Evaluation of efficacy and safety of PARP inhibitors in breast cancer: A systematic review and meta-analysis.

BACKGROUND: Many breast cancer clinical trials with PARPi have been completed or are currently carried out, either by monotherapy or combined with chemotherapy. We aim to assess the efficacy and safety of PARPi in breast cancer patients as compared to chemotherapy. METHODS: A comprehensive literature search of PubMed, EMBASE, CENTRAL, conference meetings and clinical trial registry was performed. The primary outcomes were progression-free survival (PFS), overall survival (OS), overall response rate (ORR). The secondary outcome was safety profile. The comparative effects were measured using hazard ratio (HR) or relative risk (RR) with 95% confidence interval. Subgroup analyses were conducted based on types of intervention and baseline characteristics of patients. RESULTS: Six RCTs (n = 1953) were included. Two RCTs were recognized as high risk. PARPi was associated with an improved PFS (HR, 0.65; 95% CI, 0.56-0.74), OS (HR, 0.86; 95% CI, 0.73-1.01), and a higher ORR (RR, 1.38; 95% CI, 1.05-1.82). PARPi, however, significantly increased risk of grade 3-4 thrombocytopenia (RR, 1.63; 95% CI, 1.06-2.52). Monotherapy was observed with lower risk of disease progression and higher ORR rate than combination therapy, 0.56 to 0.65 and 2.21 to 1.05, respectively. For patients without prior platinum treatment, PARPi significantly improved PFS (HR, 0.64; 95% CI, 0.52-0.79). CONCLUSIONS: PARPi was observed with a significantly improved efficacy in aspects of PFS and ORR, but also higher risk of grade 3-4 thrombocytopenia as compared to chemotherapy. PARPi was a better choice for patients who had not received previous platinum treatment.

Identification of gene expression profiling in hepatocellular carcinoma using cDNA microarrays.

The aim of this study was systematic investigation of the differentially expressed genes during carcinogenesis in hepatocellular carcinoma (HCC) using cDNA microarray technology. The differentially expressed genes between 22 fresh HCC tissues and para-cancerous liver tissues (PCLT) were displayed using cDNA microarray technology. The result was verified by the reverse transcriptase polymerase chain reaction. Among the 8,464 human genes, 507 (5.99%) genes were expressed differentially at the mRNA levels between HCC and PCLT. Two hundred (2.36%) genes were down-regulated, whereas 307 (3.63%) genes were up-regulated. The mRNA expression levels of RhoC and protocadherin LKC detected by reverse transcription polymerase chain reaction (RT-PCR) were consistent with the microarray experiment. This study describes a gene expression profiling of HCC, which provides an extensive list of potential molecular markers for early diagnosis and molecular targets for the development of drugs to treat patients with primary HCC.

Elevated expression of autocrine motility factor receptor correlates with overexpression of RhoC and indicates poor prognosis in hepatocellular carcinoma.

Our previous study identified RhoC as an invasion and metastasis marker in hepatocellular carcinoma patients. Recent document suggested RhoGTPase is required for autocrine motility factor signaling. In this study, we questioned whether there is a correlation between expression of autocrine motility factor receptor and RhoC. Furthermore, we questioned whether elevated expression of autocrine motility factor correlates with metastasis and poor prognosis of HCC. The mRNA expression level of AMFR and RhoC were examined by RT-PCR in 25 cases of HCC and pericarcinomatous liver tissues (PCLT). In addition, the correlation between the expression level of AMFR and clinical pathologic parameters was analyzed. Furthermore, follow-up information was collected to evaluate the prognostic value of AMFR for HCC patients. Our results showed that the expression of AMFR and RhoC significantly increased in HCC compared with PCLT; extrahepatic metastatic lesions expressed significantly higher levels of AMFR and RhoC than corresponding intrahepatic HCC tissues. There is a highly significant correlation of AMFR expression levels with tumor vein invasion, number of tumor nodes, and tumor stage. Anticipatively, positive correlation was observed between mRNA expression of AMFR and RhoC gene. Furthermore, the HCC patients with high-expression of AMFR had significant high recurrence/metastasis and shorter survival than those with low-expression of AMFR. Together, our findings suggested a strong correlation between the expression of AMFR and RhoC and also a correlation between overexpression of them and invasion and metastasis of HCC. Furthermore, our data indicated AMFR as a potential prognosis for HCC.

