Bone-targeted erythrocyte-cancer hybrid membrane-camouflaged nanoparticles for enhancing photothermal and hypoxia-activated chemotherapy of bone invasion by OSCC.

BACKGROUND: Jaw bones are the most common organs to be invaded by oral malignancies, such as oral squamous cell carcinoma (OSCC), because of their special anatomical relationship. Various serious complications, such as pathological fractures and bone pain can significantly decrease the quality of life or even survival outcomes for a patient. Although chemotherapy is a promising strategy for bone invasion treatment, its clinical applications are limited by the lack of tumor-specific targeting and poor permeability in bone tissue. Therefore, it is necessary to develop a smart bone and cancer dual targeting drug delivery platform. RESULTS: We designed a dual targeting nano-biomimetic drug delivery vehicle Asp8[H40-TPZ/IR780@(RBC-H)] that has excellent bone and cancer targeting as well as immune escape abilities to treat malignancies in jaw bones. These nanoparticles were camouflaged with a head and neck squamous cell carcinoma WSU-HN6 cell (H) and red blood cell (RBC) hybrid membrane, which were modified by an oligopeptide of eight aspartate acid (Asp8). The spherical morphology and typical core-shell structure of biomimetic nanoparticles were observed by transmission electron microscopy. These nanoparticles exhibited the same surface proteins as those of WSU-HN6 and RBC. Flow cytometry and confocal microscopy showed a greater uptake of the biomimetic nanoparticles when compared to bare H40-PEG nanoparticles. Biodistribution of the nanoparticles in vivo revealed that they were mainly localized in the area of bone invasion by WSU-HN6 cells. Moreover, the Asp8[H40-TPZ/IR780@(RBC-H)] nanoparticles exhibited effective cancer growth inhibition properties when compared to other TPZ or IR780 formulations. CONCLUSIONS: Asp8[H40-TPZ/IR780@(RBC-H)] has bone targeting, tumor-homing and immune escape abilities, therefore, it is an efficient multi-targeting drug delivery platform for achieving precise anti-cancer therapy during bone invasion.

MicroRNA-33b regulates hepatocellular carcinoma cell proliferation, apoptosis, and mobility via targeting Fli-1-mediated Notch1 pathway.

MicroRNAs (miRNAs) have been confirmed to play pivotal roles in hepatocellular carcinoma (HCC) carcinogenesis. However, the underlying function of microRNA-33b (miR-33b) in HCC remains unclear. Here, we found that miR-33b level was significantly reduced in both HCC tissues and tumor cell lines. Further, luciferase reporter assay and western blot analysis confirmed that Friend leukemia virus integration 1 (Fli-1) was a direct target of miR-33b. Overexpression of miR-33b dramatically suppressed HCC tumor cell proliferation and cell mobility, but facilitated tumor cell apoptosis in vitro. Besides, restoration of Fli-1 partially attenuated miR-33b-mediated inhibition of cell growth and metastasis via activating Notch1 signaling and its downstream effectors. Our findings demonstrate the important role of miR-33b/Fli-1 axis in HCC progression and provide novel therapeutic candidates for HCC clinical treatment.

Contrast of therapeutic effects between CBD incision and LLHD stump in biliary tract exploration of LLS for hepatolithiasis.

BACKGROUND: Laparoscopic left lateral sectionectomy (LLS) followed by a biliary tract exploration is used to treat left lateral hepatolithiasis. The purpose of this study was to compare the efficacy of two methods of biliary tract explorations in LLSs: biliary tract exploration through a common bile duct (CBD) incision or through the left lateral hepatic duct (LLHD) stump. METHODS: One hundred eight patients were retrospectively analyzed in our hospital from 2009 to 2018. To compare different methods of biliary tract explorations during LLSs, the patients were divided into 2 groups: 36 patients underwent biliary tract exploration through the LLHD stump (LLSS group), and 72 patients underwent biliary tract exploration through the CBD incision (LLSC group). Clinical data on disease characteristics, surgical outcomes, and surgery-related complications were compared between the 2 groups. RESULTS: Bile duct stones were successfully cleared in all patients. For 2 patients in the LLSS group and 3 patients in the LLSC group, treatment was switched to laparotomy. There were no significant differences in the total operation time (P = 0.09), incidence of bleeding volume (P = 0.33), and bile leakage (P = 0.12) between the two groups. The time of choledochoscopy in the LLSS group was significantly lower than that in the LLSC group (P = 0.03). No bile duct injuries, strictures, recurrent stones, or other adverse events were observed in any patients during follow-up. CONCLUSIONS: Exploration of the biliary tract through the LLHD stump is safe and provides satisfactory results for select patients.

