Association between polymorphisms of ABCB1 and prognosis in esophageal squamous cell carcinoma patients treated with taxane.

BACKGROUND: In China, most esophageal cancer patients are squamous cell carcinomas and are treated with taxane-containing regimens; however, few studies have examined taxane pharmacokinetics genes and esophageal squamous cell carcinoma (ESCC) prognosis. METHODS: In total, 227 pathologically confirmed ESCC patients receiving chemotherapy with taxane were included in the analysis. We genotyped seven SNPs (rs1045642, rs2032582 and rs3213619 of ABCB1; rs2231137 and rs2231142 of ABCG2; and ABCC1 rs246221 and ABCC2 rs3740066) and analyzed their relationship with overall survival. RESULTS: With a retrospective cohort study design, by Cox regression and semi-Bayesian shrinkage, in the genetic recessive model, the variant homozygote of ABCB1 rs1045642 was inversely associated with survival (semi-Bayesian shrinkage crude hazard ratio = 1.82, 95% confidence interval = 1.00, 3.31; p = 0.0482). CONCLUSIONS: Because of inherent defects of the research itself, the finding that the ABCB1 rs1045642 variant was related to poor prognosis in ESCC patients treated with taxane-containing regimens needs to be tested in a larger population and by using more genetic and molecular mechanism experiments.

Polymorphism of FGD4 and myelosuppression in patients with esophageal squamous cell carcinoma.

Background: Chemotherapy-related adverse events may restrain taxane/cisplatin administration as a regimen for patients with esophageal squamous cell carcinoma. Genetic polymorphisms may contribute to adverse event susceptibility. Method & results: The authors genotyped ten SNPs from five genes (rs1045642, rs2032582 and rs3213619 of ABCB1; rs2231137 and rs2231142 of ABCG2; rs246221 of ABCC1; rs3740066 of ABCC2; and rs10771973, rs12296975 and rs1239829 of FGD4) in 219 patients with esophageal squamous cell carcinoma treated with taxane/cisplatin. Patients with severe toxicities were compared with those with minor or no adverse events by unconditional logistic regression models and semi-Bayesian shrinkage. After adjustment for age and sex, with the null prior, FGD4 rs1239829 was statistically significantly related to grade 3-4 leukopenia (odds ratio [95% CI] in dominant model = 1.77 [1.04-3.03]). Conclusion: The minor allele of FGD4 rs1239829 was related to grade 3-4 leukopenia in patients with esophageal squamous cell carcinoma treated with taxane/cisplatin, with unclear biological mechanism.

Lay abstract Taxane/cisplatin is the main chemotherapy regimen in patients with esophageal squamous cell carcinoma in China. Many patients suffer from neurotoxicity or bone marrow suppression, such as decreased white blood cells. Higher-grade adverse events, in particular, usually result in chemotherapy dose reduction or treatment termination. Researchers explored the associations between genetics and chemotherapy toxicity and found that the genetic variant (SNP rs1239829) of the gene FGD4 was related to serious white blood cell decline in patients with esophageal squamous cell carcinoma who were treated with the taxane/cisplatin regimen.

Exposure of few layer graphene to Limnodrilus hoffmeisteri modifies the graphene and changes its bioaccumulation by other organisms.

While graphene has substantial commercial promise, numerous aspects regarding its ecological effects such as its potential for bioaccumulation are not well known. 14C-labeled few layer graphene (FLG) was dispersed in artificial freshwater and uptake of FLG by Limnodrilus hoffmeisteri, an oligochaete, was assessed. After exposure for 36 h to a 1 mg/L FLG suspension, the FLG body burden in the organism was nearly 60 ng/mg (on a dry mass basis). Multiple characterization results confirmed that the proteins secreted by the organisms during the exposure period coated the FLG, thus increasing its stability and decreasing its size in suspension. Uptake behaviors of Eisenia foetida exposed to FLG and protein-coated FLG at concentrations of approximately 1 mg/kg or to Daphnia magna at 100 µg/L were also quantified. Protein-coated FLG demonstrated different bioaccumulation behaviors for both organisms compared to uncoated FLG, with the FLG body burden in E. foetida increased but that in D. magna reduced. The data provide the first evidence that the proteins secreted by Limnodrilus hoffmeisteri after exposure to FLG can coat FLG, thus increasing the aqueous stability of FLG, decreasing its size, and changing its bioaccumulation potential.

