Several studies were carried out to explore the prognostic role of neutrophil-to-lymphocyte ratio (NLR) in pancreatic cancer, however, with contradictory results. The objectives of this study were to ...summarize the prognostic value of NLR in pancreatic cancer. Embase, PubMed and Cochrane Library were comprehensively retrieved. All the cohort studies focusing on the prognostic value of NLR in pancreatic cancer were eligible. 37 papers containing 43 cohort studies with pancreatic cancer were finally included into this study. The results presented that patients with low NLR might have longer OS when compared to the patients with high NLR (HR = 1.81, 95%CI = 1.59–2.05, P < 0.00001; I2 = 82%). Similar results were detected in the subgroup analyses of OS, which was based on the analysis model, ethnicity, treatment, sample size and cut-off value. In additions, low NLR was significantly associated with longer DFS when compared to high NLR in pancreatic cancer (HR = 1.66, 95%CI = 1.17–2.35, P = 0.005; I2 = 67%). Moreover, patients with low NLR had significantly smaller tumor size (P = 0.0007), better differentiation (P = 0.003), earlier stage (P = 0.02) and low CA-199 level (P = 0.007). In conclusion, it was revealed that low NLR was a favorable predictor of OS and DFS in patients with pancreatic cancer, and NLR is a promising prognostic biomarker for pancreatic cancer.
•Low NLR was obviously associated with longer OS and DFS compared to high NLR in pancreatic cancer.•The association between NLR and clinical parameters was explored.•The relatively large sample size strengthened the convincing of the results.•NLR might be a promising prognostic biomarker for pancreatic cancer.
A critical role of the Toll-like receptor(TLR) and its downstream molecules, including IL-1 receptor-associated kinase 1(IRAK1) and tumor necrosis factor receptor- associated factor 6(TRAF6), in the ...pathogenesis of liver ischemia/reperfusion (I/R) injury has been documented. Recently a microRNA, miR-146a, was identified as a potent negative regulator of the TLR signaling pathway. In this study, we investigated the role of miR-146a to attenuate TLR signaling and liver I/R injury in vivo and in vitro. miR-146a was decreased in mice Kupffer cells following hepatic I/R, whereas IRAK1 and TRAF6 increased. Overexpression of miR-146a directly decreased IRAK1 and TRAF6 expression and attenuated the release of proinflammatory cytokines through the inactivation of NF-κB P65 in hypoxia/reoxygenation (H/R)-induced macrophages, RAW264.7 cells. Knockdown experiments demonstrated that IRAK1 and TRAF6 are two potential targets for reducing the release of proinflammatory cytokines. Moreover, co-culture assays indicated that miR-146a decreases the apoptosis of hepatocytes after H/R. In vivo administration of Ago-miR-146a, a stable version of miR-146a in vivo, protected against liver injury in mice after I/R via inactivation of the TLR signaling pathway. We conclude that miR-146a ameliorates liver ischemia/reperfusion injury in vivo and hypoxia/reoxygenation injury in vitro by directly suppressing IRAK1 and TRAF6.
Objectives
Feline sarcoma-related protein (FER) is known to play a critical regulatory role in several carcinomas. However, the exact biological function of FER in hepatocellular carcinoma (HCC) ...still needs to be investigated. The primary objective of this research was to investigate the unknown function and molecular mechanisms of FER in HCC.
Materials and Methods
The expression level of FER in HCC tissue samples and cells was examined by RT-qPCR, immunohistochemistry and western blot. Cellular and animal experiments were used to explore the effect of FER on the proliferative and metastatic capacities of HCC cells. The crosstalk between FER and NF-κB signaling was explored by western blot. The upstream factors that regulate FER were evaluated through dual-luciferase experiments and western blot assays.
Results
FER was overexpressed in HCC specimens and HCC cell lines. FER expression levels were positively associated with unfavorable clinicopathological characteristics. The higher the expression of FER was, the worse the overall survival of HCC patients was. The results of loss-of-function and gain-of-function experiments indicated that knockdown of FER decreased, while overexpression of FER increased, the proliferation, invasion and metastasis of HCC cells
in vitro
and
in vivo
. Mechanistically, we found that FER activated the NF-κB signaling pathway and stimulated epithelial-to-mesenchymal transition (EMT). We also found that FER was directly regulated by miR-206, and the downregulation of miR-206 was associated with proliferation and metastatic progression in HCC.
