Holliday Cross-Recognition Protein HJURP: Association With the Tumor Microenvironment in Hepatocellular Carcinoma and With Patient Prognosis.

Background: Hepatocellular carcinoma is the most common type of primary liver cancer, and it is associated with poor prognosis. It often fails to respond to immunotherapy, highlighting the need to identify genes that are associated with the tumor microenvironment and may be good therapeutic targets. We and others have shown that the Holliday cross-recognition protein HJURP can promote the proliferation, migration, and invasion by hepatocellular carcinoma cells, and that HJURP overexpression is associated with poor survival. Here we explored the potential relationship between HJURP and the tumor microenvironment in hepatocellular carcinoma. Methods: We used the Immuno-Oncology-Biological-Research (IOBR) software package to analyze the potential roles of HJURP in the tumor microenvironment. Using single-cell RNA sequencing data, we identified the cell clusters expressing abundant HJURP, then linked some of these clusters to certain bioprocesses using Gene Set Enrichment Analysis (GSEA). We validated the differential expression of HJURP in tumor-infiltrating CD8+ T cells, sorted by flow cytometry into populations based on the expression level of PD-1. We used weighted gene co-expression network analysis (WGCNA) to identify immunity-related genes whose expression strongly correlated with that of HJURP. The function of these genes was validated based on enrichment in Gene Ontology (GO) terms, and they were used to establish a prognosis prediction model. Results: IOBR analysis suggested that HJURP is significantly related to the immunosuppressive tumor microenvironment and was significantly related to T cells, dendritic cells, and B cells. Based on single-cell RNA sequencing, HJURP was strongly expressed in T cells, erythrocytes, and B cells from normal liver tissues, as well as in CD8+ T cells, dendritic cells, and one cluster of hepatocytes in hepatocellular carcinoma tissues. Malignant hepatocytes strongly expressing HJURP were associated with the downregulation of immune bioprocesses. HJURP expression was significantly higher in CD8+ T cells strongly expressing PD-1 than in those expressing no or intermediate levels of PD1. WGCNA identified two module eigengenes (comprising 397 and 84 genes) related to the tumor microenvironment. We identified 24 hub genes and confirmed that they were related to immune regulation. A prognostic risk score model based on expression of HJURP, PPT1, PML, and CLEC7A showed moderate ability to predict survival. Conclusion: HJURP is associated with tumor-infiltrating immune cells, immune checkpoints, and immune suppression in hepatocellular carcinoma. HJURP-related genes involved in immune responses may be useful for predicting patient prognosis.

Case Report: A Case of Locally Advanced Pancreatic Cancer Which Achieved Progression Free for Over 12 Months by Subsequent Therapy with Anlotinib Hydrochloride Plus Tegafur-Gimeracil-Oteracil Potassium (TS-1).

Titled the "most destructive of all cancers", pancreatic cancer is a malignant tumor with a very poor prognosis and has a poor response to systemic therapy. At present, several studies have shown that tegafur-gimeracil-oteracil potassium (hereinafter referred to as TS-1) is no less superior to gemcitabine in the treatment of advanced pancreatic cancer. In addition, a number of current clinical studies have shown that targeted therapy combined with chemotherapy reflects therapeutic advantages in pancreatic cancer. Moreover, in vitro and in vivo experiments have also demonstrated that anlotinib can curb the proliferation of pancreatic cancer cells and induce their apoptosis. Here, we report for the first time that a patient with locally advanced pancreatic cancer achieved good efficacy after switching to TS-1 chemotherapy combined with anlotinib targeted therapy. Previously, the disease of the patient still rapidly progressed without control following the first switch to abraxane combined with gemcitabine chemotherapy (AG regimen) due to the progression after chemo-radiotherapy. In this case, the patient achieved progression-free survival (PFS) of over 14 months via the treatment with anlotinib targeted therapy combined with TS-1 chemotherapy and secondary radiotherapy (prior to secondary radiotherapy, the patient achieved a PFS of nearly 12 months via the treatment with oral anlotinib combined with TS-1). Up to now, the progress of the disease is ceased. The oral administration of targeted therapy and chemotherapy are still in progress and the general condition of the patient is good. This suggests that patients with advanced pancreatic cancer may benefit from treatment with the anlotinib targeted therapy combined with TS-1 chemotherapy.

