Relationship Between the Use of Statins and Patient Survival in Colorectal Cancer: A Systematic Review and Meta-Analysis

Background

Studies have indicated that statins influence the risks and mortality rates of several types of solid tumors. However, the association between statin use and survival in patients with colorectal cancer (CRC) remains unclear.

Methods

We searched the PubMed and Embase databases for relevant studies published up to September 2014 that assessed statin use and CRC prognosis. The primary outcomes were overall survival (OS) and cancer-specific survival (CSS). The secondary outcomes were disease-free survival (DFS) and recurrence-free survival (RFS). Hazard ratios (HRs) and 95% confidence intervals (CIs) were extracted and pooled with Mantel–Haenszel random-effect modeling. All statistical tests were two-sided.

Results

Four studies on post-diagnosis statin therapy and five studies on pre-diagnosis statin use were included in our meta-analysis of 70,608 patients. Compared with the non-users, the patients with post-diagnosis statin use gained survival benefits for OS (HR 0.76; 95% CI: 0.68 to 0.85, P<0.001) and CSS (HR 0.70; 95% CI: 0.60 to 0.81, P<0.001). In addition, we observed that pre-diagnosis statin use prolonged the survival of patients with CRC for OS (HR 0.70; 95% CI: 0.54 to 0.91, P=0.007) and CSS (HR 0.80; 95% CI: 0.74 to 0.86, P<0.001). However, we did not observe a survival benefit for DFS (HR 1.13; 95% CI: 0.78 to 1.62, P=0.514) or RFS (HR 0.98; 95% CI: 0.36 to 2.70, P=0.975) in the CRC patients with post-diagnosis statin use.

Conclusions

Statin use before or after cancer diagnosis is related to reductions in overall and cancer-specific mortality in colorectal cancer survivors.     

Salivary MicroRNA in Pancreatic Cancer Patients

Background

Pancreatic cancer is the fourth leading cause of cancer death in Western countries, with the lowest 1-year survival rate among commonly diagnosed cancers. Reliable biomarkers for pancreatic cancer diagnosis are lacking and are urgently needed to allow for curative surgery. As microRNA (miRNA) recently emerged as candidate biomarkers for this disease, we explored in the present pilot study the differences in salivary microRNA profiles between patients with pancreatic tumors that are not eligible for surgery, precancerous lesions, inflammatory disease or cancer-free patients as a potential early diagnostic tool.

Methods

Whole saliva samples from patients with pancreatic cancer (n = 7), pancreatitis (n = 4), IPMN (n = 2), or healthy controls (n = 4) were obtained during endoscopic examination. After total RNA isolation, expression of 94 candidate miRNAs was screened by q(RT)PCR using Biomark Fluidgm. Human-derived pancreatic cancer cells were xenografted in athymic mice as an experimental model of pancreatic cancer.

Results

We identified hsa-miR-21, hsa-miR-23a, hsa-miR-23b and miR-29c as being significantly upregulated in saliva of pancreatic cancer patients compared to control, showing sensitivities of 71.4%, 85.7%, 85,7% and 57%, respectively and excellent specificity (100%). Interestingly, hsa-miR-23a and hsa-miR23b are overexpressed in the saliva of patients with pancreatic cancer precursor lesions. We found that hsa-miR-210 and let-7c are overexpressed in the saliva of patients with pancreatitis as compared to the control group, with sensitivity of 100% and 75%, and specificity of 100% and 80%, respectively. Last hsa-miR-216 was upregulated in cancer patients as compared to patients diagnosed with pancreatitis, with sensitivity of 50% and specificity of 100%. In experimental models of PDAC, salivary microRNA detection precedes systemic detection of cancer cells markers.

Conclusions

Our novel findings indicate that salivary miRNA are discriminatory in pancreatic cancer patients that are not eligible for surgery. In addition, we demonstrate in experimental models that salivary miRNA detection precedes systemic detection of cancer cells markers. This study stems for the use of salivary miRNA as biomarker for the early diagnosis of patients with unresectable pancreatic cancer.     

