Search

Background: We conducted this meta-analysis to compare the efficacy and safety of PARP inhibitors with or without chemotherapy versus chemotherapy alone for advanced breast cancer. Methods: A meta-analysis and trial sequential analysis were performed using RevMan 5.2 analysis software. Results: Six eligible randomized clinical trials involving 2080 patients were included. Regimens containing PARP inhibitors were significantly associated with higher objective response rate, longer progression-free survival and overall survival. The PARP inhibitor regimen group had a significantly higher rate of grade ≥3 thrombocytopenia than the chemotherapy-only group. Conclusion: Regimens containing PARP inhibitors are effective and safe for BRCA-mutated advanced breast cancer patients. The efficacy appears to be only marginal in patients with BRCA status unselected.

Background: The purpose of this study was to establish a radiomics nomogram based on multiphase contrast-enhanced computed tomography (CT) to demonstrate the outcome of the patients after resection of intrahepatic cholangiocarcinoma (ICC).Methods: A cohort of 96 (7:3 in the training/validation cohort) ICC patients was enrolled in this study. All patients underwent a preoperative enhanced CT examination and then accepted the ICC resection. Radiomic features were extracted from arterial phase (AP) and portal venous phase (PVP) contrast-enhanced CT images. The least absolute shrinkage and selection operator (LASSO) Cox regression was used to select the features. Radiomic features and clinical data were combined to build the nomogram to predict the overall survival (OS). ICC patients were divided into high- and low- risk groups based on their probability of survival. The Kaplan–Meier analysis and the log-rank test were applied to analyze the patients, difference from different risk groups.Results: The C-index of the radiomics and clinical-nomogram for the prediction of OS in ICC patients was 0.869 and 0.632, 0.873 and 0.628 in the training and validation cohorts, respectively. The C-index of the combined nomogram for the prediction of OS in ICC patients was 0.912 and 0.696 in the training and validation cohorts, respectively. The calibration curve indicated that the predicted survival time was close to the actual survival time. Decision curve analysis showed that the combined nomogram has better clinical prediction than clinical or radiomics features alone. For ICC patients after surgical resection, the combined model showed that the low-risk group and high-risk group had a significant statistical difference in both the training cohort (p < 0.001) and the validation cohort (p = 0.01).Conclusion: Based on the application of preoperative enhanced CT radiomics in ICC, this study proposed a new personalized clinical decision nomogram, which can be used to predict the survival state of patients and play a certain role in assisting clinical treatment decision-making.

Mitochondria and lysosomes, as the important subcellular organelles, play vital roles in cell metabolism and physiopathology. However, there is still no general method to precisely regulate the lysosomal and mitochondrial localization behavior of fluorescent probes except by selecting specific targeting groups. Herein, we proposed a pH-induced structure switch (pHISS) strategy to solve this tricky puzzle. For the proof-of-concept, we have rationally designed and synthesized a series of cationic flavylium derivatives FL-1-9 with tunable pH-induced structure switch through adjusting the electron-donating ability of the substituents. As expected, the co-localization imaging experiments revealed that the lysosomal and mitochondrial localization behavior of FL-1-9 dyes is closely related to their pHISS ability. It is noteworthy that FL cationic dyes with strong electron-donors are not prone to pHISS and can be well enriched in mitochondria, while FL cationic dyes with weak electron-donors are highly susceptible to pHISS and display an unusual lysosome-targeting capability. This also provided a feasible strategy for lysosomal localization without basic groups and presented new application options for some flavylium dyes previously thought to be less stable. Furthermore, FL cationic dyes with medium electron-donor exhibit certain localization abilities both in mitochondria and lysosomes. Finally, through a detailed study of pH-induced structure switch and exploiting the pH inertia brought by the strong electron-donors, a novel NIR ratiometric fluorescent probe with large wavelength-shift was constructed for monitoring mitochondrial H

Although platinum-based chemotherapeutics such as cisplatin are the cornerstone of treatment for ovarian cancer, their clinical application is profoundly limited due to chemoresistance and severe adverse effects. Sporoderm-broken spores of

Lay abstract The present meta-analysis was conducted to compare the efficacy and safety of PARP inhibitors with or without chemotherapy versus chemotherapy alone for advanced breast cancer. Six eligible randomized clinical trials involving 2080 patients were included. Regimens containing PARP inhibitors were significantly associated with higher objective response rate, longer progression-free survival and better overall survival, but a higher rate of grade ≥3 thrombocytopenia. Regimens containing PARP inhibitors are effective and safe for patients with advanced breast cancer who have a