Homologous Recombination Pathway Alternation Predicts Prognosis of Colorectal Cancer With Chemotherapy.

Background: Chemotherapy is the basic treatment for colorectal cancer (CRC). However, colorectal cancer cells often develop resistance to chemotherapy drugs, leading to recurrence and poor prognosis. More and more studies have shown that the Homologous recombination (HR) pathway plays an important role in chemotherapy treatment for tumors. However, the relationship between HR pathway, chemotherapy sensitivity, and the prognosis of CRC patients is still unclear. Methods: We collected 35 samples of CRC patients after chemotherapy treatment from Guangxi Medical University Cancer Hospital, then collected mutation data and clinical prognosis data from the group. We also downloaded Mondaca-CRC, TCGA-CRC cohorts for chemotherapy treatment. Result: We found that HR mutant-type (HR-MUT) patients are less likely to experience tumor metastasis after receiving chemotherapy. Additionally, our univariate and multivariate cox regression models showed that HR-MUT can be used as an independent predictor of the prognosis of chemotherapy for CRC patients. The KM curve showed that patients with HR-MUT CRC had significantly prolonged overall survival (OS) time (log-rank p = 0.017; hazard ratio (HR) = 0.69). Compared to HR mutant-type (HR-WT), HR-MUT has a significantly lower IC50 value with several chemotherapeutic drugs. Pathway enrichment analysis further revealed that the HR-MUT displayed a significantly lower rate of DNA damage repair ability, tumor growth, metastasis activity, and tumor fatty acid metabolism activity than HR-WT, though its immune response activity was notably higher. Conclusion: These findings indicate that HR-MUT may be a relevant marker for CRC patients receiving chemotherapy, as it is closely related to improving OS time and reducing chemotherapy resistance.

Synergistic action of microwave-induced mild hyperthermia and paclitaxel in inducing apoptosis in the human breast cancer cell line MCF-7.

Microwave mild hyperthermia and paclitaxel have been reported to be involved in variety of solid tumors. However, rare related researches have been accomplished via directly killing tumor cells using thermochemotherapy. In order to clarify the potential synergy between microwave-induced hyperthermia at temperatures <41°C and paclitaxel chemotherapy for inhibiting the growth of the human breast cancer cell line MCF-7, an MTT assay was used. The MCF-7 cells cultured in vitro were treated with paclitaxel alone, treated with microwave-induced hyperthermia for 2 h alone (at 40, 40.5 or 41°C), or treated with a combination of paclitaxel and 2 h of hyperthermia (at 40, 40.5 or 41°C). Flow cytometry was used to determine the cell apoptosis rate and it was demonstrated that paclitaxel decreased cell viability in a dose-dependent manner. Alone, hyperthermia for 2 h at 41°C induced apoptosis in MCF-7 cells, to a greater extent compared with hyperthermia for 2 h at 40.0 or 40.5°C (P<0.05). Together, paclitaxel and 2 h of hyperthermia at 40.5°C induced significantly increased apoptosis compared with either treatment alone (P<0.05). Increasing the temperature to 41°C in combination with paclitaxel increased the apoptotic ratio from 12.21±1.02% to 16.36±2.39%. The apoptotic ratio correlated positively with hyperthermia temperature and duration following hyperthermia, as did the synergistic effect obtained by combining hyperthermia and paclitaxel. Notably, the combination of 5 µg/ml paclitaxel and 2 h of hyperthermia at 40°C enhanced MCF-7 cell proliferation. Mild hyperthermia may exert anti-tumor effects by inducing apoptosis, and combining hyperthermia with paclitaxel synergistically induces apoptosis. Paclitaxel dose and hyperthermia temperature require careful optimization, as low-dose paclitaxel combined with hyperthermia at an insufficient temperature may enhance breast cancer proliferation.

