Cisplatin plus gemcitabine versus paclitaxel plus gemcitabine as first-line therapy for metastatic triple-negative breast cancer (CBCSG006): a randomised, open-label, multicentre, phase 3 trial.

BACKGROUND: Platinum chemotherapy has a role in the treatment of metastatic triple-negative breast cancer but its full potential has probably not yet been reached. We assessed whether a cisplatin plus gemcitabine regimen was non-inferior to or superior to paclitaxel plus gemcitabine as first-line therapy for patients with metastatic triple-negative breast cancer. METHODS: For this open-label, randomised, phase 3, hybrid-designed trial undertaken at 12 institutions or hospitals in China, we included Chinese patients aged 18-70 years with previously untreated, histologically confirmed metastatic triple-negative breast cancer, and an ECOG performance status of 0-1. These patients were randomly assigned (1:1) to receive either cisplatin plus gemcitabine (cisplatin 75 mg/m(2) on day 1 and gemcitabine 1250 mg/m(2) on days 1 and 8) or paclitaxel plus gemcitabine (paclitaxel 175 mg/m(2) on day 1 and gemcitabine 1250 mg/m(2) on days 1 and 8) given intravenously every 3 weeks for a maximum of eight cycles. Randomisation was done centrally via an interactive web response system using block randomisation with a size of eight, with no stratification factors. Patients and investigator were aware of group assignments. The primary endpoint was progression-free survival and analyses were based on all patients who received at least one dose of assigned treatment. The margin used to establish non-inferiority was 1·2. If non-inferiority of cisplatin plus gemcitabine compared with paclitaxel plus gemcitabine was achieved, we would then test for superiority. The trial is registered with ClinicalTrials.gov, number NCT01287624. FINDINGS: From Jan 14, 2011, to Nov 14, 2013, 240 patients were assessed for eligibility and randomly assigned to treatment (120 in the cisplatin plus gemcitabine group and 120 in the paclitaxel plus gemcitabine group). 236 patients received at least one dose of assigned chemotherapy and were included in the modified intention-to-treat analysis (118 per group). After a median follow-up of 16·3 months (IQR 14·4-26·8) in the cisplatin plus gemcitabine group and 15·9 months (10·7-25·4) in the paclitaxel plus gemcitabine group, the hazard ratio for progression-free survival was 0·692 (95% CI 0·523-0·915; pnon-inferiority<0·0001, psuperiority=0·009, thus cisplatin plus gemcitabine was both non-inferior to and superior to paclitaxel plus gemcitabine. Median progression-free survival was 7·73 months (95% CI 6·16-9·30) in the cisplatin plus gemcitabine group and 6·47 months (5·76-7·18) in the paclitaxel plus gemcitabine group. Grade 3 or 4 adverse events that differed significantly between the two groups included nausea (eight [7%] vs one [<1%]), vomiting (13 [11%] vs one [<1%]), musculoskeletal pain (none vs ten [8%]), anaemia (39 [33%] vs six [5%]), and thrombocytopenia (38 [32%] vs three [3%]), for the cisplatin plus gemcitabine compared with the paclitaxel plus gemcitabine groups, respectively. In addition, patients in the cisplatin plus gemcitabine group had significantly fewer events of grade 1-4 alopecia (12 [10%] vs 42 [36%]) and peripheral neuropathy (27 [23%] vs 60 [51%]), but more grade 1-4 anorexia (33 [28%] vs 10 [8%]), constipation (29 [25%] vs 11 [9%]), hypomagnesaemia (27 [23%] vs five [4%]), and hypokalaemia (10 [8%] vs two [2%]). Serious drug-related adverse events were seen in three patients in the paclitaxel plus gemcitabine group (interstitial pneumonia, anaphylaxis, and severe neutropenia) and four in the cisplatin plus gemcitabine group (pathological bone fracture, thrombocytopenia with subcutaneous haemorrhage, severe anaemia, and cardiogenic syncope). There were no treatment-related deaths. INTERPRETATION: Cisplatin plus gemcitabine could be an alternative or even the preferred first-line chemotherapy strategy for patients with metastatic triple-negative breast cancer. FUNDING: Shanghai Natural Science Foundation.

PD-1/PD-L1 pathway in non-small-cell lung cancer and its relation with EGFR mutation.

