Prognostic Significance and Functional Role of CEP57 in Prostate Cancer

We have recently shown that centrosomal protein 57 (CEP57) is overexpressed in a subset of human prostate cancers. CEP57 is involved in intracellular transport processes, and its overexpression causes mitotic defects as well as abnormal microtubule nucleation and bundling. In the present study, we further characterized the prognostic and functional role of CEP57 in prostate cancer. Unexpectedly, we found that high CEP57 expression is an independent prognostic factor for a more favorable biochemical recurrence-free survival in two large patient cohorts. To reconcile this finding with the ability of CEP57 to cause cell division errors and thus potentially promote malignant progression, we hypothesized that alterations of microtubule-associated transport processes, in particular nuclear translocation of the androgen receptor (AR), may play a role in our finding. However, CEP57 overexpression and microtubule bundling had, surprisingly, no effect on the nuclear translocation of the AR. Instead, we found a significant increase of cells with disarranged microtubules and a cellular morphology suggestive of a cytokinesis defect. Because mitotic dysfunction leads to a reduced daughter cell formation, it can explain the survival benefit of patients with increased CEP57 expression. In contrast, we show that a reduced expression of CEP57 is associated with malignant growth and metastasis. Taken together, our findings underscore that high CEP57 expression is associated with mitotic impairment and less aggressive tumor behavior. Because the CEP57-induced microtubule stabilization had no detectable effect on AR nuclear translocation, our results furthermore suggest that microtubule-targeting therapeutics used in advanced prostate cancer such as docetaxel may have modes of action that are at least in part independent of AR transport inhibition.     

Prognostic Value of SMAD4 in Pancreatic Cancer: A Meta-Analysis

PURPOSE: The prognostic value of SMAD4 in pancreatic cancer has been evaluated in several studies. However, the conclusions remain controversial. Therefore, we aimed to evaluate the association between SMAD4 expression and the outcome of pancreatic cancer patients by performing a meta-analysis. METHODS: We systematically searched for relevant studies evaluating the relationship between SMAD4 expression and the outcome of pancreatic cancer patients until May 2015. A meta-analysis was performed using STATA 12.0, and pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were used to estimate the strength of the association between SMAD4 expression and the prognosis of pancreatic cancer patients. RESULTS: The analysis included 1762 patients from 14 studies, with 1401 patients from 11 studies and 927 patients from 8 studies included in the univariate and multivariate analyses, respectively. Loss of SMAD4 expression was found to be significantly correlated with poor overall survival, with the combined HR (95% CI) of 1.20 (1.03-1.40). After adjusting for potential confounders using the Cox regression model, the pooled HR (95% CI) was 1.88 (1.31-2.70). In subgroup analysis, study region, number of patients, follow-up duration, and cutoff value were found to affect the significance of the association between loss of SMAD4 expression and poor prognosis. In addition, there was no evidence of publication bias, as suggested by Begg’s and Egger’s test. CONCLUSIONS: Loss of SMAD4 was associated with poor survival and was a negative prognostic indicator in patients with pancreatic cancer.     

骨桥蛋白在胰腺癌中的表达及其临床意义

目的:研究骨桥蛋白OPN在胰腺癌中的表达水平及其与临床病理特征的关系。方法:采用RT-PCR和免疫组织化学方法分别检测50例胰腺癌手术切除标本和20例癌旁正常胰腺组织中OPNmRNA及其蛋白水平的表达。结果:胰腺癌组织中OPNmRNA高表达率为90%(45/50)明显高于其在癌旁正常胰腺组织中的表达15%(3/20),差异有统计学意义(P<0.01);OPN蛋白的阳性率为86.0%(43/50),明显高于癌旁正常胰腺组织中的表达30%(6/20),差异有统计学意义(P<0.01);OPN在胰腺癌组织中表达与其淋巴结转移明显相关(P<0.05)。结论:OPN在胰腺癌中的过表达对胰腺癌的生长、浸润及转移起重要作用。     

Functional Genomics Identifies Metabolic Vulnerabilities in Pancreatic Cancer

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The Significance of Ras Activity in Pancreatic Cancer Initiation

