Significant Prognostic Effect Research Articles

Treatment and survival of glioblastoma patients in Denmark: The Danish Neuro-Oncology Registry 2009-2014.

As many glioblastoma patients are in a poor condition they are unable to undergo the full treatment documented in clinical trials. We aimed to examine the survival and its relationship to clinical characteristics and treatment in a nationwide population of glioblastoma patients in Denmark. We included prospectively recorded clinical data from 1364 adult patients with histologically verified glioblastoma from the Danish Neuro-Oncology Registry, 2009-2014. The age standardized incidence rate was 6.3/100,000 person-years for males and 3.9 for females and the median age was 66years. The median overall survival was 11.2months. There was an independently significant prognostic effect of age, performance status, cognitive symptoms, tumor diameter, multifocality, crossing midline, and contrast enhancement. For partial and total resection compared to biopsy only, the adjusted risk of dying was reduced by 43% (HR [CI] 0.57 [0.48-0.68]) and 51% (0.49 [0.40-0.60]), respectively. For patients receiving a partial and full radiochemotherapy regimen compared to no postsurgical treatment, the risk reduction was 56% (HR [CI] 0.44 [0.37-0.53]) and 70% (0.30 [0.25-0.35]), respectively. The full radiochemotherapy regimen was only allocated to 50% of the patients, 29% among the oldest (70+ years) and 60% among the younger (18-69years). Glioblastoma patients had a poor overall survival but with several specific independent prognostic factors. Extensive cancer treatment was associated with an increasing survival in all age groups, but only half of the patients were sufficiently fit for a full regimen of postoperative combined radiochemotherapy.

Aquaporin 1 expression is associated with response to adjuvant chemotherapy in stage II and III colorectal cancer.

Aquaporin 1 (AQP1), which functions as a water transporter, is associated with cancer cell proliferation, invasion, metastasis and angiogenesis in numerous types of solid cancer, including colorectal cancer (CRC). The focus of the present study was to address the potential clinical use of AQP1 expression in CRC as a prognostic and predictive biomarker for disease recurrence and therapeutic outcomes. The current study investigated the expression of AQP1 in surgically resected specimens from 268 patients with stage 0-IV CRC. AQP1 expression was positive in 112 (41.8%) patients, and was significantly associated with left-sided tumors (P<0.01) and with aggressive tumor phenotypes, including depth of invasion (P=0.03), lymph node metastasis (P=0.03), lymphatic invasion (P<0.01) and venous invasion (P<0.01). However, AQP1 expression had no significant prognostic effect on disease-free survival (DFS) in patients with stage II and III CRC following curative surgery. In 84 stage II and III patients who were administered 5-fluorouracil-based adjuvant chemotherapy, positive AQP1 expression was associated with an increased DFS rate compared with that of AQP1-negative patients (P=0.05). Additionally, these results identified that receiving adjuvant chemotherapy was not beneficial to patients with AQP1-negative tumors. This suggests that the expression of AQP1 may be a candidate biomarker predictive of response to 5-fluorouracil-based adjuvant chemotherapy following surgery in patients with stage II and III CRC.

Validation of the postneoadjuvant therapy pathological stage of the American Joint Committee on Cancer (AJCC) 8th Edition for predicting outcomes of esophageal squamous cell carcinoma (ESCC) patients receiving neoadjuvant chemoradiotherapy (CRT) followed by esophagectomy.

138 Background: The AJCC 8th edition staging system introduces a new postneoadjuvant therapy staging category (ypTNM-8th) for ESCC patients receiving neoadjuvant treatment followed by esophagectomy. Whether this new staging category has better prognostic prediction than the pathological staging category of AJCC 7th edition (ypTNM-7th) needs validation. Methods: We enrolled ESCC patients receiving neoadjuvant paclitaxel/cisplatin-based CRT (RT = 40Gy) followed by esophagectomy from three phase II trials conducted in the National Taiwan University Hospital. The prognostic prediction abilities of the ypTNM-8th and the ypTNM-7th on patients’ survivals were compared using Cox regression, concordance index (C-index), R-square, and Akaike information criteria (AIC). Results: A total 135 patients (M:F = 127: 8, median age:53.0 years) were enrolled. With a median follow-up of 31.3 months, the median PFS and OS of all patients were 24.4 months (95% CI: 15.4-33.5) and 33.9 months (95% CI: 22.6-45.1), respectively. In univariate analysis, both ypTNM-8th and ypTNM-7th had statistically significant prognostic effects for PFS and OS. In multivariate analysis on OS, the ypTNM-8th demonstrated a statistically significant predicting effect (P = 0.015) while the ypTNM-7th did not (P = 0.051). Although there is no statistically different between ypTNM-8th and ypTNM-7th by R-square analysis, the ypTNM-8th had lower AIC and C-index for both PFS and OS, meaning an better efficiency of predicting survivals, than ypTNM-7th. Conclusions: The new ypTNM-8th may have better prognostic prediction for OS of locally advanced ESCC patients receiving neoadjuvant CRT than the ypTNM-7th. (Granted by 106-HCH029)

The importance of stromal and intratumoral tumor lymphocyte infiltration for pathologic complete response in patients with locally advanced breast cancer.