Conclusions
The present research was the first to reveal that a decrease in miR-206 levels results in an increase in FER expression in HCC, leading to enhanced cell growth and metastatic abilities
via
activation of the NF-κB signaling pathway.
Objective
Immune checkpoint inhibitors (ICIs) have recently been increasingly used in cancer treatment, whereas their clinical application in biliary tract cancer (BTC) patients is uncommon. This ...study aimed to evaluate the efficacy and safety of ICIs plus capecitabine and oxaliplatin (CAPOX) in the treatment of BTC patients.
Methods
This retrospective study reviewed 26 unresectable or advanced BTC patients who received ICIs plus CAPOX. The treatment continued until disease progression, uncontrollable adverse event (AE) occurrence, intolerable toxicity occurrence, or voluntary withdrawal.
Results
The median treatment cycles were 5.5 interquartile range (IQR): 3.8–8.0. Complete response, partial response, stable disease, and progressive disease rates were 0.0%, 46.2%, 23.1%, and 30.8%, respectively. Objective response rate (ORR) and disease control rate (DCR) were 46.2% and 69.2%, correspondingly. Regarding survival, the median progression-free survival (PFS) and overall survival (OS) were 6.1 (95% CI: 4.4–7.7) months and 16.5 (95% CI: 5.0–28.0) months; moreover, the 1-year PFS and OS rates were 21.5% and 54.3%, respectively. An Eastern Cooperative Oncology Group (ECOG) score of 1–3 (vs. 0) was associated with declined DCR, PFS, and OS (all
p
< 0.050). The most common AEs of ICIs plus CAPOX were thrombocytopenia (61.5%), neutropenia (26.9%), and reactive cutaneous capillary endothelial proliferation (RCCEP) (23.1%). Moreover, 13 (50.0%) patients suffered from grade 3–4 AEs, including thrombocytopenia (50.0%), neutropenia (7.7%), liver dysfunction (7.7%), and RCCEP (3.8%). Notably, the majority of AEs were controllable.
Conclusion
ICIs plus CAPOX chemotherapy exhibit a good efficacy and a manageable safety profile in the treatment of patients with unresectable or advanced BTC.
Background and Aims
The development and progression of hepatocellular carcinoma (HCC) is dependent on its local microenvironment. Tumor‐associated macrophages (TAMs) are deemed a key factor for the ...tumor microenvironment and attribute to contribute to tumor aggressiveness. However, the detailed mechanism underlying the pro‐metastatic effect of TAMs on HCC remains undefined.
Approach and Results
The present study proved that TAMs were enriched in HCC. TAMs were characterized by an M2‐polarized phenotype and accelerated the migratory potential of HCC cells in vitro and in vivo. Furthermore, we found that M2‐derived exosomes induced TAM‐mediated pro‐migratory activity. With the use of mass spectrometry, we identified that integrin, αMβ2 (CD11b/CD18), was notably specific and efficient in M2 macrophage–derived exosomes (M2 exos). Blocking either CD11b and/or CD18 elicited a significant decrease in M2 exos–mediated HCC cell metastasis. Mechanistically, M2 exos mediated an intercellular transfer of the CD11b/CD18, activating the matrix metalloproteinase‐9 signaling pathway in recipient HCC cells to support tumor migration.
Conclusions
Collectively, the exosome‐mediated transfer of functional CD11b/CD18 protein from TAMs to tumor cells may have the potency to boost the migratory potential of HCC cells, thus providing insights into the mechanism of tumor metastasis.