CDK1, CCNB1, and CCNB2 are Prognostic Biomarkers and Correlated with Immune Infiltration in Hepatocellular Carcinoma.

BACKGROUND Orderly G2/M transition in the cell cycle is controlled by the cyclin-dependent kinase 1/cyclin B (CDK1/CCNB) complex. We aimed to comprehensively investigate the roles of CDK1, CCNB1, and CCNB2 via multi-omics analysis and their relationships with immune infiltration in hepatocellular carcinoma (HCC). MATERIAL AND METHODS The transcriptional data and the epigenetic and genetic alterations of CDK1, CCNB1, and CCNB2, as well as their impacts on prognosis in HCC patients, were identified using multiple databases. The correlations between expression of these genes and immune infiltration in HCC were then explored using the TIMER database. RESULTS Overall, mRNA expression of CDK1, CCNB1, and CCNB2 was up-regulated in various tumor tissues including HCC. Higher expression of these genes was associated with poorer prognosis in HCC patients. Lower promoter methylation of these genes might cause higher expression levels in tumor tissues of HCC. Genetic alterations and several methylated-CpG sites in these genes were significantly associated with survival. Notably, expression levels of CDK1, CCNB1, and CCNB2 were positively correlated with infiltrating levels of CD4⁺ T cells, CD8⁺ T cells, neutrophils, macrophages, and dendritic cells in HCC. In addition, significant correlations between the expression of these genes and various immune markers in HCC, such as PD-1, PDL-1, and CTLA-4, were also observed. CONCLUSIONS CDK1, CCNB1, and CCNB2 are potential prognostic biomarkers and associated with immune cell infiltration in HCC. The genes may be utilized to predict the reaction of immunotherapy. Combining inhibitors of these genes with immunotherapy may improve the survival time of HCC patients.

Prognostic value of lymphocyte to monocyte ratio in pancreatic cancer: a systematic review and meta-analysis including 3338 patients.

BACKGROUND: Recently, reports have classified lymphocyte to monocyte ratio (LMR) as an effective indicator for predicting the prognosis of pancreatic cancer. Nevertheless, the prognostic value of LMR for pancreatic cancer remains controversial. Through meta-analysis, this work intends to evaluate the potential prognostic role of pretreatment LMR in patients diagnosed with pancreatic cancer. METHODS: We reviewed and extracted eligible articles from Web of Science, PubMed, Cochrane Library, and Embase. A meta-analysis was conducted using hazard ratio (HR) and 95% confidence intervals (CIs) to assess the comparison between pretreatment LMR and overall survival (OS) and disease-free survival/recurrence-free survival/time to progression (DFS/RFS/TTP). RESULTS: In total, 11 studies (16 cohorts) including 3338 patients diagnosed with pancreatic cancer (PC) were enrolled in our meta-analysis. Notably, we revealed that high pretreatment LMR predicted better overall survival (OS) (HR = 0.68, 95% CI 0.58-0.80, P < 0.001, I-squared = 69.3%, Ph < 0.001) and DFS/RFS/TTP (HR = 0.55, 95% CI 0.31-0.96, P = 0.037, I-squared = 89.9%, Ph < 0.001) in patients with pancreatic cancer. Further, through subgroup analyses, we showed that high pretreatment LMR was significantly associated with the favorable OS regardless of ethnicity, study design, treatment method, variable type, the cut-off value for LMR, and disease stages of I-IV and III-IV. CONCLUSION: The findings from our study suggest that high pretreatment LMR is associated with better OS and DFS/RFS/TTP in patients diagnosed with pancreatic cancer. As such, it can potentially serve as a novel prognostic biomarker for patients with pancreatic cancer.

miR-186 modulates hepatocellular carcinoma cell proliferation and mobility via targeting MCRS1-mediated Wnt/ß-catenin signaling.

