Cellular senescence is associated with the spatial evolution toward a higher metastatic phenotype in colorectal cancer.

In this study, we explore the dynamic process of colorectal cancer progression, emphasizing the evolution toward a more metastatic phenotype. The term "evolution" as used in this study specifically denotes the phenotypic transition toward a higher metastatic potency from well-formed glandular structures to collective invasion, ultimately resulting in the development of cancer cell buddings at the invasive front. Our findings highlight the spatial correlation of this evolution with tumor cell senescence, revealing distinct types of senescent tumor cells (types I and II) that play different roles in the overall cancer progression. Type I senescent tumor cells (p16INK4A+/CXCL12+/LAMC2-/MMP7-) are identified in the collective invasion region, whereas type II senescent tumor cells (p16INK4A+/CXCL12+/LAMC2+/MMP7+), representing the final evolved form, are prominently located in the partial-EMT region. Importantly, type II senescent tumor cells associate with local invasion and lymph node metastasis in colorectal cancer, potentially affecting patient prognosis.

Differential efficacy of tyrosine kinase inhibitors according to the types of EGFR mutations and agents in non-small cell lung cancer: a real-world study.

BACKGROUND: Both first and second-generation EGFR-TKIs are recommended in advanced NSCLC with common EGFR mutations. However, there are few data on the difference in efficacy of EGFR-TKIs based on the type of EGFR mutation and agents. METHODS: This retrospective real-world study evaluated the outcomes and clinicopathologic characteristics, including the type of EGFR mutations, of 237 advanced NSCLC patients treated with first- or second-generation (afatinib) EGFR-TKIs as first-line therapy. RESULTS: The median progression-free survival (PFS) and overall survival (OS) of all patients were 11 months (M) and 25M, respectively. In the univariate analysis, patients with exon 19 deletion (del) (n=130) had significantly longer median OS compared to those with other mutations (L858R: 84, others: 23) (30 vs. 22 M, p=0.047), without a difference in PFS (p=0.138). Patients treated with afatinib (n=60) showed significantly longer median OS compared to those treated with first-generation TKIs (gefitinib: 159, erlotinib: 18) (30 vs. 23 M, p=0.037), without a difference in PFS (p=0.179). In patients with exon 19 del, there was no significant difference in median PFS (p=0.868) or OS (p=0.361) between patients treated with afatinib and those treated with first-generation TKIs, while significantly better PFS (p=0.042) and trend in OS (p=0.069) were observed in patients receiving afatinib in other mutations. Exon 19 del was independently associated with favorable OS (p=0.028), while age >70 years (p=0.017), ECOG performance status ≥2 (p=0.001), primary metastatic disease (p=0.007), and synchronous brain metastasis (p=0.026) were independent prognostic factors of poor OS. CONCLUSIONS: The EGFR exon 19 del was associated with favorable OS in advanced NSCLC patients receiving first-line EGFR-TKIs. Moreover, in patients with exon 19 del, first-generation TKIs seem to be a reasonable treatment option if osimertinib is unavailable.

CDK4/6 inhibitors induce breast cancer senescence with enhanced anti-tumor immunogenic properties compared with DNA-damaging agents.

Since therapy-induced senescence (TIS) can either support or inhibit cancer progression, identifying which types of chemotherapeutic agents can produce the strongest anti-tumor TIS is an important issue. Here, cyclin-dependent kinase4/6 inhibitors (CDK4/6i)-induced senescence was compared to the TIS induced by conventional DNA-damaging agents. Despite both types of agents eliciting a similar degree of senescence, we observed increased expression of the senescence-associated secretory phenotype (SASP) and ligands related to pro-tumor immunity (IL6, CXCL8, TGFß, CD274, and CEACAM1) and angiogenesis (VEGFA) mainly in TIS induced by DNA-damaging agents rather than by CDK4/6i. Additionally, although all agents increased the expression of anti-tumor immunomodulatory proteins related to antigen presentation (MHC-I, B2M) and T cell chemokines (CXCL9, 10, 11), CDK4/6i-induced senescent cells still maintained this expression at a similar or even higher intensity than cells treated with DNA-damaging agents, despite the absence of nuclear factor-kappa-B (NF-κB) and p53 activation. These data suggest that in contrast with DNA-damaging agents, which augment the pro-tumorigenic microenvironment via pro-inflammatory SASP, CDK4/6i can generate TIS only with antitumor immunomodulatory proteins.

