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Selective TACE with irinotecan-loaded 40 mu m microspheres and FOLFIRI for colorectal liver metastases: phase I dose escalation pharmacokinetic study

期刊: BMC CANCER, 2019; 19 (1)

Background: Efficacy of treatments for colorectal liver metastases after failure of first-line chemotherapy is limited. The aim of this study was to prospectively evaluate the feasibility, tolerability, and pharmacokinetics of selective transarterial chemoembolization (TACE) with irinotecan-loaded 40 mu m microspheres combined with systemic FOLFIRI for colorectal liver metastases refractory to oxaliplatin regimen. Methods: The dose escalation study was conducted in three patient groups with different amounts of irinotecan loaded (50, 75 and 100 mg per mL-microspheres). Selective catheterization was performed to embolize subsegments or segments of located tumors using TACE navigation system. FOLFIRI was administrated 7 days after TACE. Plasma concentration was measured before and time points after administration. Results: Nine patients successfully underwent a total of 22 TACE procedures. Dose-limiting toxicity did not appear at any level. The overall response rate was 55.6%. The median progression free and overall survival were 8.1 and 18.2 months, respectively. The AUC and C-max of plasma SN-38 per 1 mg injected irinotecan dose were significantly higher in irinotecan-loaded microspheres compared with FOLFIRI (P = 0.009 and P < 0.001, respectively). Conclusion: Selective TACE using 40 mu m irinotecan-loaded microspheres combined with systemic FOLFIRI was feasible and safe even when a high dose of irinotecan was loaded. Irinotecan-loaded microspheres resulted in a higher plasma concentration and AUC of SN-38 than treatment with FOLFIRI. Further large scale trials to evaluate the efficacy are mandatory.

JIF:2.93

Comparative effectiveness of primary tumor resection in patients with stage III pancreatic adenocarcinoma

期刊: BMC CANCER, 2019; 19 (1)

Background: Previous studies comparing primary tumor resection (PTR) to palliative treatment for advanced-stage pancreatic ductal adenocarcinoma (PDA) were limited by strong selection bias. We used multiple methods to control for confounding and selection bias to estimate the effect of PTR on survival for late-stage PDA. Methods: Surveillance, Epidemiology, and End Results (SEER) 18 registry database for 2004 through 2014 was retrieved for the present study. A total of 4322 patients with stage III (AJCC, 6th) PDA were included in this study. Propensity score matching (PSM) was performed to eliminate possible bias. In addition, instrumental variable (IV) analysis was utilized to adjust for both measured and unmeasured confounders. Results: A total of 4322 patients with stage III PDA including 552 (12.8%) who underwent PTR, 3770 (87.2%) without PTR, were identified. In the multivariable cohort, a clear prognostic advantage of PTR was observed in overall survival (OS) (P < 0.001) and disease-specific survival (DSS) (P < 0.001) compared to patients after non-surgery therapy. In the PSM cohort, patients in PTR group showed a better OS and DSS (both P values < 0.001) compared to patients in non-surgery group. The survival benefit of PTR for stage III PDA was not observed in the two-stage residual inclusion (2SRI) model. Estimates based on this instrument indicated that patients treated with PTR had similar OS (P = 0.448) and DSS (P = 0.719). In IV analyses stratified by chemotherapy and tumor location, patients undergoing PTR had similar OS and DSS compared to patients in non-surgery group across all subgroups. Conclusions: Survival with PTR did not differ significantly from palliative treatment in marginal patients with stage III pancreatic adenocarcinoma. High-quality randomized trials are needed to validate these results.

JIF:2.93

Sphere-forming culture enriches liver cancer stem cells and reveals Stearoyl-CoA desaturase 1 as a potential therapeutic target

期刊: BMC CANCER, 2019; 19 (1)