The genetic landscape of pancreatic cancer shows nearly ubiquitous mutations of K-RAS. However, oncogenic K-Ras^mt alone is not sufficient to lead to pancreatic ductal adenocarcinoma (PDAC) in either human or in genetically modified adult mouse models. Many stimulants, such as high fat diet, CCK, LPS, PGE2 and others, have physiological effects at low concentrations that are mediated in part through modest increases in K-Ras activity. However, at high concentrations, they induce inflammation that, in the presence of oncogenic K-Ras expression, substantially accelerates PDAC formation. The mechanism involves increased activity of oncogenic K-Ras^mt. Unlike what has been proposed in the standard paradigm for the role of Ras in oncogenesis, oncogenic K-Ras^mt is now known to not be constitutively active. Rather, it can be activated by standard mechanisms similar to wild-type K-Ras, but its activity is sustained for a prolonged period. Furthermore, if the level of K-Ras activity exceeds a threshold at which it begins to generate its own activators, then a feed-forward loop is formed between K-Ras activity and inflammation and pathological processes including oncogenesis are initiated. Oncogenic K-Ras^mt activation, a key event in PDAC initiation and development, is subject to complex regulatory mechanisms. Reagents which inhibit inflammation, such as the Cox2 inhibitor celecoxib, block the feed-forward loop and prevent induction of PDAC in models with endogenous oncogenic K-Ras^mt. Increased understanding of the role of activating and inhibitory mechanisms on oncogenic K-Ras^mt activity is of paramount importance for the development of preventive and therapeutic strategies to fight against this lethal disease.     

Mitogen-Activated Protein Kinase Kinase 4 (MAP2K4) Promotes Human Prostate Cancer Metastasis

Prostate cancer (PCa) is the second leading cause of cancer death in the US. Death from PCa primarily results from metastasis. Mitogen-activated protein kinase kinase 4 (MAP2K4) is overexpressed in invasive PCa lesions in humans, and can be inhibited by small molecule therapeutics that demonstrate favorable activity in phase II studies. However, MAP2K4''s role in regulating metastatic behavior is controversial and unknown. To investigate, we engineered human PCa cell lines which overexpress either wild type or constitutive active MAP2K4. Orthotopic implantation into mice demonstrated MAP2K4 increases formation of distant metastasis. Constitutive active MAP2K4, though not wild type, increases tumor size and circulating tumor cells in the blood and bone marrow. Complementary in vitro studies establish stable MAP2K4 overexpression promotes cell invasion, but does not affect cell growth or migration. MAP2K4 overexpression increases the expression of heat shock protein 27 (HSP27) protein and protease production, with the largest effect upon matrix metalloproteinase 2 (MMP-2), both in vitro and in mouse tumor samples. Further, MAP2K4-mediated increases in cell invasion are dependent upon heat shock protein 27 (HSP27) and MMP-2, but not upon MAP2K4''s immediate downstream targets, p38 MAPK or JNK. We demonstrate that MAP2K4 increases human PCa metastasis, and prolonged over expression induces long term changes in cell signaling pathways leading to independence from p38 MAPK and JNK. These findings provide a mechanistic explanation for human studies linking increases in HSP27 and MMP-2 to progression to metastatic disease. MAP2K4 is validated as an important therapeutic target for inhibiting human PCa metastasis.     

Prognostic Significance of Deregulated Dicer Expression in Breast Cancer

Background

Dicer, an RNase III-type endonuclease, is the key enzyme involved in RNA interference and microRNA pathways. Aberrant expression of Dicer is reported in several human cancers. Our aim was to assess the prognostic role of Dicer in breast cancer.

Methods

The entire series comprised 666 invasive breast cancers (IBCs), 480 DCIS cases (397 associated with IBC and 83 pure DCIS) and 305 lymph node metastases. Cytoplasmic Dicer expression by immunohistochemistry was scored as negative (no staining) and positive (weak, moderate or strong staining).

Results

Dicer staining was assessable in 446 IBC, 128 DCIS and 101 lymph node metastases. Expression of Dicer was observed in 33% (145/446) of IBCs, 34% (44/128) of DCIS and 57% (58/101) of lymph node metastases. Dicer expression was increased in nodal metastases compared to primary tumours (p<0.001); and was associated with ER negativity (p<0.001), HER2 positivity (p<0.001), high Ki67 labeling index (p<0.001) and expression of basal-like biomarkers (p = 0.002). Dicer positivity was more frequent in the HER2 overexpressing (p<0.001) and basal-like (p = 0.002) subtypes compared to luminal A subtype. Dicer expression was associated with reduced overall survival (OS) on univariate analysis (p = 0.058) and remained an independent predictor of OS on multivariate analysis (HR 2.84, 95% CI 1.43–5.62, p = 0.003), with nodal status (HR 2.61, 95% CI 1.18–5.80, p = 0.018) and PR (HR 0.28, 95% CI 0.13–0.59, p = 0.001). Further, moderate or strong expression of Dicer was associated with improved disease-free survival in the HER2-overexpressing subtype compared to negative or weak expression (p = 0.038).

