Survival analysis of platinum‐refractory patients with advanced esophageal cancer treated with docetaxel or best supportive care alone: a retrospective study

The survival benefit of second‐line chemotherapy with docetaxel in platinum‐refractory patients with advanced esophageal cancer (AEC) remains unclear. A retrospective analysis of AEC patients with Eastern Cooperative Oncology Group performance status (PS) ≤ 2 was performed, and major organ functions were preserved, who determined to receive docetaxel or best supportive care (BSC) alone after failure of platinum‐based chemotherapy. The post‐progression survival (PPS), defined as survival time after disease progression following platinum‐based chemotherapy, was analyzed by multivariate Cox regression analysis using factors identified as significant in univariate analysis of various 20 characteristics (age, sex, PS, primary tumor location, etc) including Glasgow prognostic score (GPS), which is a well‐known prognostic factor in many malignant tumors. Sixty‐six and 45 patients were determined to receive docetaxel and BSC between January 2007 and December 2011, respectively. The median PPS was 5.4 months (95% confidence interval [CI] 4.8–6.0) in the docetaxel group and 3.3 months (95% CI 2.5–4.0) in the BSC group (hazard ratio [HR] 0.56, 95% CI 0.38–0.84, P = 0.005). Univariate analysis revealed six significant factors: treatment, PS, GPS, number of metastatic organs, liver metastasis, and bone metastasis. Multivariate analysis including these significant factors revealed three independent prognostic factors: docetaxel treatment (HR 0.62, 95% CI 0.39–0.99, P = 0.043), better GPS (HR 0.61, 95% CI 0.46–0.81, P = 0.001), and no bone metastasis (HR 0.31, 95% CI 0.15–0.68, P = 0.003). There was a trend for PPS in favor of the docetaxel group compared with patients who refused docetaxel treatment in the BSC group (adjusted HR 0.61, 95% CI 0.29–1.29, P = 0.20). Docetaxel treatment may have prolonged survival in platinum‐refractory patients with AEC.     

Genome‐wide profiling in melatonin‐exposed human breast cancer cell lines identifies differentially methylated genes involved in the anticancer effect of melatonin

Epigenetic alterations have emerged as an important mechanism involved in tumorigenesis. The epigenetic impact of DNA methylation in various types of human cancer is not completely understood. Previously, we observed melatonin‐induced differential expression of miRNA and miRNA‐related genes in human breast cancer cell lines that indicated an anticancer effect of melatonin. In this report, we further characterized epigenetic changes in melatonin‐exposed MCF‐7 cells through the analysis of DNA methylation profiles in breast cancer cells to provide new insights into the potential mechanisms of the anticancer effect of melatonin. Microarray‐based DNA methylation and gene expression profiling were carried out using human breast cancer cell lines. We further identified a number of mRNAs whose expression levels show an inverse correlation with DNA methylation levels. The mRNA expression levels and methylation status of candidate genes in melatonin‐exposed cells were confirmed by real‐time quantitative PCR and bisulfite PCR. This approach led to the detection of cancer‐related genes, which were oncogenic genes, including EGR3 and POU4F2/Brn‐3b were down‐regulated, while the tumor suppressor gene, GPC3, was up‐regulated by 1 nm melatonin‐treated MCF‐7 cells. Our results provide detailed insights into the DNA methylation patterns induced by melatonin and suggest a potential mechanism of the anticancer effect of aberrant DNA methylation in melatonin‐treated breast cancer cells.     

Effect of molecular targeted agents in chemotherapy for treating platinum-resistant recurrent ovarian cancer: A systematic review and meta-analysis

This study aimed to investigate the effect of molecular targeted agents (MTAs) in chemo on platinum-resistant recurrent ovarian cancer (ROC). We performed this meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statements. Randomized controlled trials reporting data about platinum-resistant ovarian cancer treated by MTAs were included. The endpoints for the present study included overall survival and progression-free survival. We analyzed 9 randomized controlled trials including 3631 patients with ROC. The pooled analysis indicated that a combination of MTAs with chemo could markedly increase objective response rate in those patients (P = .012). Nevertheless, the survival rate of those patients was not markedly changed (P = .19). Besides, the combination of MTAs with chemo dramatically aggravated the occurrence of adverse events (P < .05). Moreover, it resulted in the termination of treatment (P = .044) in those patients, but it had no effect on fatal adverse events (P = .16). Our results indicated that the combination of MTAs with chemo notably improved objective response rate in patients with platinum-resistant ROC, but its benefit did not translate into survival benefits.     