Clinical efficacy and safety of apatinib in patients with advanced colorectal cancer as the late-line treatment.

There is currently no standard therapeutic regimen available for patients with advanced colorectal cancer in whom the disease continues to progress after 2 or more lines of chemotherapy. The purpose of this study is to investigate the efficacy and safety of apatinib in patients with advanced colorectal cancer for whom at least two lines of prior chemotherapy had failed.Twenty seven patients with advanced colorectal cancer who had failed at least 2 lines chemotherapy were treated with apatinib (500 mg/day). As a comparison control, 26 advanced colorectal cancer patients with comparable clinical baseline characteristics including age, sex, Eastern Cooperative Oncology Group (ECOG) score, pathological type, carcinoembryonic antigen (CEA) level, tumor location, number and location(s) of metastasis, and previous chemotherapies were subject to observation. Survival analyses were performed via the Kaplan-Meier method. The toxicity were evaluated in all patients this study according to the National Cancer Institute Common Toxicity Criteria 4 (NCI CTC version 4.0).A total of 53 well-matched patients with advanced colorectal cancer were retrospectively analyzed. The median follow-up time was 6.0 months (2.0-16.0 months). The median PFS was significantly longer for apatinib group than for observation group (2.0 vs. 1.1 months; HR = 3.88; 95% confidence interval [CI], 1.91-7.88; P < .001). However, there was no significant difference between the 2 groups for median OS (5.0 vs. 4.0 months; HR = 1.03; 95% CI, 0.56-1.90; P = .914). The disease control rate of the apatinib group was significantly better than that of the observation group (70.4% vs 26.9%, P = .002). There was no significant difference in the overall remission rate between the 2 groups (3.7% vs 0%, P = .322). Advanced colorectal cancer patients with 2 or fewer metastatic sites experienced longer PFS than those with more than 2 sites. High ECOG scores, cancer localization to the right side of colon and lymph node metastasis were associated with increased risk of death and all remained independent factors affecting OS. The most common grade 3/4 treatment-related adverse events were hypertension and hand-foot skin syndrome.Apatinib treatment for patients with advanced colorectal cancer who had failed chemotherapy achieved better disease control and prolonged PFS relative to untreated controls. The toxicity was manageable.

18F-FDG PET with or without CT in the diagnosis of extrahepatic metastases or local residual/recurrent hepatocellular carcinoma.

The aim of the present study was to meta-analyze the literature on the diagnostic value of 18-fluorodeoxyglucose (F-FDG) positron emission tomography (PET) with or without computed tomography (CT) in detecting extrahepatic metastases or local residual/recurrent hepatocellular carcinoma (HCC).Systematic review of literature in MEDLINE, Embase, and Cochrane databases was conducted in March 2017, and relevant studies analyzing the diagnostic performance of F-FDG PET with or without CT were meta-analyzed.Meta-analysis was carried out on data from 11 studies involving 572 patients. F-FDG PET, with or without CT, showed pooled sensitivity of 64% and pooled specificity of 95%. Pooled sensitivity was similar with CT (74%) or without (52%; P = .279). Similarly, pooled specificity was comparable with CT (93%) or without 95% (P = .481).F-FDG PET, with or without CT, shows relatively low sensitivity but high specificity for diagnosing extrahepatic metastases or local residual/recurrent HCC. Adding CT to F-FDG PET may improve diagnostic performance, but the available evidence suggests that the improvement is not statistically significant.

The hepatoprotective role of reduced glutathione and its underlying mechanism in oxaliplatin-induced acute liver injury.