Backgrounds: The role of sphere-forming culture in enriching subpopulations with stem-cell properties in hepatocellular carcinoma (HCC) is unclear. The present study investigates its value in enriching cancer stem cells (CSCs) subpopulations and the mechanism by which HCC CSCs are maintained. Methods: HCC cell lines and fresh primary tumor cells were cultured in serum-free and ultra-low attachment conditions to allow formation of HCC spheres. In vitro and in vivo experiments were performed to evaluate CSC characteristics. Expression levels of CSC-related genes were assessed by qRT-PCR and the correlation between sphere formation and clinical characteristics was investigated. Finally, gene expression profiling was performed to explore the molecular mechanism underlying HCC CSC maintenance. Results: We found that both cell lines and primary tumor cells formed spheres. HCC spheres possessed the capacity for self-renewal, proliferation, drug resistance, and contained different subpopulations of CSCs. Of interest, 500 sphere-forming Huh7 cells or 200 primary tumor cells could generate tumors in immunodeficient animals. Sphere formation correlated with size, multiple tumors, satellite lesions, and advanced stage. Further investigation identified that the PPARa-SCD1 axis plays an important role in maintenance of the CSC properties of HCC sphere cells by promoting nuclear accumulation of beta-Catenin. Inhibition of SCD1 interfered with sphere formation, down-regulated expression of CSC-related markers, and reduced beta-Catenin nuclear accumulation. Conclusions: Sphere-forming culture can effectively enrich subpopulations with stem-cell properties, which are maintained through activation of the PPARa-SCD1 axis. Therefore, we suggest that targeting the SCD1-related CSC machinery might provide a novel insight into HCC treatment.

JIF:2.93

Mechanisms of doxorubicin-induced drug resistance and drug resistant tumour growth in a murine breast tumour model

期刊: BMC CANCER, 2019; 19 (1)

Background: Doxorubicin is currently the most effective chemotherapeutic drug used to treat breast cancer. It has, however, been shown that doxorubicin can induce drug resistance resulting in poor patient prognosis and survival. Studies reported that the interaction between signalling pathways can promote drug resistance through the induction of proliferation, cell cycle progression and prevention of apoptosis. The aim of this study was therefore to determine the effects of doxorubicin on apoptosis signalling, autophagy, the mitogen-activated protein kinase (MAPK)- and phosphoinositide 3-kinase (PI3K)/Akt signalling pathway, cell cycle control, and regulators of the epithelial-mesenchymal transition (EMT) process in murine breast cancer tumours. Methods: A tumour-bearing mouse model was established by injecting murine E0771 breast cancer cells, suspended in Hank's Balances Salt Solution and Corning (R) Matrigel (R) Basement Membrane Matrix, into female C57BL/6 mice. Fourty-seven mice were randomly divided into three groups, namely tumour control (received Hank's Balances Salt Solution), low dose doxorubicin (received total of 6 mg/ml doxorubicin) and high dose doxorubicin (received total of 15 mg/ml doxorubicin) groups. A higher tumour growth rate was, however, observed in doxorubicin-treated mice compared to the untreated controls. We therefore compared the expression levels of markers involved in cell death and survival signalling pathways, by means of western blotting and fluorescence-based immunohistochemistry. Results: Doxorubicin failed to induce cell death, by means of apoptosis or autophagy, and cell cycle arrest, indicating the occurrence of drug resistance and uncontrolled proliferation. Activation of the MAPK/ extracellularsignal-regulated kinase (ERK) pathway contributed to the resistance observed in treated mice, while no significant changes were found with the PI3K/Akt pathway and other MAPK pathways. Significant changes were also observed in cell cycle p21 and DNA replication minichromosome maintenance 2 proteins. No significant changes in EMT markers were observed after doxorubicin treatment. Conclusions: Our results suggest that doxorubicin-induced drug resistance and tumour growth can occur through the adaptive role of the MAPK/ERK pathway in an effort to protect tumour cells. Previous studies have shown that the efficacy of doxorubicin can be improved by inhibition of the ERK signalling pathway and thereby treatment failure can be overcome.

