cholangiocarcinoma carrying FGFR2 fusions or rearrangements: A phase II study.

OBJECTIVE: This study evaluated the antitumor activity and safety of pemigatinib in previously treated Chinese patients with advanced cholangiocarcinoma and fibroblast growth factor receptor 2 (FGFR2) fusions or rearrangements. BACKGROUND: Pemigatinib provided clinical benefits for previously treated patients with cholangiocarcinoma carrying FGFR2 fusions or rearrangements and was approved for this indication in multiple countries. METHODS: In this ongoing, multicenter, single-arm, phase II study, adult patients with locally advanced or metastatic cholangiocarcinoma carrying centrally confirmed FGFR2 fusions or rearrangements who had progressed on ≥1 systemic therapy received 13.5 mg oral pemigatinib once daily (3-week cycle; 2 weeks on, 1 week off) until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was objective response rate (ORR) assessed by an independent radiology review committee. RESULTS: As of January 29, 2021, 31 patients were enrolled. The median follow-up was 5.1 months (range, 1.5-9.3). Among 30 patients with FGFR2 fusions or rearrangements evaluated for efficacy, 15 patients achieved partial response (ORR, 50.0%; 95% confidence interval [CI], 31.3-68.7); 15 achieved stable disease, contributing to a disease control rate of 100% (95% CI, 88.4-100). The median time to response was 1.4 months (95% CI, 1.3-1.4), the median duration of response was not reached, and the median progression-free survival was 6.3 months (95% CI, 4.9-not estimable [NE]). Eight (25.8%) of 31 patients had ≥grade 3 treatment-emergent adverse events. Hyperphosphatemia, hypophosphatasemia, nail toxicities, and ocular disorders were mostly

Hepatocellular carcinoma-derived exosomal miRNA-761 regulates the tumor microenvironment by targeting the SOCS2/JAK2/STAT3 pathway.

BACKGROUND: Exosomes and exosomal microRNAs have been implicated in tumor occurrence and metastasis. Our previous study showed that microRNA-761 (miR-761) is overexpressed in hepatocellular carcinoma (HCC) tissues and that its inhibition affects mitochondrial function and inhibits HCC metastasis. The mechanism by which exosomal miR-761 modulates the tumor microenvironment has not been elucidated. METHODS: Exosomal miR-761 was detected in six cell lines. Cell counting kit-8 (CCK-8) and transwell migration assays were performed to determine the function of exosomal miR-761 in HCC cells. The luciferase reporter assay was used to analyze miR-761 target genes in normal fibroblasts (NFs). The inhibitors AZD1480 and C188-9 were employed to determine the role of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway in the transformation of cancer-associated fibroblasts (CAFs). RESULTS: In this study, we characterized the mechanism by which miR-761 reprogrammed the tumor microenvironment. We found that HCC-derived exosomal miR-761 was taken up by NFs. Moreover, HCC exosomes affected the tumor microenvironment by activating NFs via suppressor of cytokine signaling 2 (SOCS2) and the JAK2/STAT3 signaling pathway. CONCLUSIONS: These results demonstrated that exosomal miR-761 modulated the tumor microenvironment via SOCS2/JAK2/STAT3 pathway-dependent activation of CAFs. Our findings may inspire new strategies for HCC prevention and therapy.

Aldehyde Dehydrogenase 2 Family Member (ALDH2) Is a Therapeutic Index for Oxaliplatin Response on Colorectal Cancer Therapy with Dysfunction p53.

Oxaliplatin resistance is a major issue in the treatment of p53 mutant colorectal cancer (CRC). Finding the specific biomarkers would improve therapeutic efficacy of patients with CRC. In order to figure out the biomarker for CRC patients with mutant p53 access oxaliplatin, a Gene Expression Omnibus dataset (GSE42387) was used to determine differentially expressed genes (DEGs). The Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape software were used to predict protein-protein interactions. The Database for Annotation, Visualization, and Integrated Discovery online tool was used to group the DEGs into their common pathways. 138 DEGs were identified with 46 upregulated and 92 downregulated. In the PPI networks, 7 of the upregulated genes and 13 of the downregulated genes were identified as hub genes (high degrees). Four hub genes, aldehyde dehydrogenase 2 family member (ALDH2), aldo-keto reductase family 1 member B1 (AKR1B1), aldo-keto reductase family 1 member B10 (AKR1B10), and monoglyceride lipase (MGLL) were enriched in the most significant pathway, glycerolipid metabolism. Further, we found that low expression of ALDH2 is correlated with poor overall survival and oxaliplatin resistance. Finally, we found that combined treatment with ALDH2 inhibitor and oxaliplatin will reduce the sensitivity to oxaliplatin in p53 mutant HT29 cells. In conclusion, we demonstrate that ALDH2 may be a biomarker for oxaliplatin resistance status in CRC patients and bring new insight into treatment strategy for p53 mutant CRC patients.