Statin Use Is Associated with Reduced Mortality in Patients with Interstitial Lung Disease

Introduction

We hypothesized that statin use begun before the diagnosis of interstitial lung disease is associated with reduced mortality.

Methods

We studied all patients diagnosed with interstitial lung disease in the entire Danish population from 1995 through 2009, comparing statin use versus no statin use in a nested 1:2 matched study.

Results

The cumulative survival as a function of follow-up time from the date of diagnosis of interstitial lung disease (n = 1,786+3,572) and idiopathic lung fibrosis (n = 261+522) was higher for statin users versus never users (log-rank: P = 7·10⁻⁹ and P = 0.05). The median survival time in patients with interstitial lung disease was 3.3 years in statin users and 2.1 years in never users. Corresponding values in patients with idiopathic lung fibrosis were 3.4 versus 2.4 years. After multivariable adjustment, the hazard ratio for all-cause mortality for statin users versus never users was 0.73 (95% confidence interval, 0.68 to 0.79) in patients with interstitial lung disease and 0.76 (0.62 to 0.93) in patients with idiopathic lung fibrosis. Results were robust in all sensitivity analyses.

Conclusion

Among patients with interstitial lung disease statin use was associated with reduced all-cause mortality.     

Improved Pancreatic Adenocarcinoma Diagnosis in Jaundiced and Non-Jaundiced Pancreatic Adenocarcinoma Patients through the Combination of Routine Clinical Markers Associated to Pancreatic Adenocarcinoma Pathophysiology

Background

There is still no reliable biomarker for the diagnosis of pancreatic adenocarcinoma. Carbohydrate antigen 19–9 (CA 19–9) is a tumor marker only recommended for pancreatic adenocarcinoma follow-up. One of the clinical problems lies in distinguishing between this cancer and other benign pancreatic diseases such as chronic pancreatitis. In this study we will assess the value of panels of serum molecules related to pancreatic cancer physiopathology to determine whether alone or in combination could help to discriminate between these two pathologies.

Methods

CA 19–9, carcinoembryonic antigen (CEA), C-reactive protein, albumin, insulin growth factor-1 (IGF-1) and IGF binding protein-3 were measured using routine clinical analyzers in a cohort of 47 pancreatic adenocarcinoma, 20 chronic pancreatitis and 15 healthy controls.

Results

The combination of CA 19–9, IGF-1 and albumin resulted in a combined area under the curve (AUC) of 0.959 with 93.6% sensitivity and 95% specificity, much higher than CA 19–9 alone. An algorithm was defined to classify the patients as chronic pancreatitis or pancreatic cancer with the above specificity and sensitivity. In an independent validation group of 20 pancreatic adenocarcinoma and 13 chronic pancreatitis patients, the combination of the four molecules classified correctly all pancreatic adenocarcinoma and 12 out of 13 chronic pancreatitis patients.

Conclusions

Although this panel of markers should be validated in larger cohorts, the high sensitivity and specificity values and the convenience to measure these parameters in clinical laboratories shows great promise for improving pancreatic adenocarcinoma diagnosis.     

Negative Impact of Skeletal Muscle Loss after Systemic Chemotherapy in Patients with Unresectable Colorectal Cancer

Background

Skeletal muscle depletion (sarcopenia) is closely associated with limited physical ability and high mortality. This study evaluated the prognostic significance of skeletal muscle status before and after chemotherapy in patients with unresectable colorectal cancer (CRC).

Methods

We conducted a retrospective analysis of 215 consecutive patients with unresectable CRC who underwent systemic chemotherapy. Skeletal muscle cross-sectional area was measured by computed tomography. We evaluated the prognostic value of skeletal muscle mass before chemotherapy and the rate of skeletal muscle change in cross-sectional area after chemotherapy.

Results

One-hundred-eighty-two patients met our inclusion criteria. There were no significant differences in progression-free survival (PFS) or overall survival (OS) associated with skeletal muscle mass before chemotherapy. However, 22 patients with skeletal muscle loss (>5%) after chemotherapy showed significantly shorter PFS and OS compared with those without skeletal muscle loss (PFS, log-rank p = 0.029; OS, log-rank p = 0.009). Multivariate Cox regression analysis revealed that skeletal muscle loss after chemotherapy (hazard ratio, 2.079; 95% confidence interval, 1.194–3.619; p = 0.010) was independently associated with OS.