JIF:2.93

Valproic acid-induced amphiregulin secretion confers resistance to temozolomide treatment in human glioma cells

期刊: BMC CANCER, 2019; 19 (1)

Background: Glioblastoma multiforme (GBM) is the most severe type of primary brain tumor with a high mortality rate. Although extensive treatments for GBM, including resection, irradiation, chemotherapy and immunotherapy, have been tried, the prognosis is still poor. Temozolomide (TMZ), an alkylating agent, is a front-line chemotherapeutic drug for the clinical treatment of GBM; however, its effects are very limited because of the chemoresistance. Valproic acid (VPA), an antiepileptic agent with histone deacetylase inhibitor activity, has been shown to have synergistic effects with TMZ against GBM. The mechanism of action of VPA on TMZ combination therapy is still unclear. Accumulating evidence has shown that secreted proteins are responsible for the cross talking among cells in the tumor microenvironment, which may play a critical role in the regulation of drug responses. Methods: To understand the effect of VPA on secreted proteins in GBM cells, we first used the antibody array to analyze the cell culture supernatant from WA-treated and untreated GBM cells. The results were further confirmed by lentivirus-mediated knockdown and exogenous recombinant administration. Results: Our results showed that amphiregulin (AR) was highly secreted in WA-treated cells. Knockdown of AR can sensitize GBM cells to TMZ. Furthermore, pretreatment of exogenous recombinant AR significantly increased EGFR activation and conferred resistance to TMZ. To further verify the effect of AR on TMZ resistance, cells pre-treated with AR neutralizing antibody markedly increased sensitivity to TMZ. In addition, we also observed that the expression of AR was positively correlated with the resistance of TMZ in different GBM cell lines. Conclusions: The present study aimed to identify the secreted proteins that contribute to the modulation of drug response. Understanding the full set of secreted proteins present in glial cells might help reveal potential therapeutic opportunities. The results indicated that AR may potentially serve as biomarker and therapeutic approach for chemotherapy regimens in GBM.

JIF:2.93

Screening antiproliferative drug for breast cancer from bisbenzylisoquinoline alkaloid tetrandrine and fangchinoline derivatives by targeting BLM helicase

期刊: BMC CANCER, 2019; 19 (1)

Background: The high expression of BLM (Bloom syndrome) helicase in tumors involves its strong association with cell expansion. Bisbenzylisoquinoline alkaloids own an antitumor property and have developed as candidates for anticancer drugs. This paper aimed to screen potential antiproliferative small molecules from 12 small molecules (the derivatives of bisbenzylisoquinoline alkaloids tetrandrine and fangchinoline) by targeting BLM642-1290 helicase. Then we explore the inhibitory mechanism of those small molecules on proliferation of MDA-MB-435 breast cancer cells. Methods: Fluorescence polarization technique was used to screen small molecules which inhibited the DNA binding and unwinding of BLM642-1290 helicase. The effects of positive small molecules on the ATPase and conformation of BLM642-1290 helicase were studied by the malachite green-phosphate ammonium molybdate colorimetry and ultraviolet spectral scanning, respectively. The effects of positive small molecules on growth of MDA-MB-435 cells were studied by MTT method, colony formation and cell counting method. The mRNA and protein levels of BLM helicase in the MDA-MB-435 cells after positive small molecule treatments were examined by RT-PCR and ELISA, respectively. Results: The compound HJNO (a tetrandrine derivative) was screened out which inhibited the DNA binding, unwinding and ATPase of BLM642-1290 helicase. That HJNO could bind BLM642-1290 helicase to change its conformationcontribute to inhibiting the DNA binding, ATPase and DNA unwinding of BLM642-1290 helicase. In addition, HJNO showed its inhibiting the growth of MDA-MB-435 cells. The values of IC50 after drug treatments for 24 h, 48 h and 72 h were 19.9 mu mol/L, 4.1 mu mol/L and 10.9 mu mol/L, respectively. The mRNA and protein levels of BLM helicase in MDA-MB-435 cells increased after HJNO treatment. Those showed a significant difference (P < 0.05) compared with negative control when the concentrations of HJNO were 5 mu mol/L and 10 mu mol/L, which might contribute to HJNO inhibiting the DNA binding, ATPase and DNA unwinding of BLM helicase. Conclusion: The small molecule HJNO was screened out by targeting BLM642-1290 helicase. And it showed an inhibition on MDA-MB-435 breast cancer cells expansion.