Immunotherapy has become a crucial modality for non-small-cell lung cancer treatment. Recently, two immune checkpoints, PD-1 and PD-L1, have emerged as important targets for immunotherapy. Their antitumor efficacy has been confirmed by in vitro and in vivo studies. But the correlation between PD-1/PD-L1 expression and EGFR expression was controversial and needs more evidences to support the combination of PD-1/PD-L1 inhibitors and tyrosine kinase inhibitors.

Evaluation of tumor response to cytokine-induced killer cells therapy in malignant solid tumors.

CIK cells therapy has been evaluated as an adoptive cell immunotherapy for cancer patients, but there still have not been any standardized systems for evaluating the antitumor efficacy yet. The WHO and RECIST criteria have already been established for a few years but not sufficient to fully characterize the activity of immunotherapy. Based on these two criteria, the irRC was proposed for evaluating the efficacy of immunotherapy. A variety of bioassays for immune monitoring including the specific and non-specific methods, have been established. We recommend detect levels of various immunocytes, immune molecules and soluble molecules to find the correlations among them and clinicopathological characteristics to establish criteria for immunological classification. We also recommend a paradigm shift for the oncologists in the evaluation of immune therapies to ensure assessment of activity based on clinically relevant criteria and time points.

Report of clinical studies on chronochemotherapy for advanced non-small cell lung cancer in China.

Chronochemotherapy has been proposed as a promising modality to provide timely optimized medication to achieve maximum efficacy with minimum side effect for patients with non-small cell lung cancer for years. We collected the data of 11 clinical studies performed in China with the purpose to compare the difference between chronochemotherapy and traditional chemotherapy. Results showed that chronochemotherapy has a more favorable efficacy and safety than traditional chemotherapy.

Clinical significance of serum ferritin in elderly patients with primary lung carcinoma.

This study determined the levels of serum ferritin (SF) and carcinoembryonic antigen (CEA) in elderly patients with advanced primary lung cancer (PLC), and aimed to investigate the correlation between the SF level and clinical characteristics and compare the positive rates of SF and CEA levels in PLC patients and those in normal subjects. The SF and CEA levels of 69 elderly cases of advanced PLC and 63 elderly controls were determined by electrochemiluminescence method. The correlation between each independent clinicopathological characteristic and levels of SF and CEA was calculated. The positive rates of SF and CEA levels in PLC patients and those in normal subjects were compared. The results revealed that the level of SF in controls was significantly lower than those in patients with advanced LC (145.04 ± 141.77 vs. 293.57 ± 274.95 ng/ml, t = -3.845, P = 0.000). There was a statistically significant difference between SF level and gender, smoking, and regional lymph node metastasis, respectively (P < 0.05). The positive rate of SF combining with CEA was significantly higher than those of SF and CEA alone in patients with advanced PLC. High serum level of SF is helpful for diagnosing PLC in elderly patients and indicates poor prognosis.

CD40 mutant expression and its clinical significance to prognosis in gastric cancer patients.

BACKGROUND: We aimed to detect CD40 mutant expression and evaluate its clinical significance in gastric cancer. METHODS: CD40 mutant expression in 78 cases of gastric cancer tissues, 10 cases of normal gastric tissues, and 10 cases of gastric adenoma tissues by immunohistochemical test. Survival analyses were also performed. RESULTS: The positive CD40 mutant rate in gastric cancer was 55.1% (43/78). No positive CD40 mutant staining was observed in the normal gastric tissue or the gastric adenoma. CD40 mutants expression was significantly correlated with invasive depth, lymph metastasis, and TNM stage (P <0.05). Cases with negative CD40 mutant expression had a significantly longer median survival time than those with positive CD40 mutant expression (40 vs. 14 months, P <0.05). A lower death risk in negative CD40 mutant cases was observed comparing with positive CD40 mutant cases. CONCLUSIONS: Positive CD40 mutant expression suggests a poorer prognosis of gastric cancer cases.

Higher numbers of T-bet(+) intratumoral lymphoid cells correlate with better survival in gastric cancer.