Thromboembolic events in patients who received adjuvant chemotherapy for gastric cancer: a single-center retrospective study.

BACKGROUND: Thromboembolic events (TEEs) are significant adverse events that can cause serious morbidities and mortality in cancer patients receiving chemotherapy. Patients with gastric cancer (GC) treated with palliative chemotherapy have been reported to experience a TEE incidence of 5-27%. However, very few reports have addressed TEEs in adjuvant chemotherapy (AC) for GC. METHODS: This study retrospectively analyzed 611 GC patients (stage II: 309, III: 302) who started AC with capecitabine/oxaliplatin (167 patients) or S-1 (444 patients) after undergoing curative resection between January 2013 and June 2020 at a single center. The incidence of TEEs during AC or within 1 year after AC completion was investigated, while analyzing the factors that influenced the TEEs' occurrence. RESULTS: TEEs were confirmed in 20 patients (3.3%), and TEEs occurred in almost all patients in the S-1 group (19 patients). The most common TEE types were cerebral infarction and pulmonary thromboembolism (five patients each). Although old age (≥ 70 years, p < 0.0001), S-1 treatment (p = 0.021), and hypertension (p = 0.017) were identified as significant risk factors for TEEs in univariate analysis, only old age showed a statistically significant correlation with TEEs' occurrence in multivariate analysis (odds ratio: 3.07; 95% confidence interval 1.11-8.48; p = 0.031). CONCLUSIONS: TEEs occurred in fewer patients with GC who had been treated with AC than patients who had received palliative chemotherapy in previous reports. However, elderly GC patients who are undergoing AC require more careful surveillance for possible TEEs, considering relatively higher incidence of them.

Gemcitabine and rapamycin-loaded mixed polymeric thermogel for metastatic pancreatic cancer therapy.

Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer-related death and has a poor 5-year overall survival. The superior therapeutic benefits of combination or co-administration of drugs as intraperitoneal chemotherapy have increased interest in developing strategies to deliver chemotherapeutic agents to patients safely. In this study, we prepared a gel comprising the thermosensitive poly(lactide-co-glycolide)-b-poly(ethylene glycol)-b-poly(lactide-co-glycolide) (PLGA-PEG-PLGA) polymer and gemcitabine (GEM), which is currently used as the primary chemotherapy for PDAC and rapamycin (RAPA), a mammalian TOR (mTOR) inhibitor, to deliver the drug through intraperitoneal injection. We performed in vitro cytotoxicity experiments to verify the synergistic effects of the two drugs at different molar ratios and characterized the physicochemical properties of the GEM, RAPA, and GEM/RAPA-loaded thermosensitive PLGA-PEG-PLGA gels, hereafter referred to as (g(G), g(R), and g(GR)), respectively. The g(GR) comprising PLGA-PEG-PLGA polymer (25% w/v) and GEM and RAPA at a molar ratio of 11:1 showed synergism and was optimized. An in vitro cytotoxicity assay was performed by treating Panc-1-luc2 tumor spheroids with g(G), g(R), or g(GR). The g(GR) treatment group showed a 2.75-fold higher inhibition rate than the non-treated (NT) and vehicle-treated groups. Furthermore, in vivo drug release assay in mice by intraperitoneal injection of g(G), g(R), or g(GR) showed a more rapid release rate of GEM than RAPA, similar to the in vitro release pattern. The drugs in the gel were released faster in vivo than in vitro and degraded in 48 h. In addition, g(GR) showed the highest anti-tumor efficacy with no toxicity to mice. These results provide evidence for the safety and efficacy of g(GR) for intraperitoneal drug delivery. This study will assist in developing and clinically administering topical anti-cancer formulations.

p15INK4B is an alternative marker of senescent tumor cells in colorectal cancer.