JIF:2.93

Combined quantitation of HMGA2 mRNA, microRNAs, and mitochondrial-DNA content enables the identification and typing of thyroid tumors in fine-needle aspiration smears

期刊: BMC CANCER, 2019; 19 (1)

Background: Analysis of molecular markers in addition to cytological analysis of fine-needle aspiration (FNA) samples is a promising way to improve the preoperative diagnosis of thyroid nodules. Nonetheless, in clinical practice, applications of existing diagnostic solutions based on the detection of somatic mutations or analysis of gene expression are limited by their high cost and difficulties with clinical interpretation. The aim of our work was to develop an algorithm for the differential diagnosis of thyroid nodules on the basis of a small set of molecular markers analyzed by real-time PCR. Methods: A total of 494 preoperative FNA samples of thyroid goiters and tumors from 232 patients with known histological reports were analyzed: goiter, 105 samples (50 patients); follicular adenoma, 101 (48); follicular carcinoma, 43 (28); Hurthle cell carcinoma, 25 (11); papillary carcinoma, 121 (56); follicular variant of papillary carcinoma, 80 (32); and medullary carcinoma, 19 (12). Total nucleic acids extracted from dried FNA smears were analyzed for five somatic point mutations and two translocations typical of thyroid tumors as well as for relative concentrations of HMGA2 mRNA and 13 microRNAs and the ratio of mitochondrial to nuclear DNA by real-time PCR. A decision tree-based algorithm was built to discriminate benign and malignant tumors and to type the thyroid cancer. Leave-p-out cross-validation with five partitions was performed to estimate prediction quality. A comparison of two independent samples by quantitative traits was carried out via the Mann-Whitney U test. Results: A minimum set of markers was selected (levels of HMGA2 mRNA and miR-375, -221, and -146b in combination with the mitochondrial-to-nuclear DNA ratio) and yielded highly accurate discrimination (sensitivity = 0.97; positive predictive value = 0.98) between goiters with benign tumors and malignant tumors and accurate typing of papillary, medullary, and Hurthle cell carcinomas. The results support an alternative classification of follicular tumors, which differs from the histological one. Conclusions: The study shows the feasibility of the preoperative differential diagnosis of thyroid nodules using a panel of several molecular markers by a simple PCR-based method. Combining markers of different types increases the accuracy of classification.

JIF:2.93

Predictive factors of disease-free survival after complete pathological response to neoadjuvant radiotherapy for rectal adenocarcinoma: retrospective case series

期刊: BMC CANCER, 2019; 19 (1)

Background: Many data suggest that patients with low rectal adenocarcinoma who achieved ypT0N0 status have improved survival and disease-free survival (DFS) compared to all other stages however only few data are available regarding the specific prognosis factors of this subgroup. This study aimed to evaluate predictive factors for disease free survival after complete pathological response (CPR) in cases of low rectal adenocarcinoma. Materials and methods: From January 2005 to December 2013, all patients with low rectal adenocarcinoma who underwent neoadjuvant chemoradiotherapy followed by total mesorectal excision and achieved CPR were included at 7 Moroccan and 1 Algerian centres. Predictive factors for disease-free survival were analysed by uni and multivariate analysis. Results: Eigthy-four (12.1%) patients achieved a CPR (ypT0N0). Multivariate analysis revealed that both poorly differentiated tumors (OR, 9.23; 95 CI 1.35-62.82; P = 0.023) and the occurrence of perineal sepsis (OR, 13.51; 95 CI 1.96-93.12; P = 0.008) were independently associated with impaired DFS. Conclusions: Patients with low rectal cancer who exhibited a CPR after neoadjuvant therapy have good prognoses; however, the occurrence of perineal sepsis and/or poor initial differentiation may be associated with impaired DFS in these patients.

JIF:2.93

SUPR-3D: A randomized phase iii trial comparing simple unplanned palliative radiotherapy versus 3d conformal radiotherapy for patients with bone metastases: study protocol

期刊: BMC CANCER, 2019; 19 (1)

Background: Bone metastases in the lower spine and pelvis are effectively palliated with radiotherapy (RT), though this can come with side effects such as radiation induced nausea and vomiting (RINV). We hypothesize that high rates of RINV occur in part because of the widespread use of inexpensive simple unplanned palliative radiotherapy (SUPR), over more complex and resource intensive 3D conformal RT, such as volumetric modulated arc therapy (VMAT). Methods: This is a randomized, multi-centre phase III trial of SUPR versus VMAT. We will accrue 250 patients to assess the difference in patient-reported RINV. This study is powered to detect a difference in quality of life between patients treated with VMAT vs. SUPR. Discussion: This trial will determine if VMAT reduces early toxicity compared to SUPR and may provide justification for this more resource-intensive and costly form of RT.