Cytocidal action of anticancer antigens: evaluation of the sensitivity of cultured animal and human cancer cells.

The cultured cell lines Yoshida ascites sarcoma, L-1210 mouse leukemia, OAT cell line derived from human lung cancer of the oat cell type, and P3HR-1 cell line derived from Burkitt's lymphoma have been used for the cell-killing kinetics study of anticancer agents and evaluation of the sensitivity of cells using the soft agar cloning assay method. It has been found that there are 2 types of actions: 1) Type I (cytocidal and concentration-dependent action). The dose survival curves of Type I agents fit the equation log S=log nminuskD (S, surviving fraction; D, concentration of agents; n and k are constant). The sensitivity of cells can be expressed by mean lethal dose 90% (MLD90=1/k). Four cell lines were compared on this basis, and some problems concerning the chemotherapy of human cancer are discussed. Alkylating agents and anticancer antibiotics belonged to this group.2) Type II (cytostatic and time-dependent action). The dose survival curves fit the Gompertz equation S=exp[(minusbeta/alpha)(1minus e-aD)] (beta, population reduction parameter; alpha, constant). The exposure survival curve is negative exponential, indicating that exposure time rather than concentration is the key fo effective cell killing of Type II agents. Difficulties in expression of sensitivity to Type II agents are discussed. Antimetabolites, Vinca alkaloids, and L-asparaginase belonged to this group. The cell-killing kinetics of anticancer agents and comparison of the sensitivity of cells may provide some indications not only of optimal dosage schedules but also of a new approach in screening systems for truly effective agents for human cancer.     

Ultrasound-guided intertumoral injection of contrast agents combined with human p53 gene for the treatment of breast cancer

The objective of this study was to investigate the effects of ultrasound-guided injection of ultrasound contrast agents (UCAs) and the p53 gene on the treatment of rats with breast cancer (BC). Assembly of the p53 expression vector as well as that of a rat model with BC consisted of 200 successfully modeled rats randomly divided into 5 groups: p53 gene introduction, p53 gene introduction + ultrasound irradiation, p53 gene introduction + UCAs, p53 gene introduction + UCA + ultrasound irradiation, and UCA + ultrasound irradiation groups. Expression of p53 was detected via quantitative real-time polymerase chain reaction (qRT-PCR), western blotting and immunohistochemical staining. In the p53 gene introduction + ultrasound irradiation group, we observed increased tumor volume with blood flow signals around and necrotic tumor tissues with an inhibition rate of 36.30%, as well as higher expression of p53 than that in the p53 gene introduction group and p53 gene introduction + UCA group. In the p53 gene introduction + UCA + ultrasound irradiation group, tumor volume increased slightly with reduced blood flow signals and massive degenerative necrosis of tumor cells was identified with inhibition rate of 62.62%, and expression of p53 was higher than that in the rest groups. Taken together, the key findings obtained from the present study elucidate that injection of p53 gene and UCA microbubbles guided by ultrasound could increase the expression of p53, thus inhibiting the tumor growth in rats with BC.     

Initial failure of angiography to demonstrate a bleeding pancreatic cancer: a case for provocative agents

BackgroundMesenteric angiography is commonly employed in the modern-day investigation of gastro-intestinal bleeding if the bleeding sites cannot be identified by endoscopic means. Angiography is optimally sensitive in the presence of active bleeding. However, vasospasm may occasionally account for a negative study shortly after bleeding.Case outlineA 70-year-old lady with inoperable carcinoma of the pancreas presented with gastro-intestinal bleeding. Although upper endoscopy visualised active bleeding from the tumour, which had invaded into the duodenum, haemostasis could not be achieved endoscopically. Therefore, mesenteric angiography was arranged.ResultsThe initial angiography failed to demonstrate the bleeding site, which only became obvious on a repeat study, when embolisation was performed to achieve haemostasis.DiscussionVasospasm probably accounted for the initial negative study, as the second angiography was able to demonstrate contrast extravasation without the use of any anticoagulant or thrombolytic agent. It is not our routine to give pharmacological agents to provoke bleeding after a negative angiography, but for selected patients this manoeuvre may turn out to be more cost-effective.     