Senescent tumor cells are nonproliferating tumor cells which are closely related to cancer progression by secreting senescence-related molecules, called senescence-associated secreting phenotypes. Therefore, the presence of senescent tumor cells is considered a prognostic factor in various cancer types. Although senescence-associated ß-galactosidase staining is considered the best marker for detection of senescent tumor cells, it can only be performed in fresh-frozen tissues. p16INK4A, a cyclin-dependent inhibitor, has been used as an alternative marker to detect senescent tumor cells in formalin-fixed paraffin-embedded tissues. However, other reliable markers to detect senescent tumor cells is still lacking. In the present study, using public single-cell RNA-sequencing data, we found that p15INK4B, a cyclin-dependent kinase inhibitor, is a novel marker for detection of senescent tumor cells. Moreover, p15INK4B expression was positively correlated with that of p16INK4A in colorectal cancer tissues. In in vitro studies, mRNA expression of p15INK4B was increased together with that of p16INK4A in H2O2- and therapy-induced cancer senescence models. However, the mRNA level of p15INK4B did not increase in the oncogene-induced senescence model in primary colonic epithelial cells. In conclusion, p15INK4B is a potential alternative marker for detection of senescent tumor cells together with conventional markers in advanced stages of colorectal cancer.

Analysis of treatment outcomes according to the cycles of adjuvant chemotherapy in gastric cancer: a retrospective nationwide cohort study.

BACKGROUND: One-year S-1 or six-month capecitabine/oxaliplatin (CAPOX) has been the standard adjuvant chemotherapy for gastric cancer (GC). We investigated outcomes according to the cycles of adjuvant chemotherapy, using data from the Korean Health Insurance and Assessment Service. METHODS: A total of 20,552 patients, including 13,614 patients who received S-1 and 6,938 patients who received CAPOX extracted from 558,442 patients were retrospectively analyzed. The five-year overall survival rate was evaluated according to the duration of adjuvant chemotherapy. RESULTS: The five-year overall survival rate gradually increased according to the increase in adjuvant chemotherapy cycles in both the S-1 (≤ 5 cycles: 48.4%, hazard ratio [HR] 4.06, 95% confidence interval [CI] 3.74-4.40, P < 0.0001; 5 < cycles ≤ 6: 55.4%, HR 3.08, 95% CI 2.65-3.57, P < 0.0001; 6 < cycles ≤ 7: 64.1%, HR 2.11, 95% CI 1.84-2.41, P < 0.0001; 7 < cycles < 8: 71.1%, HR 1.60, 95% CI 1.39-1.84, P < 0.0001; ≥ 8 cycles: 77.9%) and the CAPOX groups (≤ 4 cycles: 43.5%, HR 3.20, 95% CI 2.84-3.61, P < 0.0001; 5 cycles: 45.3%, HR 2.63, 95% CI 2.11-3.27, P < 0.0001; 6 cycles: 47.1%, HR 2.09, 95% CI 1.76-2.49, P < 0.0001; 7 cycles: 55.3%, HR 1.63, 95% CI 1.35-1.96, P < 0.0001; ≥ 8 cycles: 67.2%). CONCLUSIONS: Reducing the treatment cycles of adjuvant chemotherapy in GC with S-1 or CAPOX showed inferior survival outcomes. Completing the standard duration of adjuvant chemotherapy with S-1 or CAPOX would be strongly recommended.

Analysis of thromboembolic events in patients with non-small cell lung cancer who received adjuvant chemotherapy: single-center real-world data.

