Prognostic Significance of Overexpressed p16^INK4a in Patients with Cervical Cancer: A Meta-Analysis

<div><p>Background</p><p>p16^INK4a is a tumor suppressor protein which is induced in cells upon the interaction of high-risk HPV E7 with the retinoblastoma protein by a positive feedback loop, but cannot exert its suppressing effect. Previous reports suggested that p16^INK4a immunostaining allows precise identification of even small CIN or cervical cancer lesions in biopsies. The prognostic value of overexpressed p16^INK4a in cervical cancer has been evaluated for several years while the results remain controversial. We performed a systematic review and meta-analysis of studies assessing the clinical and prognostic significance of overexpression of p16^INK4a in cervical cancer.</p><p>Methods</p><p>Identification and review of publications assessing clinical or prognostic significance of p16^INK4a overexpression in cervical cancer until March 1, 2014. A meta-analysis was performed to clarify the association between p16^INK4a overexpression and clinical outcomes.</p><p>Results</p><p>A total of 15 publications met the criteria and comprised 1633 cases. Analysis of these data showed that p16^INK4a overexpression was not significantly associated with tumor TNM staging (I+II vs. III+IV) (OR = 0.75, 95% confidence interval [CI]: 0.35–1.63, P = 0.47), the tumor grade (G1+ G2 vs. G3) (OR = 0.78, 95% CI: 0.39–1.57, P = 0.49), the tumor size (<4 vs. ≥4 cm) (OR = 1.10, 95% CI: 0.45–2.69, P = 0.83), or vascular invasion (OR = 1.20, 95% CI: 0.69–2.08, P = 0.52). However, in the identified studies, overexpression of p16^INK4a was highly correlated with no lymph node metastasis (OR = 0.51, 95% CI: 0.28–0.95, P = 0.04), increased overall survival (relative risk [RR]: 0.42, 95% CI: 0.24–0.72, P = 0.002) and increased disease free survival (RR: 0.60, 95% CI: 0.44–0.82, P = 0.001).</p><p>Conclusions</p><p>This meta-analysis shows overexpression of p16^INK4a in cervical cancer is connected with increased overall and disease free survival and thus marks a better prognosis.</p></div

Analysis of p16^INK4a expression and survival of cervical cancer patients.

<p>Forest plot of RR for OS (A) and DFS (B) among included studies. Combined RR was calculated by a random mode.</p

Egger’s test of funnel plot asymmetry.

<p>df: deflection.</p><p>Egger’s test of funnel plot asymmetry.</p

Forest plot depiction of p16^INK4a expression and OR for clinical pathologic features.

<p>Clinicopathological parameters investigated are lymph node status (A), TMN classification (B), tumor grade (C), size of tumor (D), vascular invasion (E). OR with corresponding confidence intervals are shown.</p

Main characteristics and results of the eligible studies.

<p>IHC; immunohistochemistry; ND: not documented.</p><p>Main characteristics and results of the eligible studies.</p

Literature search strategy and selection of articles.

<p>A total of 346 articles were selected for the meta-analysis by browsing the databases PubMed, Embase and Wanfang, of which 324 were excluded after reviewing the title and abstract, seven articles were excluded after reviewing the full publications, the reasons for exclusion were: (a) Non-association studies (b) researchers in the article did not use neither histopathologic analysis nor close clinical and imaging follow-up for at least 6 months, (c) association studies for other diseases (d), non-original articles, (e) data couldn’t be extracted or (f) repeated data from the same or similar population. Finally, a total of 15 studies with 1633 patients, who fulfilled all of the inclusion criteria, were considered for the analysis.</p

Aldehyde dehydrogenase 1 isoenzyme expression as a marker of cancer stem cells correlates to histopathological features in head and neck cancer: A meta-analysis

<div><p>There is a lack of predictive biomarkers that can identify patients with head and neck squamous cell carcinoma (HNSCC) who will experience treatment failure and develop drug resistance, recurrence, and metastases. Cancer stem-like cells (CSC) were identified as a subset of cells within the tumor in a variety of solid tumors including HNSCC. CSC are considered the tumor-initiating population responsible for recurrence or metastasis and are associated with therapy resistance. This meta-analysis including fourteen studies with altogether 1258 patients updates and summarizes all relevant data on the impact of ALDH1⁺ CSC on the prognosis of HNSCC and its association with clinicopathological parameters. ALDH1 expression is highly correlated with tumor differentiation (G3 vs. G1+G2; odds ratio = 2.85. 95% CI: 1.72–4.73, P<0.0001) and decreased overall survival (relative risk = 1.77. 95% CI: 1.41–2.22, P<0.0001) if one out of seven studies was excluded because of heterogeneity. These findings provide insights into the understanding of more aggressive tumor phenotypes and also suggest that the prognostic value provided by HNSCC-subtyping by CSC frequency warrant further clinical investigation.</p></div

Flow-chart for identification of eligible studies.

<p>Flow-chart for identification of eligible studies.</p

Main characteristics and results of the eligible studies.

<p>Main characteristics and results of the eligible studies.</p

Egger's test of funnel plot asymmetry.

<p>Egger's test of funnel plot asymmetry.</p