In the present study, we studied the expression of T-bet, a key marker for type 1 immune responses, within the tumor microenvironment of gastric cancer, and analyzed its association with clinicopathological parameters. One hundred and fifty-two archival paraffin-embedded gastric tumor tissues were collected, and the expression of T-bet in these cancer tissue specimens was examined by immunohistochemistry. T-bet(+) tumor-infiltrating lymphocytes (TILs) in some gastric cancer tissues were further characterized by flow cytometric analysis. The density of T-bet(+) TILs in gastric cancer tissues in relation to patient's clinicopathological parameters and postoperative prognosis has been analyzed. Herein, we have found significant increases in T-bet(+) lymphocytes in tumor tissues as compared with normal stomach tissues, gastritis tissues or gastric polyp specimens. T-bet(+) cells mainly consisted of CD4(+), CD8(+) and CD56(+) TILs. In addition, lower numbers of T-bet(+) TILs were associated with poor clinicopathological parameters such as invasion to muscular layer, larger tumor size and advanced cancer stages. Moreover, patients with higher numbers of T-bet(+) TILs have longer disease-free survival and overall survival. Thus, our study supports the idea that tumor growth elicits spontaneous type 1 cellular immune responses and tumor progression is associated with suppression of antitumor immunity. T-bet expression within tumor can serve as a prognostic indicator for gastric cancer and a potential biomarker for immunotherapy.

Relationship between glutathione S-transferase P1 (GSTP1), X-ray repair cross complementing group 1 (XRCC1) and 5,10-methylenetetrahydrofolate reductase (5,10-MTHFR) gene polymorphisms and response to chemotherapy in advanced gastric cancer.

BACKGROUND: Our study aimed to investigate the relationship between glutathione S-transferase P1 (GSTP1), 5,10-methylenetetrahydrofolate reductase (5,10-MTHFR) and X-ray repair cross complementing group 1 (XRCC1) gene polymorphisms and the response to chemotherapy in advanced gastric cancer. PATIENTS AND METHODS: 59 cases of advanced gastric cancer were enrolled. All patients were treated with the DCF regimen comprising docetaxel, cisplatin, and 5-fluorouracil. All patients' genotypes regarding GSTP1, XRCC1, and 5,10-MTHFR were analyzed by polymerase chain reaction/ligase detection reaction (PCR-LDR). RESULTS: There were 15 (25.42%) cases of G/G genotype, 21 (35.59%) of G/A genotype, and 23 (38.98%) of A/A genotype for GSTP1, 16 (27.12%) cases of A/A genotype, 18 (30.51%) of G/A genotype, and 25 (42.37%) of G/G genotype for XRCC1, and 21 (35.59%) cases of C/C genotype, 22 (37.29%) of C/T genotype, and 16 (27.12%) of T/T genotype for 5,10-MTHFR. After 2 cycles of chemotherapy, there were 4 cases of complete remission, 14 of partial remission, 19 of stable disease, and 22 of advanced disease, with a total effective rate of 30.51%. Better survival was shown for GSTP1 G/G genotype, XRCC1 A/A genotype, and 5,10-MTHFR T/T genotype (p < 0.05). CONCLUSION: The gene polymorphisms of GSTP1 G/G, XRCC1 A/A, and 5,10-MTHFR T/T have clinical value for predicting the response to the DCF regimen for advanced gastric cancer.

Characteristic analysis of α-fetoprotein-producing gastric carcinoma in China.

α-Fetoprotein-producing gastric cancer (AFPGC) is a rare type of gastric cancer. The largest population of patients with AFPGC is found in China. In the present study, a total of 4,779 GC patients, including 317 AFPGC patients, from 11 clinical studies in China with a general AFPGC/GC ratio of 6.63% were summarized and analyzed. On the basis of analysis of the clinical data, the patients with AFPGC had larger tumor size, weaker cell differentiation, worse histopathological types, deeper serosal infiltration, more lymph node and liver metastases, poorer stages, shorter survival time and more positive expression of vascular endothelial growth factors than the patients without AFPGC. Our observation is consistent with previous results reported in studies of AFPGC. Overall, AFPGC is a subtype of GC with a poor prognosis.

miR-17-5p inhibitor enhances chemosensitivity to gemcitabine via upregulating Bim expression in pancreatic cancer cells.