Thromboembolic events (TEEs) are common in cancer patients, with increased risk of TEE by chemotherapy in patients with lung cancer. However, TEEs in patients with non-small cell lung cancer (NSCLC) who received adjuvant chemotherapy have rarely been reported. This study retrospectively analyzed real-world data of 275 patients with NSCLC treated with adjuvant chemotherapy after surgery from October, 2005 to June, 2020, in a single institution. The incidence of TEEs during or within one year of completion of adjuvant chemotherapy was investigated, and factors related to TEEs were analyzed. TEEs were confirmed in nine patients (3.3%), without fatal event related to TEEs. None of the factors, including Khorana score, was significantly associated with the occurrence of TEEs. All patients with TEEs had pathologic stage IIB or higher and a history of smoking, except for one patient. In conclusion, TEEs occurred in a smaller proportion of patients with NSCLC treated with adjuvant chemotherapy in the real world compared with those treated with palliative chemotherapy in previous reports. Furthermore, prophylactic anticoagulation in patients with NSCLC receiving adjuvant chemotherapy may not be needed except for high-risk patients, although those patients should be informed about the possible risk of TEEs.

Analysis of thromboembolic events in head and neck cancer patients who underwent concurrent chemoradiotherapy with cisplatin.

BACKGROUND/AIMS: The study investigated the incidence of thromboembolic events (TEE) in head and neck (H&N) cancer patients who received concurrent chemoradiotherapy (CCRT) with cisplatin, and analyzed the factors affecting TEE occurrence. METHODS: Two hundred and fifty-seven patients who started CCRT with cisplatin for H&N cancer from January 2005 to December 2019 were analyzed. RESULTS: TEE occurred in five patients, an incidence rate of 1.9%. The 2-, 4-, and 6-month cumulative incidences of TEE were 0.8%, 1.6%, and 1.9%, respectively. Khorana score was the only factor associated with TEE occurrence (p = 0.010). CONCLUSION: The incidence of TEE in H&N cancer patients who underwent CCRT with cisplatin was relatively low when compared to other types of cancer. However, patients with a high Khorana score require more careful surveillance for possible TEE occurrence.

The efficacy of EGFR-tyrosine kinase inhibitor in non-small cell lung cancer patients with synchronous brain metastasis: a real-world study.

BACKGROUND/AIMS: The optimal treatment (Tx) for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) patients with brain metastasis (BM) remains to be determined. METHODS: A retrospective review was conducted on 77 NSCLC patients with synchronous BM who underwent first-line EGFR-tyrosine kinase inhibitor (TKI) Tx. The outcomes of patients were analyzed according to the clinicopathological characteristics including local Tx modalities. RESULTS: Fifty-nine patients underwent local Tx for BM (gamma knife surgery [GKS], 37; whole brain radiotherapy [WBRT], 18; others, four) concurrently or sequentially with EGFR-TKI. Patients treated with TKI alone showed significantly lower incidence of central nervous system (CNS) symptoms. The median progression-free survival (PFS) and overall survival (OS) after the initiation of EGFR-TKI for all patients were 9 and 19 months, respectively. In 60 patients with follow-up brain imaging, the median time to CNS progression was 15 months. Patients with EGFR exon 19 deletion had a significantly longer median OS than those with other mutations including L858R (23 months vs. 17 months). Other clinical characteristics, including CNS symptoms, number of BM, and the use of local Tx were not associated with OS, as well as PFS. In terms of the local optimal Tx modality, no difference was found between GKS and WBRT in the OS and PFS. CONCLUSION: This study suggests that EGFR-TKI may result in a favorable outcome in NSCLC patients with synchronous BM, especially in deletion 19 mutant, regardless of the extent of BM lesions or local Tx modalities. Patients with asymptomatic BM can be treated with EGFR-TKI and careful surveillance.

Senescent tumor cells: an overlooked adversary in the battle against cancer.