Conclusion

Deregulated Dicer expression is associated with aggressive tumour characteristics and is an independent prognostic factor for OS. Our findings suggest that Dicer is an important prognostic marker in breast cancer and that its prognostic role may be subtype specific.     

MAP4K4: an emerging therapeutic target in cancer

The serine/threonine kinase MAP4K4 is a member of the Ste20p (sterile 20 protein) family. MAP4K4 was initially discovered in 1995 as a key kinase in the mating pathway in Saccharomyces cerevisiae and was later found to be involved in many aspects of cell functions and many biological and pathological processes. The role of MAP4K4 in immunity, inflammation, metabolic and cardiovascular disease has been recognized. Information regarding MAP4K4 in cancers is extremely limited, but increasing evidence suggests that MAP4K4 also plays an important role in cancer and MAP4K4 may represent a novel actionable cancer therapeutic target. This review summarizes our current understanding of MAP4K4 regulation and MAP4K4 in cancer. MAP4K4-specific inhibitors have been recently developed. We hope that this review article would advocate more basic and preclinical research on MAP4K4 in cancer, which could ultimately provide biological and mechanistic justifications for preclinical and clinical test of MAP4K4 inhibitor in cancer patients.     

Prognostic Significance of CD26 in Patients with Colorectal Cancer

Background

CD26, dipeptidyl peptidase IV, was discovered firstly as a membrane-associated peptidase on the surface of leukocyte. We previously demonstrated that a subpopulation of CD26⁺ cells were associated with the development of distant metastasis, enhanced invasiveness and chemoresistance in colorectal cancer (CRC). In order to understand the clinical impact of CD26, the expression was investigated in CRC patient''s specimens. This study investigated the prognostic significance of tumour CD26 expression in patients with CRC. Examination of CD26⁺ cells has significant clinical impact for the prediction of distant metastasis development in colorectal cancer, and could be used as a selection criterion for further therapy.

Methods

Tumour CD26 expression levels were studied by immunohistochemistry using Formalin-fixed paraffin embedded (FFPE) tissues in 143 patients with CRC. Tumour CD26 expression levels were correlated with clinicopathological features of the CRC patients. The prognostic significance of tumour tissue CD26 expression levels was assessed by univariate and multivariate analyses.

Result

CD26 expression levels in CRC patients with distant metastasis were significantly higher than those in non-metastatic. High expression levels of CD26 were significantly associated with advanced tumour staging. Patients with a high CD26 expression level had significantly worse overall survival than those with a lower level (p<0.001).

Conclusions

The expression of CD26 was positively associated with clinicopathological correlation such as TNM staging, degree of differentiation and development of metastasis. A high CD26 expression level is a predictor of poor outcome after resection of CRC. CD26 may be a useful prognostic marker in patients with CRC.     

Studies on the Expression Patterns of Class I PI3K Catalytic Subunits and Its Prognostic Significance in Colorectal Cancer

The phosphatidylinositol 3-kinase/AKT (PI3K/AKT) pathway plays a critical role in human cancer. We determined the expression patterns of class I PI3K catalytic subunits and evaluated their importance in the development or progression of colorectal cancer (CRC). For this purpose, expression of class I PI3K isoforms was evaluated in 82 primary CRC and paired non-cancerous mucosa samples by qRT-PCR. P-AKT-Ser473 and P-AKT-Thr308 expression were measured by western blot. We found that, compared with paired non-cancerous mucosa samples, mRNA expression of p110α and p110β in CRCs was significantly increased to 2.02-fold (95% confidence interval [CI] 1.25–3.28 fold) and 1.76-fold (95% CI 1.19–2.60 fold), respectively; while slight differences were found regarding the expression of p110δ (0.57-fold; 95% CI 0.31–1.07 fold) and p110γ (0.97-fold; 95% CI 0.50–1.88 fold). Increased p110α and p110β expression correlated with primary tumor size, regional lymph node metastases, and AJCC stage. Increased p110β expression also correlated with distant metastasis. P-AKT-Thr308 and P-AKT-Ser473 expression showed significant direct correlations with p110α and p110β mRNA expression. Besides, CRC patients with p110β mRNA overexpression had a worse disease-free survival after radical surgery compared with those with normal or decreased levels (P = 0.043). It was, therefore, concluded that the altered p110α and p110β expression might contribute to the CRC development or progression.     