Combinations of interferon with platinum complexes: synergistic and antagonistic effects on growth inhibition of MCF-7 and MDA-MB231 breast cancer cells

The growth-inhibitory effects of combining interferons (IFN) with platinum(II) complexes were tested with the aim of comparing these in cultures of estrogen-receptor(ER)-negative MDA-MB₂₃₁ and ER-positive MCF-7 breast cancer cell lines. Another aim was to test whether IFN as a biological response modifier could enhance the effect of the Pt complexes in vitro in an attempt to find an explanation for their more potent antitumor effects in in vivo models. Here it is shown that in both cell lines the combinations of different IFN with all three Pt complexes generally resulted in additive growth inhibition, as calculated by the product of the fraction of surviving cells obtained with each compound alone. Moreover, in MCF-7 cells natural IFN (nIFN) combined with aqua[meso-1,2-bis-(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]sulfatoplatinum(II) (meso-6-Pt) resulted in synergistic inhibition. This synergy could be attributed to the estrogenic property of meso-6-Pt, since the ligand and estradiol also enhanced the inhibitory effect of nIFN. In contrast, the combination of recombinant IFN and meso-6-Pt was antagonistic in MDA-MB₂₃₁ cells. These results show that, in spite of the similar responses of the ER-negative and ER-positive cells to each compound alone, these cells show unexpected differences in their sensitivity to combinations of IFN and the new Pt complex meso-6-Pt.Abbreviations ER estrogen receptor - IFN interferon(s) - nIFN natural interferon - rIFN recombinant interferon - meso-4-Pt aqua[meso-1,2-bis(2,6-difluoro-3-hydroxyphenyl)ethylenediamine]sulfatoplatinum(II) - meso-6-Pt aqua[meso-1,2-bis-(2,6-dichloro-4-hydroxyphenyl) ethylenediamine]sulfatoplatinum(II)     

Generation and regulation of human CD4+ IL-17-producing T cells in ovarian cancer

Despite the important role of Th17 cells in the pathogenesis of many autoimmune diseases, their prevalence and the mechanisms by which they are generated and regulated in cancer remain unclear. Here, we report the presence of a high percentage of CD4⁺ Th17 cells at sites of ovarian cancer, compared with a low percentage of Th17 cells in peripheral blood mononuclear cells from healthy donors and cancer patients. Analysis of cytokine production profiles revealed that ovarian tumor cells, tumor-derived fibroblasts, and antigen-presenting cells (APCs) secreted several key cytokines including IL-1β, IL-6, TNF-α and TGF-β, which formed a cytokine milieu that regulated and expanded human IL-17-producing T-helper (Th17) cells. We further show that IL-1β was critically required for the differentiation and expansion of human Th17 cells, whereas IL-6 and IL-23 may also play a role in the expansion of memory Th17 cells, even though IL-23 levels are low or undetectable in ovarian cancer. Further experiments demonstrated that coculture of naïve or memory CD4⁺ T cells with tumor cells, APCs, or both could generate high percentages of Th17 cells. Treatment with anti-IL-1 alone or a combination of anti-IL-1 and anti-IL-6 reduced the ability of tumor cells to expand memory Th17 cells. Thus, we have identified a set of key cytokines secreted by ovarian tumor cells and tumor-associated APCs that favor the generation and expansion of human Th17 cells. These findings should accelerate efforts to define the function of this important subset of CD4⁺ T cells in the human immune response to cancer.     