JIF:2.93

Comprehensive transcriptomic analyses of tissue, serum, and serum exosomes from hepatocellular carcinoma patients

期刊: BMC CANCER, 2019; 19 (1)

Background: The expression of microRNAs (miRNAs) is a promising prognostic and diagnostic tool in hepatocellular carcinoma (HCC). Here we performed small RNA sequencing (sRNA-seq) of tissue, serum and serum exosomes to investigate changes in miRNA expression between the different sample types and correlated the expression with clinical parameters. We also performed gene expression arrays on tumor and normal tissue. Results: Paired tissue, serum and serum exosomes sequencing revealed consistent positive correlation of miR-21 between serum exosomes and tumor tissue, indicating that miR-21 could be exported from tissue to circulation via exosomes. We found that let-7 miRNAs are generally upregulated in serum exosomes compared to whole serum, indicating that these miRNAs could be preferentially loaded into exosomes. Comparing serum from HCC patients with serum from healthy individuals revealed a global increase of miRNAs in serum from HCC patients, including an almost 4-fold increase of several miRNAs, including the liver-specific miR-122. When correlating miRNA expression with clinical parameters we detected significant association between hepatitis B virus (HBV) infection and miR-122 in serum as well as several serum and tissue-miRNAs that correlated with surgery type. We found that miR-141 and miR-146 correlated with cirrhosis in tumor tissue and normal tissue, respectively. Finally, high expression of miR-21 in tumors were associated with poor survival. Focusing on gene expression we found several significant messenger RNAs (mRNAs) between tumor and normal tissue and a Gene Ontology (GO) analysis revealed that these changes were mainly related to cell cycle and metabolism. Further, we detected mRNAs that correlated with cirrhosis and HBV infection in tissue. Finally, GO analysis of predicted targets for miRNAs down-regulated in tumor found that these were enriched for functions related to collagen synthesis. Conclusions: Our combined data point to altered miRNA and mRNA expression contributing to both generally impaired lipid metabolism and increased cell proliferation and a miRNA-driven increase in collagen synthesis in HCC. Our results further indicate a correlation in miRNA expression between exosomes, serum, and tissue samples suggesting export from tumors via exosomes. This correlation could provide a basis for a more tumor-specific miRNA profile in serum.

JIF:2.93

Flemish breast cancer screening programme: 15 years of key performance indicators (2002-2016)

期刊: BMC CANCER, 2019; 19 (1)

Background: We examined 15 years of key performance indicators (KPIs) of the population-based mammography screening programme (PMSP) in Flanders, Belgium. Methods: Individual screening data were linked to the national cancer registry to obtain oncological follow-up. We benchmarked crude KPI results against KPI-targets set by the European guidelines and KPI results of other national screening programmes. Temporal trends were examined by plotting age-standardised KPIs against the year of screening and estimating the Average Annual Percentage Change (AAPC). Results: PMSP coverage increased significantly over the period of 15 years (+ 7.5% AAPC), but the increase fell to + 1.6% after invitation coverage was maximised. In 2016, PMSP coverage was at 50.0% and opportunistic coverage was at 14.1%, resulting in a total coverage by screening of 64.2%. The response to the invitations was 49.8% in 2016, without a trend. Recall rate decreased significantly (AAPC -1.5% & -5.0% in initial and subsequent regular screenings respectively) while cancer detection remained stable (AAPC 0.0%). The result was an increased positive predictive value (AAPC + 3.8%). Overall programme sensitivity was stable and was at 65.1% in 2014. In initial screens of 2015, the proportion of DCIS, tumours stage II+, and node negative invasive cancers was 18.2, 31.2, and 61.6% respectively. In subsequent regular screens of 2015, those proportions were 14.0, 24.8, and 65.4% respectively. Trends were not significant. Conclusion: Besides a suboptimal attendance rate, most KPIs in the Flemish PMSP meet EU benchmark targets. Nonetheless, there are several priorities for further investigation such as a critical evaluation of strategies to increase screening participation, organising a biennial radiological review of interval cancers, analysing the effect that preceding opportunistic screening has on the KPI for initial screenings, and efforts to estimate the impact on breast cancer mortality.

