We tested the hypothesis that high plasma YKL-40 and IL-6 associate with pancreatic cancer and short overall survival.
Patients and Methods
In all, 559 patients with pancreatic cancer from prospective biomarker studies from Denmark (n = 448) and Germany (n = 111) were studied. Plasma YKL-40 and IL-6 were determined by ELISAs and serum CA 19.9 by chemiluminescent immunometric assay.
Odds ratios (ORs) for prediction of pancreatic cancer were significant for all biomarkers, with CA 19.9 having the highest AUC (CA 19.9: OR = 2.28, 95% CI 1.97 to 2.68, p<0.0001, AUC = 0.94; YKL-40: OR = 4.50, 3.99 to 5.08, p<0.0001, AUC = 0.87; IL-6: OR = 3.68, 3.08 to 4.44, p<0.0001, AUC = 0.87). Multivariate Cox analysis (YKL-40, IL-6, CA 19.9, age, stage, gender) in patients operated on showed that high preoperative IL-6 and CA 19.9 (dichotomized according to normal values) were independently associated with short overall survival (CA 19.9: HR = 2.51, 1.22–5.15, p = 0.013; IL-6: HR = 2.03, 1.11 to 3.70, p = 0.021). Multivariate Cox analysis of non-operable patients (Stage IIB-IV) showed that high pre-treatment levels of each biomarker were independently associated with short overall survival (YKL-40: HR = 1.30, 1.03 to 1.64, p = 0.029; IL-6: HR = 1.71, 1.33 to 2.20, p<0.0001; CA 19.9: HR = 1.54, 1.06 to 2.24, p = 0.022). Patients with preoperative elevation of both IL-6 and CA 19.9 had shorter overall survival (p<0.005) compared to patients with normal levels of both biomarkers (45% vs. 92% alive after 12 months).
Plasma YKL-40 and IL-6 had less diagnostic impact than CA 19.9. Combination of pretreatment YKL-40, IL-6, and CA 19.9 may have clinical value to identify pancreatic cancer patients with the poorest prognosis.
Extrahepatic bile duct cancer is an uncommon disease, and few cases are curable by surgery. We report a case of extrahepatic biliary cystadenocarcinoma (BCAC) associated with atrophy of the left hepatic lobe. A 54-year old male was admitted with painless obstructive jaundice and a hepatic palpable mass noticed one month before presentation. Liver functions tests were consistent with cholestatic damage and serum carbohydrate antigen 19.9 (CA 19-9) was increased before treatment. Magnetic resonance imaging (MRI) disclosed dilatation of the left hepatic bile duct with irregular wall thickening close to the hepatic confluence, and atrophy of left hepatic lobe. The patient was submitted to en bloc extended left hepatectomy with resection of caudate lobe, hilar lymphadenectomy, and suprapancreatic biliary tree resection. All surgical margins were grossly negative, and postoperative course was uneventful, except for a minor bile leak. The patient was discharged on the 15th postoperative day; he is alive without tumor recurrence one year after primary therapy. Although technically challenging, extended en bloc resection is feasible in adults with extrahepatic BCAC and can improve survival with acceptable and manageable morbidity.
biliary tract neoplasms; biliary tract surgical procedure; cystadenocarcinoma.
AIM: To develop a fuzzy classification method to score the texture features of pancreatic cancer in endoscopic ultrasonography (EUS) images and evaluate its utility in making prognosis judgments for patients with unresectable pancreatic cancer treated by EUS-guided interstitial brachytherapy.
METHODS: EUS images from our retrospective database were analyzed. The regions of interest were drawn, and texture features were extracted, selected, and scored with a fuzzy classification method using a C++ program. Then, patients with unresectable pancreatic cancer were enrolled to receive EUS-guided iodine 125 radioactive seed implantation. Their fuzzy classification scores, tumor volumes, and carbohydrate antigen 199 (CA199) levels before and after the brachytherapy were recorded. The association between the changes in these parameters and overall survival was analyzed statistically.
