Zhi-Rui Zhou

Short-course preoperative radiotherapy with immediate surgery versus long-course chemoradiation with delayed surgery in the treatment of rectal cancer: A systematic review and meta-analysis

BACKGROUNDnLong-course chemoradiotherapy (LCRT) with delayed surgery or short-course radiotherapy (SCRT) with immediate surgery is probably the most frequent regimen in the treatment of rectal cancer. Debate is still going on whether SCRT or LCRT is more effective. So we performed this meta-analysis to evaluate the safety and efficacy of SCRT with immediate surgery versus LCRT with delayed surgery for the management of rectal cancer.nnnMETHODSnLiterature were searched from PubMed, Embase, Web of science, Cochrane Library up to May, 2014. Quality of the randomized controlled trials (RCTs) was evaluated according to the Cochranes risk of bias tool of RCT. RevMan 5.3 was used for statistical analysis. Pooled risk ratio (RR) and 95% confidence interval (CI) were calculated. Subgroup analysis and sensitivity analysis were employed to explore heterogeneity.nnnRESULTSn16 trials were included in the qualitative systematic review. 12 trials were included in meta-analyses. 4 of them were RCTs; other 8 were non-RCTs. Meta-analysis demonstrated that there were no significant differences in overall survival (OS), disease free survival (DFS), local recurrence rate (LRR), distant metastasis rate (DMR), sphincter preservation rate, R0 resection rate and late toxicity. Compared with SCRT, LCRT obviously increased pCR rate [RR=0.15, 95%CI (0.08, 0.28), P=0.003], while LCRT obviously increased the grade 3-4 acute toxicity [RR=0.13, 95%CI (0.06, 0.28), P<0.00001].nnnCONCLUSIONSnSCRT with immediate surgery is as effective as LCRT with delayed surgery for treatment of rectal cancer in terms of OS, DFS, LRR, DMR, Sphincter preservation rate, R0 resection rate and late toxicity. Though LCRT increased pCR rate, LCRT also increased acute toxicity compared with SCRT. SCRT is a better choice in centers with a long waiting list or lack of medical resources.

Fluorouracil-based neoadjuvant chemoradiotherapy with or without oxaliplatin for treatment of locally advanced rectal cancer: An updated systematic review and meta-analysis.

To measure the safety and efficacy of oxaliplatin (OX) application in neoadjuvant chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC), EMBASE, PubMed, Cochrane Library, and Web of Science were used for a literature search. Cochranes risk of bias tool of randomized controlled trials (RCTs) was used for quality evaluation. The statistical analyses were performed using RevMan 5.3. In addition, 95% confidence intervals (CIs) and pooled risk ratios (RRs) were calculated. Seven RCTs were included in our meta-analysis. After adding OX to fluoropyrimidine (FU), a marginal significant improvement in disease-free survival was noted compared with FU alone (RR = 0.89, 95% CI: 0.78–1.00; P = 0.05). Neoadjuvant CRT with OX significantly decreased the distant metastasis rate (RR = 0.79, 95% CI: 0.67–0.94, P = 0.007). However, no improvement in the local recurrence rate (RR = 0.86, 95% CI: 0.68–1.08; P = 0.19) was noted. In addition, neoadjuvant CRT with OX also significantly increased the pathologic complete response (RR = 1.24, 95% CI: 1.02–1.51; P = 0.03). Grade 3–4 acute toxicity and grade 3–4 diarrhea was considerably higher for OX/FU compared with FU alone. In conclusion, the use of OX on the basis of FU/capecitabine in preoperative CRT is feasible. LARC patients are likely to benefit from CRT regimens with OX.

Comparison of psychological placebo and waiting list control conditions in the assessment of cognitive behavioral therapy for the treatment of generalized anxiety disorder: a meta-analysis