BACKGROUND: miR-17-5p is reported to be overexpressed in pancreatic cancer, and it plays an important role in carcinogenesis and cancer progression. Gemcitabine is the standard first-line chemotherapeutic agent for pancreatic cancer, however the chemoresistance limits the curative effect. AIMS: In the present study, we investigated whether inhibition of miR-17-5p could enhance chemosensitivity to gemcitabine in pancreatic cancer cells. METHODS: miR-17-5p inhibitor was transfected to pancreatic cancer cell lines Panc-1 and BxPC3, and then cell proliferation, cell apoptosis, caspase-3 activation, and chemosensitivity to gemcitabine were measured in vitro. RESULTS: Our data showed that Panc-1 and BxPC3 cells transfected with miR-17-5p inhibitor showed growth inhibition, spontaneous apoptosis, higher caspase-3 activation, and increased chemosensitivity to gemcitabine. In addition, miR-17-5p inhibitor upregulated Bim protein expression in a dose-dependent manner without changing the Bim mRNA level, and it increased the activity of a luciferase reporter construct containing the Bim-3' untranslated region. CONCLUSIONS: These results prove that miR-17-5p negatively regulates Bim at the posttranscriptional level. We suggest that miR-17-5p inhibitor gene therapy would be a novel approach to chemosensitization for human pancreatic cancer.

Expression of costimulatory molecule B7-H4 in human malignant tumors.

Costimulatory molecule B7-H4, a member of the B7 family, negatively regulates the immune response of T cells through inhibiting their proliferation, cytokine production and cell cycle. The overexpression of B7-H4 plays an important role in initiation, progression and regression of tumors by promoting malignant transformation of epithelial cells and protecting epithelial cells from anoikis. B7-H4 expression in malignant tumors is useful for clinical diagnosis, and may provide a novel molecular target for cancer treatment.

Would foot arch development in children characterize a body maturation process? A prospective longitudinal study.

BACKGROUND: Flatfoot (Pes Planus), often regarded as a physiological deviation in children, is of concern to parents because there is no test to predict the development of foot arch. This study aimed to use a new diagnostic flatfoot criterion to determine 1) how the footprint index changes during the development of foot arches, 2) what factors can predict a foot arch development, and 3) whether foot arch development could be a process of body growth. METHODS: 572 children were enrolled in a prospective longitudinal study of anthropometrical parameters and physical fitness twice at age of 6.7 and 8.2 years. The bimodal frequency distribution of the Chippaux-Smirak index (CSI) of the footprint was used to define flatfoot as CSI <0.58 and non-flatfoot as CSI >0.61. Body measurements and physical fitness tests were compared between children with flatfeet who developed foot arches and children who did not. RESULTS: Of 263 children with flatfeet, the CSI significantly changed from 0.72 to 0.46 in 70 children who developed foot arches over 1.5 years and the others had minimal change in the index. Children with foot arch development had a lower initial CSI, improved boys' performance in one-leg balance, and less increase in girls' body height than children who remained flatfooted, whereas sex and weight were similar in both groups. CONCLUSION: This longitudinal study with the bimodal distribution of the CSI investigated how the development of foot arch advances in children around age 7. A significant and unique pattern in change of the CSI suggests involvement of a maturational stage in foot arch development. Along with the improved performance in one-leg balance, the unidirectional transition from flatfoot to non-flatfoot is associated with improvement in motor control of the ankle. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR-OCS-14004300).

The regimen of gemcitabine and cisplatin combined with radio frequency hyperthermia for advanced non-small cell lung cancer: a phase II study.

PURPOSE: This phase II randomised trial was designed to evaluate the therapeutic efficacy and feasibility of radio frequency regional hyperthermia in combination with chemotherapy for patients with advanced non-small lung cancer (NSCLC). METHODS: Eighty patients with pathologically proven advanced NSCLC, were enrolled and divided into two groups. Group A patients were treated by radio frequency regional hyperthermia in combination with the regimen of gemcitabine and cisplatin (GP). Group B patients were treated with the GP regimen alone. RESULTS: In group A, one patient achieved a complete response (CR), 18 achieved a partial response (PR), 18 achieved a stable disease and three experienced a progression of the disease. Thirty-three patients had a positive Clinical Benefit Response (CBR). In group B, no patient achieved CR, 17 achieved PR, 19 achieved a stable disease and four experienced a progression of the disease. Nineteen patients had a positive CBR. Significant differences between the two groups were observed for the CBR (P < 0.05), but not for RR. Major toxicities included bone marrow depression, nausea, vomiting, without significant differences between the two groups (P > 0.05). CONCLUSIONS: Radio-frequency regional hyperthermia in combination with chemotherapy (GP) is a safe, well tolerated, and effective therapeutic modality for patients with advanced NSCLC. The addition of hyperthermia improved quality of life.