The Prognostic Significance of Wnt-5a Expression in Primary Breast Cancer Is Extended to Premenopausal Women

Wnt-5a protein expression in primary tumors from unselected breast cancer patients has revealed a tumor suppressive function of the protein. However, in vitro experiments on human breast cancer cells have reported contradictory results, indicating both a tumor suppressive and promoting functions of Wnt-5a. This could be due to various functions of Wnt-5a in different subgroups of patients. The unselected cohorts analyzed to date for Wnt-5a protein expression contained few premenopausal patients. The aim of the present investigation was to evaluate the prognostic significance of Wnt-5a protein expression in a cohort of premenopausal women with comprehensive data on biomarkers, molecular subtypes and long-term outcome. In a randomized trial of adjuvant tamoxifen versus no adjuvant treatment, 564 premenopausal primary breast cancer patients were included. The median follow-up time was 14 years. A tumor tissue array was constructed and 361 samples were evaluated for Wnt-5a reactivity by immunohistochemistry. The primary end-point was recurrence-free survival. Wnt-5a protein expression was reduced or lost in 146/361 of tumors and correlated to younger age, estrogen receptor (ER) negativity and triple-negative phenotype. Wnt-5a was a prognostic factor in the whole cohort (p = 0.003). In patients with ER-positive tumors, Wnt-5a was an independent positive prognostic marker (HR 0.51 95% CI: 0.33–0.78 p = 0.002) and HER2 a negative prognostic marker (HR 2.84 95% CI: 1.51–5.31, p = 0.001) in a Cox multivariate analysis adjusted for standard prognostic markers and tamoxifen treatment. In the ER-negative subset, Wnt-5a added no prognostic information. In a subgroup analysis, Wnt-5a was significantly associated with better prognosis in patients with Luminal A tumors (p = 0.04). Conclusively, our results suggest that loss of Wnt-5a is a valuable prognostic marker in premenopausal breast cancer patients in particular in patients with ER-positive tumors and out-performed conventional prognostic factors in this subset of patients.     

Functional analysis of microtubule-binding domain of bovine MAP4

Bovine microtubule-associated protein 4 (MAP4) consists of an amino-terminal projection domain and a carboxyl-terminal microtubule-binding domain. The carboxyl-terminal domain of MAP4 is further divided into three subdomains: a region rich in proline and basic residues (Pro-rich region), a region containing four repeats of an assembly-promoting (AP) sequence, which consists of 22 amino acid residues (AP sequence region), and a hydrophobic tail region (Tail region). The subdomain structure of MAP4 microtubule binding domain is similar to those of other MAPs (MAP2 and tau). In order to study the function of each subdomain per se of bovine MAP4 microtubule-binding domain, we purified a series of truncated fragments of MAP4, expressed in Escherichia coil. Binding affinity of the PA4T fragment (containing the Pro-rich region, the AP sequence region and the Tail region) is only four times higher than that of the A4T fragment (containing the AP sequence region and the Tail region), while the microtubule nucleating activity of the PA4T fragment is far greater. We propose that the Pro-rich region promotes the nucleation of microtubule assembly. The A4 fragment (corresponding to the AP sequence region) stimulated the assembly of tubulin into coldstable amorphous aggregates. The AP sequence region of MAP4 failed to promote microtubule assembly. On the other hand, the fragment has an activity to stimulate microtubule elongation. The function of the MAP4 Tail region is not clear at present. The A4T fragment (containing the AP sequence region and the Tail region) promote both microtubule nucleation and elongation step, but the A4 fragment only promotes microtubule elongation, suggesting that the Tail region is indispensable for the nucleation step. However, the fragment containing only the Tail region could not bind to microtubule. Although MAP4 was considered to be long, thin and flexible molecule, never the Tail region may contribute to be the proper folding of MAP4, and/or may interact with other molecules. We concluded that both the Pro-rich region and the AP sequence region take part in the promotion of tubulin polymerization, and that the former is important for the lateral protofilament-protofilament interaction, and the latter is important for the longitudinal affinity between each tubulin dimer in a protofilament.     