Sufficiently activated mature natural killer cells derived from peripheral blood mononuclear cells substantially enhance antitumor activity.

BACKGROUND: Peripheral blood-derived natural killer (NK) cells spontaneously lyse tumor cells without prior sensitization. However, NK cells in peripheral blood (PBNK cells) are in a resting state and exhibit inhibitory phenotypes and impaired cytotoxicity. Thus, strengthening the cytotoxic effector function of PBNK cells and improving NK cell expansion in vitro for a convenient allogeneic therapy are essential. MATERIALS AND METHODS: Pure cytokine activation and expansion of NK cells (super NK [SNK]) from peripheral blood mononuclear cells were studied. Markers of activated and inhibited NK cells and cytokine secretion by NK cells were examined using flow cytometry. NK cell antitumor activity in vitro was assessed using lactate dehydrogenase (LDH) cytotoxicity assay and an Incucyte real-time imaging system. Additionally, the function of SNK cells against ascites caused by ovarian cancer in NOD-Prkdc(em26Cd52)il2rg(em26Cd22)/Nju (NCG) mice was determined. In a further investigation of the differences between PBNK and SNK, the mRNA of both cells was sequenced and analyzed. RESULTS: Human peripheral blood mononuclear cells showed selective NK cell expansion upon cytokine activation and culture. Both SNK and PBNK cells expressed activation markers, but at different levels, and SNK cells secreted more cytokines related to cytotoxicity than PBNK cells did. Accordingly, SNK cells exhibited strong antitumor activity ex vivo and improved NCG mice survival after intraperitoneal ovarian cancer transplantation. Mechanistically, SNK cells expressed more genes associated with nucleotide metabolism, fatty acid, and ATP metabolism than PBNK cells. CONCLUSION: SNK cells derived from peripheral blood mononuclear cells have sufficiently activated mature characteristics and high antitumor activity, rendering them a highly promising and essential therapeutic approach for cancer treatment.

A real-world study of immune checkpoint inhibitors in advanced triple-negative breast cancer.

Background: Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer. Immune checkpoint inhibitors (ICIs) have been widely used to treat various tumors and have changed the landscape of tumor management, but the data from real-world studies of ICIs for TNBC treatment remain limited. The aim of this study was to evaluate the efficacy of ICIs in the treatment of patients with advanced TNBC in a real-world setting and to explore possible correlates. Methods: The clinical data of advanced TNBC patients who received ICI treatment in the Chinese People's Liberation Army (PLA) General Hospital were collected. Treatment responses, outcomes and adverse events (AEs) were assessed. Results: Eighty-one patients were included in the study. The confirmed objective response rate (ORR) was 32.1%, and the disease control rate (DCR) was 64.2%. The median progression-free survival (PFS) was 4.2 months, and the median overall survival (OS) was 11.0 months. PFS and OS were longer in patients who achieved clinical benefit from ICIs and shorter in patients who received later-line ICIs and higher levels of inflammation; specifically, patients with higher TILs had longer PFS. Overall AEs were tolerable. Conclusions: ICIs are effective in the treatment of advanced TNBC, and the adverse reactions are tolerable. A panel of biomarkers including LDH, ALP, and bNLR were identified to predict the efficacies of ICIs in TNBC treatment.

Phase 1 dose-escalation study of apatinib and irinotecan in esophageal squamous cell carcinoma patients.