Background There is ongoing debate about the efficacy of placebos in the treatment of mental disorders. In randomized control trials (RCTs) about the treatment of generalized anxiety disorder, the administration of a psychological placebo or placement on a waiting list are the two most common control conditions. But there has never been a systematic comparison of the clinical effect of these different strategies. Aim Compare the change in symptom severity among individuals treated with cognitive behavioral therapy, provided a psychological placebo, or placed on a waiting list using data from RCTs on generalized anxiety disorder. Methods The following databases were searched for RCTs on generalized anxiety disorder: PubMed, PsycInfo, EMBASE, The Cochrane Library, CNKI, Chongqing VIP, Wanfang, Chinese Biological Medical Literature Database, and Taiwan Electronic Periodical Services. Studies were selected based on pre-defined inclusion and exclusion criteria and the quality of each included study – based on the risk of bias and the level of evidence – was formally assessed. Meta-analysis was conducted using RevMan5.3 and network meta-analyses comparing the three groups were conducted using R. Results Twelve studies with a combined sample size of 531 were included in the analysis. Compared to either control method (placebo or waiting list), cognitive behavioral therapy was more effective for generalized anxiety disorder. Provision of a psychological placebo was associated with a significantly greater reduction of symptoms than placement on a waiting list. Eight of the studies were classified as ‘high risk of bias’, and the overall level of evidence was classified as ‘moderate’, indicating that further research could change the overall results of the meta-analysis. Conclusions RCTs about the treatment of generalized anxiety disorders are generally of moderate quality; they indicate the superiority of CBT but the results cannot, as yet, be considered robust. There is evidence of a non-negligible treatment effect of psychological placebos used as control conditions in research studies. This effect should be considered when designing and interpreting the results of randomized controlled trials about the effectiveness of psychotherapeutic interventions.

Systematic review and meta-analysis comparing hypofractionated with conventional fraction radiotherapy in treatment of early breast cancer.

BACKGROUNDnThe purpose of this meta-analysis is to evaluate the efficacy and safety of altered radiation fraction size on outcomes for early breast cancer patients.nnnMETHODSnA search of MEDLINE, EMBASE, WEB OF SCIENCE, Cochrane Library and ClinicalTrials.gov was conducted. Quality of the randomized controlled trials (RCTs) or non-RCTs were evaluated according to Cochranes risk of bias tool or Methodological Index for non-Randomized Studies (MINORS). Pooled risk ratio (RR) and 95% confidence interval (CI) were calculated. Subgroup analysis was applied according to different fraction dose and sensitivity analysis was performed according to RCTs or non-RCTs.nnnRESULTSn23 studies were included in this systematic review. Meta-analysis demonstrated hypofractionation radiotherapy (HFRT) was associated with decreased grade 2/3 acute skin reactions compared with conventional fraction RT (CFRT), either 2.5-3.0 Gy per fraction or 5.0-6.5 Gy per fraction. HFRT with 2.5-3.0 Gy per fraction significantly decreased moderate/marked photographic changes in breast appearance compared with CFRT [RR = 0.80, 95% CI (0.70, 0.91), P = 0.001], while HFRT with more than 3.0 Gy per fraction significantly increased moderate/marked photographic changes [RR = 1.21, 95% CI (1.06, 1.38), P = 0.004]. In addition HFRT cost one-third lower than CFRT. Regarding to local regional recurrence, distant metastasis, overall survival, disease free survival, excellent/good cosmetic comes, symptomatic radiation pneumonitis, ischemic heart disease and symptomatic rib fracture, there was no significant difference between two arms.nnnCONCLUSIONSnBased on available evidence, HFRT with 2.5-3.0 Gy per fraction should be the better choice for treatment of early breast cancer patients.

Comparison of Bone Mineral Density in Lumbar Spine and Fracture Rate among Eight Drugs in Treatments of Osteoporosis in Men: A Network Meta-Analysis.

Context The preferred treatment for osteoporosis in men is debated, and pairwise meta-analysis cannot obtain hierarchies of these treatments. Objective The objective of this study was to integrate the evidence and provide hierarchies of eight drugs based on their effect on the bone mineral density in the lumbar spine (BMD in LS) and the fracture rate. Data Sources Eligible studies were identified by searching Amed, British Nursing Index, EMBASE, PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), Google Scholar, SIGLE, the National Technical Information Service, the National Research Register (UK), and the Current Controlled Trials databases. Study Selection RCTs or quasi-RCTs reporting at least two drugs (two active drugs or one active drug and a placebo) used to treat osteoporosis in men were selected by two authors. Data Extraction Two authors independently extracted the data. Data Synthesis Thirteen studies involving 3647 patients were included. Compared with placebo therapy, zoledronate (SMDs 13.48, 95% credible intervals 11.88-15.08) yielded the most significant effect on increasing the BMD in LS, followed by alendronate (11.04, 9.68-12.41), teriparatide (20mcg) + risedronate (10.98, 8.55-13.48), risedronate (10.33, 8.68-12.01), teriparatide (20mcg) (9.33, 6.87-11.76), strontium ranelate (8.88, 7.51-10.24), ibandronate (5.49, 3.82-7.16), parathyroid hormone (1-84) (4.89, 3.12-6.62) and alfacalcidol (3.42, 1.7-5.2). Placebo therapy had a significantly higher fracture rate in contrast to risedronate (OR 2.51, 95% CrI 1.23-4.24) or zoledronate (2.92, 1.29-5.62) or teriparatide (20mcg) (4.04, 1.36-8.49) or teriparatide (40mcg) (3.5, 1.14-8.34). Zoledronate ranked first for increasing the BMD in LS, and teriparatide (20mg) was ranked first for decreasing the fracture rate. Conclusions Zoledronate might be the best choice to increase the BMD in LS and teriparatide (20mg) might lead to the lowest fracture rate.