ADAMl0在胰腺癌患者血清中表达及其临床意义

目的：探讨ADAM10在胰腺癌患者外周血中的表达及其临床意义。方法：应用酶联免疫吸附试验法（ELISA）检测40例胰腺癌患者和20例健康体检者的外周血ADAM10的表达水平,分析其与临床病理特征的关系。结果：胰腺癌患者血清ADAM10水平显著高于正常对照组（P〈0.01）;胰腺癌患者血清中ADAM10的表达水平与胰腺癌淋巴结转移、远处转移及TNM分期密切相关（P〈0.05）,且行根治性手术切除的胰腺癌患者ADAM10表达水平低于姑息性手术切除的患者（P〈0.05）;ADAM10对胰腺癌诊断的敏感度、特异性分别为51.7%、76.9%,联合检测CA19-9有助于提高胰腺癌诊断敏感度,但特异性有所下降;根治性切除后胰腺癌患者血清中ADAM10水平明显下降。结论：胰腺癌癌患者血清中ADAM10水平明显增高,检测血清ADAM10有助于胰腺癌的诊断和治疗。     

Prognostic Significance of Substance P and Neurokinin-1 Receptor in Bladder Cancer

Background:Bladder cancer is one of the most common genitourinary cancers with significant mortality. Finding reliable tumor markers and potential drug targets can improve early diagnosis, prognosis, and more effective therapeutic protocols. Previous studies have reported the involvement of the substance P (SP)/neurokinin-1 receptor (NK-1R) system in cancers. The potential prognostic role and the interaction of SP and NK-1R in bladder tumor are yet to be elucidated.Methods:Serum samples from 22 primarily diagnosed patients with bladder cancer as well as 22 healthy controls were examined for SP level using ELISA method. Tissue distribution of NK-1R in tumor samples and their adjacent normal tissues was evaluated through immunohistochemistry.Results:Serum SP levels in patients with bladder cancer were higher than the healthy group (p< 0.001) and had a significant correlation with NK-1R staining intensity (p< 0.001), percentage of stained cells (p< 0.001), and NK-1R tissue distribution. Also, the immunoreactivity of NK-1R in cancer samples increased significantly without correlation with tumor characteristics. However, no significant association was found between SP and NK-1R levels with clinical characteristics including tumor size (p= 0.33), tumor stage (p= 0.29), grade (p= 0.93), NK-1R staining intensity (p= 0.53), and percentage of stained cells (p= 0.32).DiscussionAccording to our findings, despite the lack of association between SP and NK-1R with clinical characteristics of bladder cancer, their serum levels were higher in patients with bladder cancer. Further studies are needed to confirm the potential prognostic role of SP and NK-1R in bladder cancer.Key Words: Biomarker, Bladder cancer, Neurokinin-1 receptor, Substance P, Prognosis     

Prognostic Significance of B-Cells and pSTAT3 in Patients with Ovarian Cancer

Background

Several previous studies have identified a strong association between T-cell infiltration and clinical outcome in ovarian cancer. The role of B-cells remains controversial, however.

Methods

Forty-nine paraffin-embedded omental specimens derived from patients with high grade epithelial ovarian cancer were assessed. Immunohistochemical analyses were performed to characterize expression of CD19⁺ B-cells and pSTAT3 as high (>50% positively staining cells [PSCs]) or low (<50% PSCs). The Kaplan-Meier method with log-rank test was used to determine the association between clinicopathologic parameters and overall survival (OS). A multi-variate Cox proportional hazards regression analysis including nature of debulking (primary vs secondary), histology, tumor grade, receipt of prior chemotherapy, B-cell infiltration and pSTAT3 expression was performed.

Results

Median OS was 160.6 months in those patients with low B-cell expression vs 47.3 months in those with high B-cell expression (P = 0.0015). Similarly, median OS was improved in those patients with low pSTAT3 expression (160.6 vs 47.9 months, P = 0.02). In a multivariate model to predict survival, only the degree of B-cell infiltration and clinical stage were retained. pSTAT3 expression did not enter the final model, possibly be due to a high positive correlation with B-cell infiltration (r = 0.82, P<0.0001).

Conclusions

Increased B-cell infiltration and pSTAT3 expression in omental tissue are associated with poorer survival.     

