Observational studies in systematic [corrected] reviews of comparative effectiveness: AHRQ and the Effective Health Care Program.

OBJECTIVE: Systematic reviewers disagree about the ability of observational studies to answer questions about the benefits or intended effects of pharmacotherapeutic, device, or procedural interventions. This study provides a framework for decision making on the inclusion of observational studies to assess benefits and intended effects in comparative effectiveness reviews (CERs). STUDY DESIGN AND SETTING: The conceptual model and recommendations were developed using a consensus process by members of the methods workgroup of the Effective Health Care Program of the Agency for Healthcare Research and Quality. RESULTS: In considering whether to use observational studies in CERs for addressing beneficial effects, reviewers should answer two questions: (1) Are there gaps in the evidence from randomized controlled trials (RCTs)? (2) Will observational studies provide valid and useful information? The latter question involves the following: (a) refocusing the study questions on gaps in the evidence from RCTs, (b) assessing the risk of bias of the body of evidence of observational studies, and (c) assessing whether available observational studies address the gap review questions. CONCLUSIONS: Because it is unusual to find sufficient evidence from RCTs to answer all key questions concerning benefit or the balance of benefits and harms, comparative effectiveness reviewers should routinely assess the appropriateness of inclusion of observational studies for questions of benefit. Furthermore, reviewers should explicitly state the rationale for inclusion or exclusion of observational studies when conducting CERs.

Systematic review: comparative effectiveness of core-needle and open surgical biopsy to diagnose breast lesions.

BACKGROUND: Most women undergoing breast biopsy are found not to have cancer. PURPOSE: To compare the accuracy and harms of different breast biopsy methods in average-risk women suspected of having breast cancer. DATA SOURCES: Databases, including MEDLINE and EMBASE, searched from 1990 to September 2009. STUDY SELECTION: Studies that compared core-needle biopsy diagnoses with open surgical diagnoses or clinical follow-up. DATA EXTRACTION: Data were abstracted by 1 of 3 researchers and verified by the primary investigator. DATA SYNTHESIS: 33 studies of stereotactic automated gun biopsy; 22 studies of stereotactic-guided, vacuum-assisted biopsy; 16 studies of ultrasonography-guided, automated gun biopsy; 7 studies of ultrasonography-guided, vacuum-assisted biopsy; and 5 studies of freehand automated gun biopsy met the inclusion criteria. Low-strength evidence showed that core-needle biopsies conducted under stereotactic guidance with vacuum assistance distinguished between malignant and benign lesions with an accuracy similar to that of open surgical biopsy. Ultrasonography-guided biopsies were also very accurate. The risk for severe complications is lower with core-needle biopsy than with open surgical procedures (<1% vs. 2% to 10%). Moderate-strength evidence showed that women in whom breast cancer was initially diagnosed by core-needle biopsy were more likely than women with cancer initially diagnosed by open surgical biopsy to be treated with a single surgical procedure (random-effects odds ratio, 13.7 [95% CI, 5.5 to 34.6]). LIMITATION: The strength of evidence was rated low for accuracy outcomes because the studies did not report important details required to assess the risk for bias. CONCLUSION: Stereotactic- and ultrasonography-guided core-needle biopsy procedures seem to be almost as accurate as open surgical biopsy, with lower complication rates. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

Computer-aided detection mammography for breast cancer screening: systematic review and meta-analysis.