Previous studies have revealed that miR-186 is involved in the pathogenesis of many malignancies. However, the role of miR-186 in hepatocellular carcinoma (HCC) carcinogenesis and its detailed mechanism are poorly understood. This study was to investigate the function of miR-186 in modulating HCC cell proliferation, cell cycle, migration, and invasion. We found that miR-186 was decreased in HCC tissues and cell lines. Loss-of-function experiments showed that reduction of miR-186 dramatically enhanced tumor cell proliferation and metastasis. Besides, miR-186 also participated in the modulation of the cell cycle. In addition, luciferase reporter assays and Western blot analysis showed that MCRS1 was a novel target of miR-186 in HCC cells. Notably, upregulation of miR-186 suppressed the nuclear ß-catenin accumulation and blocked the activation of Wnt/ß-catenin signaling in HCC cells. Forced MCRS1 expression abrogated the inhibitory effect of miR-186 on cell growth, metastasis and Wnt/ß-catenin signaling in HCC cells. Our findings may provide new insight into the pathogenesis of HCC and miR-186/ MCRS1 might function as new therapeutic targets for HCC.

LncRNA MAGI2-AS3 inhibits hepatocellular carcinoma cell proliferation and migration by targeting the miR-374b-5p/SMG1 signaling pathway.

Long noncoding RNAs (lncRNAs) have been proven to play critical roles in cancer progression. Recently, lncRNA MAGI2-AS3 has been revealed to be a tumor suppressor and inhibit cell growth by targeting the Fas/FasL signalling pathway in breast cancer. However, the role and underlying mechanism of MAGI2-AS3 in hepatocellular carcinoma (HCC) remain largely unknown. In the current study, we found that MAGI2-AS3 expression is downregulated in HCC tissues and closely associated with some clinical characteristics (tumor size, lymph node metastasis, and TNM stage) and poor overall survival. Overexpression of MAGI2-AS3 inhibits HCC cell proliferation and migration in vitro, while impedes tumor growth in vivo accordantly. In addition, our data suggest that MAGI2-AS3 could function as an endogenous sponge of miR-374b-5p by directly binding to it and suppressing its expression. Furthermore, miR-374b-5p upregulation could restore the inhibitory effect of MAGI2-AS3 on HCC cells processes. Moreover, suppressor with morphogenetic effect on genitalia family member 1 (SMG1) is positively regulated by MAGI2-AS3 via absorbing miR-374b-5p in HCC cells. More important, SMG1 knockdown reverses the suppressive function of MAGI2-AS3 in HCC cell processes. Taken together, we reveal a functional MAGI2-AS3/miR-374b-5p/SMG1 axis that suppresses HCC progression, potently suggesting a new road for HCC treatment.

Real-Time Navigation Guidance Using Fusion Indocyanine Green Fluorescence Imaging in Laparoscopic Non-Anatomical Hepatectomy of Hepatocellular Carcinomas at Segments 6, 7, or 8 (with Videos).

BACKGROUND The right area and posterior area of the liver are considered relatively unfavorable portions for laparoscopic hepatectomy (LH) due to the limited gross inspection and poor tactile feedback. Fusion indocyanine green fluorescence fusion imaging (ICGFI) may be a reliable real-time navigation tool for LH. The aim of the present study was to evaluate the usefulness of ICGFI for laparoscopic non-anatomical hepatectomy in patients with hepatocellular carcinoma at the right area and posterior area. MATERIAL AND METHODS We conducted a retrospective comparison of surgical and perioperative outcomes for 21 hepatocellular carcinoma patients who had undergone LH with fusion ICGFI guidance and 21 matched patients who underwent the procedure without the guidance of ICGFI between November 2017 to August 2018. RESULTS Preoperative characteristics were comparable between the groups. Tumor fluorescence images were clearly displayed in all 21 ICGFI patients, providing precise information about tumor location. Laparoscopic parenchymal transection could be performed safely and quickly through tracing the fusion ICGFI on the cutting surface. Operation time was significantly reduced in the ICGFI group. Postoperative complications were comparable between the groups. There was no positive margin in either group. CONCLUSIONS These preliminary data suggest that fusion ICGFI may be a useful tool that provides real-time navigation for non-anatomical LH. It may assist in the safe and accurate completion of LH for tumors located at the right posterior areas. Further studies are needed to fully clarify the advantages and disadvantages of ICGFI in LH, including short-term perioperative outcomes and long-term prognosis.

IL-6/STAT3 pathway intermediates M1/M2 macrophage polarization during the development of hepatocellular carcinoma.