Dynamic associations between anxiety, stress, physical activity, and eating regulation over the course of a behavioral weight loss intervention.

Negative emotional experiences are associated with dysregulated eating behaviors that impede weight management. While weight loss interventions promote physical activity and self-regulation of eating, no studies have examined how physical activity may directly influence eating by attenuating associations between negative emotions and eating. OBJECTIVE: The current study examined how momentary negative emotions (stress and anxiety), moderate-to-vigorous intensity physical activity (MVPA), and their interactions predict eating dysregulation (i.e., intensity of eating temptations, inability to resist eating tempting foods, overeating), as well as how these associations change during a weight loss intervention. METHODS: Women with overweight/obesity (N = 55) completed 14-day ecological momentary assessment (EMA) protocols with objective measurement of physical activity (i.e., bout-related MVPA time) before and after a three-month internet-based weight loss program. RESULTS: Three-way interactions emerged predicting overeating and eating tempting foods. When women experienced higher than usual levels of momentary anxiety or stress at end-of-treatment, they were less likely to subsequently overeat or eat tempting foods when they had recently engaged in more MVPA (relative to their usual level). No significant associations were found for ratings of temptation intensity. CONCLUSIONS: Findings suggest MVPA may exert direct effects on eating regulation. Specifically, MVPA appears to increasingly buffer the effect of negative emotional states on dysregulated eating behavior over the course of a weight loss intervention. Future work is needed to develop ways of communicating to patients how activity can have both indirect and direct effects on body weight, and examine whether such knowledge improves outcomes.

Model for liver hardness using two-dimensional shear wave elastography, durometer, and preoperative biomarkers.

BACKGROUND: Post-hepatectomy liver failure (PHLF) increases morbidity and mortality after liver resection for patients with advanced liver fibrosis and cirrhosis. Preoperative liver stiffness using two-dimensional shear wave elastography (2D-SWE) is widely used to evaluate the degree of fibrosis. However, the 2D-SWE results were not accurate. A durometer measures hardness by quantifying the ability of a material to locally resist the intrusion of hard objects into its surface. However, the durometer score can only be obtained during surgery. AIM: To measure correlations among 2D-SWE, palpation by surgeons, and durometer-measured objective liver hardness and to construct a liver hardness regression model. METHODS: We enrolled 74 hepatectomy patients with liver hardness in a derivation cohort. Tactile-based liver hardness scores (0-100) were determined through palpation of the liver tissue by surgeons. Additionally, liver hardness was measured using a durometer. Correlation coefficients for durometer-measured hardness and preoperative parameters were calculated. Multiple linear regression models were constructed to select the best predictive durometer scale. Receiver operating characteristic (ROC) curves and univariate and multivariate analyses were used to calculate the best model's prediction of PHLF and risk factors for PHLF, respectively. A separate validation cohort (n = 162) was used to evaluate the model. RESULTS: The stiffness measured using 2D-SWE and palpation scale had good linear correlation with durometer-measured hardness (Pearson rank correlation coefficient 0.704 and 0.729, respectively, P < 0.001). The best model for the durometer scale (hardness scale model) was based on stiffness, hepatitis B virus surface antigen, and albumin level and had an R 2 value of 0.580. The area under the ROC for the durometer and hardness scale for PHLF prediction were 0.807 (P = 0.002) and 0.785 (P = 0.005), respectively. The optimal cutoff value of the durometer and hardness scale was 27.38 (sensitivity = 0.900, specificity = 0.660) and 27.87 (sensitivity = 0.700, specificity = 0.787), respectively. Patients with a hardness scale score of > 27.87 were at a significantly higher risk of PHLF with hazard ratios of 7.835 (P = 0.015). The model's PHLF predictive ability was confirmed in the validation cohort. CONCLUSION: Liver stiffness assessed by 2D-SWE and palpation correlated well with durometer hardness values. The multiple linear regression model predicted durometer hardness values and PHLF.