By investigating the migration and invasion ability in pancreatic cancer, this study probed into the lncRNA MALAT1 molecular mechanism on Hippo‐YAP signaling. The expression of lncRNA MALAT1 in PC ...tissues and cells was detected by qRT‐PCR and Western blot. The effect of si‐MALAT1 on proliferation was determined by CCK‐8 assay. Cell apoptosis, migration, and invasion were respectively detected by flow cytometry assay, wound healing assay, and transwell assay. Western blot and immunohistochemistry were successively used for detecting LATS1 and YAP1 expression in pancreatic cancer tissues. The microarray analysis determined that lncRNA MALAT1 in pancreatic cancer was highly expressed. LncRNA MALAT1 presented an extremely high expression level in pancreatic cancer tissues and cells. After transfected with si‐MALAT1, the proliferation of AsPC‐1 cells decreased, induce apoptosis of AsPC‐1 cells, and migration and invasion ability were reduced. The tendency of LATS1 expression level was down‐regulated and YAP1 show the opposite trend in the Hippo‐YAP signaling. The in vivo assay was found that the tumor to be small in size and volume, and the expression of Ki‐67 was decreased. High expression of lncRNA MALAT1 in PC disorder the proliferation, apoptosis, and migration and invasion ability via influence Hippo‐YAP signaling pathway.
By investigating the migration and invasion ability in pancreatic cancer, this study probed into the lncRNA MALAT1 molecular mechanism on Hippo‐YAP signaling. High expression of lncRNA MALAT1 in PC disorder the proliferation, apoptosis, and migration and invasion ability via influence Hippo‐YAP signaling pathway.
e16118
Background: The development of ICIs has promoted a major breakthrough in the field of cancer therapy. A number of patients experience primary or acquired resistance to ICIs based first line ...therapy. Because of the similar mechanisms, PD-(L)1 inhibitors replacement after PD-(L)1 inhibitors-based therapy resistance is difficult to sustain benefits. Therefore, whether suspending immunotherapy, or maintenance immunotherapy and switching the combination drugs in the follow-up strategy is worth to explore. Regorafenib is an oral multikinase inhibitor that blocks the activity of protein kinases involved in angiogenesis, oncogenesis and metastasis. Besides, regorafenib could regulate the immune microenvironment. This retrospective trial aims to evaluate the efficacy of regorafenib in combinations with previous ICI in advanced HCC patients who failed to previous ICI-TKI treatment. Methods: In this study, eligible patients were advanced HCC, who failed to previous treatment with TKIs and PD-1 inhibitors. 17 patients were received PD-1 inhibitor the same as the first-line treatment (dosage and mode of administration according to instructions) and regorafenib (40, 80, 120mg/m
2
, po, qd, d1-21) every 4 weeks, until disease progression, intolerable toxicities, or physician/patient withdrawal. The safety and efficacy were assessed by investigators per CTCAE v5.0 and RECIST v1.1, respectively. The primary endpoint was objective response rate (ORR), the secondly endpoints were progression-free survival (PFS), disease control rate (DCR), overall survival (OS), duration of response (DOR) and safety. Results: From Nov 15, 2020 to Jan 31, 2022, 17 patients with advanced HCC, Child-Pugh class A liver disease, and ECOG PS 0-1 (16 male vs. 1 female, 13 second-line recipients vs. 4 third-line recipients, median age of 55 years) had been enrolled. 52.94% of the patients had BCLC stage B and others had BCLC stage C. The median follow-up was 8.8 months (range, 2.7-14.7). Confirmed ORR and DCR were 41.2% and 64.7%, respectively. The median PFS was 5.21 months (95% CI, 2.65-7.77). For 13 second line patients, confirmed ORR and DCR were 46.2% and 69.2%, respectively. Median OS and DOR had not yet been reached. 12 recipients had treatment-related adverse events (TRAEs). Most frequent TEAEs (≥5%) included fatigue (15.8%), diarrhea (15.8%), periodontal disease (10.5%), hypertension (10.5%), albuminuria (5.3%). Grade 3 TRAEs occurred in 3 (17.6%) patients included gastrointestinal bleeding, hand-foot syndrome and albuminuria. No Grade 4 TRAE and new safety signal were identified. Conclusions: Regorafenib plus PD-1 inhibitor showed a promising efficacy with favorable safety in HCC patients with PD-1 inhibitor resistance, especially in the standard second line patients. Moreover, the strategy showed a higher ORR than RESORCE study (46.2% vs. 10.6%).
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