Conclusions

Skeletal muscle loss after chemotherapy was an independent, negative prognostic factor in unresectable CRC.     

MicroRNA-486 as a Biomarker for Early Diagnosis and Recurrence of Non-Small Cell Lung Cancer

Background

Non-small cell lung cancer (NSCLC) is a leading cause of cancer death worldwide. Early diagnosis is essential for improvements of prognosis and survival of the patients. Currently, there is no effective biomarker available in clinical settings for early detection of lung cancer. Altered expressions in many cancer types including NSCLC and stable existence in plasma make microRNAs (miRNAs) a group of potentially useful biomarkers for clinical assessments of patients with NSCLC.

Objectives

To evaluate the potential values of miRNAs as blood-based biomarkers for early diagnosis and prognosis in NSCLC patients.

Methods

Peripheral blood samples from healthy volunteers and early-staged NSCLC patients before and after surgery were collected, and plasma was separated. Expression of ten miRNAs in the plasma and tumor sections of the patients was detected by quantitative real-time polymerase chain reaction.

Results

MiRNA (miR)-486 and miR-150 were found to significantly distinguish lung cancer patients from healthy volunteers. Area under curve of miR-486 and miR-150 were 0.926 (sensitivity, 0.909; specificity, 0.818) and 0.752 (sensitivity, 0.818; specificity, 0.818), respectively. In response to therapy, patients with down-regulated miR-486 expression showed prolonged recurrence-free survival than those with un-reduced miR-486 expression (median, unreached vs. 19 months; hazard ratio, 0.1053; 95% confidence interval, 0.01045 to 1.060; P=0.056).

Conclusions

The results suggest that miR-486 and miR-150 could be potential blood-based biomarkers for early diagnosis of NSCLC. Monitoring change of miR-486 expression in plasma might be an effective and non-invasive method for recurrence prediction of early-staged NSCLC patients.     

SIRT3 & SIRT7: Potential Novel Biomarkers for Determining Outcome in Pancreatic Cancer Patients

Purpose

The sirtuin gene family has been linked with tumourigenesis, in both a tumour promoter and suppressor capacity. Information regarding the function of sirtuins in pancreatic cancer is sparse and equivocal. We undertook a novel study investigating SIRT1-7 protein expression in a cohort of pancreatic tumours. The aim of this study was to establish a protein expression profile for SIRT1-7 in pancreatic ductal adenocarcinomas (PDAC) and to determine if there were associations between SIRT1-7 expression, clinico-pathological parameters and patient outcome.

Material and Methods

Immunohistochemical analysis of SIRT1-7 protein levels was undertaken in a tissue micro-array comprising 77 resected PDACs. Statistical analyses determined if SIRT1-7 protein expression was associated with clinical parameters or outcome.

Results

Two sirtuin family members demonstrated significant associations with clinico-pathological parameters and patient outcome. Low level SIRT3 expression in the tumour cytoplasm correlated with more aggressive tumours, and a shorter time to relapse and death, in the absence of chemotherapeutic intervention. Low levels of nuclear SIRT7 expression were also associated with an aggressive tumour phenotype and poorer outcome, as measured by disease-free and disease-specific survival time, 12 months post-diagnosis.

Conclusions

Our data suggests that SIRT3 and SIRT7 possess tumour suppressor properties in the context of pancreatic cancer. SIRT3 may also represent a novel predictive biomarker to determine which patients may or may not respond to chemotherapy. This study opens up an interesting avenue of investigation to potentially identify predictive biomarkers and novel therapeutic targets for pancreatic cancer, a disease that has seen no significant improvement in survival over the past 40 years.     

Marital status and survival in pancreatic cancer patients: a SEER based analysis

Background

Recent findings suggest that marital status affects survival in patients with different types of cancer. However, its role in the survival of patients with pancreatic ductal adenocarcinoma is unknown. In this study, we investigated whether there was an association between marital status and overall survival (OS) in patients with pancreatic ductal adenocarcinoma (PDAC).