RESULTS: EUS images of 153 patients with pancreatic cancer and 63 non-cancer patients were analyzed. A total of 25 consecutive patients were enrolled, and they tolerated the brachytherapy well without any complications. There was a correlation between the change in the fuzzy classification score and overall survival (Spearman test, r = 0.616, P = 0.001), whereas no correlation was found to be significant between the change in tumor volume (P = 0.663), CA199 level (P = 0.659), and overall survival. There were 15 patients with a decrease in their fuzzy classification score after brachytherapy, whereas the fuzzy classification score increased in another 10 patients. There was a significant difference in overall survival between the two groups (67 d vs 151 d, P = 0.001), but not in the change of tumor volume and CA199 level.
CONCLUSION: Using the fuzzy classification method to analyze EUS images of pancreatic cancer is feasible, and the method can be used to make prognosis judgments for patients with unresectable pancreatic cancer treated by interstitial brachytherapy.
Digital image processing; Fuzzy classification; Endoscopic ultrasonography; Pancreatic cancer; Interstitial brachytherapy; Prognosis
Background: Serum carbohydrate antigen 19-9 (CA 19-9) has been shown to be a sensitive and specific serum marker for pancreatic cancer. Little has been published about correlations between baseline CA 19-9 level or changes to CA 19-9 level and median overall survival (mOS). Its impact on monitoring treatment efficacy remains under discussion, however.
Methods: CA 19-9 serum level was measured in 181 consecutive patients with advanced pancreatic cancer (APC) being treated with gemcitabine-based first-line chemotherapy. We separated the patients into several groups depending on baseline CA 19-9 levels and the CA 19-9 response after 6–8 weeks of treatment. Evaluations were made using SPSS 19.9.
Results: Median baseline CA 19-9 level was 1,493 U/ml (range 40–1,043,301). Patients with baseline CA 19-9 ≤1,000 U/ml had a mOS of 14.9 months (95% CI: 11.36:18.44), whereas patients with CA 19-9>1,000 U/ml had a mOS of 7.4 months [(95% CI: 5.93:8.87) p < 0.001, HR 2.12]. With regard to the change in CA 19-9 after 6–8 weeks of treatment: patients with increased CA 19-9 levels had a mOS of 8.1 months, those with stabilized CA 19-9 levels 11.6 months, and those with decreased CA 19-9 levels 11.1 months (p < 0.019).
Conclusion: CA 19-9 levels can separate patients with differing mortality risks at baseline. Patients with stabilization or high response of CA 19-9 after 6–8 weeks of treatment had no significant differences in survival rates, whereas patients with increased CA 19-9 had significantly lower survival rates, indicating an early treatment failure.
pancreatic neoplasms; CA 19-9; response; therapy control; prediction
Intramuscular myxoma is a rare benign soft tissue tumor. The lack of specific symptoms and widely used laboratory tests makes the diagnosis quite difficult. We present a case of an Intramuscular myxoma associated with an increased carbohydrate antigen 19.9 level. To the best of our knowledge, there have not been any reported cases of an association of Intramuscular myxoma with tumor markers in the literature.
A 45-year-old Caucasian woman presented to our department for resection of a mass in her left groin area, discovered incidentally on a triplex ultrasonography of her lower extremities. The diagnosis of Intramuscular myxoma was confirmed on histopathology after the complete surgical excision of the tumor. On laboratory examination, the serum level of carbohydrate antigen 19.9 was found to be elevated, but it returned to normal six months after resection of the mass.
Carbohydrate antigen 19.9 is a tumor marker that increases in a variety of malignant and benign conditions. After the exclusion of all other possible reasons for carbohydrate antigen 19.9 elevation, we assumed a possible connection of carbohydrate antigen 19.9 elevation and Intramuscular myxoma, an issue that requires needs further investigation.
As the real clinical significance of carcinoembryonic antigen (CEA) and carbohydrate antigen 19.9 (CA19.9) evolution during preoperative chemotherapy for colorectal liver metastases (CLM) is still unknown, we explored the correlation between biological and radiological response to chemotherapy, and their comparative impact on outcome after hepatectomy.
All patients resected for CLM at our hospital between 1990 and 2004 with the following eligibility criteria were included in the study: (1) preoperative chemotherapy, (2) complete resection of CLM, (3) no extrahepatic disease, and (4) elevated baseline tumor marker values. A 20% change of tumor marker levels while on chemotherapy was used to define biological response (decrease) or progression (increase). Correlation between biological and radiological response at computed tomography (CT) scan, and their impact on overall survival (OS) and progression-free survival (PFS) after hepatectomy were determined.