Senescent cells in cancer tissue, including senescent fibroblasts and macrophages, have been reported to increase the malignant potency of cancer cells by secreting senescence-associated secretory phenotype (SASP). Otherwise, Senescence of tumor cells has been believed to inhibit tumor growth by halting the massive proliferation and increasing the chances of immune clearance. In particular, senescent tumor cells (STCs) have been thought that they rarely exist in carcinomas because oncogene-induced senescence needs to be overcome for protumorigenic cells to become malignant. However, recent studies have revealed that a considerable number of STCs are present in cancer tissue, even in metastatic sites. In fact, STCs are widely involved in cancer progression by leading to collective invasion and building a cytokine barrier to protect nonsenescent tumor cells from immune attack. Furthermore, therapy-induced STCs can induce tumor progression and recurrence by increasing stemness. However, obscure causative factors and their heterogeneity in various cancers make it difficult to establish the physiological role of STCs. Here, we summarize and review the current knowledge of the pathophysiology and role of STCs. We also outline the current status of therapeutic strategies for directly removing STCs or modulating the SASPs to maximize the positive functions of STCs while suppressing the negative functions.

The chromatin remodeler RSF1 coordinates epigenetic marks for transcriptional repression and DSB repair.

DNA lesions impact on local transcription and the damage-induced transcriptional repression facilitates efficient DNA repair. However, how chromatin dynamics cooperates with these two events remained largely unknown. We here show that histone H2A acetylation at K118 is enriched in transcriptionally active regions. Under DNA damage, the RSF1 chromatin remodeling factor recruits HDAC1 to DSB sites. The RSF1-HDAC1 complex induces the deacetylation of H2A(X)-K118 and its deacetylation is indispensable for the ubiquitination of histone H2A at K119. Accordingly, the acetylation mimetic H2A-K118Q suppressed the H2A-K119ub level, perturbing the transcriptional repression at DNA lesions. Intriguingly, deacetylation of H2AX at K118 also licenses the propagation of γH2AX and recruitment of MDC1. Consequently, the H2AX-K118Q limits DNA repair. Together, the RSF1-HDAC1 complex controls the traffic of the DNA damage response and transcription simultaneously in transcriptionally active chromatins. The interplay between chromatin remodelers and histone modifiers highlights the importance of chromatin versatility in the maintenance of genome integrity.

Early removal of central venous catheter may not impact the in-hospital mortality in patients with acute leukemia.

Central venous catheters (CVCs) are generally required for chemotherapy in patients with acute leukemia, but catheter-related infection is one of the common causes of neutropenic fever. We investigated the in-hospital mortality according to early removal of CVCs and the factors influencing the mortality in patients with acute leukemia undergoing remission induction chemotherapy. This study retrospectively analyzed the hospital record data of 278 patients with acute leukemia treated with non-tunneled CVCs and remission induction chemotherapy in a single institution. Bloodstream infection was more common (p < 0.0001) and median peak C-reactive protein (CRP) levels after neutropenic fever were significantly higher (23.3 vs. 14.5 mg/dl, p = 0.003) in the group with early removal than in the group with maintenance of the CVC. Multivariate analysis of the patients revealed a significant decrease in the mortality with female gender (odds ratio (OR): 0.19, 95% confidence interval (CI): 0.06-0.54, p = 0.002) and a significant increase in the mortality according to the peak CRP (OR 1.12, 95% CI: 1.07-1.17, p < 0.0001). By contrast, early removal of the CVC had no significant effect on the mortality (OR = 1.16, 95% CI: 0.54-2.47, p = 0.706) in univariate analysis. Furthermore, subsequent bloodstream infection after clinical decision for maintenance or early removal of the CVC was confirmed more frequently in the group with early removal (early removal, 22.6%; maintenance, 7.6%, p < 0.0001). Early removal of the CVC had no benefit regarding the mortality and prophylaxis of bloodstream infection in patients with acute leukemia undergoing remission induction chemotherapy. Therefore, maintaining a CVC for as long as possible may be considered, if catheter-related bloodstream infection is not strongly suspected.

Clinical Benefits of Oral Anticoagulant Use in Cancer Patients at Increased Risk for Venous Thromboembolism per Khorana Index.