Methods

Adult patients diagnosed with PDAC between 1998 and 2003 with known marital statuses were identified from the Surveillance, Epidemiology, and End Results registry of the National Cancer Institute. OS for these patients was plotted using the Kaplan-Meier method. Comparative risks of mortality were evaluated by using univariate and multivariate-adjusted Cox regression models.

Results

Using Kaplan-Meier analysis, we found that the median overall survival of patients was 4 months and 3 months (p<0.001) for married and unmarried patients, respectively. Subgroup analysis on patients with cancer-directed surgery showed that the median survival was 16 months and 13 months (P<0.0005) for married and unmarried groups, respectively. Multivariate analysis adjusting for age, race, sex, stage, year of diagnosis, radiation therapy and cancer-directed surgery showed that patients who were married at the time of diagnosis had a significantly decreased risk of death at both 2 months (15% risk reduction) and 3 years (13% risk reduction) post diagnosis.

Conclusions

Marital status is an independent prognostic factor of both perioperative and long-term survival in patients with PDAC. This observation may suggest a suboptimally met psychosocial need among PDAC patients that is partially fulfilled by the support system provided by marriage.     

Prognostic and Functional Significance of MAP4K5 in Pancreatic Cancer

Objectives

MAP4K5 plays an important role in regulating a range of cellular responses and is involved in Wnt signaling in hematopoietic cells. However, its functions in human malignancies have not been studied. The major objectives of this study are to examine the expression, functions and clinical significance of MAP4K5 in pancreatic ductal adenocarcinoma (PDAC).

Materials and Methods

The expression levels of MAP4K5, E-cadherin, vimentin, and carboxylesterase 2 (CES2) were examined by immunohistochemistry in 105 PDAC and matched non-neoplastic pancreas samples from our institution. The RNA sequencing data of 112 PDAC patients were downloaded from the TCGA data portal. Immunoblotting and RNA sequencing analysis were used to examine the expression of MAP4K5 and E-cadherin in pancreatic cancer cell lines. The effect of knockdown MAP4K5 using siRNA on the expression of CDH1 and vimentin were examined by Real-time RT-PCR in Panc-1 and AsPC-1 cells. Statistical analyses were performed using IBM SPSS Statistics.

Results

MAP4K5 protein is expressed at high levels specifically in the pancreatic ductal cells of 100% non-neoplastic pancreas samples, but is decreased or lost in 77.1% (81/105) of PDAC samples. MAP4K5-low correlated with the loss of E-cadherin (P = 0.001) and reduced CES2 expression (P = 0.002) in our patient populations. The expression levels of MAP4K5 mRNA directly correlated with the expression levels of CDH1 mRNA (R = 0.2490, P = 0.008) in the second cohort of 112 PDAC patients from The Cancer Genome Atlas (TCGA) RNA-seq dataset. Similar correlations between the expression of MAP4K5 and E-cadherin were observed both at protein and mRNA levels in multiple pancreatic cancer cell lines. Knockdown MAP4K5 led to decreased CDH1 mRNA expression in Panc-1 and AsPC-1 cells. MAP4K5-low correlated significantly with reduced overall survival and was an independent prognosticator in patients with stage II PDAC.

Conclusions

MAP4K5 expression is decreased or lost in majority of PDACs. The strong associations between low MAP4K5 expression and loss of E-cadherin, reduced CES2 expression and decreased overall survival may suggest an important role of MAP4K5 in epithelial-to-mesenchymal transition, chemotherapy resistance and tumor progression in pancreatic cancer. Targeting impaired MAP4K5 signaling may represent a new therapeutic strategy for pancreatic cancer.     

Characteristics of the Delayed or Refusal Therapy in Breast Cancer Patients: A Longitudinal Population-Based Study in Taiwan

Background

The evidence indicated breast cancer was a cancer with high survival rate. However, there were still some breast cancer patients delaying or refusing therapy. So we conducted a cohort study to explore the relationship between characteristics of breast cancer patients and delay or refusal of therapy within four months after cancer diagnosed.