Increased tumor-infiltrating lymphocytes (TILs) in breast carcinoma tissues is an independent predictive factor for pathologic complete response (pCR). The increased intratumoral and stromal TILs (sTILs) in breast cancer (BC) have significant prognostic effects. In this study, we evaluated whether pCR rates to neoadjuvant chemotherapy (NACT) are higher in tumors with increased number of TILs in the pretreatment biopsy. We retrospectively evaluated the number of TILs in intratumoral TILs (iTILs) and sTILs compartments from pretreatment full-face hematoxylin and eosin-stained sections of 62 patients with locally advanced BC (LABC) who received NACT. The capacity of sTILs and iTILs in predicting pCR to NACT in LABC analyzed using receiver operating characteristic (ROC) curve analysis. According to ROC curve analysis, the optimum sTILs and iTILs cut-off points (the number of positive cells per square millimeter of tissue) for patients with LABC patients with pCR (+) were 19 (area under the curve (AUC): 0.668, 95% confidence interval [CI] [0.501-0.835],P = 0.064) and 4 (AUC: 0.786, 95%CI [0.666-0.907],P = 0.002), respectively. Of the 62 patients, 26 had sTILs >19 and 25 had iTILs >4. The patients were divided into two according to percent of sTILs (sTILs >19 and sTILs ≤19 groups) and iTILs (iTILs >4 and iTILs ≤4 groups). Both sTILs >19 and iTILs >4 patients were associated with development higher pCR. While pCR was significantly higher in iTILs >4 patients (P = 0.002), it was not significantly in sTILs >19 patients (P = 0.107). There is significantly an association between pCR and increased number of intratumoral TILs (>4 cells/mm 2 of tissue) in BC who received NACT.

Prognostic and Clinicopathological Value of Rac1 in Cancer Survival: Evidence from a Meta-Analysis.

Purpose: The role of Rac1 in cancer survival has been widely studied. However, the prognostic and clinicopathological value of Rac1 remains inconclusive. We performed a meta-analysis to clarify the role of Rac1 in cancer survival as well as its association with clinicopathological features.Methods: Eligible studies were searched from PubMed, Cochrane Library, Embase, and Web of Science databases. The pooled hazard ratios (HRs) and odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were used to detect the prognostic and clinicopathological role of Rac1.Results: A total of 14 studies including 1793 patients were enrolled in the present meta-analysis. Pooled HR for overall survival (OS) (HR=2.02, 95% CI: 1.70-2.39) and disease-free survival (DFS) (HR=2.64, 95% CI: 1.71-4.09) indicated a significant poor prognostic effect for Rac1. Positive Rac1 expression was found to be correlated with tumor stage, blood vessel invasion, and lymph metastasis, but not with histological differentiation. Sensitivity test showed no single study altered OS or DFS significantly. No publication bias was detected by Egger's test and Begg's funnel plot test.Conclusion: This meta-analysis indicated that Rac1 could be used as a potential marker to predict cancer prognosis. Additionally, Rac1 expression was associated with the malignancy-related phenotype.

Outcomes in women with invasive ductal or invasive lobular early stage breast cancer treated with anastrozole or exemestane in CCTG (NCIC CTG) MA.27