Surgical treatment of Epstein-Barr virus-associated lymphoepithelioma-like carcinoma occurring in both the posterior mediastinum and liver: Case report.

RATIONALE: Lymphoepithelioma-like carcinoma (LELC) is a rare malignant tumor that can occur in many areas of the body. The pathogenesis of LELC remains unknown, but Epstein-Barr virus (EBV) has been shown to be strongly correlated with LELC at several anatomic sites, including the lungs and thymus. To the best of our knowledge, EBV-associated LELC has never been reported in both the posterior mediastinum and liver. Herein, we report the case of a 41-year-old female diagnosed with LELC in both the posterior mediastinum and liver and discuss whether it is beneficial to perform surgery on advanced LELC when resectable metastases are found. PATIENT CONCERNS: The patient was a 41-year-old woman who had been suffering from intermittent pain in the upper right quadrant for 3 months without obvious cause and was admitted to our hospital with occasional nausea without vomiting. DIAGNOSIS: Her cancer antigen 125 and cytokeratin 19 fragment levels were elevated, whereas alpha-fetoprotein and alanine aminotransferase were normal. Computed tomography (CT) and magnetic resonance imaging revealed a mass in the S6 segment of the liver. Whole-body positron emission tomography/computed tomography (PET/CT) revealed a 3.2-cm mass in the posterior mediastinum and a 6.7-cm mass on the right side of the liver. We made a diagnosis of LELC based on the histological and immunohistochemical findings of specimens obtained by operation. However, it was difficult to determine the primary origin of the tumor. INTERVENTIONS: The patient underwent mediastinal tumor resection, hepatectomy, and diaphragmatic repair. Thereafter, she was administered paclitaxel and cisplatin as adjuvant chemotherapy. OUTCOMES: The postoperative course was uneventful, and the patient was discharged 10 days later. Although she was administered paclitaxel and cisplatin as adjuvant chemotherapy, we noted recurrence during the 4-month follow-up examination. Then, the patient passed away 5 months after surgery. LESSONS: We present the first case of LELC found in both the posterior mediastinum and liver and describe the functionality of PET/CT for finding occult carcinomas and identifying their primary tumor origin. Additional studies are urgently needed to discover whether it is beneficial to perform surgery on advanced LELC when resectable metastases are revealed by PET/CT.

Prevalence, diagnosis, and treatment of primary hepatic gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GIST), which is the most common mesenchymal tumor of the digestive tract, account for 1%-3% of gastrointestinal tumors. Primary stromal tumors outside the gastrointestinal tract are collectively referred to as extra GISTs, and stromal tumors in different regions often have different prognoses. A primary hepatic GIST is a rare tumor with an unknown origin, which may be related to interstitial Cajal-like cells. Although primary hepatic GIST has certain characteristics on imaging, it lacks specific symptoms and signs; thus, the final diagnosis depends on pathological and genetic evidence. This review summarizes all cases of primary hepatic GIST described in the literature and comprehensively analyzes the detailed clinical data of all patients. In terms of treatment, local resection alone or with adjuvant therapy was the prioritized choice to obtain better disease-free survival and longer survival time. For advanced unresectable cases, imatinib mesylate was applied as the first-line chemotherapy agent. Moreover, transcatheter arterial chemoembolization, radiofrequency ablation, and microwave ablation were shown to improve overall survival for selected patients. Liver transplantation was a final treatment option after resistance to chemotherapy developed.

Impact of examined lymph node count on prognosis in patients with lymph node-negative pancreatic body/tail ductal adenocarcinoma.