Calcium ionophore: a single reagent for the differentiation of primary human acute myelogenous leukaemia cells towards dendritic cells

Blood monocytes and CD34(+) haemopoietic progenitor cells, as well as certain leukaemic cell lines, acquire characteristics of mature dendritic cells (DC) after stimulation with calcium ionophore (CI). We studied whether the in vitro treatment of primary human acute myelogenous leukaemia (AML) cells with CI leads to differentiation towards DC. Blast cells derived from nine AML patients were cultured in the presence of either CI or an established differentiation cocktail consisting of granulocyte-macrophage colony-stimulating factor plus interleukin 4 and tumour necrosis factor-alpha for 5-7 d. Microscopic examination revealed that under both conditions, AML cells were shifted along the DC pathway. In seven out of nine cases, CI-cultivation led to a higher proportion of cells with dendritic morphology. The percentage of CD40 and CD86 expressing cells was significantly increased upon CI treatment compared with cytokine-cultured cells. DC molecules as CD80 and CD83 were up-regulated upon calcium mobilization of AML cells in four out of nine samples. In four cases, CI-treated stimulator cells induced an enhanced proliferative allogeneic T-cell response compared with cytokine-treated stimulator cells. In conclusion, these data demonstrate that CI treatment is an alternative in vitro strategy to differentiate human AML cells into DC.     

Effects of lymphokine-activated killer cells and interleukin-2 on the ascites formation and the survival time of nude mice bearing human ovarian cancer cells

Summary The effect of intraperitoneal instillations of interleukin-2 (IL-2) and/or lympokine-activated killer (LAK) cells on the ascites formation and the survival time was examined using nude mice as a model, with malignant ascites produced by intraperitoneal inoculation of human ovarian cancer cells derived from ascites of a patient with serous cystadenocarcinoma of the ovary. Twenty-eight days after tumor inoculation, all nude mice in the untreated group and in the group treated with spleen cells alone formed ascites. Two of ten nude mice treated with IL-2 alone after tumor inoculation survived without forming ascites during the experimental period. On the other hand, all nude mice treated with LAK cells alone had formed ascites 14 days after tumor inoculation. When LAK cells and IL-2 were combined, five of ten mice survived without forming ascites during the experimental period. The survival time of the group treated with IL-2 alone was significantly prolonged compared to the groups that received medium alone, spleen cells alone and LAK cells alone. When administration of LAK cells was followed by IL-2, the survival time was further prolonged.Supported in part by a grant from the Special Scientific Research Program of the Defense Agency in Japan Offprini requests to: Y. Kikuchi     

Clinical impact of pretreatment albumin–globulin ratio in patients with colorectal cancer: A meta-analysis

Background:Accumulating evidence have revealed that pretreatment albumin to globulin ratio (AGR) may be a predictor of prognosis among patients with colorectal cancer (CRC). However, these findings are inconsistent. The aim of the present study was to investigate the prognostic value of pretreatment AGR in CRC.Methods:A systematic meta-analysis was conducted by searching MEDLINE, EMBASE, and Cochrane Library databases.Results:A total of 9 studies with 7939 patients were finally included. Low pretreatment AGR was associated with worse overall survival (pooled hazard ratio [HR]: 2.07, 95% CI: 1.60–2.67, P < .001) and disease-free survival/progress-free survival (pooled hazard ratio [HR]: 2.10, 95% confidence interval [CI]: 1.34–3.31, P = .001). Subgroup analyses revealed that the pooled correlation did not alter these results. Moreover, low pretreatment AGR were associated with elderly patients, tumor diameter (≥50 mm), tumor node metastasis stage (III–IV), depth of tumor (T3–4), and CA19-9 (>37 U/mL).Conclusion:The present meta-analysis suggests that low pretreatment AGR was associated with advanced clinicopathological features and worse prognosis, suggesting AGR is a useful prognostic biomarker for CRC patients.     

LncRNA NEAT1 promotes proliferation of ovarian cancer cells and angiogenesis of co-incubated human umbilical vein endothelial cells by regulating FGF9 through sponging miR-365: An experimental study