BackgroundHistological subtype, (invasive ductal breast cancer (IDBC)/invasive lobular breast cancer (ILBC)), might be a marker for differential response to endocrine therapy in breast cancer. MethodsClinical trial MA.27 compared 5 years of adjuvant anastrozole or exemestane in postmenopausal patients with hormone receptor positive early breast cancer. We evaluated IDBC versus ILBC (based on original pathology reports) as predictor for event-free survival (EFS) and overall survival (OS). ResultsA total of 5709 patients (5021 with IDBC and 688 with ILBC) were included (1876 were excluded because of missing or other histological subtype). Median follow-up was 4.1 years. Overall, histological subtype did not influence OS or EFS (HR (hazard ratio) 1.14, 95% confidence interval (CI) [0.79–1.63], P = 0.49 and HR 1.04, 95% CI [0.77–1.41], P = 0.81, respectively). There was no significant difference in OS between treatment with exemestane versus treatment with anastrozole in the IDBC group (HR = 0.92, 95% CI [0.73–1.16], P = 0.46). In the ILBC group, a marginally significant difference in favour of treatment with anastrozole was seen (HR = 1.79, 95% CI [0.98–3.27], P = 0.055). In multivariable analysis a prognostic effect of the interaction between treatment and histological subtype on OS (but not on EFS) was noted, suggesting a better outcome for patients with ILBC on anastrozole (HR 2.1, 95% CI [0.99–4.29], P = 0.05). After stepwise selection in the multivariable model, a marginally significant prognostic effect for the interaction variable (treatment with histological subtype) on OS (but not on EFS) was noted (Ratio of HR 2.1, 95% CI [1.00–4.31], P = 0.05). ConclusionOur data suggest an interaction effect between treatment and histology (P = 0.05) on OS. Here, patients with ILBC cancers had a better OS when treated with anastrozole versus exemestane, whereas no difference was noted for patients with IDBC. Clinical Trial informationNCT00066573.

Impact of tumor burden on prognostic prediction for patients with terminal stage hepatocellular carcinoma: A nomogram study.

BackgroundThe recently proposed nomogram of Barcelona Clinic Liver Cancer (BCLC) lacks predictive accuracy for patients with stage D hepatocellular carcinoma (HCC). Tumor burden is crucial in prognostic prediction but is not included in the criteria of stage D HCC. This study aims to develop a nomogram with tumor burden as the core element for BCLC stage D patients.MethodsA total of 386 patients were randomly grouped into derivation and validation sets (1:1 ratio). The multivariate Cox proportional hazards model was used to select factors with significant prognostic effect and generate the nomogram. Concordance indices and calibration plots were used to evaluate the performance of nomogram.ResultsOverall survival of study patients was significantly associated with tumor burden as well as hepatitis B, serum α-fetoprotein level, cirrhosis and performance status in multivariate Cox regression (all p<0.05). Beta-coefficients of these variables in derivation set were used to generate the nomogram. Each patient was assigned with a total nomogram point that predicted individualized 6-month and 1-year survival. The derivation and validation sets had a c-index of 0.759 (95% confidence interval [CI]: 0.552–0.923) and 0.741 (95% CI: 0.529–0.913), respectively. The calibration plots were close to the 45-degree line for 6-month and 1-year survival prediction for all quarters of patients in both derivation and validation sets.ConclusionTumor burden is significantly associated with the outcome for patients with stage D HCC. The tumor burden-incorporated nomogram may serve as a feasible and easy-to-use tool in predicting survival on an individual level.

Expression and prognosis analyses of the Tob/BTG antiproliferative (APRO) protein family in human cancers.

BackgroundDespite advances in early diagnosis and treatment, cancer remains the major cause of mortality in the world. The Tob/BTG antiproliferative (APRO) protein family is reported to participate in diverse human diseases. However, there’s little known about their expression and prognostic values in most human cancers.MethodsWe performed a detailed cancer vs. normal analysis. The mRNA expression levels of APRO family in various cancers were analyzed via the Oncomine database. Moreover, the Kaplan-Meier Plotter and PrognScan databases were used to evaluate the prognostic values.ResultsWe observed that the mRNA expression levels of TOB1-2 and BTG2 were decreased in most cancers compared with normal tissues, while BTG3 was upregulated in most cancers. In survival analyses based on Kaplan-Meier Plotter, TOB1, BTG1 and BTG4 showed significant associations with survival outcome of different subtypes of breast cancer. Decreased BTG2 was related with poor relapse free survival (RFS) in all subtypes of breast cancer. Especially, besides RFS, reduced BTG2 also indicated worse overall survival and distant metastasis free survival in breast cancer patients who were classified as luminal A. Significant prognostic effects of the whole APRO family were also found in lung adenocarcinoma, but not in squamous cell lung carcinoma. In addition, potential correlations between some APRO family members and survival outcomes were also observed in ovarian, colorectal and brain cancer.ConclusionsSome members of APRO family showed significant expression differences between cancer and normal tissues, and could be prognostic biomarkers for defined cancer types.