Human cancers, including hepatocellular carcinoma (HCC), are characterized by a high degree of drug resistance in chemotherapy. However, the underlying molecular mechanism remains unknown. To the role of interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) signaling pathway in the regulation of macrophage polarization, M1-type and M2-type macrophages were separately induced using lipopolysaccharide and interleukin-4 (IL-4), and we found that the IL-6/STAT3 signaling pathway was inhibited in M1-type macrophages but activated in M2-type macrophages. After anti-IL-6-treated macrophages were separately induced by lipopolysaccharide and IL-4, we found that the inhibition of IL-6/STAT3 signaling pathway turned macrophages into M1-type. Co-culture with M1-type macrophages reduced HCC cell viability, proliferation, invasion, migration, drug resistance, but increased apoptosis. Co-culture with M2-type macrophages yielded reciprocal results. The inhibition of IL-6/STAT3 signaling pathway mediated by anti-IL6 was shown to significantly enhance the effects of M1-type macrophages on HCC cells and rescue HCC cells from co-culture with M2-type macrophages. Tumor xenografts of co-cultured HCC cells were established in nude mice and the results showed that the inhibition of IL-6/STAT3 signaling pathway mediated by anti-IL6 was found to reduce tumor formation of HCC cells co-cultured with M1- or M2-type macrophages and lung metastases. The current study reveals a novel mechanism of IL-6/STAT3 signaling pathway in the regulation of macrophage polarization, thus contributing to HCC metastasis and drug resistance in chemotherapy.

A Predictive Risk Scoring System for Clinically Relevant Pancreatic Fistula After Pancreaticoduodenectomy.

BACKGROUND Postoperative pancreatic fistula remains a challenge after pancreaticoduodenectomy (PD). This study aimed to establish a scoring system to predict clinically relevant postoperative pancreatic fistula (CR-POPF) after PD. MATERIAL AND METHODS The clinical records of 361 consecutive patients who underwent PD between 2009 and 2017 were reviewed retrospectively. Patients were divided into a study group (225 patients) and a validation group (136 patients). CR-POPF was defined and classified based on the 2016 ISGPS definition and classification system. Univariate and multivariate logistic regression analyses were performed and we thus developed a scoring system based on the regression coefficient of the multivariate logistic regression model. The predictive value was determined using the receiver operating characteristic (ROC) curve. RESULTS A predictive scoring system with a maximum of 6 points for CR-POPF was established using the following 4 factors: 1 point for soft pancreatic texture (OR 2.09, 95%CI 1.10-3.98, P=0.025), 1.5 points for main pancreatic duct diameter ≤2.5 mm (OR 2.72, 95%CI 1.23-5.99, P=0.013), 0.5 points for extended lymphadenectomy (OR 1.57, 95%CI 1.13-2.18, P=0.007), 0.5 points for a 25-30 g/L postoperative day 1 serum albumin (OR 1.43, 95%CI 1.02-2.00, P=0.037), and 3 points for postoperative day 1 serum albumin ≤25 g/L (OR 5.12, 95%CI 1.82-14.41, P=0.002). The ROC curve showed that this scoring system was highly predictive for CR-POPF in the validation group (AUC=0.806, 95%CI: 0.735-0.878). CONCLUSIONS This 6-point risk scoring system will be useful for perioperative risk management of CR-POPF.

Safety and Feasibility of a Laparoscopy-Assisted Non-Anatomic Resection Technique for Hepatocellular Carcinoma Located at Right Posterior Segments in Cirrhotic Patients: A Case-Controlled Study with Propensity Score Matching.

PURPOSE: The aim of this study was to compare the short- and long-term outcomes of laparoscopy-assisted resection for right posterior segment (LAR-RPS) with open resection (OR-RPS) performed by experienced hepatobiliary surgeons. METHODS: This was a prospective comparative nonrandomized study. RESULTS: The groups were comparable in terms of baseline demographics and clinicopathological data. Reduced operative time (254.88 ± 78.56 vs. 347.95 ± 82.56 min; p = 0.04) and estimated blood loss (477 ± 756 vs. 712 ± 836 mL; p = 0.03) were observed in LAR-RPS. Also, significant less duration of hospital stay (7.53 ± 2.68 vs. 12.57 ± 3.21 days; p < 0.001) was associated with LAR-RPS compared to OR-RPS. Long-term oncologic outcomes were comparable in 2 groups, in terms of both the overall and disease-free survival rates (p = 0.450 and 0.463, respectively). CONCLUSIONS: This study confirms that laparoscopic-assisted resection is a safe and effective operative procedure in those cirrhotic patients with a lesion in the right posterior section of the liver. When compared to the open approach, the laparoscopic-assisted approach reduces operative time and blood loss, as well as the length of hospital stay.