Objective:To uncover the function of lncRNA NEAT1 in ovarian cancer (OC) cells and its mechanism.Methods:The expression patterns of lncRNA NEAT1 and FGF9 in human OC cells and human ovarian epithelial cells was determined. OC cells were transfected with sh-NEAT1, pcDNA3.1-NEAT1, miR-365 mimic, miR-365 inhibitor or pcDNA3.1-NEAT1 + sh-NEAT1 before cell proliferation rate and cell clone formation rate were measured. After the transfected OC cells were co-cultivated with human umbilical vein endothelial cells (HUVECs), Matrigel angiogenesis assay tested angiogenesis of HUVECs; qRT-PCR and Western blot tested the expressions of vascular endothelial growth factor (VEGF), angiogenin 1 (Ang-1) and matrix metalloproteinase 2 (MMP2). Dual-luciferase reporter assay determined the targeted binding of NEAT1 and FGF9 to miR-365.Results:LncRNA NEAT1 and FGF9 are over-expressed in OC cells. Knockdown of NEAT1 or FGF9, or over-expression of miR-365 results in decreased proliferation rate and cell clones as well as inhibited angiogenesis and down-regulated expressions of VEGF, Ang-1 and MMP2. Over-expression of NEAT1 or knockdown of miR-365 can reverse the effect caused by FGF9 knockdown. NEAT1 can down-regulate the expression of miR-365 while up-regulating that of FGF9. Dual-luciferase reporter assay determined that NEAT1 competes with FGF9 for binding to miR-365.Conclusion:LncRNA NEAT1 up-regulates FGF9 by sponging miR-365, thus promoting OC cell proliferation and angiogenesis of HUVECs.     

The Role of Phylogenetics in Unravelling Patterns of HIV Transmission towards Epidemic Control: The Quebec Experience (2002–2020)

Phylogenetics has been advanced as a structural framework to infer evolving trends in the regional spread of HIV-1 and guide public health interventions. In Quebec, molecular network analyses tracked HIV transmission dynamics from 2002–2020 using MEGA10-Neighbour-joining, HIV-TRACE, and MicrobeTrace methodologies. Phylogenetics revealed three patterns of viral spread among Men having Sex with Men (MSM, n = 5024) and heterosexuals (HET, n = 1345) harbouring subtype B epidemics as well as B and non-B subtype epidemics (n = 1848) introduced through migration. Notably, half of new subtype B infections amongst MSM and HET segregating as solitary transmissions or small cluster networks (2–5 members) declined by 70% from 2006–2020, concomitant to advances in treatment-as-prevention. Nonetheless, subtype B epidemic control amongst MSM was thwarted by the ongoing genesis and expansion of super-spreader large cluster variants leading to micro-epidemics, averaging 49 members/cluster at the end of 2020. The growth of large clusters was related to forward transmission cascades of untreated early-stage infections, younger at-risk populations, more transmissible/replicative-competent strains, and changing demographics. Subtype B and non-B subtype infections introduced through recent migration now surpass the domestic epidemic amongst MSM. Phylodynamics can assist in predicting and responding to active, recurrent, and newly emergent large cluster networks, as well as the cryptic spread of HIV introduced through migration.     

Synergistic growth inhibitory effects of Phyllanthus emblica and Terminalia bellerica extracts with conventional cytotoxic agents：Doxorubicin and cisplatin against human hepatocellular carcinoma and lung cancer cells

AIM： To examine the growth inhibitory effects of Phyllanthus emblica （P. emblica） and Terminalia bellerica （T. bellerica） extracts on human hepatocellular carcinoma （HepG2）, and lung carcinoma （A549） cells and their synergistic effect with doxorubicin or cisplatin. METHODS： HepG2 and A549 cells were treated with P. emblica and T. bellerica extracts either alone or in combination with doxorubicin or cisplatin and effects on cell growth were determined using the sulforhodamine B （SRB） assay. The isobologram and combination index （CI） method of Chou-Talalay were used to evaluate interactions between plant extracts and drugs. RESULTS： P. emblica and T. bellerica extracts demonstrated growth inhibitory activity, with a certain degree of selectivity against the two cancer cell lines tested. Synergistic effects （CI 〈 1） for P. emblica /doxorubicin or cisplatin at different dose levels were demonstrated in A549 and HepG2 cells. The T. bellerica/ cisplatin or doxorubicin also showed synergistic effects in A549 and HepG2 cells. In some instances, the combinations resulted in antagonistic effects. The dose reduction level was different and specific to each combination and cell line. CONCLUSION： The growth inhibitory activity of doxorubicin or cisplatin, as a single agent, may be modified by combinations of P. emblica or T. bellerica extracts and be synergistically enhanced in some cases. Depending on the combination ratio, the doses for each drug for a given degree of effect in the combination may be reduced. The mechanisms involved in this interaction between chemotherapeutic drugs and plant extracts remain unclear and should be further evaluated.