1725P - Impact of global epigenetics machinery on clinical outcome of colorectal cancer patients treated with fluoropyrimidine-based therapy

Background: The pathogenesis of colorectal cancer (CRC) is complex and influenced by many factors related to genetic, epigenetics and chronic inflammatory processes. Methods: This is a prospective study, conducted on 102 Egyptian patients, diagnosed with CRC. Blood samples were collected at baseline and after 3 & 6 months of receiving fluoropyrimidine (FP) based therapy. DNA methylation was measured by LC/MS/MS spectroscopy, acetylated histones (H3) and (H4) were measured by ELISA and RNA expression of FP metabolizing enzymes (TS, TP and DPD), DNA methyl transferases (DNMT3A and B) in addition to inflammatory markers (COX2, IL6, and IL1B) by qRT-PCR. Results: The median age of the studied patients was 46 years, 47% of them were ≤ 45 years. Forty patients (38.8%) had rectal cancer, they exhibited significant H3 hyperacetylation and upregulation of COX2 and IL1B along with significantly lower median overall survival compared to colonic patients (14.6 versus 23 months respectively). FP therapy produced significant decrease in global methylation, acetylated H3 & H4 levels, downregulation in TP and DNMT3B but significant upregulation in TS and DPD over treatment time. Significant positive correlations were found between global methylation and IL1B (r2= 0.25, P = 0.01), acetylated H3 with DPD and COX2 (r2= 0.28, P = 0.02 and r2= 0.27, P = 0.03 respectively) and 5 methylated cytosine content (5MC) with DNMT3A and IL6 (r2= 0.25, P = 0.04 and r2= 0.34, P = 0.004 respectively). Overexpression of COX2 > 17 had a significant poor prognostic effect on overall and event free survivals (HR = 0.58, P = 0.003 and HR = 0.72, P = 0.008 respectively). Also patients who had global methylation> 30 showed significant reduced event free survival by 39% (P = 0.04). Conclusions: Global methylation and H3 acetylation regulated COX2, IL6 and IL1B which were not affected by the therapy, however H3 upregulated TS and DPD. Rectal cancer patients showed significant H3 hyperacetylation, upregulation of COX2 and IL1B along with significant lower overall survival. Legal entity responsible for the study: National Cancer Institute, Cairo University Funding: National Cancer Institute, Cairo University Disclosure: All authors have declared no conflicts of interest.

Role of Cytotoxic Tumor-Infiltrating Lymphocytes in Predicting Outcomes in Metastatic HER2-Positive Breast Cancer

Accumulating evidence indicates that tumor-infiltrating lymphocytes (TILs) are associated with clinical outcomes and may predict the efficacy of chemotherapy and human epidermal growth factor receptor 2 (HER2, encoded by the gene ERBB2)-targeted therapy in patients with HER2-positive breast cancer. To investigate the role of TILs, particularly cytotoxic CD8+ T cells, in the prediction of outcomes in patients with HER2-positive metastatic breast cancer randomized to an antibody-based (trastuzumab) vs a small molecule-based (lapatinib) anti-HER2 therapy. The Canadian Cancer Trials Group MA.31 phase 3 clinical trial accrued patients from 21 countries and randomized 652 with HER2-positive metastatic breast cancer to receive trastuzumab or lapatinib, in combination with a taxane, from January 17, 2008, through December 1, 2011. Patients had received no prior chemotherapy or HER2-targeted therapy in the metastatic setting. The median follow-up was 21.5 months (interquartile range, 14.3-31.0). The tumor tissue collected for primary diagnosis was used in this ad hoc substudy. Sections were scored for TILs on hematoxylin-eosin (H&E)-stained sections, and immunohistochemical analysis was performed to assess CD8, FOXP3, CD56, and programmed cell death protein 1 (PD-1) expression on stromal (sTILs) and intratumoral TILs. Data were analyzed from July 15, 2015, through July 27, 2016. Treatment with trastuzumab or lapatinib in combination with taxane chemotherapy (paclitaxel or docetaxel) for 24 weeks. Prognostic effects of biomarkers were evaluated for progression-free survival by stratified univariate log-rank test with Kaplan-Meier curves and by multivariate Cox proportional hazards regression; predictive effects were examined with a test of interaction between treatment allocation and biomarker classification. Of the 647 treated women (mean [SD] age, 55.0 [10.8] years), 614 had tumor tissue samples scored for H&E sTILs and 427 for CD8 biomarker assessments. Overall H&E sTIL counts of greater than 5% (high) were present in 215 cases (35%) but did not show significant prognostic or predictive effects. Univariate stratified analyses detected a significant predictive effect on risk for progression with lapatinib compared with trastuzumab among patients with low CD8+ sTIL counts (observed hazard ratio, 2.94; 95% CI, 1.40-6.17; P = .003) and among those with high CD8+ sTIL counts (observed hazard ratio, 1.36; 95% CI, 1.05-1.75; P = .02), confirmed in stepwise multivariate analysis (interaction P = .04). Other immunohistochemistry biomarkers were not associated with prognostic or predictive effects. In this secondary analysis of a phase 3 randomized clinical trial, a low level of preexisting cytotoxic sTILs predicted the most benefit from an antibody- vs a small molecule-based drug against the same target. clinicaltrials.gov Identifier: NCT00667251.