Methods

This was a retrospective national population-based study from 2004 to 2010 in Taiwan. This study included 35,095 patients with new diagnosis breast cancer from Taiwan Cancer Registry Database. Several analysis methods, including t test, Chi-square test, generalized estimating equations of logistic regression analysis, and Cox proportional hazards model, were performed to explore the characteristics of these patients and the relative risk of mortality with delay or refusal of therapy.

Results

Our study showed that the overall survival rates were significantly different (p <0.05) between the breast cancer patients who delayed or refused therapy and those with treatment. The patients who delayed or refused therapy had lower 5-year overall survival rate compared with the treated group. The related factors included age, Charlson comorbidity index, cancer staging (OR = 1.30–19.69; p <0.05), other catastrophic illnesses or injuries and the level of diagnostic hospitals. However, the patients with different income levels and degree of urbanization in living area were not statistically significant factors.

Conclusion

Our results demonstrated that age and cancer staging were the main patient characteristics affecting whether the patients delayed or refused therapy. The delay or refusal of treatment was associated with the level of diagnosing hospital.     

Association of Body Composition with Outcome of Docetaxel Chemotherapy in Metastatic Prostate Cancer: A Retrospective Review

Background

Docetaxel, a lipophilic drug, is indicated for castration-resistant metastatic prostate cancer. Most men with such disease would have had androgen-deprivation therapy, which decreases muscle and increases body fat. Obesity and body composition changes may influence the outcomes of docetaxel therapy.

Methods

We conducted a retrospective review of 333 patients with metastatic prostate cancer treated with docetaxel at a comprehensive cancer center between October 7, 2004 and December 31, 2012. Body composition parameters were measured based on the areas of muscle and adipose tissues in the visceral and subcutaneous compartments on CT images at L3-4 levels. Dose calculations, toxicity and adverse reaction profiles, and overall survival were analyzed.

Results

Obese patients were younger at the diagnosis of prostate cancer and had a shorter duration from diagnosis to docetaxel therapy. Analysis of body composition found that a high visceral fat-to-subcutaneous fat area ratio (VSR) was associated with poor prognosis but a high visceral fat-to-muscle area ratio (VMR) and high body mass index were associated with increased duration from starting docetaxel to death, allowing such men to catch up with patients with normal body mass index in overall survival from cancer diagnosis to death. Cox proportional hazard regression showed that age ≥65 years, high VSR, abnormal serum alkaline phosphatase, and >10% reduction of initial dosage were significant predictors of shorter time between starting docetaxel and death, and that high VMR, obesity, and weekly regimens were significant predictors of longer survival after docetaxel.

Conclusion

Obese and overweight patients may benefit more from weekly docetaxel regimens using the reference dosage of 35 mg/m² without empirical dosage reduction.     

Smad4 Loss Synergizes with TGFα Overexpression in Promoting Pancreatic Metaplasia,PanIN Development,and Fibrosis

Aims

While overexpression of TGFα has been reported in human pancreatic ductal adenocarcinoma (PDAC), mice with overexpressed TGFα develop premalignant pancreatic acinar-to-ductal metaplasia (ADM) but not PDAC. TGF-β signaling pathway is pivotal to the development of PDAC and tissue fibrosis. Here we sought to investigate the interplay between TGFα and TGF-β signaling in pancreatic tumorigenesis and fibrosis, namely via Smad4 inactivation.

Methods

The MT-TGFα mouse was crossed with a new Smad4 conditional knock-out mouse (Smad4^flox/flox;p48-Cre or S4) to generate Smad4^flox/flox;MT-TGFα;p48-Cre (STP). After TGFα overexpression was induced with zinc sulfate water for eight months, the pancreata of the STP, MT-TGFα, and S4 mice were examined for tumor development and fibrotic responses. PanIN lesions and number of ducts were counted, and proliferation was measured by Ki67 immunohistochemistry (IHC). Qualitative analysis of fibrosis was analyzed by Trichrome Masson and Sirius Red staining, while vimentin was used for quantification. Expression analyses of fibrosis, pancreatitis, or desmoplasia associated markers (α-SMA, Shh, COX-2, Muc6, Col1a1, and Ctgf) were performed by IHC and/or qRT-PCR.