LncRNA HCG18 suppresses CD8+ T cells to confer resistance to cetuximab in colorectal cancer via miR-20b-5p/PD-L1 axis.

Aim: We aimed to explore the effect of long noncoding RNA HCG18 in colorectal cancer (CRC). Materials & methods: Relative gene and protein expression were screened. Colony formation and flow cytometry assays were performed to determine proliferation and apoptosis. Dual luciferase and RNA immunoprecipitation assays were conducted to validate the interaction between indicated molecules. Xenograft in nude mice was applied to verify the conclusion in vivo. Results:HCG18 and PD-L1 were upregulated while miR-20b-5p was downregulated in CRC tissue. Functional analysis revealed that lncRNA HCG18 promoted proliferation, migration and resistance to cetuximab of CRC cells via the miR-20b-5p/PD-L1 axis. Conclusion:HCG18 facilitated progress of the tumor, conferred to cetuximab resistance and suppressed CD8+ T cells via the miR-20b-5p/PD-L1 axis.

Lay abstract In the present study, we found a long noncoding RNA (lncRNA), HCG18 (a recently discovered lncRNA that facilitates tumor progression via multiple mechanisms), was upregulated in colorectal cancer (CRC). Further studies revealed that HCG18 suppressed CD8⁺ T-cell (cytotoxic T lymphocyte which kills cancer cell) activation to induce cetuximab (a first-line drug in CRC) resistance. Mechanically, HCG18 elevated expression of PD-L1 (a receptor in T-cell membranes, thus suppressing the proliferation of CD8⁺ cytotoxic T lymphocytes) via sponging (lncRNA binds with miRNA) miR-20b-5p. This study might provide a deeper insight into understanding cetuximab resistance in CRC.

Hsa_circ_0136666 activates Treg-mediated immune escape of colorectal cancer via miR-497/PD-L1 pathway.

PURPOSE: In the rankings of cancer mortality and incidence worldwide, colorectal cancer ranks fourth and the third, respectively. Circular RNA hsa_circ_0136666 (hsa_circ_0136666) is reported to participate in the growth of colorectal cancer. However, the mechanism by which hsa_circ_0136666 regulates the tumorigenesis of colorectal cancer needs to be further explored. In this study, we report here the role of hsa_circ_0136666 in the aberrant activation of Treg cells and immune evasion of tumor cells, providing a new strategy for the treatment of colorectal cancer. METHODS: Western blotting assay and qRT-PCR assay were used to determine protein and mRNA expression levels. Dual-luciferase reporter assay was used to evaluate the targeted regulatory relationship. RNA immunoprecipitation was used to detect RNA binding. Colony formation assay was utilized to measure the cell proliferation. Flow cytometry was used to assess cell apoptosis. Xenograft model was setup to evaluate tumor growth. RESULTS: The results showed that hsa_circ_0136666 and PD-L1 was increased in colorectal cancer cells while miR-497 was decreased in colorectal cancer cells when compared with normal colon epithelial cell line. Hsa_circ_0136666 was demonstrated to directly target miR-497, which also regulated PD-L1 by binding to its 3'UTR. Further mechanistic studies identified that hsa_circ_0136666 controlled cell proliferation and apoptosis via targeting miR-497 and regulating PD-L1 expression. Of note, hsa_circ_0136666 stimulated Treg cells mediated by miR-497/PD-L1 axis and its downstream signal pathway in Treg cells. Finally, hsa_circ_0136666 was found to accelerate the tumor growth in vivo. CONCLUSIONS: Our findings demonstrated that hsa_circ_0136666 promoted the expression of PD-L1 by inhibiting miR-497 level in colorectal cancer, thus inducing the activation of Treg cells and leading to the immune escape of tumor, providing a novel mechanistic insight into the pathogenesis of colorectal cancer.