// Qi Jiang 1, * , Mixue Xie 2, * , Mengye He 1 , Feifei Yan 1 , Xiaochen Zhang 1 and Sufen Yu 1 1 Department of Medical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310003, China 2 Senior Department of Haematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, 310003, China * These authors contributed equally to this work and share the first authorship Correspondence to: Sufen Yu, email: zdyyysf@163.com Xiaochen Zhang, email: zhangxiaochen74@163.com Keywords: PD-1; PD-L1; immune checkpoint inhibitor; non-small cell lung cancer; meta-analysis Received: June 03, 2017 Accepted: December 13, 2017 Published: December 21, 2017 ABSTRACT Anti- PD-1/PD-L1 antibodies have been proved one of the most promising treatments against non-small-cell lung cancer (NSCLC); however, whether anti-PD-1/PD-L1 antibodies can provide added benefits for pretreated patients with advanced NSCLC and which patients are most likely to benefit from anti-PD-1/PD-L1 therapy remain controversial. This meta-analysis evaluated the efficacy and safety between anti-PD-1/PD-L1 antibodies and docetaxel in previously treated, advanced NSCLC. PubMed, EMBASE and Cochrane library databases were systematically searched for eligible studies. Five studies with a total of 3,025 patients were included. Our results showed that, for all patients, anti-PD-1/PD-L1 therapy prolonged overall survival (OS) (hazard ratio [HR] = 0.69; 95% CI, 0.63–0.75) and progression-free survival (PFS) (HR = 0.87; 95% CI, 0.80–0.94). For patients with PD-L1 expression ≥1%, anti-PD-1/PD-L1 therapy had higher objective response rates. In subgroup analysis according to the tumor PD-L1 expression level, anti-PD-1/PD-L1 therapy was associated with longer OS and PFS in patients with high PD-L1 expression (≥1%, ≥5%, ≥10% and ≥50%), but not in those with low expressions. In subgroup analysis of patients’ characteristics, anti-PD-1/PD-L1 antibodies showed OS benefits across most prespecified subgroups, except for patients with EGFR mutation-positive and never smokers. For patients with EGFR mutation, anti-PD-1/PD-L1 therapy was an unfavorable factor of PFS. The grade 3 or 4 adverse events rates of anti-PD-1/PD-L1 treatment were significantly lower than that of docetaxel. Our results suggest that anti-PD-1/PD-L1 therapy significantly improves survival compared with docetaxel in patients with previously treated, PD-L1-positive, advanced NSCLC, and has a distinct safety profile from chemotherapy.

Aims: Prostate cancer is one of the most common malignancies in men. Biochemical recurrence (BCR) and progression following curative treatment pose a significant public health challenge. Thus, it is essential to explore effective biomarkers for disease progression monitoring and risk stratification. The promoter region of the paired-like homeodomain transcription factor 2 (PITX2) gene has been found to be frequently methylated in prostate cancer. However, the prognostic role of PITX2 methylation in prostate cancer and which patients most likely to be recommended for PITX2 methylation tests to assess BCR risk remain controversial. Therefore, a systematic review was performed to explore the relationship of PITX2 methylation with the BCR risk of prostate cancer. Methods: The PubMed, EMBASE, and Cochrane Library databases were systematically searched for eligible studies. Seven studies with a total of 2185 patients were included. Pooled hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were calculated. Results: The overall HR was 2.71 (95% CI, 2.21–3.31), suggesting that PITX2 methylation has an adverse impact on BCR of prostate cancer. The pooled estimate of 5-year BCR-free survival for patients with a high methylation status was significantly lower than that for patients with a low methylation status (71% vs 90%; odds ratio [OR] = 3.50; 95% CI, 2.67–4.60, P = .000). A subgroup analysis was conducted according to detection method; the combined HRs were 2.68 (95% CI, 2.02–3.55) for quantitative methylation-specific PCR (qMSP) and 3.29 (95% CI, 2.31–4.68) for microarray EpiChip. In subgroups defined by region, Gleason score, pathological stage, surgical margin status and ethnicity, high methylation status was also associated with BCR of prostate cancer. Conclusions: As an effective biomarker, PITX2 methylation is feasible for individualized BCR risk assessment of prostate cancer following radical prostatectomy.

Several clinical trials revealed that estrogen receptor (ER) status had relevance to the response of mammary malignancy to chemotherapy. Autophagy has emerged as an important cellular mechanism of tumor cells in response to anticancer therapy. The aim of this study is to investigate whether gemcitabine induces autophagy, and more importantly, whether such autophagy is functional relevant to the therapeutic effects of gemcitabine in breast cancer cells in relation to the ER status. In our study, autophagy was induced both in ER+ MCF-7 and ER- MDA-MB-231 cells by gemcitabine markedly, while the autophagy plays distinct roles - cytoprotective in ER- MDA-MB-231 and cytotoxic in ER+ MCF-7 cells. Gemcitabine treatment leads to the activation of ERα-ERK-P62 signal pathway in MCF-7 cells which may augment the autophagic degradation, thus results in the excessive activation of autophagy and irreversible autophagic cell death eventually. Inhibition of ERα-ERK-P62 cascades in MCF-7 cells by small interfering RNA or PD98059 impairs the autophagic degradation, and leads to "autophagic switch" - from cytotoxic autophagy to cytoprotection. Moreover, stable overexpression of ERα in the ER- BCap37 breast cancer cell line enhances the gemcitabine-induced autophagy flux and switches the autophagic cytoprotection in ER- BCap37 to cytotoxicity effect in ER+ BCap37 cells. Our study firstly demonstrated that ER status influences gemcitabine efficacy via modulating the autophagy in breast cancer cells.