Role of AFP mRNA expression in peripheral blood as a predictor for postsurgical recurrence of hepatocellular carcinoma: a systematic review and meta-analysis.

AIM: To identify the role of alpha-fetoprotein (AFP) mRNA expression in peripheral blood one week after surgery as a predictor for recurrence of hepatocellular carcinoma (HCC). METHODS: Published studies fulfilling the selection criteria were identified by searching several databases online. After a methodology assessment using a quality scale designed by European Lung Cancer Working Party, data in each research were aggregated by means of meta-analysis. RESULTS: Altogether 368 cases were included in the 9 selected studies, which fulfilled the selection criteria. The quality scores ranged from 35% to 84% with a median score of 55%. The 'design' subscore had the lowest median value (38%). By aggregating the data, a high chi2 value (77.576) was presented. The fail-safe number was 136 and 64 for P = 0.05 and 0.01, respectively. CONCLUSION: AFP mRNA expression in peripheral blood 1 wk after surgery correlated with the recurrence of HCC and was a good predictor for tumor recurrence.

Differentially expressed genes between solitary large hepatocellular carcinoma and nodular hepatocellular carcinoma.

AIM: To study the difference in gene expression between solitary large hepatocellular carcinoma (SLHCC) and nodular hepatocellular carcinoma (NHCC). METHODS: Polymerase chain reaction (PCR) products of 8464 human genes were spotted on a chip in array. DNAs were then fixed on a glass plate. Total RNA was isolated from freshly excised human SLHCC (n = 7) and NHCC (n = 15) tissues, and was reversely transcribed to cDNAs with the incorporation of fluorescent dUTP for preparation of hybridization probes. The mixed probes were then hybridized to the cDNA microarray. After highly stringent washing, cDNA microarray was scanned for the fluorescent signals to display the difference between the two kinds of HCC. In addition, the expression of RhoC and protocadherin LKC was also detected with the reverse transcriptase polymerase chain reaction (RT-PCR) method. RESULTS: Among the 8464 human genes, 668 (7.89%) genes were expressed differentially at the mRNA levels between SLHCC and NHCC. Three hundred and fifty five (4.19%) genes, including protocadherin LKC, were up-regulated, whereas 313 (3.70%) genes, including RhoC, were down-regulated. The mRNA expression levels of RhoC and protocadherin LKC were confirmed by RT-PCR. Analysis of differentially expressed genes confirmed that our molecular data obtained by cDNA microarray were consistent with the published biochemical and clinical observations of SLHCC and NHCC. CONCLUSION: cDNA microarray is an effective technique in screening the difference in gene expression between SLHCC and NHCC. Many of these differentially expressed genes are involved in the invasion and metastasis of HCC. Further analysis of these genes will help to understand the different molecular mechanisms of SLHCC and NHCC.

[Overexpression of the RhoC gene correlates with invasion and metastasis of hepatocellular carcinoma].

OBJECTIVE: Rho, a ras homologous gene, encodes a group of GTP-binding proteins. Our previous study suggested that one member of the Rho gene family, RhoC, was related to the progression of human hepatocellular carcinoma (HCC). This study is to elucidate correlation of Rho overexpression with invasion and metastasis of HCC. METHODS: The expression level of RhoC mRNA and protein in 25 cases of HCC and adjacent non-cancerous liver tissue was examined by RT-PCR and Western blot. Mutation of RhoC gene was examined by PCR-SSCP. RESULTS: The expression of RhoC mRNA and protein was found in all HCC and adjacent non-cancerous liver tissue. The expression level of RhoC mRNA and protein was significantly higher in tumor tissue than in adjacent non-cancerous liver tissue (1.8 +/- 1.1 vs 1.0 +/- 0.7; 33 992 +/- 10 384 vs 17 342 +/- 9998, P < 0.01). The degree of RhoC overexpression was even more marked in metastatic lesions than in primary tumors (P < 0.01). Overexpression of the rhoC gene was significantly correlated with such clinic-pathological findings as cell differentiation, portal vein invasion, number of primary tumor nodules and metastatic lesions (P < 0.05). Mutation of RhoC gene was found in none of the HCC specimens examined. CONCLUSION: Overexpression of RhoC gene may play an important role in carcinogenesis and progression of HCC.