The impact of MET, IGF-1, IGF1R expression and EGFR mutations on survival of patients with non-small-cell lung cancer.

IntroductionTo compare the efficacy of silver in situ hybridization (SISH) and immunohistochemistry (IHC) in detecting MET and IGF1R alterations and to investigate their prevalence and prognostic significance. A possible correlation between MET receptor expression, MET gene alterations and the two most frequent occurring EGFR gene mutations was also investigated.Materials and methodsStage I to IIIA tumors from 326 patients with NSCLC were immunohistochemically tested for protein expression of MET and IGF-1. Their cytoplasmic expression was compared with the gene copy number of the MET and IGF1Rgenes by SISH in paraffin-embedded, formalin-fixed material. Correlations were made with the immunohistochemical expression of two frequent EGFR mutations and clinicopathological variables. Univariate and multivariate survival analyses was used to evaluate the prognostic efficacy of the tested markers.ResultsIn univariate analyses, high cytoplasmic MET expression showed a significant negative prognostic effect in adenocarcinoma patients (p = 0.026). MET gene to chromosome 7 ratio was a significant positive prognostic marker (p = 0.005), probably only due to the highly negative prognostic significance of chromosome 7 polysomy (p = 0.002). High IGF1R gene copy number was a negative prognostic marker for all NSCLC patients (p = 0.037). In the multivariate analysis, polysomy of chromosome 7 in tumor cells correlated significantly and independently with a poor prognosis (p = 0.011). In patients with adenocarcinoma, a high cytoplasmic MET expression was an independent negative prognostic marker (p = 0.013). In males a high IGF1R gene copy number to chromosome 15 count ratio was significantly and independently correlated to a poor prognosis (p = 0.018).ConclusionMET protein expression provides superior prognostic information compared with SISH. Polysomy of chromosome 7 is an independent negative prognostic factor in NSCLC patients. This finding has an important implication while examining genes located on chromosome 7 by means of SISH. High IGF1R gene copy number to chromosome 15 count ratio is an independent predictor of inferior survival in male patients with primary NSCLC.

Association between insulin-like growth factor-1 receptor (IGF1R) expression in circulating tumor cells (CTCs) and prognosis in patients with metastatic breast cancer (MBC).

1086 Background: CTCs are strongly associated with prognosis in MBC. In a recent metanalysis on 1944 patients, a CTC count &gt; 5/7.5 ml was associated with a 2-fold increased risk of progression and death. Little evidence is available on the prognostic role of phenotypic CTC assessment, however. In this study, nested in a randomized clinical trial of Ist line chemotherapy ± metformin, we evaluated the prognostic role of IGF1R expression in CTCs, given its potential growth promoting effect. Methods: CTCs were isolated from blood samples of enrolled patients; an automated sample preparation and analysis system (CellSearch) was customized for detecting IGF1R positive CTCs. The prognostic role of total CTCs, IGF1R positive (+ve) and negative (-ve) CTCs was assessed by fitting different PFS and OS multivariate Cox’s models.Results: CTC evaluation at baseline was performed in 72 of 126 patients, of whom 30 (42%) had CTCs ≥5/7,5ml and 41 (57%) had at least one IGF1R+ve CTC. In univariate analysis the prognostic role of total CTCs was confirmed: PFS ( &lt; 5 vs ≥5) HR = 1.69, 95%CI 1.01-2.69, p 0.042 and OS HR = 2.80, 95%CI 1.47-5.30, p 0.002).However, when total CTCs were split in IGF1R+ve and IGF1R–ve, a striking difference was seen in the prognostic effect of these cell types.While no association was detected between an increasing number of IGF1R+ve CTCs and PFS or OS (p = 0.56 and p = 0.99), the number of IGF1R-ve CTCs ( &lt; 4 vs ≥4) was strongly associated with an increased risk of progression and death: HR 1.93 (95%CI 1.15-3.23, p 0.013) and 3.65 (95%CI 1.88-7.09, p 0.001). In multivariate analysis, adjusted for metformin, the prognostic role of the number of IGF1R-ve CTCs was confirmed, while no residual prognostic role of total CTCs or number of IGF1R+ve cells was found (p = 0.55 and p = 0.64 for PFS; p = 0.86 in both cases for OS). Conclusions: In our study, the loss of IGF1R expression in CTCs exhibited a significant adverse prognostic effect, whereas no significant effect of total CTCs and IGF1R+ve CTCs was observed. This finding supports the biological characterization of CTCs as a critical step for further definition of their prognostic significance.