Background Primary pulmonary enteric adenocarcinoma (PEAC) is an extremely rare variant of invasive lung cancer. It is highly heterogeneous while shares some common morphologic and immunohistochemical features with usual pulmonary adenocarcinoma (PAC) and colorectal adenocarcinoma (CRAC), making the differential diagnosis difficult. At present there are only limited studies about distinctive features of primary PEAC and the results are often inconsistent. Methods We retrospectively analyzed total 129 primary PEACs and 50 CRACs that were published since 1991 or diagnosed in our centre. Among them eight typical samples of primary PEACs and usual PACs were detected by targeted exome sequencing. Results The combination of CK7+/CDX2+ acquires high sensitivity (71.3%) and specificity (82%) in differential diagnosis of PEACs from CRAC. The primary PEACs harbor a high incidence of KRAS mutation but almost absent of EGFR mutation. Moreover, compared with usual PACs, the primary PEACs have higher nonsynonymous tumor mutation burden and more frequent MMR mutation. Conclusions The combination of CK7+/CDX2+ immunostaining and the distinctive genetic signatures, including low incidence of sensitivity genes mutations and high tumor mutation burden, is an important supplementary to the clinical differential diagnosis of primary PEACs. Our findings thus have significant implications for development of individualized treatment strategy in these patients.

In recent years, PET-CT has an increasing importance in the diagnosis and treatment of breast cancer. PET-CT scan can be used as a noninvasive method for molecular subtyping of breast cancer, and prediction of therapeutic effect and prognosis of patients. Studies have revealed that luminal A subtype has a significantly lower maximum standard intake value (SUVmax) than the other subtypes; triple-negative and human epidermal growth factor receptor 2 (HER2) positive tumors have relatively high SUVmax than luminal B subtype, but the specificity and sensitivity of SUVmax in diagnosis of molecular subtypes are very low, so its clinical application is limited. In predicting the effectiveness of the treatment and the prognosis of the patients, the decreased uptake of fluorodeoxyglucose (FDG) is correlated with better therapeutic effect. In addition, patients with high FDG uptake have worse survival outcomes. New tracers, such as

Triple-negative breast cancer (TNBC), which is estrogen receptor (ER)-negative, progesterone receptor‑negative and is also negative for HER2 expression, remains a great clinical challenge due to its strong resistance to chemotherapy at the late stage of treatment and relatively unfavorable prognosis. Gemcitabine has been approved by the FDA/SFDA for use as a first-line therapeutic drug against advanced or metastatic breast cancer. Therefore, the clarification of the mechanisms underlying gemcitabine-acquired resistance is of particular importance for the optimal management of TNBC. A number of studies have revealed that autophagy, which has been found to protect cancer cells from anti-cancer drug-induced death, may contribute to the development of drug resistance. However, the association between autophagy and gemcitabine treatment in TNBC cells has yet to be defined. Our study clearly demonstrates that gemcitabine is able to induce mTOR-independent autophagy in human triple‑negative MDA-MB-231 breast cancer cells. In addition, we demonstrate that autophagy protects MDA-MB-231 cells from gemcitabine-induced cell growth inhibition and apoptosis, indicating that gemcitabine can activate autophagy to impair the sensitivity of MDA-MB‑231 cells. Furthermore, as shown by our results, the inhibition of gemcitabine-induced autophagy by chloroquine shifts the expression of the p53 protein, Bcl-2 family proteins and the relative Bax/Bcl-xL ratio in favor of promoting apoptosis. These results reveal that the inhibition of apoptosis may be one of the mechanisms of autophagy-induced cytoprotection in gemcitabine-treated MDA-MB-231 cells. The apoptotic and autophagic processes constitute a mutual inhibition system and jointly seal the fate of TNBC cells that are exposed to gemcitabine. Thus, our study suggests that the combination of an autophagic inhibitor and gemcitabine as a therapeutic strategy may represent a promising approach with greater clinical efficacy for patients with TNBC. However, extended preclinical trials are required to further determine the positive effects of the inhibition of autophagy on the efficacy of gemcitabine.