JIF:2.93

Severe colitis after PD-1 blockade with nivolumab in advanced melanoma patients: potential role of Th1-dominant immune response in immune-related adverse events: two case reports

期刊: BMC CANCER, 2019; 19 (1)

Background: Nivolumab is an immune checkpoint inhibitor specific to the programmed death 1 (PD-1) receptor. Nivolumab has shown clinical responses in many malignancies. Although immune-related adverse events (irAEs) associated with nivolumab are largely tolerable, severe irAEs have occurred in some patients. However, the mechanisms underlying the development of irAEs are not fully clarified. Case presentation: We report 2 patients with metastatic melanoma who developed colitis, an irAEs caused by nivolumab. Both patients experienced colitis after nivolumab administration. Pathological examination of the colon showed robust infiltration of CD8(+) cells and T-bet expressing CD4(+) cells in both cases, indicating helper T cells (Th) 1 to be responsible for the dominant response. Additionally, we observed the serum C-reactive protein level (CRP) as well as interleukin-6 (IL-6) reflected the clinical course of irAEs clearly in the two cases. Conclusion: Our two cases suggested that the development of irAEs due to nivolumab is associated with Th1 dominant response. CRP as well as IL-6 was found to be a potential biomarker for irAEs. Our findings may help to understand the mechanisms underlying irAEs caused by nivolumab and manage irAEs in clinical practice.

JIF:2.93

The release of tryptase from mast cells promote tumor cell metastasis via exosomes

期刊: BMC CANCER, 2019; 19 (1)

Background: Cancer cells release exosomes and can be taken up by mast cells (MCs), but the potential functional effects of MCs on tumor metastasis remain unknown. Method: Exosomes were isolated from the lung adenocarcinoma cell line A549, and the uptake of PKH26-labeled exosomes by bone marrow MCs was examined via flow cytometry and fluorescence microscopy. Cytokines and tryptase in MC supernatant were analyzed using an ELISA kit, and the presence of tryptase was evaluated by Western blotting. Cell proliferation and migration were determined through CCK-8 and transwell assays. Proteins in the tryptase-JAK-STAT signaling pathway were detected by Western blotting. Results: In this study, we show that exosomes from A549 cells can be taken up by MCs. Moreover, A549 exosomes contain stem cell factor (SCF) to MCs and subsequently induce the activation of MCs through SCF-KIT signal transduction, which leads to MC degranulation and the release of tryptase. Tryptase accelerates the proliferation and migration of human umbilical vein endothelial cells (HUVECs) through the JAK-STAT signaling pathway. Conclusions: Our results reveal a mechanism for metastasis in which exosomes can transfer SCF to and activate MCs, which can affect the release of tryptase and the angiogenesis of HUVECs.

JIF:2.93

Metachronous ovarian endometrioid carcinomas in a patient with a PTEN variant: case report of incidentally detected Cowden syndrome

期刊: BMC CANCER, 2019; 19 (1)

Background: Somatic PTEN mutation occurs in a proportion of ovarian endometrioid carcinomas. However, these cancers have seldom been reported in diseases associated with germline PTEN variants, such as Cowden syndrome (CS). Case presentation: The present case was a 39-year-old woman with a left ovarian carcinoma who demonstrated a germline splice variant of PTEN (c.1026 + 1G > T) following genome-wide whole exome sequencing of her germline DNA. Histology of her resected tumor revealed endometrioid carcinoma of the same type as a right ovarian cancer resected eight years previously. These tumors showed null immunostaining for PTEN. She was genetically diagnosed with CS. Despite her clinical examinations had demonstrated several characteristic findings of CS, including mammary fibroma, esophageal and skin papilloma, colonic hamartoma, uterine myoma, and lipoma, the clinicians could not approach this diagnosis. Conclusion: Ovarian endometrioid carcinoma is generally thought to develop from endometrial tissue menstruated from the uterus and implanted on the ovary. To date, ovarian cancers have not been listed as CS-related cancers; however, ovarian endometrioid cancer can have a potential association with CS in endometriosis cases.

JIF:2.93

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