BACKGROUND: Cancer patients are at increased risk for venous thromboembolism (VTE) due to cancer-induced hypercoagulability. However, current guidelines do not routinely recommend prophylactic use of oral anticoagulants to prevent VTE in cancer patients. OBJECTIVE: To evaluate the efficacy and safety of novel oral anticoagulants (NOACs) versus no anticoagulant use (no-use) and, additionally, differential effects between NOACs and warfarin, in VTE and adverse bleeding prevention among cancer patients, in consideration of risk stratification by gender, high-risk chemotherapy exposure, and Khorana index. METHODS: This national health insurance data-based study with a 180-day follow-up enrolled cancer patients with or without oral anticoagulant use in 2017. The primary outcome was VTE risk in oral anticoagulant users vs non-users. Four propensity score-matched comparison pairs were designed: use vs no-use, NOAC vs no-use, warfarin vs no-use, and NOAC vs warfarin. A logistic regression model was used to investigate between-group differences in VTE and bleeding risk. RESULTS: When compared to no-use, NOACs showed substantial effects in preventing VTE complications (OR=0.40, p<0.001), primarily deep vein thrombosis (DVT) events (OR=0.38, p<0.001), in both male and female cancer patients as well as those with a Khorana score ≥1. Adverse bleeding risk was comparable or lower in NOAC-receiving female patients (p=0.13) and male patients (p=0.04), respectively. In contrast, no protective effects were found with warfarin compared to no-use in controlling thrombosis and adverse bleeding risk. In a head-to-head comparison of NOACs versus warfarin, DVT risk in those patients exposed to high-risk chemotherapy was significantly decreased with NOAC use (OR=0.19, p=0.03). CONCLUSION: NOACs can be a promising thromboprophylactic option in both male and female cancer patients with VTE risk.

Trastuzumab-based palliative chemotherapy for HER2-positive gastric cancer: a single-center real-world data.

BACKGROUND: Since the results of the ToGA trial were published, trastuzumab-based chemotherapy has been used as the standard first-line treatment for HER2-positive recurrent or primary metastatic gastric cancer (RPMGC). However, the real-world data has been rarely reported. Therefore, we investigated the outcomes of trastuzumab-based chemotherapy in a single center. METHODS: This study analyzed the real-world data of 47 patients with HER2-positive RPMGC treated with trastuzumab-based chemotherapy in a single institution. RESULTS: With the median follow-up duration of 18.8 months in survivors, the median overall survival (OS) and progression-free survival were 12.8 and 6.9 months, respectively, and the overall response rate was 64%. Eastern Cooperative Oncology Group performance status 2 and massive amount of ascites were independent poor prognostic factors for OS, while surgical resection before or after chemotherapy was associated with favorable OS, in multivariate analysis. In addition, 5 patients who underwent conversion surgery after chemotherapy demonstrated an encouraging median OS of 30.8 months, all with R0 resection. CONCLUSIONS: Trastuzumab-based chemotherapy in patients with HER2-positive RPMGC in the real world demonstrated outcomes almost comparable to those of the ToGA trial. Moreover, conversion surgery can be actively considered in fit patients with a favorable response after trastuzumab-based chemotherapy.

Senescent Tumor Cells Build a Cytokine Shield in Colorectal Cancer.

Cellular senescence can either support or inhibit cancer progression. Here, it is shown that intratumoral infiltration of CD8+ T cells is negatively associated with the proportion of senescent tumor cells in colorectal cancer (CRC). Gene expression analysis reveals increased expression of C-X-C motif chemokine ligand 12 (CXCL12) and colony stimulating factor 1 (CSF1) in senescent tumor cells. Senescent tumor cells inhibit CD8+ T cell infiltration by secreting a high concentration of CXCL12, which induces a loss of CXCR4 in T cells that result in impaired directional migration. CSF1 from senescent tumor cells enhance monocyte differentiation into M2 macrophages, which inhibit CD8+ T cell activation. Neutralization of CXCL12/CSF1 increases the effect of anti-PD1 antibody in allograft tumors. Furthermore, inhibition of CXCL12 from senescent tumor cells enhances T cell infiltration and results in reducing the number and size of tumors in azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced CRC. These findings suggest senescent tumor cells generate a cytokine barrier protecting nonsenescent tumor cells from immune attack and provide a new target for overcoming the immunotherapy resistance of CRC.