The hepatic microenvironment promotes lung adenocarcinoma cell proliferation, metastasis, and epithelial-mesenchymal transition via METTL3-mediated N6-methyladenosine modification of YAP1.

The inflammatory microenvironment plays an important role in the onset and progression of lung adenocarcinoma (LUAD), and the liver is a suitable site of metastasis for LUAD cells. However, whether the inflammatory microenvironment of the liver is conducive to the proliferation, invasion, and metastasis of LUAD cells remains unclear. In this study, we confirmed that the hepatic inflammatory microenvironment stimulated by IL-6 promoted the proliferation, migration, invasion, and epithelial-mesenchymal transition of LUAD cells, increased the m6A methylation of total RNA, and transcriptionally activated METTL3 expression. Additionally, METTL3 activated the YAP1/TEAD signaling pathway by increasing the m6A modification and expression of YAP1 mRNA. These results indicate that the hepatic inflammatory microenvironment plays a role in regulating the biological functions of LUAD cells. Further, our study identifies a molecular mechanism that may provide a new strategy for the early diagnosis, treatment, and prognosis of liver metastasis in LUAD patients.

GPC5 suppresses lung cancer progression and metastasis via intracellular CTDSP1/AhR/ARNT signaling axis and extracellular exosome secretion.

Lung cancer is the leading cause of cancer-related death worldwide. Glypican-5 (GPC5) is a member of heparan sulfate proteoglycans, and its biological importance in initiation and progression of lung cancer remains controversial. In the present study, we revealed that GPC5 transcriptionally enhanced the expression of CTDSP1 (miR-26b host gene) via AhR-ARNT pathway, and such up-regulation of CTDSP1 intracellularly contributed to the inhibited proliferation of lung cancer cells. Moreover, exosomes derived from GPC5-overexpressing human lung cancer cells (GPC5-OE-derived exosomes) had an extracellular repressive effect on human lymphatic endothelial cells (hLECs), leading to decreased tube formation and migration. Comparison between GPC5-WT- and GPC5-OE-derived exosomes showed that miR-26b (embedded within introns of CTDSP1 gene) was significantly up-regulated in GPC5-OE-derived exosomes and critical to the influence on hLECs. On the mechanism, we demonstrated that miR-26b transferred into hLECs directly targeted to PTK2 3'-UTR and led to PTK2 down-regulation, resulting in defects in tube formation and migration of hLECs. By uncovering the regulation network among GPC5, miR-26b, miR-26b host gene (CTDSP1), and target gene (PTK2), our findings demonstrated that GPC5 functioned as a tumor suppressor in human lung cancer.

Restoration of gefitinib efficacy following chemotherapy in a patient with metastatic non-small cell lung cancer.

BACKGROUND: Gefitinib has shown evidence of antitumor activity in advanced non-small cell lung cancer (NSCLC). CASE REPORT: A female Asian nonsmoker with adenocarcinoma was given gefitinib as first-line treatment with significant efficacy. However, after approximately 1.5 years, progression occurred. She then received chemotherapy (pemetrexed/carboplatin) until progression, followed by treatment with gefitinib to which the patient responded a second time. After progression, treatment with chemotherapy (docetaxel/cisplatin) was instituted and again followed by gefitinib. A recent positron emission tomography/computed tomography (PET/CT) scan showed complete remission under gefitinib. CONCLUSIONS: This case report indicates that resistance to gefitinib in NSCLC can be reversed after chemotherapy. Thus, re-exposure to gefitinib may be justified in selected cases.

A novel mutation in CD40 and its functional characterization.

CD40 is a costimulatory protein expressed on the surface of many different cells. It delivers signals regulating diverse cellular responses, including proliferation, differentiation, growth suppression, and cell death. In this study, we report a novel CD40 mutant (c.234C>A or p.H78Q) that is expressed in the U266 cell line and in freshly isolated tumor cells. Three-dimensional structural model and Scatchard analysis revealed that the mutated residue located in a region is important for binding to CD40L (CD154). Functional analysis indicated that the mutated CD40 was translocated to the CD40 signalosome and involved in CD40 signal transduction. In conclusion, the mutation in CD40 can lead to an alteration of function, including the change of antigen epitope and the binding affinity with CD40L.