Among 119 of 695 consecutive patients resected for CLM who fulfilled the inclusion criteria, serial CEA and CA19.9 were available in 113 and 68 patients, respectively. Of patients with radiological response or stabilization, 94% had similar biological evolution for CEA and 91% for CA19.9. In patients with radiological progression, similar biological evolution was observed in 95% of cases for CEA and in 64% for CA19.9. On multivariate analysis, radiological response (but not biological evolution) independently predicted OS. However, progression of CA19.9, but not radiological response, was an independent predictor of PFS.
In patients with CLM and elevated tumor markers, biological response is as accurate as CT imaging to assess “clinical” response to chemotherapy. With regards to PFS, CA19.9 evolution has even better prognostic value than does radiological response. Assessment of tumor markers could be sufficient to evaluate chemotherapy response in a nonsurgical setting, limiting the need of repeat imaging.
KRAS2 mutations in codon 12 have been detected in about 80% of pancreatic cancers. The aim of this study was to evaluate the value of KRAS2 mutations detection in circulating deoxyribo nucleic acid to differentiate pancreatic cancer from chronic pancreatitis. Circulating deoxyribo nucleic acid was isolated from serum in 47 patients with histologically proven pancreatic adenocarcinomas (26 males, median age 65 years) and 31 controls with chronic pancreatitis (26 males, median age 48 years). Mutations at codon 12 of KRAS2 gene were searched for using polymerase chain reaction and allele specific amplification. Serum carbohydrate antigen 19.9 levels were also determined. KRAS2 mutations were found in 22 patients (47%) with pancreatic cancer and in four controls with chronic pancreatitis (13%) (P<0.002). None of the latter developed a pancreatic cancer within the 36 months of median follow-up. The sensitivity, specificity, positive and negative predictive values of serum serum KRAS2 mutations for the diagnosis of pancreatic cancer were 47, 87, 85 and 52%, respectively. KRAS2 mutations were not related to age, gender, smoking habit, tumour stage, or survival. Among the 26 patients with normal or non-contributive (due to cholestasis) serum carbohydrate antigen 19.9 levels, 14 (54%) had KRAS2 mutations. The combination of KRAS2 and carbohydrate antigen 19.9 gave a sensitivity, specificity, positive and negative predictive values for the diagnosis of pancreatic cancer of 98, 77, 87 and 96%, respectively. Detection of KRAS2 mutations in circulating deoxyribo nucleic acid has a low sensitivity but a specificity about 90% for the diagnosis of pancreatic cancer. It seems particularly useful when serum carbohydrate antigen 19.9 levels are normal or inconclusive. A combined normal serum carbohydrate antigen 19.9 and absence of circulating KRAS2 mutations makes the diagnosis of pancreatic cancer extremely unlikely.
British Journal of Cancer (2002) 87, 551–554. doi:10.1038/sj.bjc.6600475 www.bjcancer.com
© 2002 Cancer Research UK
KRAS2 mutations; circulating DNA; pancreatic adenocarcinoma; chronic pancreatitis
BACKGROUND: Some adjuvant or neoadjuvant therapy could be important for patients operated on for tumours of the ampulla of Vater, especially for those having a higher risk of recurrence. AIM: To evaluate prognostic factors after curative surgery based on a series of 45 cases of malignant tumours of the Oddi sphincter. PATIENTS: From 1970 to 1992, a curative resection was performed in 45 patients (age 62.8 (SD 10.1) years) with adenocarcinoma of the ampulla. Surgical procedures included pancreatoduodenectomy (n = 42) and resection of the ampulla (n = 3). Actuarial survival was 44 (SD 9)% at five years. METHODS: Various prognostic variables were studied: clinical manifestations, macroscopic aspect, differentiation, noninvasive adenomatous component, mucin histochemistry, immunohistochemistry (CEA, CA19.9, p53, Ki67), and accepted classifications (Blumgart and Kennedy, Martin, Yamaguchi and Enjoji, Talbot et al, pTNM). RESULTS: Variables with prognostic power, in order of importance were: Classification of Talbot et al; CA19.9; pTNM; sialomucins; classification of Yamaguchi and Ejoji; Martin classification; sulphomucins; non-invasive adenomatous component (positive > negative); jaundice; tumour localisation. CONCLUSIONS: This series confirmed the prognostic power of former classifications and showed the prognostic power of other variables (mucin, non-invasive adenomatous component, CA19.9).