Laparoscopic hepatectomy for colorectal liver metastases located in all segments of the liver.

PURPOSE: Laparoscopic hepatectomy is not a well-established treatment modality for colorectal liver metastases. Moreover, most reports have been limited to tumors in the anterolateral segments (segments 2, 3, 4b, 5, and 6). In this study we evaluated the short- and long-term outcomes after laparoscopic hepatectomy for colorectal liver metastases located in all segments, including tumors located in the posterosuperior segments (segments 1, 4a, 7, and 8). METHODS: This retrospective study included 102 patients who underwent laparoscopic hepatectomy for colorectal liver metastases with radical intent between January 2009 and January 2016. The patients were divided into two groups (anterolateral and posterosuperior group) according to tumor location. The clinical and follow-up data of the two groups were reviewed. RESULTS: There was no 30-day postoperative mortality. Most of the postoperative 30-day complications were classified as minor complications (Clavien-Dindo classification). There was no difference in clinicopathologic characteristics between the two groups. Although posterosuperior group patients had significantly longer operative time (p=0.008) and postoperative hospital stay duration (p=0.041), as well as a greater blood loss (p=0.012), there was no significant difference in the rate and severity of postoperative complications (p=0.314 and 1.000 respectively). During a median follow-up of 41 months, the 5-year overall survival (OS) (p=0.449), and disease-free survival (DFS) (p=0.370) showed no significant difference between the two groups. CONCLUSIONS: Laparoscopic hepatectomy for colorectal liver metastases located in all segments of the liver can be safely performed in selected patients, with acceptable postoperative morbidity and oncologic results.

Laparoscopic hepatectomy for colorectal liver metastases located in all segments of the liver.

PURPOSE: Laparoscopic hepatectomy is not a well-established treatment modality for colorectal liver metastases. Moreover, most reports have been limited to tumors in the anterolateral segments (segments 2, 3, 4b, 5, and 6). We evaluated the short- and long-term outcomes after laparoscopic hepatectomy for colorectal liver metastases located in all segments, including tumors located in the posterosuperior segments (segments 1, 4a, 7, and 8). METHODS: TThis retrospective study included 102 patients who underwent laparoscopic hepatectomy for colorectal liver metastases with radical intent between January 2009 and January 2016. The patients were divided into two groups (anterolateral and posterosuperior group) according to tumor location. The clinical and follow-up data of the two groups were retrospectively reviewed. RESULTS: There was no 30-day postoperative mortality. Most of the postoperative 30-day complications were classified as minor complications (Clavien-Dindo classification). There was no difference in clinicopathologic characteristics between the two groups. Although posterosuperior group patients had significantly longer operative time (p=0.008) and postoperative hospital stay duration (p=0.041), as well as a greater blood loss (p=0.012), there was no significant difference in rate and severity of postoperative complications (p=0.314 and 1.000 respectively). During a median follow-up period of 41 months, the 5-year overall survival (OS) (p=0.449), and disease-free survival (DFS) (p=0.370) was no significant difference between the two groups. CONCLUSIONS: Laparoscopic hepatectomy for colorectal liver metastases located in all segments of the liver can be safely performed in selected patients, with acceptable postoperative morbidity and oncologic results.

Is the era of intravenous proton pump inhibitors coming to an end in patients with bleeding peptic ulcers? Meta-analysis of the published literature.