Currently, the underlying mechanism of oxaliplatin (OXA) induced live injury is unclear. In addition, there is no standard clinical treatment for OXA-induced acute liver injury (ALI). In this study, we established an animal model of OXA-induced ALI, and studied the role of oxidative stress in OXA-induced ALI and the impacts of reduced glutathione (GSH) treatment on OXA-induced ALI. To establish an OXA-induced ALI model, KM mice received intraperitoneal injection of OXA (8 mg/kg) for 4 days. Serum alanine aminotransferase (ALT), aspartate aminotransferase levels (AST), hepatic pathology and oxidative stress indicators in liver tissues were analyzed. To study the impact of GSH treatment on OXA-induced ALI, mice were treated with GSH (400 mg/kg, i.p). In this ALI mouse model, ALT and AST levels were significantly increased (P<0.01). Liver pathological examination revealed varying degrees of liver cell turbidity and degeneration, even balloon-like changes and focal necrosis, and sinusoidal hemorrhage in some cells. Compared with control group, the malondialdehyde (MDA) and GSH levels were significantly increased in OXA-treated group (P<0.01), while the superoxide dismutase SOD and GSH-peroxidase levels were decreased after OXA withdrawal (P<0.01). When GSH was used to treat OXA-induced ALI mice, the pathological injury of liver tissues was alleviated, and serum ALT and AST were significantly decreased. In addition, GSH treatment could reduce the OXA-induced increase of MDA level (P<0.05) in liver tissues, but had no impact on SOD level (P>0.05). We have successfully established an OXA-induced ALI model. Using this model, we discover that oxidative stress plays an important role in OXA-induced ALI. GSH-based hepatoprotective therapy can partially inhibit oxidative stress and alleviate OXA-induced ALI.

Seven-day capecitabine plus docetaxel and oxaliplatin regimen for the treatment of advanced gastric cancer: A phase-I clinical trial.

Docetaxel, cisplatin and 5-fluorouracil (DCF regimen) are currently applied as an effective combination treatment for various human malignancies; however, the efficacy of this regimen is impaired by severe adverse events associated with it. Therefore, better-tolerated regimens with comparable efficiency are required for patients with gastric cancer. To explore such possibilities, a phase-I clinical trial was performed to evaluate the safety and tolerability of a modified regimen replacing cisplatin and 5-fluorouracil with oxaliplatin and capecitabine, respectively (DOX program). The maximum-tolerated dose (MTD) and dose-limited toxicity (DLT) of capecitabine in this regimen were determined and a dose for subsequent phase-II clinical trials was identified. A total of 24 patients with advanced gastric cancer were sequentially enrolled in the present capecitabine dose-escalation trial. The patients were treated with docetaxel and oxaliplatin at fixed doses [75 and 100 mg/m2, respectively, intravenously, on day 1 (d1)], and with capecitabine at increasing doses (1,500, 2,000 and 2,500 mg/m2, per os, d1-7). The MTD of capecitabine was 2,000 mg/m2 (d1-7), repeated every 21 days for at least two cycles. The most frequent DLTs for this regimen were leukopenia (15/24, 62.5%, all at grade-III/IV) and neutropenia (13/24, 54.2%, all at grade-III/IV), nausea (14/24, 58.3%, all at grade-III) and vomiting (13/24, 54.2%, all at grade-III). The effective rate of the DOX regimen was 75.0% (18/24). Based on the results, the combination of docetaxel (75 mg/m2, d1), oxaliplatin (100 mg/m2, d1) and capecitabine (2,000 mg/m2, d1-7) is recommended for a future phase-II trial. While these doses for the DOX regimen were generally well tolerated, the efficacy of this modified regimen in patients with advanced gastric cancer remains to be further evaluated in subsequent phase-II trials.

Clinical efficacy of bevacizumab concomitant with pemetrexed in patients with advanced non-small cell lung cancer.