The American Joint Committee on Cancer staging system for hilar cholangiocarcinoma may be inaccurate because the bile duct lacks discrete tissue boundaries.
To examine the accuracy of the American Joint Committee on Cancer staging schemes and to determine the prognostic implications of tumor depth.
Design, Setting, and Patients
From January 1, 1987, through December 31, 2009, there were 106 patients who underwent resection of hilar cholangiocarcinoma who had pathologic slides available for re-review.
Main Outcome Measures
Tumor depth and overall survival.
Overall median survival was 19.9 months. The 6th and 7th editions of the T-classification criteria were unable to discriminate among T1, T2, and T3 lesions (P>.05 for all). Median survival was associated with the invasion depth of the tumor (≥5 mm vs <5 mm): 18 months vs 30 months (P=.01). On multivariate analysis, tumor depth remained predictive of disease-specific death (hazard ratio,1.70; P=.03).
The American Joint Committee on Cancer T-classification criteria did not stratify patients with regard to prognosis. Depth of tumor invasion is a better predictor of long-term outcome.
Despite major improvements in the perioperative outcome of pancreas surgery, the prognosis of pancreatic cancer after curative resection remains poor. Adjuvant chemotherapy increases disease-free and overall survival, but this treatment cannot be offered to a significant proportion of patients due to the surgical morbidity. In contrast, almost all patients can receive (neo)adjuvant chemotherapy before surgery. This treatment is safe and effective, and has resulted in a median survival of 26.5 months in a recent phase II trial. Moreover, neoadjuvant chemotherapy improves the nutritional status of patients with pancreatic cancer. This multicenter phase III trial (NEOPAC) has been designed to explore the efficacy of neoadjuvant chemotherapy.
This is a prospective randomized phase III trial. Patients with resectable cytologically proven adenocarcinoma of the pancreatic head are eligible for this study. All patients must be at least 18 years old and must provide written informed consent. An infiltration of the superior mesenteric vein > 180° or major visceral arteries are considered exclusion criteria. Eligible patients will be randomized to surgery followed by adjuvant gemcitabine (1000 mg/m2) for 6 months or neoadjuvant chemotherapy (gemcitabine 1000 mg/m2, oxaliplatin 100 mg/m2) followed by surgery and the same adjuvant treatment. Neoadjuvant chemotherapy is given four times every two weeks. The staging as well as the restaging protocol after neoadjuvant chemotherapy include computed tomography of chest and abdomen and diagnostic laparoscopy. The primary study endpoint is progression-free survival. According to the sample size calculation, 155 patients need to be randomized to each treatment arm. Disease recurrence will be documented by scheduled computed tomography scans 9, 12, 15, 21 and thereafter every 6 months until disease progression. For quality control, circumferential resection margins are marked intraoperatively, and representative histological sections will be centrally reviewed by a dedicated pathologist.
The NEOPAC study will determine the efficacy of neoadjuvant chemotherapy in pancreatic cancer for the first time and offers a unique potential for translational research. Furthermore, this trial will provide the unbiased overall survival of all patients undergoing surgery for resectable cancer of the pancreatic head.
Recent studies have emphasized causative links between microRNAs (miRNAs) deregulation and tumor development. In hepatocellular carcinoma (HCC), more and more miRNAs were identified as diagnostic and prognostic cancer biomarkers, as well as additional therapeutic tools. This study aimed to investigate the functional significance and regulatory mechanism of the miR-199a2/214 cluster in HCC progression.
Methods and Findings
In this study, we showed that miR-214, as well as miR-199a-3p and miR-199a-5p levels were significantly reduced in the majority of examined 23 HCC tissues and HepG2 and SMMC-7721 cell lines, compared with their nontumor counterparts. To further explore the role of miR-214 in hepatocarcinogenesis, we disclosed that the ER stress-induced pro-survival factor XBP-1 is a target of miR-214 by using western blot assay and luciferase reporter assay. Re-expression of miR-214 in HCC cell lines (HepG2 and SMMC-7721) inhibited proliferation and induced apoptosis. Furthermore, ectopic expression of miR-214 dramatically suppressed the ability of HCC cells to form colonies in vitro and to develop tumors in a subcutaneous xenotransplantation model of the BALB/c athymic nude mice. Moreover, reintroduction of XBP-1s attenuated miR-214-mediated suppression of HCC cells proliferation, colony and tumor formation. To further understand the mechanism of the miR-199a/214 cluster down-expression in HCC, we found that thapsigargin (TG) and tunicamycin (TM) or hypoxia-induced unfolded protein response (UPR) suppresses the expression of the miR-199a/214 cluster in HCC cells. By promoter analysis of the miR-199a2/214 gene, we conjectured NFκB as a potential negative regulator. We further found that UPR and LPS-induced NFκB activation suppressed miR-199a2/214 transcription, and this suppression was reversed by NFκB inhibition in HCC cells.