Abiraterone for treatment of metastatic castration-resistant prostate cancer: a systematic review and meta-analysis.

INTRODUCTIONnAlthough most prostate cancers initially respond to castration with luteinizing hormone- releasing analogues or bilateral orchiectomy, progression eventually occurs. Based on the exciting results of several randomized controlled trials (RCTs), it seems that patients with metastatic castration-resistant prostate cancer (mCRPC) might benefit more from treatment withabiraterone. Therefore we conducted a systematic review to evaluate the efficacy and toxicity of abiraterone in the treatment of mCRPC.nnnMETHODSnLiterature was searched from Embase, PubMed, Web of Science, and Cochrane Library up to July, 2013. Quality of the study was evaluated according to the Cochranes risk of bias of randomized controlled trial (RCT) tool, then the Grading of Recommendations Assessment, Development and Evaluation (GRADE) System was used to rate the level of evidence. Stata 12.0 was used for statistical analysis. Summary data from RCTs comparing abiraterone plus prednisone versus placebo plus prednisone for mCRPC were meta-analyzed. Pooled hazard ratios (HRs) for overall survival (OS), radiographic progression-free survival (RPFS) and time to PSA progression (TTPP); Pooled risk ratios (RR) for PSA response rate, objective response rate and adverse event were calculated.nnnRESULTSnTen trials were included in the systematic review; Data of 2,283 patients (1,343 abiraterone; 940 placebo) from two phase 3 trials: COU-AA-301 and COU-AA-302 were meta-analyzed. Compared with placebo, abiraterone significantly prolonged OS (HR, 0.74; 95% confidence interval [CI], 0.66 to 0.84), RPFS (HR, 0.59; 95% CI, 0.48 to 0.74) and time to PSA progression (HR, 0.55; 95% CI, 0.43 to 0.70); it also significantly increased PSA response rate (RR, 3.63; 95% CI, 1.72 to 7.65) and objective response rate (RR, 3.05; 95% CI, 1.51 to 6.15). This meta-analysis suggested that the adverse events caused by abiraterone are acceptable and can be controlled. CONCLUTIOS: Abiraterone significantly prolonged OS, RPFS and time to progression patients with mCRPC, regardless of prior chemotherapy or whether chemotherapy-naive, and no unexpected toxicity was evident. Abiraterone can serve as a new standard therapy for mCRPC.

The Chk1 inhibitor MK-8776 increases the radiosensitivity of human triple-negative breast cancer by inhibiting autophagy

MK-8776 is a recently described inhibitor that is highly selective for checkpoint kinase 1 (Chk1), which can weaken the DNA repair capacity in cancer cells to achieve chemo-sensitization. A number of studies show that MK-8776 enhances the cytotoxicity of hydroxyurea and gemcitabine without increasing normal tissue toxicities. Thus far, there is no evidence that MK-8776 can be used as a radiotherapy sensitization agent. In this study, we investigated the effects of MK-8776 on the radiosensitivity of 3 human triple-negative breast cancer (TNBC) cell lines MDA-MB-231, BT-549 and CAL-51. MK-8776 dose-dependently inhibited the proliferation of MDA-MB-231, BT-549 and CAL-51 cells with IC50 values of 9.4, 17.6 and 2.1 μmol/L, respectively. Compared with irradiation-alone treatment, pretreatment with a low dose of MK-8776 (100–400 nmol/L) significantly increased irradiation-induced γH2A.X foci in the 3 TNBC cell lines, suggesting enhanced DNA damage by MK-8776, inhibited the cell proliferation and increased the radiosensitivity of the 3 TNBC cell lines. Similar results were obtained in MDA-MB-231 xenograft tumors in nude mice that received MK-8776 (15 or 40 mg/kg, ip) 26 d after irradiation. To explore the mechanisms underlying the radio-sensitization by MK-8776, we used TEM and found that irradiation significantly increased the numbers of autophagosomes in the 3 TNBC cell lines. Moreover, irradiation markedly elevated the levels of Atg5, and promoted the transformation of LC3-I to LC3-II in the cells. Pretreatment with the low dose of MK-8776 suppressed these effects. The above results suggest that MK-8776 increases human TNBC radiosensitivity by inhibiting irradiation-induced autophagy and that MK-8776 may be a potential agent in the radiosensitization of human TNBC.