Results

Our STP mice exhibited advanced ADM, increased fibrosis, increased numbers of PanIN lesions, overexpression of chronic pancreatitis-related marker Muc6, and elevated expression of desmoplasia-associated marker Col1A1, compared to the MT-TGFα mice. The inactivation of Smad4 in the exocrine compartment was responsible for both the enhanced PanIN formation and fibrosis in the pancreas. The phenotype of the STP mice represents a transient state from ADMs to PanINs, closely mimicking the interface area seen in human chronic pancreatitis associated with PDAC.

Conclusion

We have documented a novel mouse model, the STP mice, which displayed histologic presentations reminiscent to those of human chronic pancreatitis with signs of early tumorigenesis. The STP mice could be a suitable animal model for interrogating the transition of chronic pancreatitis to pancreatic cancer.     

Apolipoprotein A-II Plus Lipid Emulsion Enhance Cell Growth via SR-B1 and Target Pancreatic Cancer In Vitro and In Vivo

Background

Apolipoprotein A-II (ApoA-II) is down regulated in the sera of pancreatic ductal adenocarcinoma (PDAC) patients, which may be due to increase utilization of high density lipoprotein (HDL) lipid by pancreatic cancer tissue. This study examined the influence of exogenous ApoA-II on lipid uptake and cell growth in pancreatic cancer (PC) both in vitro and in vivo.

Methods

Cryo transmission electron microscopy (TEM) examined ApoA-II’s influence on morphology of SMOFLipid emulsion. The influence of ApoA-II on proliferation of cancer cell lines was determined by incubating them with lipid+/-ApoA-II and anti-SR-B1 antibody. Lipid was labeled with the fluorophore, DiD, to trace lipid uptake by cancer cells in vitro by confocal microscopy and in vivo in PDAC patient derived xenograft tumours (PDXT) by fluorescence imaging. Scavenger receptor class B type-1(SR-B1) expression in PDAC cell lines and in PDAC PDXT was measured by western blotting and immunohistochemistry, respectively.

Results

ApoA-II spontaneously converted lipid emulsion into very small unilamellar rHDL like vesicles (rHDL/A-II) and enhanced lipid uptake in PANC-1, CFPAC-1 and primary tumour cells as shown by confocal microscopy. SR-B1 expression was 13.2, 10.6, 3.1 and 2.3 fold higher in PANC-1, MIAPaCa-2, CFPAC-1 and BxPC3 cell lines than the normal pancreatic cell line (HPDE6) and 3.7 fold greater in PDAC tissue than in normal pancreas. ApoA-II plus lipid significantly increased the uptake of labeled lipid and promoted cell growth in PANC-1, MIAPaCa-2, CFPAC-1 and BxPC3 cells which was inhibited by anti SR-B1 antibody. Further, ApoA-II increased the uptake of lipid in xenografts by 3.4 fold.

Conclusion

Our data suggest that ApoA-II enhance targeting potential of lipid in pancreatic cancer which may have imaging and drug delivery potentialities.     

Thyroid Fine-Needle Aspiration Biopsy and Thyroid Cancer Diagnosis: A Nationwide Population-Based Study

Background

Thyroid cancer is the most common endocrine gland malignancy and fine-needle aspiration biopsy is widely used for thyroid nodule evaluation. Repeated aspiration biopsies are needed due to plausible false-negative results. This study aimed to investigate the overall relationship between aspiration biopsy and thyroid cancer diagnosis, and to explore factors related to shorter diagnostic time.

Methods

This nationwide retrospective cohort study retrieved data from the Longitudinal Health Insurance Database in Taiwan. Subjects without known thyroid malignancies and who received the first thyroid aspiration biopsy after 2004 were followed-up from 2004 to 2009 (n = 7700). Chi-square test, Kaplan-Meier survival analysis, and Cox proportional hazards model were used for data analysis.

Results

Of 7700 newly-aspirated patients, 276 eventually developed thyroid cancer (malignancy rate 3.6%). Among the 276 patients with thyroid cancer, 61.6% underwent only one aspiration biopsy and 81.2% were found within the first year after the initial aspiration. Cox proportional hazards model revealed that aspiration frequency (HR 1.07, 95% CI 1.06–1.08), ultrasound frequency (HR 1.02, 95% CI 1.01–1.03), older age, male sex, and aspiration biopsies arranged by surgery, endocrinology or otolaryngology subspecialties were all associated with shorter time to thyroid cancer diagnosis.