Our study suggest that modulation of miR-214 levels may provide a new therapeutic approach for cancer treatment and revealed that UPR may offer a new explanation for why the miR-199a/214 cluster were down-regulated in the progression in HCC.
Serum carbohydrate antigen (CA 19-9) is the most common tumor marker assessed in pancreatic cancer patients; nevertheless few articles have comprehensively evaluated the evidence for its utility in pancreatic cancer management.
Literature search was performed using Medline with keywords "pancreatic cancer", "tumor markers", "CA 19-9", "diagnosis", "screening", "prognosis", "resectability" and "recurrence". All English language articles pertaining to the role of CA 19-9 in pancreatic cancer were critically analyzed to determine its utility as a biomarker for pancreatic cancer.
Serum CA 19-9 is the most extensively validated pancreatic cancer biomarker with multiple clinical applications. CA 19-9 serum levels have a sensitivity and specificity of 79-81% and 82-90% respectively for the diagnosis of pancreatic cancer in symptomatic patients; but are not useful as a screening marker because of low positive predictive value (0.5-0.9%). Pre-operative CA 19-9 serum levels provide useful prognostic information as patients with normal levels (<37 U/mL) have a prolonged median survival (32-36 months) compared to patients with elevated levels (>37 U/mL) (12-15 months). A CA 19-9 serum level of <100 U/mL implies likely resectable disease whereas levels >100 U/mL suggest unresectablity or metastatic disease. Normalization or a decrease in post-operative CA 19-9 serum levels by ≥20-50% from baseline following surgical resection or chemotherapy is associated with prolonged survival compared to failure of CA 19-9 serum levels to normalize or an increase. Important limitations to CA 19-9 serum level evaluation in pancreatic cancer include poor sensitivity, false negative results in Lewis negative phenotype (5-10%) and increased false positivity in the presence of obstructive jaundice (10-60%).
CA 19-9 is the most extensively studied and validated serum biomarker for the diagnosis of pancreatic cancer in symptomatic patients. CA 19-9 serum levels can provide important information with regards to prognosis, overall survival, and response to chemotherapy as well as predict post-operative recurrence. However, non-specific expression in several benign and malignant diseases, false negative results in Lewis negative genotype and an increased false positive results in the presence of obstructive jaundice severely limit the universal applicability of serum CA 19-9 levels in pancreatic cancer management.
Pancreatic cancer; tumor markers; CA 19-9; diagnosis; screening; prognosis; resectability; recurrence
The serum level of carcinoembryonic antigen (CEA) is a clinical prognostic factor in the follow-up evaluation of patients with colon cancer. We aimed to evaluate the prognostic significance of the rate of decrease of the perioperative serum CEA level in patients with colon cancer after a curative resection.
A total of 605 patients who underwent a curative resection for colon cancer between January 2000 and December 2007 were enrolled retrospectively. The rate of decrease was calculated using the following equation: ([preoperative CEA - postoperative CEA]/[preoperative CEA] ×100).
In the group with a preoperative serum CEA level of >5 ng/mL, the normalized group with a postoperative serum CEA level of ≤5 ng/mL showed a better overall survival (OS) rate and disease-free survival (DFS) rate than those of the non-normalized group (P ≤ 0.0001). The "cutoff values" of the rate of decrease in the perioperative serum CEA that determined the OS and the DFS were 48.9% and 50.8%, respectively. In the multivariate analysis of preoperative serum CEA levels >5 ng/mL, the prognostic factors for the OS and the DFS were the cutoff value (P < 0.0001) and the pN stage (P < 0.0001).