AIMS: Oral and intravenous proton pump inhibitors (PPIs) are equipotent in raising gastric pH. However, it is not known whether oral PPIs can replace intravenous PPIs in patients with bleeding peptic ulcers. METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials to compare oral and intravenous PPIs among patients with peptic ulcer bleeding. A search of all major databases and relevant journals from inception to April 2015, without a restriction on languages, was performed. RESULTS: A total of 859 patients from seven randomized controlled trials were included in the meta-analysis. Similar pooled outcome measures were demonstrated between the two groups in terms of oral PPIs vs. intravenous PPIs in the rate of recurrent bleeding within the 30-day follow-up period [risk ratio = 0.90; 95% confidence interval (CI): 0.58, 1.39; P = 0.62; I(2)  = 0%). In terms of the rate of mortality, both oral and intravenous PPIs showed similar outcomes, and the pooled risk ratio was 0.88 (95% CI: 0.29, 2.71; P = 0.82; I(2)  = 0%). Likewise, no significant difference was detected in the need for blood transfusion and length of hospital stay; the pooled mean differences were -0.14 (95% CI: -0.39, 0.12; P = 0.29; I(2)  = 32%) and -0.60 (95% CI: -1.42, 0.23; P = 0.16; I(2)  = 79%), respectively. CONCLUSIONS: Our results suggest that oral PPIs are a feasible, safe alternative to intravenous PPIs in patients with bleeding peptic ulcers, and may be able to replace intravenous PPIs as the treatment of choice in these patients.

Postoperative complications affect long-term survival outcomes following hepatic resection for colorectal liver metastasis.

BACKGROUND: The impact of postoperative complications (POCs) on long-term survival outcomes following hepatic resection for colorectal liver metastasis (CRLM) is in controversy. The aim of the present meta-analysis was to systematically evaluate the POC effect on overall survival (OS) and disease-free survival (DFS) in patients undergoing hepatic resection for CRLM. METHODS: We conducted a systematic review and meta-analysis of all observational studies to evaluate the POC effect on OS and DFS in patients undergoing hepatic resection for CRLM. A search for all major databases and relevant journals from inception to January 2014 without restriction on languages or regions was performed. POCs were extracted and graded according to a validated system of classification. Outcome measures were postoperative 1-, 2-, 3-, and 10-year OSs and DFSs. Both random-effects and fixed-effect models were used to pool the hazard ratios (HRs) of the survival outcomes. Test of heterogeneity was performed with the Q statistic. RESULTS: A total of 2370 patients were included in the meta-analysis. Both 5- and 10-year postoperative OSs showed significant decreases in patients with POCs (HR = 1.52; 95 % CI 1.27-1.83; P < 0.001 and HR = 1.36; 95 % CI 1.18-1.58; P < 0.001, respectively). Similar outcomes were also observed in terms of DFSs, with the 5- and 10-year HRs found to be 1.37 (95 % CI 1.23-1.53; P < 0.001) and 1.34 (95 % CI 1.17-1.53; P < 0.001), respectively, compared to no POC group. CONCLUSIONS: POCs are strongly related to long-term oncologic outcomes following hepatic resection for CRLM. Further efforts to refine surgical technique and postoperative management to avoid complications may improve the long-term oncological outcomes of the selected patients.

Efficacy and safety of the FOLFOX4 regimen versus doxorubicin in Chinese patients with advanced hepatocellular carcinoma: a subgroup analysis of the EACH study.

BACKGROUND: The EACH study assessed the efficacy of oxaliplatin, 5-fluorouracil, and leucovorin (the FOLFOX4 regimen) compared with doxorubicin alone in terms of overall survival (OS), progression-free survival (PFS), and safety in patients with advanced hepatocellular carcinoma (HCC). We present the results of this study in Chinese patients. METHODS: In a multicenter, open-label, randomized, phase III study (NCT00471965), 371 patients (279 patients from the People's Republic of China) were randomized 1:1 to receive either FOLFOX4 or doxorubicin until disease progression, intolerable toxicity, death, or surgical resection. RESULTS: Baseline characteristics of the Chinese patients enrolled in the study were similar for the 2 treatment groups and in comparison with the whole EACH cohort. Median OS at the prespecified time point of treatment was 5.7 months with FOLFOX4 and 4.3 months with doxorubicin (hazard ratio [HR]: 0.74; 95% confidence interval [CI]: 0.55-0.98; p = .03). At the end of the follow-up period, median OS was 5.9 months with FOLFOX4 and 4.3 months with doxorubicin (HR: 0.75; 95% CI: 0.58-0.98; p = .03). Median PFS was 2.4 months and 1.7 months in the FOLFOX4 and doxorubicin groups, respectively (HR: 0.55; 95% CI: 0.45-0.78; p = .0002). The response rate (RR) and disease control rate (DCR) were significantly higher in the FOLFOX4 group than in the doxorubicin group (RR: 8.6% vs. 1.4%, p = .006; DCR: 47.1% vs. 26.6%, p = .0004). Hematological toxicity was more frequently reported in the FOLFOX4 group. CONCLUSION: For Chinese HCC patients enrolled in the EACH study, FOLFOX4 significantly improved the RR and DCR and prolonged survival compared with doxorubicin. Systemic chemotherapy with oxaliplatin-based regimens may play an important role in the treatment of Chinese patients with advanced HCC.