Conclusions

About 17.4% of thyroid cancer cases received more than two aspiration biopsies and 18.8% were diagnosed one year after the first biopsy. Regular follow-up with repeated aspiration or ultrasound may be required for patients with clinically significant thyroid nodules.     

Preoperative Glycemic Control Status as a Significant Predictor of Biochemical Recurrence in Prostate Cancer Patients after Radical Prostatectomy

Background

The effect of diabetes mellitus (DM) on prostate cancer (PCa) outcome remains controversial. Thus, we investigated the association of DM history, glycemic control, and metformin use with oncologic outcomes after radical prostatectomy (RP).

Methods

We reviewed the records of 746 contemporary patients who had hemoglobin A1c (HbA1c) measured within the 6 months preceding RP. The associations between clinical variables and risk of adverse pathological features and biochemical recurrence (BCR) were tested using a multivariate logistic regression and multiple Cox-proportional hazards model, respectively. BCR was defined as prostatic specific antigen (PSA) > 0.2 ng/mL in 2 consecutive tests.

Results

There were no significant differences in the rates of adverse pathologic features and BCR-free survival between patients with (n = 209) and without (n = 537) a history of DM diagnosis (all p > 0.05). In multivariate analyses, high HbA1c level (≥ 6.5%) was significantly related with high pathologic Gleason score (≥ 4+3; odds ratio [OR] 1.704, p = 0.019) and BCR-free survival (OR 1.853, p = 0.007). Metformin use was not associated with BCR-free survival (OR 0.662, p = 0.125).

Conclusions

Poor glycemic control was significantly associated with BCR after RP. Meanwhile, metformin use was not associated with biochemical outcome after RP. Further investigation would be needed to identify exact mechanism underlying the impact of glycemic control on PCa treatment outcome.     

Expression of Beclin Family Proteins Is Associated with Tumor Progression in Oral Cancer

Background

Beclin 1 and Beclin 2 are autophagy-related proteins that show similar amino acid sequences and domain structures. Beclin 1 established the first connection between autophagy and cancer. However, the role of Beclin 2 in cancer is unclear. The aims of this study were to analyze Beclin 1 and Beclin 2 expressions in oral cancer tissues and in cell lines, and to evaluate their possible roles in cancer progression.

Methods

We investigated Beclin 1 and Beclin 2 expressions by immunohistochemistry in 195 cases of oral cancer. The prognostic roles of Beclin 1 and Beclin 2 were analyzed statistically. In vitro, overexpression and knockdown of Beclin proteins were performed on an oral cancer cell line, SAS. The immunofluorescence and autophagy flux assays confirmed that Beclin proteins were involved in autophagy. The impacts of Beclin 1 and Beclin 2 on autophagy and tumor growth were evaluated by conversion of LC3-I to LC3-II and by clonogenic assays, respectively.

Results

Oral cancer tissues exhibited aberrant expressions of Beclin 1 and Beclin 2. The cytoplasmic Beclin 1 and Beclin 2 expressions were unrelated in oral cancer tissues. In survival analyses, high cytoplasmic Beclin 1 expression was associated with low disease specific survival, and negative nuclear Beclin 1 expression was associated with high recurrent free survival. Patients with either high or low cytoplasmic Beclin 2 expression had significantly lower overall survival and disease specific survival rates than those with moderate expression. In oral cancer cells, overexpression of either Beclin 1 or Beclin 2 led to autophagy activation and increased clonogenic survival; knockdown of Beclin 2 impaired autophagy and increased clonogenic survival.

Conclusions

Our results indicated that distinct patterns of Beclin 1 and Beclin 2 were associated with aggressive clinical outcomes. Beclin 1 overexpression, as well as Beclin 2 overexpression and depletion, contributed to tumor growth. These findings suggest Beclin proteins are associated with tumorigenesis.     