A rate of decrease of more than 50% in the perioperative serum CEA level, as well as the normalization of the postoperative serum CEA level, may be useful factors for determining a prognosis for colon cancer patients with high preoperative CEA levels.
Colon neoplasms; Carcinoembryonic antigen; Prognostic factor
Current histo-pathological prognostic factors are not very helpful in predicting the clinical outcome of breast cancer due to the disease's heterogeneity. Molecular profiling using a large panel of genes could help to classify breast tumours and to define signatures which are predictive of their clinical behaviour.
To this aim, quantitative RT-PCR amplification was used to study the RNA expression levels of 47 genes in 199 primary breast tumours and 6 normal breast tissues. Genes were selected on the basis of their potential implication in hormonal sensitivity of breast tumours. Normalized RT-PCR data were analysed in an unsupervised manner by pairwise hierarchical clustering, and the statistical relevance of the defined subclasses was assessed by Chi2 analysis. The robustness of the selected subgroups was evaluated by classifying an external and independent set of tumours using these Chi2-defined molecular signatures.
Hierarchical clustering of gene expression data allowed us to define a series of tumour subgroups that were either reminiscent of previously reported classifications, or represented putative new subtypes. The Chi2 analysis of these subgroups allowed us to define specific molecular signatures for some of them whose reliability was further demonstrated by using the validation data set. A new breast cancer subclass, called subgroup 7, that we defined in that way, was particularly interesting as it gathered tumours with specific bioclinical features including a low rate of recurrence during a 5 year follow-up.
The analysis of the expression of 47 genes in 199 primary breast tumours allowed classifying them into a series of molecular subgroups. The subgroup 7, which has been highlighted by our study, was remarkable as it gathered tumours with specific bioclinical features including a low rate of recurrence. Although this finding should be confirmed by using a larger tumour cohort, it suggests that gene expression profiling using a minimal set of genes may allow the discovery of new subclasses of breast cancer that are characterized by specific molecular signatures and exhibit specific bioclinical features.
The aim of this study is to evaluate long-term survival and prognostic factors for radio-frequency ablation (RFA) in colorectal liver metastases.
We retrospectively reviewed 35 colorectal liver metastases patients who underwent RFA between 2004 and 2008. We analyzed survival after RFA and prognostic factors for survival.
Of the 35 patients, 23 patients were male and 12 were female. Their mean age was 62.40 ± 12.52 years. Mean overall survival was 38.8 ± 4.6 months, and mean progression free survival was 19.9 ± 3.4 months. Three- and 5-year overall survival rates were 42.7 ± 0.1% and 26.0 ± 0.1%, respectively. Three- and 5-year progression-free survival rates were 19.6 ± 0.1% and 4.9 ± 0.04%, respectively. Overall survival and progression-free survival were significantly improved in male and in patients with carcinoembryonic antigen (CEA) ≤ 100 ng/mL, carbohydrate antigen (CA) 19-9 ≤ 100 ng/mL, absence of extrahepatic disease, and a unilobar hepatic lesion. In addition, progression-free survival was improved in patients with a solitary hepatic lesion. On the multivariate analysis, significant survival factors were the absence of extrahepatic disease and the presence of a unilobar hepatic lesion.
RFA for colorectal liver metastases is an effective treatment option in male patients and in patients with CEA or CA19-9 ≤ 100, absence of extrahepatic disease, a solitary hepatic lesion, and a unilobar hepatic lesion.
Radiofrequency ablation; Colorectal liver matastasis; Survival; Prognostic factor
Cutaneous melanoma is an aggressive form of human skin cancer characterized by high metastatic potential and poor prognosis. Biomarkers of metastatic risk are critically needed to instigate new auxiliary measures in high-risk patients. In clinical specimens of skin melanoma, we previously found that let-7b, microRNA-199a and microRNA-33 were significantly associated with metastatic melanoma, and thus may be the key to melanoma treatment. In this study, we examined the effect of overexpression and inhibition of let-7b and microRNA-199a. Plasmids overexpressing these genes were transfected into B16F10 melanoma cells, and let-7b and microRNA-199a expression were evaluated at the RNA, protein and cellular level. Cyclin D1 expression was significantly higher in cells transfected with let-7b plasmid and let-7b inhibitor compared with control cells (P<0.05). In turn, Met expression in the microRNA-199a plasmid group and microRNA-199a inhibitor group was significantly higher than in the control group (P<0.05). The proliferation rate of B16F10 cells transfected with let-7b or microRNA-199a was lower than that of the control group, particularly until the third day after transfection when the proliferation rate dropped to the lowest value (P<0.05). In addition, the apoptosis rates of the let-7b plasmid group and microRNA-199a plasmid group were significantly higher compared to that of the control group (P<0.05). These results suggest that let-7b and microRNA-199a may be negative regulators of B16F10 cell proliferation.