BACKGROUND: Apatinib, an inhibitor of vascular endothelial growth factor receptor (VEGFR), has been used to treat esophagogastric adenocarcinoma. However, the dosage of apatinib varies greatly in clinical practice, and its safety in esophageal squamous cell carcinoma (ESCC) patients is unclear. Therefore, we initiated a phase 1 dose-escalation trial to identify the maximum tolerated dose (MTD) of apatinib when combined with irinotecan in ESCC. METHODS: The trial had a standard 3+3 design. The dosage of irinotecan was fixed at 150 mg/m2 repeated every 2 weeks, while the daily dosage of apatinib was escalated from 250 mg, to 500 mg, to 750 mg. Dose-limiting toxicity (DLT) was defined as grade 4 hematological or grade 3-4 non-hematological adverse events (AEs). RESULTS: Twelve patients were enrolled. Three DLTs occurred, comprising a grade 3 perianal abscess and a grade 3 case of kaliopenia in the level 3 cohort, and a grade 4 leukopenia in the level 2 cohort. Based on these DLTs, the MTD of apatinib was 500 mg daily. The most common AEs were leukopenia (91.7%), fatigue (91.7%), anemia (66.7%), and diarrhea (58.3%). One case of grade 2 hematochezia and one case of grade 2 subclavian vein thrombosis were observed. In the nine evaluable cases, the disease control rate (DCR) was 66.7% (6/9). The median progression-free and overall survival (OS) times were 3.6±1.2 and 6.6±3.4 months, respectively. CONCLUSIONS: This phase 1 dose-escalation trial showed that, when combined with irinotecan, a daily dose of 500 mg apatinib was the optimum dose to treat ESCC.

Association Between Multiple Lines of Active Therapy and Prognosis in Esophageal Squamous Cell Carcinoma.

PURPOSE: Esophageal squamous cell carcinoma (ESCC) is a critical threat to health and life. More than half of ESCC patients have recurrent or metastatic disease. Most late-stage patients undergo first-line treatment but experience further progression. Many of these patients have good performance status and are able to receive second-line therapy and even further treatments rather than best supportive care. Our analysis aimed to explore whether multiple lines of active treatment are beneficial in ESCC patients. METHODS: We conducted a retrospective cohort study. Univariate and multivariate survival analyses were used to identify whether the number of active treatment lines was related to prognosis. All analyses and the corresponding survival curves were based on the Cox proportional hazard regression model and the Kaplan-Meier method. Comparisons between groups were conducted using the t-test, chi-square test, and Fisher's exact test, as applicable. RESULTS: Of a total of 138 patients with recurrent or metastatic disease, 66 (61.1%) received one line of active treatment, and 42 (38.9%) patients received two and more lines. Multiple lines of active therapy were statistically significantly associated with better prognosis (crude hazard ratio (HR) (95% confidence interval (CI))=0.21 (0.06-0.73)), even after adjusting for relevant confounders (adjusted HR (95% CI)=0.19 (0.04-0.86)). More grade 3-4 hepatotoxicity patients were observed in the multiple-line treatment group (p=0.033). A small number of patients were cured by palliative management; these patients were more likely to have received both systematic and local treatment than other patients with repeated progression (9/15 versus 40/117, p=0.051). CONCLUSION: Multiple lines of active treatment are related to prolonged survival in recurrent and metastatic ESCC patients, and adverse effects are acceptable. Comprehensive therapy modalities are recommended.

Clinical significance of serum tumor markers for advanced gastric cancer with the first-line chemotherapy.