A propensity score analysis exploring the impact of adjuvant chemotherapy (aCT) in a multi-center series of resected early stage pure invasive lobular breast carcinoma (ILC).

539 Background: Patients (pts) resected for early breast cancer are assigned to receive aCT according to international guidelines based upon immunophenotype and clinical/pathological features, regardless of the histotype, given the lack of prospective data for ILC. Thus, the magnitude of the benefit of aCT for ILC is still not sizable. The aim of this analysis was to investigate the effect of aCT in a multi-center series of early stage pure ILC. Methods: Clinical-pathological data of consecutive pts affected by pure ILC, undergone surgery at 3 Italian institutes, were correlated with disease-free and overall survival (DFS/OS) using a Cox model. A propensity score analysis was performed to evaluate the prognostic impact of aCT. Kaplan-Meier curves were compared with Log-Rank analysis. Results: Data from 739 pts were gathered (median age 57 years (yrs); Luminal/Triple-Negative/HER2 pos.: 98%/1.6%/0.4%). At median follow-up of 78 months, 5-/10-yrs DFS and OS were 79.4%/66.0% and 91.4%/76.5%, respectively. Tumor-size according to TNM (T, HR 1.34, 95% CI 1.04-1.72, p=0.025) and lymph-node (N) status (HR 2.39, 95% CI 1.47-3.89, p&lt;0.0001) were independent predictors for DFS at multivariate analysis. T (HR 1.87, 95% CI 0.99-3.54, p=0.05), N status (HR 3.24, 95% CI 1.69-6.22, p&lt;0.0001), Ki67 (HR 2.48, 95% CI 0.95-6.42, p=0.06), and age (HR 2.23, 95% CI 1.16-4.30, p=0.016) were predictors for OS. A significant prognostic effect of aCT upon OS was found after adjusting for independent factors with the propensity score method, as shown in the table below. Particularly, aCT significantly prolongs OS and DFS in pts with T &gt;1, with an absolute difference of 17%/35% and 15%/13% at 5 and 10 yrs, respectively ( p=0.003 and p=0.04). OS was longer for pts with positive N ( p=0.02), Ki67 &gt;4% ( p=0.01) and grading &gt;1 ( p=0.01). Conclusions: Despite the retrospective nature of this analysis, the propensity score analysis indicates that pts with ILC may significantly benefit from aCT in terms of long-term survival, particularly for larger and more aggressive tumors. [Table: see text]

Negative prognostic effect of low nuclear GLI1 expression in glioblastomas.

The hedgehog signaling plays supportive roles in various aspects of tumorigenesis. Increased expression of the key component, GLI1, has been shown to correlate with poor prognosis in many types of cancers. We aimed to investigate the effect of GLI1 expression in glioblastoma focusing on the nuclear localization. Immunohistochemistry for GLI1, GLI2, PTCH1, SMO, and SHH were done in 140 glioblastoma tissues, and the staining was graded. For GLI1, nuclear and cytoplasmic expression was separately assessed. No significant correlation was found between clinicopathologic parameters and expression grades of the five proteins. Low nuclear GLI1 expression was associated with a worse progression-free survival while overall survival was not significantly affected. In contrast, cytoplasmic GLI1 expression did not have a prognostic effect. PTCH1 expression correlated with nuclear GLI1 expression without exerting a significant prognostic effect. Analysis of the TCGA-glioblastoma dataset revealed that low GLI1 mRNA level also correlated with a poor prognosis for both overall and progression-free survival. The adverse effect of low nuclear GLI1 expression in glioblastomas is in contrast with the negative prognostic effect of high GLI1 expression reported in non-cranial malignancies. The relative impact of hedgehog signaling among other oncogenic pathways in the brain may be responsible for the difference. The different implication of GLI1 expression in glioblastomas needs to be considered in studies of hedgehog signaling-targeted therapy.