Aim Myeloid-derived suppressor cells (MDSC) can be induced or expanded in tumor-bearing mice and cancer patients. The frequency of MDSC denoted here as Lin−/lowCD33+HLA-DR− was investigated in hepatocellular carcinoma (HCC) patients. The clinical relevance of MDSC and patients' characteristics were examined. Also, MDSC-related immune regulatory pathways in these patients were discussed. Methods The quantity of MDSC was tested in peripheral blood of patients with HCC (n = 63) and healthy donors (n = 56). The expressions of interferon (IFN)-γ, vascular endothelial growth factor (VEGF), cyclooxygenase (COX)-2, matrix metalloproteinase (MMP)-13, nitric oxide synthase (NOS)-2 and arginase (ARG)-1 were analyzed. Co-culturing with anti-CD3/CD28-stimulated T lymphocytes was used to determine the suppressive effect of MDSC on the T lymphocytes. Results Patients with treatment-naive HCC had an increased subpopulation of Lin−/lowCD33+HLA-DR− cells in the peripheral blood mononuclear cells (PBMC) with characteristics of MDSC and associated to the stage (P = 0.0004). Patients with splenomegaly had a higher frequency of circulating MDSC. Also, COX-2, MMP-13 and VEGF were expressed differently associated with the alteration of MDSC. Conclusion Our study provides evidence showing an increased population of Lin−/lowCD33+HLA-DR− MDSC in the peripheral blood of HCC patients. Our data also suggest that MMP-13 and COX-2 in PBMC may play a new important role companied with MDSC in HCC patients.

Myeloid-derived suppressor cells (MDSC) can be induced or expanded in tumor-bearing mice and cancer patients. The frequency of MDSC denoted here as Lin(-/low) CD33(+) HLA-DR(-) was investigated in hepatocellular carcinoma (HCC) patients. The clinical relevance of MDSC and patients' characteristics were examined. Also, MDSC-related immune regulatory pathways in these patients were discussed.The quantity of MDSC was tested in peripheral blood of patients with HCC (n = 63) and healthy donors (n = 56). The expressions of interferon (IFN)-γ, vascular endothelial growth factor (VEGF), cyclooxygenase (COX)-2, matrix metalloproteinase (MMP)-13, nitric oxide synthase (NOS)-2 and arginase (ARG)-1 were analyzed. Co-culturing with anti-CD3/CD28-stimulated T lymphocytes was used to determine the suppressive effect of MDSC on the T lymphocytes.Patients with treatment-naive HCC had an increased subpopulation of Lin(-/low) CD33(+) HLA-DR(-) cells in the peripheral blood mononuclear cells (PBMC) with characteristics of MDSC and associated to the stage (P = 0.0004). Patients with splenomegaly had a higher frequency of circulating MDSC. Also, COX-2, MMP-13 and VEGF were expressed differently associated with the alteration of MDSC.Our study provides evidence showing an increased population of Lin(-/low) CD33(+) HLA-DR(-) MDSC in the peripheral blood of HCC patients. Our data also suggest that MMP-13 and COX-2 in PBMC may play a new important role companied with MDSC in HCC patients.

e22094 Background: The immune therapy of human cancer is a promising therapeutic approach. Myeloid-derived suppressor cells (MDSCs) have been confirmed as an indispensable component of immune system and associated with tumor induced immune suppression. Thus, MDSCs play an important role in immune therapy. Although a lot of research work has been done, currently there exists limited data about MDSCs status in cancer patients. The aim of this study was to determine whether MDSCs levels in peripheral blood were different in healthy volunteers, benign breast tumor patients and breast cancer patients, and to investigate the relation between MDSCs and several characteristics in breast cancer patients. Methods: Peripheral blood cells (PBC) were collected from 36 normal healthy volunteers, 52 patients with breast cancer and 62 patients with benign breast tumor. Peripheral blood samples of breast cancer patients were obtained before treatment. Circulating MDSCs (identified as Lin-/Lo HLA-DR-CD33+) were measured by flow cytometry. Statistical methods included two sample t tests and one way ANOVA. Results: The percentage of MDSCs was higher in breast cancer than benign breast tumor patients and healthy volunteers (2.017% vs 1.578% vs1.594%; p=0.0002), and the stage III/IV breast cancer patients had more MDSCs accumulation than those in stage I/II (2.92% vs 2.155%; P=0.0806). The levels of MDSCs in peripheral blood showed a significant correlation with HER-2/neu expression in breast cancer patients, but had no correlation with incidence age, ER status, PR status and P53 expression respectively. The percentage of MDSCs was lower in HER-2/neu over expression breast cancer patients than HER-2/neu negative patients (1.715% vs 2.882%, GP=0.0012). Conclusions: MDSCs seemed to have positive correlation with clinical stage and negative correlation with HER-2/neu expression in breast cancer patients . Further research will contribute to the better understanding of the connection between MDSCs and breast cancer, to develop better approaches to breast cancer therapy.