MAP4K3 regulates body size and metabolism in Drosophila

The TOR pathway mediates nutrient-responsive regulation of cell growth and metabolism in animals. TOR Complex 1 activity depends, amongst other things, on amino acid availability. MAP4K3 was recently implicated in amino-acid signaling in cell culture. We report here the physiological characterization of MAP4K3 mutant flies. Flies lacking MAP4K3 have reduced TORC1 activity detected by phosphorylation of S6K and 4EBP. Furthermore MAP4K3 mutants display phenotypes characteristic of low TORC1 activity and low nutrient availability, such as reduced growth rate, small body size, and low lipid reserves. The differences between control and MAP4K3 mutant animals diminish when animals are reared in low-nutrient conditions, suggesting that the ability of TOR to sense amino acids is most important when nutrients are abundant. Lastly, we show physical interaction between MAP4K3 and the Rag GTPases raising the possibility they might be acting in one signaling pathway.     

Prognostic Significance of Capn4 Overexpression in Intrahepatic Cholangiocarcinoma

Background

Calpain small subunit 1 (Capn4) has been shown to correlate with the metastasis/invasion of hepatocellular carcinoma. This study aimed to investigate the role of Capn4 in intrahepatic cholangiocarcinoma (ICC).

Methods

Capn4 expression was measured in 33 ICC tissues by quantitative real-time polymerase chain reaction and western blot. The role of Capn4 in the migration, invasion and proliferation of ICC cells and matrix metalloproteinase 2 (MMP2) expression were assessed after Capn4 depletion by specific small interfering RNA. Capn4 expression was further examined by immunohistochemistry in a tissue microarray consisting of 140 ICC patients and 13 normal liver tissues, and the prognostic role of Capn4 in ICC was evaluated by Kaplan-Meier and Cox regression analyses.

Results

Capn4 expression was significantly higher in the ICC tissues compared to the peritumor tissues. Capn4 down-regulation impaired the migration/invasion ability of HCCC-9810 and QBC939 cells in vitro and decreased MMP2 expression. Capn4 overexpression significantly correlated with the presence of lymphatic metastasis of ICC (p = 0.026) and the tumor-node-metastasis (TNM) stage (p = 0.009). The postoperative 2- and 5-year overall survivals in patients with Capn4^low were higher than those in the Capn4^high group. The cumulative recurrence rate in patients with Capn4^low was much lower than in the Capn4^high group. Multivariate analysis showed that Capn4 overexpression was an independent prognostic marker in ICC.

Conclusions

Capn4 overexpression was implicated in ICC metastasis/invasion, and Capn4 overexpression may be used as a molecular therapeutic target for ICC.     

Prognostic Significance of Overexpressed p16INK4a in Patients with Cervical Cancer: A Meta-Analysis

Background

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.

Methods

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.

Results

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).

Conclusions

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.     

The Prognostic Significance of Metabolic Response Heterogeneity in Metastatic Colorectal Cancer

Background

Tumoral heterogeneity is a major determinant of resistance in solid tumors. FDG-PET/CT can identify early during chemotherapy non-responsive lesions within the whole body tumor load. This prospective multicentric proof-of-concept study explores intra-individual metabolic response (mR) heterogeneity as a treatment efficacy biomarker in chemorefractory metastatic colorectal cancer (mCRC).

Methods

Standardized FDG-PET/CT was performed at baseline and after the first cycle of combined sorafenib (600mg/day for 21 days, then 800mg/day) and capecitabine (1700 mg/m²/day administered D1-14 every 21 days). MR assessment was categorized according to the proportion of metabolically non-responding (non-mR) lesions (stable FDG uptake with SUVmax decrease <15%) among all measurable lesions.

Results

Ninety-two patients were included. The median overall survival (OS) and progression-free survival (PFS) were 8.2 months (95% CI: 6.8–10.5) and 4.2 months (95% CI: 3.4–4.8) respectively. In the 79 assessable patients, early PET-CT showed no metabolically refractory lesion in 47%, a heterogeneous mR with at least one non-mR lesion in 32%, and a consistent non-mR or early disease progression in 21%. On exploratory analysis, patients without any non-mR lesion showed a significantly longer PFS (HR 0.34; 95% CI: 0.21–0.56, P-value <0.001) and OS (HR 0.58; 95% CI: 0.36–0.92, P-value 0.02) compared to the other patients. The proportion of non-mR lesions within the tumor load did not impact PFS/OS.

Conclusion

The presence of at least one metabolically refractory lesion is associated with a poorer outcome in advanced mCRC patients treated with combined sorafenib-capecitabine. Early detection of treatment-induced mR heterogeneity may represent an important predictive efficacy biomarker in mCRC.

Trial Registration

ClinicalTrials.gov NCT01290926