Absent progesterone receptor expression in the lymph node metastases of ER-positive, HER2-negative breast cancer is associated with relapse on tamoxifen

AimsProgesterone receptor (PR) expression is prognostic in early stage breast cancer. There are several reports of discordant expression between primary tumour and axillary lymph node (ALN) metastasis expression of oestrogen...

The prognostic role of pretreatment epidermal growth factor receptor T790M mutation in advanced non-small cell lung cancer patients treated with EGFR tyrosine kinase inhibitors.

PurposeThe outcome of pretreatment epidermal growth factor receptor (EGFR) T790M mutation in EGFR mutant non-small cell lung cancer (NSCLC) patients treated with EGFR tyrosine kinase inhibitors (TKIs) is controversial, this study aimed to evaluate the prognostic role of pretreatment T790M in advanced NSCLC patients treated with EGFR TKIs.ResultsA total of 7 eligible studies containing 179 cases and 281 controls were included in the meta-analysis. The pooled hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) were 2.21 (95% CI 1.49-3.29, P<0.001) and 1.24 (95% CI 0.90-1.71, P=0.186), respectively. We also did subgroup analyses on OS and PFS according to patients from various districts.MethodsIdentified literatures from various databases were reviewed. A meta-analysis was performed to evaluate the prognostic role of pretreatment EGFR T790M in advanced EGFR mutant patients treated with EGFR TKIs.ConclusionsPretreatment T790M may be a poor prognostic factor for PFS in advanced NSCLC patients treated with EGFR TKIs. However, no significant prognostic effect was found between pretreatment T790M mutation and OS. More studies are needed to demonstrate the prognostic role of pretreatment T790M mutation in advanced NSCLC patients.

KRAS-mutation incidence and prognostic value are metastatic site-specific in lung adenocarcinoma: poor prognosis in patients with KRAS mutation and bone metastasis

Current guidelines lack comprehensive information on the metastatic site-specific role of KRAS mutation in lung adenocarcinoma (LADC). We investigated the effect of KRAS mutation on overall survival (OS) in this setting. In our retrospective study, 500 consecutive Caucasian metastatic LADC patients with known KRAS mutational status were analyzed after excluding 32 patients with EGFR mutations. KRAS mutation incidence was 28.6%. The most frequent metastatic sites were lung (45.6%), bone (26.2%), adrenal gland (17.4%), brain (16.8%), pleura (15.6%) and liver (11%). Patients with intrapulmonary metastasis had significantly increased KRAS mutation frequency compared to those with extrapulmonary metastases (35% vs 26.5%, p = 0.0125). In contrast, pleural dissemination and liver involvement were associated with significantly decreased KRAS mutation incidence (vs all other metastatic sites; 17% (p < 0.001) and 16% (p = 0.02) vs 33%, respectively). Strikingly, we found a significant prognostic effect of KRAS status only in the bone metastatic subcohort (KRAS-wild-type vs KRAS-mutant; median OS 9.7 v 3.7 months; HR, 0.49; 95% CI, 0.31 to 0.79; p = 0.003). Our study suggests that KRAS mutation frequency in LADC patients shows a metastatic site dependent variation and, moreover, that the presence of KRAS mutation is associated with significantly worse outcome in bone metastatic cases.

Prognostic Effect of Albumin-to-Globulin Ratio in Patients with solid tumors: A Systematic Review and Meta-analysis.

Background: Albumin and globulin are main components of serum protein. The level of albumin and globulin partially represents the nutrition status and immune system. Albumin-to-globulin ratio (AGR) has been reported as a prognostic factor in various cancers. We therefore performed a meta-analysis to elucidate the prognosis effect of AGR on survival outcomes in solid tumors.Method: Six electronic database were searched for the relevant articles that assessing the prognostic value of pre-treatment AGR in solid tumor patients. The primary outcome was overall survival (OS) and the secondary outcomes were cancer-specific survival (CSS), disease-free survival (DFS) and disease-metastasis-free survival (DMFS). The time-to-event outcomes were summarized in hazard ratio (HR) and 95% confidence interval (CI).Result: A total of 13890 solid tumor patients in 24 studies were included. The AGR higher than the cut-off values ranging from 1.15-1.75 was related to better OS (HR=0.58, 95%CI 0.537-0.626, p<0.0001), CSS (HR=0.287, 95%CI 0.187-0.438, p<0.0001), DFS (HR=0.792, 95%CI 0.715-0.878, p<0.0001) and DMFS (HR=0.595, 95%CI 0.447-0.792, p<0.0001). According to the cut-off values, subgroup analysis showed that AGR had significant prognostic effect on OS in each cut-off intervals (≤1.20, 1.20-1.40 and ≥1.40).Conclusion: Pre-treatment AGR is an effective prognostic factor and high AGR represents an ideal clinical outcome in the solid tumor patients.