OBJECTIVE: To observe the clinical efficacy of bevacizumab concomitant with pemetrexed in patients with advanced non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: A total of 72 patients were randomly divided into a combination group (pemetrexed+bevacizumab, n=36) and a pemetrexed group (n=36) and assessed for disease control (CR+PR+SD) after 4-cycles of first-line GP chemotherapy (gemcitabine+cisplatin). Clinical efficacy, progression-free survival time (PFS), overall survival time (OS), overall response rate (ORR), disease control rate (DCR) and rate of adverse responses between two groups were observed and compared. RESULTS: ORR and DCR were 27.8% and 83.4% in combination group, and 16.7% and 69.5% in the pemetrexed group, respectively, but there were no significant differences (P>0.05). PFS in combination group and pemetrexed group were 4.6 months and 3.9 months respectively (P=0.09), whereas OS in the combination group was 14 months, evidently higher than in the pemetrexed group (11 months, P=0.004). Adverse responses in both groups included high blood pressure, bleeding, thrombocytopenia, anemia, elevated transaminase, diarrhea, vomiting and proteinuria, but there were no significant differences (P>0.05). CONCLUSIONS: Bevacizumab concomitant with pemetrexed has better clinical efficacy and safety, giving rise to prolonged survival time in patients with advanced NSCLC.

Combination of oxaliplatin and S-1 versus sorafenib alone in patients with advanced hepatocellular carcinoma.

Sorafenib and conventional systemic cytotoxicity chemotherapy are currently being used in parallel for the patients with advanced hepatocellular carcinoma (HCC). While sorafenib has been proven to improve the prognosis in patients with this malignant disease, however, the outcome of other newly developed systemic chemotherapeutic regimens remains controversial. We evaluated the outcome and safety of patients treated with the SOX regimen (oxaliplatin + S-1) and those treated with sorafenib in a single-center cohort. This retrospective study involved a total of 46 patients with advanced HCC, 22 of which were treated with SOX regimen (oxaliplatin [130 mg/m2] on day 1 and S-1 [80 mg/m2/day] on day 1-14, every 3 weeks), and 24 were daily treated with sorafenib (400 mg, b.i.d.). The median progression-free survival was 3.6 months (95% confidence interval [CI], 1.7 to 5.6) with SOX and 1.7 months (95% CI, 1.5 to 1.9) with sorafenib, respectively (P = 0.444). The median overall survival in SOX and sorafenib group was 7.6 months (95% CI, 4.3 to 10.9) and 4.7 months (95% CI, 2.7 to 7.3), respectively (P = 0.246). Response rate was 22.2% with SOX and 5.6% with sorafenib, respectively (P = 0.154). The frequent side effects in SOX-treated patients were thrombocytopenia, elevation of transaminase levels and neuropathy, whereas hand-foot syndrome, diarrhea and pruritus were common in sorafenib-treated patients. These preliminary results suggest that the SOX regimen may serve as an effective treatment for patients with advanced HCC, and the treatment-related toxicities were generally well-tolerated.

Short-term hyperthermia promotes the sensitivity of MCF-7 human breast cancer cells to paclitaxel.

As a physical adjuvant approach in the treatment of solid tumors, regional hyperthermia plays a synergistic role in enhancing the efficacy of simultaneous chemotherapy. Paclitaxel (PTX) is an anti-mitotic taxane drug that is widely used in chemotherapy for the treatment of various human malignancies such as lung, ovarian, breast, and head and neck cancers. Since the possibility that hyperthermia can enhance the anti-tumor effects of PTX has not yet been investigated, the present study was designed to evaluate the effects of short-term hyperthermia on PTX-induced antitumor activity in the human breast cancer line MCF-7. It was found that short-term hyperthermia promoted PTX-induced suppression of cell proliferation. The IC for PTX was reduced from 18.2±1.0 to 15.0±0.45 nM (p<0.05). The level of PTX-induced cell apoptosis was increased from 8.5±1.2 to 16.4±2.4% (p<0.05) and from 15.2±1.4 to 34.9±2.8% (p<0.05), at the end of the first and second hyperthermia cycles, respectively; both the activity and expression of caspase-7 were enhanced. In addition, PTX-induced cell cycle arrest in the G2/M phase was further promoted by short-term hyperthermia, from 9.3±0.7 to 12.5±0.9% (p<0.05). In contrast, short-term hyperthermia affected neither tumor cell migration nor invasion in the presence or absence of PTX. The presented data thus suggest that short-term hyperthermia may serve as a feasible approach in the promotion of breast cancer cell sensitivity to PTX.