Overexpression of COL11A1 by Cancer-Associated Fibroblasts: Clinical Relevance of a Stromal Marker in Pancreatic Cancer

Background

The collagen11A1 (COL11A1) gene is overexpressed in pancreatic cancer. The expression of COL11A1 protein could be involved in desmoplastic events in pancreatic cancer, but an antibody that specifically stains the COL11A1 protein is not currently available.

Methods and findings

A total of 54 pancreatic ductal adenocarcinomas (PDAC), 23 chronic pancreatitis (CP) samples, and cultured peritumoral stromal cells of PDAC (passages 3-6) were studied. Normal human pancreas tissue samples were obtained through a cadaveric organ donation program.1) Validation of COL11A1 gene overexpression by q-RT-PCR. Findings: the expression of COL11A1 gene is significantly increased in PDAC samples vs. normal and CP samples.2) Analysis of COL11A1 by immunohistochemistry using highly specific anti-proCOL11A1 antibodies. Findings: anti-proCOL11A1 stains stromal cells/cancer-associated fibroblasts (CAFs) of PDAC but it does not stain chronic benign condition (chronic pancreatitis) stromal cells, epithelial cells, or normal fibroblasts.3) Evaluation of the discrimination ability of the antibody. Findings: anti-proCOL11A1 immunostaining accurately discriminates between PDAC and CP (AUC 0.936, 95% CI 0.851, 0.981).4) Phenotypic characterization of proCOL11A1+ stromal cells co-staining with mesenchymal, epithelial and stellate cell markers on pancreatic tissue samples and cultured peritumoral pancreatic cancer stromal cells. Findings: ProCOL11A1+ cells present co-staining with mesenchymal, stellate and epithelial markers (EMT phenotype) in different proportions.

Conclusions/Significance

Detection of proCOL11A1 through immunostaining with this newly-developed antibody allows for a highly accurate distinction between PDAC and CP. Unlike other available antibodies commonly used to detect CAFs, anti-proCOL11A1 is negative in stromal cells of the normal pancreas and almost absent in benign inflammation. These results strongly suggest that proCOL11A1 is a specific marker for CAFs, and thus, anti-proCOL11A1 is a powerful new tool for cancer research and clinical diagnostics.     

Post-Progression Survival after EGFR-TKI for Advanced Non-Small Cell Lung Cancer Harboring EGFR Mutations

Background

Non-small cell lung cancer (NSCLC) patients that harbor epidermal growth factor receptor (EGFR) mutations benefit from receiving an EGFR-tyrosine kinase inhibitor (TKI); however, post-progression survival (PPS) after EGFR-TKI treatment has not been sufficiently studied.

Methods

We retrospectively reviewed the clinical data from stage IV or recurrent NSCLC patients who harbored EGFR mutations and who received EGFR-TKI as their first-line treatment in our institute between 2009 and 2011.

Results

In total, 36 patients received EGFR-TKI treatment as their first-line therapy. Of those 36 patients, 30 experienced recurrence and were enrolled in this study. The median progression-free survival (PFS) of these patients was 8.2 months. Twelve patients received EGFR-TKI treatment beyond the diagnosis of progressive disease (PD), and 8 received second-line therapy. The PPS after EGFR-TKI treatment was 9.1 months, and survival after the termination of EGFR-TKI treatment in those patients treated with second-line chemotherapy was 13.9 months. The site of relapse was investigated and PFS in EGFR-TKI-treated patients with relapse in the brain (11.6 months) showed a trend toward a longer PFS compared with patients with relapse at other sites (8.2 months). The median PPS after EGFR-TKI treatment also showed the same trend in each group (12.9 and 9.2 months, respectively).

Conclusions

The PPS after EGFR-TKI treatment failure was 9.1 months, while the survival of patients who underwent second-line chemotherapy after the termination of EGFR-TKI treatment was 13.9 months, comparable with the overall survival of EGFR mutation-negative patients, as previously reported. The prognosis of these NSCLC patients with EGFR mutations varied according to the sites of recurrence after first-line EGFR-TKI treatment. Of particular note was the prognosis of patients with brain metastases, which tended to be better than that of patients with metastases to other sites.