BACKGROUND: Because the overall prognosis remains dismal for patients with resected pancreatic cancer (PC), we aimed to explore the prognostic impact of examined lymph node (ELN) count on lymph node (LN)-negative pancreatic body/tail ductal adenocarcinoma. METHODS: Patients' data were extracted from the Surveillance, Epidemiology, and End Results (SEER) database (National Cancer Institute, USA) to investigate the relationship between ELN count and survival outcomes of LN-negative pancreatic body/tail ductal adenocarcinoma. RESULTS: A total of 700 patients were included, and the median number of ELNs was 11. The respective 1-, 3-, 5-year overall survival (OS) rates were 75.3%, 37.7%, 30.3%, and the 1-, 3-, 5-year cancer-specific survival (CSS) were 78.3%, 41.7%, 34.5%. The X-tile analysis showed that 14 was the most optimal cutoff for both OS and CSS. Kaplan-Meier survival analysis indicated that patients with ELNs >14 had better OS and CSS than ELNs ≤14. Multivariate Cox analysis showed ELNs ≤14 was an independent risk factor for both OS [hazard ratio (HR), 1.357; 95% confidence interval (CI), 1.080-1.704; P=0.009] and CSS (HR, 1.394; 95% CI, 1.092-1.778; P=0.008). CONCLUSIONS: ELN count is associated with the survival rate in patients with LN-negative pancreatic body/tail ductal adenocarcinoma. Accurate nodal staging for these patients requires more than 14 ELNs.

Clinicopathological Characteristics and Survival Outcomes of Primary Hepatic Neuroendocrine Tumor: A Surveillance, Epidemiology, and End Results (SEER) Population-Based Study.

BACKGROUND Primary hepatic neuroendocrine tumor (PHNET) is a rare primary liver tumor that remains poorly understood. Here, we explored the clinicopathological characteristics and survival outcomes of PHNET patients. MATERIAL AND METHODS PHNET patients diagnosed between 1988 and 2015 in the Surveillance, Epidemiology, and End Results (SEER) database were enrolled in the cohort. Kaplan-Meier analysis was used to determine the survival outcomes. Multivariable Cox regression models were used to identify the risk factors for overall survival (OS) and disease-specific survival (DSS). RESULTS A total of 291 PHNET patients from the SEER database met the inclusion criteria for analysis. The majority of the patients were female (53.6%), white (77.7%), and married (49.5%). The 1-, 3-, and 5-year OS were 57.1%, 39.4%, and 30.2%, and the 1-, 3-, and 5-year DSS rates were 61.3%, 44.3%, and 36.7%, respectively. Multivariate Cox regression models showed that older age, unmarried status, poor differentiated grade, and no tumor-directed surgery were independent risk factors for poor OS and DSS. CONCLUSIONS Older age, unmarried status, poor differentiated grade, and no tumor-directed surgery were associated with poorer prognosis of PHNET. Surgical resection is an effective and reliable treatment method for patients with PHNET.

Do Elderly Patients With Stage I-II Hepatocellular Carcinoma Benefit From More Radical Surgeries? A Population-Based Analysis.

Background and Aims: The best treatment modalities for elderly patients with stage I-II HCC (hepatocellular carcinoma) remain controversial in an era of a shortage of liver donors. Methods: From the SEER database (Surveillance, Epidemiology, and End Results program), 2,371 elderly patients were sampled as Cohort 1. OS (Overall Survival) and CSS (Cancer-Specific Survival) were compared between the Non-surgery and Surgery groups. A stratification analysis in a CSS Cox model was also conducted among sub-groups, and propensity score matching was performed to generate Cohort 2 (746 pairs), reducing the influences of confounders. Results: For Cohort 1, the median follow-up times of the Non-surgery and Surgery groups were 11 months (95% CI, confidence interval: 9.74-12.26) vs. 49 months (44.80-53.21) in OS, and 14 months (12.33-15.67) vs. 74 months (64.74-83.26) in CSS, respectively. In the stratification analysis, for the elderly patients (age >= 70 years), Larger Resection was associated with a higher HR (hazard ratio) than Segmental Resection: 0.30 (95% CI, confidence interval: 0.22-0.41) vs. 0.29 (0.21-0.38) in 70-74 year-olds; 0.26 (0.18-0.38) vs. 0.23 (0.16-0.32) in 75-79 year-olds; 0.32 (0.21-0.49) vs. 0.21 (0.13-0.32) in those 80+ years old. For Cohort 2, a similar result could be seen in the CSS Cox forest plot. The HRs of Larger Resection and Segmental Resection were 0.27 (0.21-0.33) and 0.25 (0.20-0.31), respectively. Conclusions: It is cautiously recommended that, when liver transplantation is not available, segmental or wedge liver resection is the better treatment choice for elderly patients with stage I-II HCC (AJCC edition 6), especially those over 70 years old, compared with other surgeries, based on the SEER data.