Phyllodes tumors of the breast: diagnosis, treatment and prognostic factors related to recurrence

Phyllodes tumors of the breast are rare tumor types that consist of 0.3-1.0% in all breast tumors. The naming and classification of breast phyllodes tumor have been debated for years. Based on the classification criteria modified by WHO in 2003, this review mainly introduced the clinicopathologic characteristics, pre-operational diagnosis and the treatment of breast phyllodes tumors, and also summarized the prognostic factors related to tumor recurrence.

HER2 reduces breast cancer radiosensitivity by activating focal adhesion kinase in vitro and in vivo

Growing evidence has demonstrated that human epidermal growth factor receptor 2 (HER2) is involved in the radiation response to breast cancer. However, the underlying mechanism remains elusive. Therefore, we investigated if HER2 overexpression is associated with radiosensitivity of breast cancer. We constructed breast cancer cell lines differing in HER2 expression by transducing HER2 cDNA or short hairpin RNA against HER2. We then assessed the radiosensitivity and investigated the potential mechanism by using cell proliferation assay, cell adhesion assays, anoikis assays, colony formation assays, and western blotting analyses. We found that HER2 introduction in breast cancer cell lines MCF-7 (low HER2 expression) and MDA-MB-231 (HER2 is not expressed) promoted cell proliferation and invasion and enhanced cell adhesion and resistance to anoikis. Moreover, HER2 reduced radiosensitivity in these two cells compared with the corresponding control. The opposite results were observed when HER2 was silenced in breast cancer cell lines ZR-7530 and SK-BR-3 (both cells with high expression of HER2) using HER2 shRNA. In addition, animal experiment results showed HER2 could enhance the radioresistance of xenograft tumors. Further studies showed HER2 promoted the phosphorylation of focal adhesion kinase (Fak) and thereby up-regulated the expression of proteins associated with the epithelial-to-mesenchymal transition such as Claudin-1, ZO-1, and ZEB-1. The inhibition of Fak activity using the Fak inhibitor (PF-562281) restored the radiosensitivity in HER2-overexpressing cells. In conclusion, HER2 reduces the radiosensitivity of breast cancer by activating Fak in vitro and in vivo. Fak might be a potential target for the radiosensitization of HER2-overexpressed breast cancer.

Short-course Versus Long-course Preoperative Radiotherapy plus Delayed Surgery in the Treatment of Rectal Cancer: a Meta-analysis.

BACKGROUNDnShort-course preoperative radiation (SCRT) with delayed surgery was found to increase pathologic complete response (pCR) rates in several trials. However, there was no clear answer on whether SCRT or long-course chemo-radiotherapy (LCRT) is more effective. Therefore we conducted this meta-analysis to evaluate the safety and efficacy of SCRT versus LCRT, both with delayed surgery, for treatment of rectal cancer.nnnMATERIALS AND METHODSnThe literature was searched from PubMed, EMBASE, Web of Science, Cochrane Library and clinicaltrials.gov up to November, 2014. Quality of the randomized controlled trials (RCTs) was evaluated according to the Cochranes risk of bias tool of RCT. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to rate the level of evidence. Review Manager 5.3 was employed for statistical analysis. Pooled risk ratios (RRs) and 95% confidence intervals (CIs) were calculated.nnnRESULTSnThree RCTs, with a total of 357 rectal cancer patients, were included in this systematic review. Meta- analysis results demonstrated there were no significantly differences in sphincter preservation rate, local recurrence rate, grade 3~4 acute toxicity, R0 resection rate and downstaging rate. Compared with SCRT, LCRT was associated with significant increase in the pCR rate [RR=0.49, 95%CI (0.31, 0.78), P=0.003].nnnCONCLUSIONSnIn terms of sphincter preservation rate, local recurrence rate, grade 3~4 acute toxicity, R0 resection rate and downstaging rate, SCRT with delayed surgery is as effective as LCRT with delayed surgery for management of rectal cancer. LCRT significantly increased pCR rate compared with SCRT. Due to risk of bias and imprecision, further multi-center large sample RCTs were needed to confirm this conclusion.