BACKGROUND: Tumor markers play an important role in the diagnosis, monitoring and prognostic prediction of cancers. But the predictive value of serum tumor markers in gastric cancer is still unclear. METHODS: In this study, we detected serum levels of tumor markers to evaluate their relation to treatment response and prognosis in patients with unresectable advanced or metastatic gastric cancer. RESULTS: We collected the clinical data of 109 patients with unresectable advanced or metastatic gastric cancer who had received the first-line chemotherapy in Peking University Cancer Hospital from July 2013 to May 2015, and collected the value of serum carcinoembryonic antigen (CEA), carbohydrate antigen 199 (CA199), carbohydrate antigen 72.4 (CA72.4) and carbohydrate antigen 125 (CA125) before and after chemotherapy. At diagnosis, the positive rates of CEA, CA199, CA72.4 and CA125 were 46.8%, 40.2%, 53.5% and 35.0%, respectively. And the positive rate of combined detection of the four markers was 87.2%. Although patients with prechemotherapy CA199 ≥80 U/mL (92.3% vs. 68.5%, P=0.016) or CA72.4 ≥20 U/mL (91.4% vs. 62.5%, P=0.003) had higher clinical benefit rate after chemotherapy, they showed poorer prognosis (P=0.023 and P=0.006, respectively). CA72.4 ≥20 U/mL was an independent unfavorable prognostic factor (Hazard Ratio 4.84; 95% confidence interval: 1.910-12.262; P=0.001). In patients with increased levels of tumor markers before treatment, the levels of tumor markers decreased after chemotherapy, especially in those with clinical benefit (CEA, CA72.4 reached statistical significance, P=0.013 and P=0.029, respectively). A decrease of CEA ≥35%, CA199 ≥30%, or CA72.4 ≥40% after chemotherapy had positive prediction value for the response to chemotherapy (P=0.016, P=0.029, and P=0.008, respectively). CONCLUSIONS: The results showed that both high pre-chemotherapy serum levels of tumor markers (CA199 ≥80 U/mL or CA72.4 ≥20 U/mL) and a substantial decrease in tumor markers after chemotherapy (CEA ≥35%, CA199 ≥30%, or CA72.4 ≥40%) could predict a higher clinical benefit rate in patients with unresectable advanced or metastatic gastric cancer. However, this advantage in short-term response to chemotherapy failed to convert into prolonged survival benefits.

Nimotuzumab Plus Paclitaxel and Cisplatin as a 1st-Line Treatment for Esophageal Cancer: Long Term Follow-up of a Phase II Study.

The effect of anti-epidermal growth factor receptor targeted treatment in esophageal squamous cell carcinoma (ESCC) is still unclear. We conducted a prospective phase II study of paclitaxel, cisplatin, and nimotuzumab (TPN) as a first-line treatment for unresectable or metastatic ESCC and the objective response rate was 51.8%. Here, we report the long-term follow-up results of the initial trial. Fifty-nine patients were enrolled from Mar 2011 to Apr 2013 and were treated with the TPN regimen. Palliative sequential radiotherapy was given if all tumor lesions were confined to 1-2 radiation fields. Fifty-six patients were eligible for evaluation. After a median follow-up of 32.2months, the median progression-free survival (PFS) and the overall survival (OS) time were 18.1±4.2 months (95% CI: 9.8-26.4) and 26.2±10.0 months (95% CI: 6.6-45.8), respectively, in 29 patients with unresectable local-regional disease, while they were 6.6±0.4 months (95% CI: 5.8-7.5) and 11.5±3.7 months (95% CI: 4.2-18.8), respectively, in 27 patients with metastatic disease. Patients who were male, those with multiple station lymph node metastases, those with visceral metastasis, those who did not response to TPN treatment, and those who did not receive radiotherapy, had a worse OS. In 6 patients with multiple station lymph node metastasis and in 3 patients with recurrent disease and oligo-metastasis (local lymph nodes), TPN with sequential radiation resulted in a mean OS of 17.67±9.50 months and a mean OS of over 40 months, respectively. In conclusion, TPN is effective as a first-line treatment for patients with unresectable and metastatic ESCC. In addition, TPN treatment with sequential radiation might improve survival in patients with limited or oligo lymph node metastases.

Prognosis impact of clinical characteristics in patients with inoperable esophageal squamous cell carcinoma.