Significant association and synergistic adverse prognostic effect of podocalyxin-like protein and epidermal growth factor receptor expression in colorectal cancer.

BackgroundPodocalyxin-like 1 (PODXL) is an anti-adhesive transmembrane protein that has been demonstrated to be an independent factor of poor prognosis in colorectal cancer (CRC). The gene encoding PODXL is located to chromosome 7, which also harbours the gene for the epidermal growth factor receptor (EGFR). The aim of this study was to examine the associations between PODXL and EGFR expression in CRC in vitro and in vivo.MethodsEGFR expression was analysed in tumours from three independent patient cohorts; cohort 1 (n = 533), cohort 2 (n = 259) and cohort 3 (n = 310), previously analysed for immunohistochemical PODXL expression and KRAS and BRAF mutations (cohort 1 and 3). Levels of EGFR and PODXL were determined by western blot in six different CRC cell lines.ResultsHigh expression of PODXL was significantly associated with high EGFR expression (p < 0.001) in all three cohorts, and with BRAF mutation (p < 0.001) in cohort 1 and 3. High EGFR expression correlated with BRAF mutation (p < 0.001) in cohort 1. High EGFR expression was associated with adverse clinicopathological factors and independently predicted a reduced 5-year overall survival (OS) in cohort 1 (HR 1.77; 95 % CI 1.27–2.46), cohort 2 (HR 1.58; 95 % CI 1.05–2.38) and cohort 3 (HR 1.83; 95 % CI 1.19–2.81). The highest risk of death within 5 years was observed in patients with tumours displaying high expression of both EGFR and PODXL in cohort 1 and 3 (HR 1.97; 95 % CI 1.18–3.28 and HR 3.56; 95 % CI 1.75–7.22, respectively). Western blot analysis showed a uniform expression of PODXL and EGFR in all six examined CRC cell lines.ConclusionsThe results from this study demonstrate that high expression of EGFR is an independent factor of poor prognosis in CRC. Moreover, strong links have been uncovered between expression of the recently proposed biomarker candidate PODXL with EGFR expression in CRC in vivo and in vitro, and with BRAF mutation in vivo. High expression of both PODXL and EGFR may also have a synergistic adverse effect on survival. These findings suggest a potential functional link in CRC between PODXL, EGFR and BRAF, all originating from chromosome 7, which may be highly relevant in the clinical setting and therefore merit future in-depth study.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0882-0) contains supplementary material, which is available to authorized users.

Clinical significance of molecular subtypes of breast cancer in patients aged over 60 years

Objective To retrospectively analyze the distribution percentage points of molecular subtypes of breast cancer and investigate its guiding significance in the prognosis and personalized therapy in patients with breast cancer aged over 60 years. Methods A retrospective analysis of all patients with invasive breast cancer aged over 60 years from January 2009 to June 2014 in Breast Center of Beijing Hospital was performed.Based on the immunohistochemical methods recommended in the St.Gallen International Expert Consensus Report 2013, the molecular subtypes of breast cancer in these patients were identified.All patients were followed up every 6 months after operation until December 2014.Clinical pathological characteristics and prognosis indexes in different molecular subtypes of breast cancer were evaluated. Results Totally 770 patients aged over 60 years with invasive breast cancer met the criterion.The luminal A, luminal B, human epidermal growth factor receptor 2(HER2)over-expression, triple- negative subtypes accounted for 29.1%(224 cases), 47.5%(366 cases), 6.5%(50 cases)and 16.9%(130 cases)of patients, respectively.The luminal A subtype of breast cancer had larger tumor size, more lymph node metastasis and more late TNM stage as compared with other subtypes(all P<0.01). Univariate and multivariate analysis showed that aged ≥80 years and the triple- negative molecular subtype were the independent poor prognostic factors for breast cancer(both P<0.05). The luminal A subtype of breast cancer had relatively good prognosis, while the triple- negative subtype had relatively poor prognosis. Conclusions Molecular subtypes have a significant prognostic effect on breast cancer in patients aged over 60 years, which suggests molecular subtype can be considered as a reference indicator in personalized therapy.Patients aged over 80 years has poor prognosis due to less rational treatment.The reasonable and target treatment based on the molecular subtype of breast cancer should be provided for patients aged over 80 years in clinical medicine. Key words: Breast neoplasms; Molecular subtype; Prognosis