Murine double minute 2 rs2279744 polymorphism and hepatocellular carcinoma risk in East Asians: a meta-analysis.

Murine double minute 2 (MDM2) is a crucial negative regulator of p53 function through several mechanisms. There are many studies performed to assess the association between MDM2 rs2279744 polymorphism and hepatocellular carcinoma risk, but the impact of MDM2 rs2279744 polymorphism on hepatocellular carcinoma in East Asians is unclear owing to the inconsistent findings from previous studies. We conducted a comprehensive meta-analysis of epidemiological studies to shed some light on these contradicting results. We used pooled odds ratio (OR) with its 95 % confidence intervals (95 % CI) to assess the association. Overall, seven studies with a total of 4,993 subjects were finally included. The meta-analysis suggested that MDM2 rs2279744 polymorphism was significantly associated with increased risk of hepatocellular carcinoma in East Asians (G versus T: OR = 1.27, 95 % CI 1.06-1.52, P = 0.01; GG versus TT: OR = 1.59, 95 % CI 1.11-2.27, P = 0.01; GG/GT versus TT: OR = 1.41, 95 % CI 1.07-1.87, P = 0.02; GG versus TT/GT: OR = 1.32, 95 % CI 1.08-1.62, P = 0.008). Sensitivity analysis by excluding low-quality study still suggested that the association above was still significant. Thus, the findings from the meta-analysis support that MDM2 rs2279744 polymorphism is significantly associated with increased risk of hepatocellular carcinoma in East Asians.

Construction and validation of chemoresistance-associated tumor- infiltrating exhausted-like CD8+ T cell signature in breast cancer: cr-TILCD8TSig.

Background: Accumulating evidence has revealed that CD8+ T cell exhaustion (Tex) results in worse immunotherapy outcomes. However, the molecular functions and mechanisms of action of Tex in chemoresistance needed to be elucidated. Methods: The populations of tumor-infiltrating CD8+ T cells (TILCD8Ts) in chemoresistant and chemosensitive groups of the GSE25066 dataset were calculated using CIBERSORT. Differentially expressed genes (DEGs) between TILCD8Ts and other immune cells were explored by integrating 16 immune cell datasets downloaded from the gene expression omnibus (GEO) database. Gene ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, univariate and multivariate Cox regression, and least absolute shrinkage and selection operator (LASSO) regression of TILCD8T-specific upregulated genes were used to construct a chemoresistant TILCD8T signature (cr-TILCD8TSig). Clinical prognostic data, genomic alterations, chemotherapy response, and immunotherapy response were compared between the different cr-TILCD8TSig subgroups in the GSE25066 and the cancer genome atlas breast cancer (TCGA-BRCA) cohorts. Results: A cr-TILCD8TSig with exhausted features was identified, consisting of seven genes (TCF7, RARRES3, ARL4C, ITK, CDH3, GZMB, and KLRD1), which were identified from 104 TILCD8Ts-specific DEGs. Our results showed that compared to the cr-TILCD8TSig-low subgroup, the -high subgroup had a poorer distant relapse-free survival (DRFS) in the GSE25066 cohort and worse progression-free survival (PFS) in the TCGA-BRCA cohort. Univariate and multivariate Cox regression analyses also demonstrated that cr-TILCD8TSig was an independent prognostic factor in the two independent cohorts. Furthermore, cr-TILCD8TSig-low patients benefited more from chemotherapy and immunotherapy than cr-TILCD8TSig-high patients. Besides, we found cell transmembrane signal transduction and the ECM may provide the molecular basis for resistance to antitumor agents in the cr-TILCD8Sig-high subgroup. For genomic alterations, we revealed that mutations in PIK3CA, DMD, and APOB were more common in the cr-TILCD8Sig-high subgroup than in the cr-TILCD8Sig-low subgroup. A nomogram was finally constructed with good discrimination and calibration. Conclusions: cr-TILCD8TSig is a useful tool to independently predict prognosis, chemotherapy response, and immunotherapy outcomes in patients with breast cancer.