BACKGROUND: Patients with inoperable esophageal squamous cell carcinoma (ESCC) were not homogeneous and their outcomes were widely divergent. There was a lack of identified clinical factors related to prognosis; and there were no previous studies constructing prognosis score to predict survival and guide treatment. METHODS: In this retrospective cohort study, twelve clinical characteristics of one hundred and twenty inoperable ESCC patients were collected at diagnosis and analyzed by Cox regression model. Various methods including univariate analysis, confounding adjusted multivariate analysis and model selection were applied to determine factors associated with poor prognosis; and prognosis score was built on established factors. RESULTS: Four characters were identified as poor prognosis factors, including mid- and low-thoracic tumor (aHR = 2.20, 95% CI = 1.03, 4.72), abdominal and retroperitoneal lymph node metastasis (aHR = 1.62, 95% CI = 1.00, 2.64), albumin no more than 39g/L (aHR = 2.81, 95% CI = 1.24, 6.41) and hematogenous metastasis (aHR = 1.61, 95% CI = 0.97, 2.69). Patients were stratified into three groups by prognosis score, that was, good survival with none of four identified factors (score zero), poor survival with three to four factors (score three to four) and median with one to two factors (score one to two), survival of three groups were statistically different (ptrend = 0.020). CONCLUSION: Prognosis score based on selected clinical characteristics could predict survival among inoperable ESCC patients, which was critical for individualized treatment and central of precise medicine.

[Difference analysis of chemotherapy efficacy among different primary tumor sites in metastatic colorectal cancer].

OBJECTIVE: To analyze the relationship between primary tumor location and clinical response of chemotherapy in patients with metastatic colorectal cancer(mCRC). METHODS: Clinical data of 721 mCRC patients who received first-line and second-line chemotherapy in Peking University Cancer Hospital between January 1996 and December 2011 were collected. All the patients were divided into 5 groups according to primary tumor location: ileocecum in 61 patients(8.5%), ascending colon or hepatic flexure in 126 patients (17.5%), transverse colon or splenic flexure in 26 patients (3.6%), descending or sigmoid colon in 172 patients (23.9%), rectum in 336 patients (46.6%). Outcomes of chemotherapy were evaluated by Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1), including complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). The overall response rate (ORR) was counted with the total number of patients divided by the number of CR+PR. Differences in first-line and second-line chemotherapy efficacy among different primary tumor sites in metastatic colorectal cancer were compared by using Chi-square test. RESULTS: Of the 571 patients receiving first-line chemotherapy, no one patient was classified as CR, while there were 190 as PR (33.3%), 277 as SD (48.5%) and 104 as PD (18.2%), with ORR 33.3% (190/571). The ORRs of patients with primary tumor located at ileocecum, ascending colon or hepatic flexure, transverse colon or splenic flexure, descending or sigmoid colon, rectum were 21.3% (10/47), 35.3% (36/102), 14.3% (3/21), 41.3% (57/138) and 31.9% (84/263), respectively, with statistically significant difference(P = 0.028). Difference of oxaliplatin-based first-line chemotherapy efficacy among different tumor sites was statistically significant(P = 0.009), while differences in irinotecan-based or single-agent 5-fluorouracil chemotherapy efficacy were not statistically significant (all P>0.05). In patients with primary tumor located at transverse colon or splenic flexure, irinotecan-based first-line chemotherapy had higher ORR than oxaliplatin-based or single-agent 5-fluorouracil chemotherapy, and the difference was statistically significant (P=0.042). There was no significant difference in the efficacy of different first-line chemotherapy regimens in patients with primary tumor located at other sites (all P>0.05). Of the 353 patients receiving second-line chemotherapy, no one patient was classified as CR, while there were 43 as PR (12.2%), 187 as SD (53.0%) and 123 as PD (34.8%), with ORR 12.2%(43/353). The ORRs of patients with primary tumor located at the ileocecum, the ascending colon or the hepatic flexure, the transverse colon or the splenic flexure, the descending or sigmoid colon, the rectum were 4.2%(1/24), 12.1%(8/66), 8.3%(1/12), 15.2%(12/79) and 12.3%(21/171) respectively, without statistically significant difference (P=0.686). Differences in second-line chemotherapy efficacy with the same regimen among different tumor sites were not statistically significant, and there were also no significant differences of efficacy of different second-line chemotherapy regimens in patients with the same tumor site (all P>0.05). CONCLUSION: There are differences in first-line chemotherapy efficacy among different primary tumor sites in metastatic colorectal cancer, while their second-line chemotherapy efficacy is equivalent.