Combination versus single-agent as palliative chemotherapy for gastric cancer.

BACKGROUND: Although combination chemotherapy (CC) is generally recommended in recurrent or primary metastatic gastric cancer (RPMGC), the results of randomized trials are conflicting. METHODS: A retrospective review was conducted on 687 RPMGC patients who received palliative chemotherapy. We compared the overall survival (OS) between CC and single-agent chemotherapy (SC) among these patients, and we analyzed the clinicopathological characteristics affecting outcome including neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). RESULTS: Although 521 patients (75.8%) underwent CC, SC was more frequently performed in elderly patients (57.6%) and ECOG performance status (PS) 2 or 3 (65.8%) patients (p < 0.0001, in each case). The median OS of patients who received CC was significantly longer than that of patients who received SC (11 vs. 8 months, p < 0.0001). No difference in OS between CC and SC was observed in elderly patients (p = 0.583), poor PS (p = 0.810), signet ring cell (p = 0.347), palliative surgical resection (p = 0.307), and high PLR (p = 0.120), with a significant interaction between age and type of regimen (p = 0.012). Moreover, there was no difference in OS between CC and SC after propensity score matching (p = 0.322). Multivariate analysis revealed that palliative resection and ≥ second-line chemotherapy were independently associated with favorable OS (p < 0.0001, in each case), whereas poor PS (p = 0.004), signet ring cell (p < 0.0001), peritoneal metastasis (p = 0.04), high NLR (p = 0.001), and high PLR (p = 0.033) were independent prognostic factors of poor OS. CONCLUSIONS: Although CC is the standard of care in RPMGC, SC can be considered a reasonable option in certain subgroups, such as elderly patients.

Pachypodol, a Methoxyflavonoid Isolated from Pogostemon cablin Bentham Exerts Antioxidant and Cytoprotective Effects in HepG2 Cells: Possible Role of ERK-Dependent Nrf2 Activation.

Oxidative stress has been implicated in the pathogenesis of many diseases including chronic liver diseases. Nrf2 is a master transcriptional factor regulating the induction of cellular antioxidant defense systems. Here, the Nrf2-activating effect of the crude methanol extract of dried leaves of Pogostemon cablin Bentham was demonstrated by measuring the antioxidant response element (ARE)-driven luciferase activity and pachypodol, 4',5-dihydroxy-3,3',7-trimethoxyflavone, was isolated by bioactivity-guided fractionation and further separation using chromatographic techniques. To our knowledge, this is the first study to evaluate the antioxidant and cytoprotective effects of pachypodol in HepG2 cells as well as the underlying molecular mechanisms. Indeed, pachypodol protected HepG2 cells from cell death caused by tert-butylhydroperoxide-induced oxidative stress and also attenuated ROS production. The ability of pachypodol to activate Nrf2/ARE pathway was further confirmed by observing Nrf2 expression in nuclear fraction, mRNA levels of Nrf2 target antioxidants, and cellular glutathione content in HepG2 cells. Extracellular signal-regulated kinase (ERK) is one of the important kinases involved in Nrf2 activation. Pachypodol increased ERK phosphorylation and ERK inhibition by PD98059 totally abrogated the increase in ARE luciferase activity, nuclear Nrf2 accumulation and mRNA levels of antioxidant enzymes by pachypodol. In conclusion, pachypodol isolated from P. cablin can protect hepatocytes from oxidative injury, possibly mediated by enhancing endogenous antioxidant defense system through ERK-dependent Nrf2 activation.