CONTEXT: Mammography is generally accepted as the best available breast cancer screening method; however, some cancers detectable on mammography images are missed. Computer-aided detection (CAD) systems for mammography are intended to reduce false negatives by marking suspicious areas of the mammograms for reviewers to consider. Although the prospect of improving the sensitivity of screening mammograms has led to the diffusion of CAD for mammography, little is known about its diagnostic accuracy. OBJECTIVE: To assess the diagnostic performance of CAD for screening mammography in terms of sensitivity and specificity and incremental recall, biopsy, and cancer diagnosis rates. DATA SOURCES: Published literature identified by systematic literature searches of 17 databases, including MEDLINE, EMBASE, and the Cochrane Library, searched through 25 September 2008. STUDY SELECTION: A reviewer and an information specialist selected full-length English-language articles that enrolled asymptomatic women for routine breast cancer screening and provided data needed for our analyses using criteria established a priori. We identified 75 potentially relevant publications, of which 7 (9%) were included. DATA EXTRACTION: Data were extracted and internal validity was assessed by a single review author, and forms were approved by the co-authors. RESULTS: Three studies (n = 347,324) reported sensitivity and specificity, or data to calculate them, and five studies (n = 51,162) reported data to calculate incremental rates of cancer diagnoses and recall and biopsy of women who did not have breast cancer. The pooled sensitivity was 86.0% (95% CI 84.2-87.6%) and specificity was 88.2% (95% CI 88.1-88.3%). Of the 100,000 women screened, CAD yielded an additional 50 (95% CI 30-80) correct breast cancer diagnoses, 1,190 (95% CI 1,090-1,290) recalls of healthy women, and 80 (95% CI 60-100) biopsies of healthy women. A total of 96% (95% CI 93.9-97.3%) of women recalled based upon CAD and 65.1% (95% CI 52.3-76.0%) of women biopsied based upon CAD were healthy. No studies reported patient-oriented clinical outcomes.

Involvement of RHO GTPases and ERK in synuclein-gamma enhanced cancer cell motility.

Synuclein-gamma is aberrantly expressed in more than 70% of stage III/IV breast and ovarian carcinomas. Ectopic overexpression of synuclein-gamma enhanced MDA-MB-435 cell migration in vitro and metastasis in a nude mouse model. However, the mechanism of how synuclein-gamma promotes cell motility is not clear. In our previous studies, we showed that synuclein-gamma overexpression activates ERK. In the present study, we overexpressed synuclein-gamma in several breast and ovarian cancer cell lines and evaluated the effect of synuclein-gamma on the activity of small G-protein RHO family members. We found that at least one of the RHO/RAC/CDC42 GTPases showed a higher level of the GTP-bound active form. Consistent with their role in regulating the intracellular motile machinery, inhibition of the RHO/RAC/CDC42 by C. difficile Toxin B blocked cell migration in both parental cells and synuclein-gamma overexpressing cells. The ERK inhibitor U0126 also blocked the cell migration in both parental cells and synuclein-gamma overexpressing cells. Collectively, our data indicate that synuclein-gamma might be involved in late stage breast and ovarian cancer metastasis by enhancing cell motility through activation of the RHO family small-GTPases and ERK.

Gamma-synuclein promotes cancer cell survival and inhibits stress- and chemotherapy drug-induced apoptosis by modulating MAPK pathways.

Synucleins are a family of highly conserved small proteins predominantly expressed in neurons. Recently we and others have found that gamma-synuclein is dramatically up-regulated in the vast majority of late-stage breast and ovarian cancers and that gamma-synuclein over-expression can enhance tumorigenicity. In the current study, we have found that gamma-synuclein is associated with two major mitogen-activated kinases (MAPKs), i.e. extracellular signal-regulated protein kinases (ERK1/2) and c-Jun N-terminal kinase 1 (JNK1), and have shown that over-expression of gamma-synuclein leads to constitutive activation of ERK1/2 and down-regulation of JNK1 in response to a host of environmental stress signals, including UV, arsenate, and heat shock. We also tested the effects of gamma-synuclein on apoptosis and activation of JNK and ERK in response to several chemotherapy drugs. We have found that gamma-synuclein-expressing cells are significantly more resistant to the chemotherapeutic drugs paclitaxel and vinblastine as compared with the parental cells. The resistance to paclitaxel can be partially obliterated when ERK activity is inhibited using a MEK1/2 inhibitor. Activation of JNK and its downstream caspase-3 by paclitaxel or vinblastine is significantly down-regulated in gamma-synuclein-expressing cells, indicating that the paclitaxel- or vinblastine-activated apoptosis pathway is blocked by gamma-synuclein. In contrast to paclitaxel and vinblastine, etoposide does not activate JNK, and gamma-synuclein over-expression has no apparent effect on this drug-induced apoptosis. Taken together, our data indicate that oncogenic activation of gamma-synuclein contributes to the development of breast and ovarian cancer by promoting tumor cell survival under adverse conditions and by providing resistance to certain chemotherapeutic drugs.