microRNA; let-7b; microRNA-199a; melanoma; Met; cyclin D1; cell proliferation
Because mucosal inflammation contributes to colorectal carcinogenesis, we studied the impact of intestinal infections on risk of this malignancy among people with AIDS (PWA). Using the population-based HIV/AIDS Cancer Match, which includes approximately half of all PWA in the United States, the cancer registries ascertained colorectal cancers (ICD-O3 codes C180-C189, C199, C209, and C260). During 4–120 months after AIDS onset, risk of cancer occurring after AIDS-defining intestinal infections (considered as time-dependent exposures) was estimated with hazard ratios (HR) and 95% confidence intervals (CI) calculated by Cox regression. Analyses included cancers overall and by histology and anatomic site. After excluding 118 squamous cell rectal cancers (possible anal cancers), we analyzed 320 incident colorectal cancer cases that occurred among 471,909 PWA. Colorectal cancer risk was marginally elevated following cryptosporidiosis (HR=2.08, 95% CI=0.93–4.70, p=0.08) and mucocutaneous herpes (HR=1.69, 95% CI=0.97–2.95, p=0.07) but not with Pneumocystis pneumonia (HR=0.79, 95% CI=0.57–1.10). Cryptosporidiosis was associated with rare colon squamous cell carcinoma [N=8, HR=13, 95% CI=1.5–110] and uncommon histologies [HR=4.4, 95% CI=1.1–18, p=0.04], but it was not associated with colorectal adenocarcinoma (N=269, HR=1.3, 95% CI=0.4–3.9, p=0.70). Mucocutaneous herpes was associated with colon squamous cell carcinoma (HR=13, 95% CI=2.4–67, p=0.003) but not with colorectal adenocarcinoma (HR=1.3, 95% CI=0.6–2.6, p=0.52) or uncommon histologies (HR=2.5, 95% CI=0.8–8.2, p=0.13). Colon squamous cell carcinoma risk was significantly elevated among PWA who had cryptosporidiosis or mucocutaneous herpes. These findings might suggest that HPV or inflammation from other infection may contribute to carcinogenesis.
In this article, the authors review the current status of biomarker research in the adjuvant treatment of colon cancer, drawing on their experiences and considering future strategies for biomarker discovery in the postgenomic era.
The number of agents that are potentially effective in the adjuvant treatment of locally advanced resectable colon cancer is increasing. Consequently, it is important to ascertain which subgroups of patients will benefit from a specific treatment. Despite more than two decades of research into the molecular genetics of colon cancer, there is a lack of prognostic and predictive molecular biomarkers with proven utility in this setting. A secondary objective of the Pan European Trials in Adjuvant Colon Cancer-3 trial, which compared irinotecan in combination with 5-fluorouracil and leucovorin in the postoperative treatment of stage III and stage II colon cancer patients, was to undertake a translational research study to assess a panel of putative prognostic and predictive markers in a large colon cancer patient cohort. The Cancer and Leukemia Group B 89803 trial, in a similar design, also investigated the use of prognostic and predictive biomarkers in this setting. In this article, the authors, who are coinvestigators from these trials and performed similar investigations of biomarker discovery in the adjuvant treatment of colon cancer, review the current status of biomarker research in this field, drawing on their experiences and considering future strategies for biomarker discovery in the postgenomic era.
Pancreatic cancer is among the most lethal malignancies worldwide. This study aimed to identify a novel prognostic biomarker, facilitating treatment selection, using mass spectrometry (MS)-based proteomic analysis with formalin-fixed paraffin-embedded (FFPE) tissue.
The two groups with poor prognosis (n = 4) and with better prognosis (n = 4) had been carefully chosen among 96 resected cases of pancreatic cancer during 1998 to 2007 in Tohoku University Hospital. Although those 2 groups had adjusted background (UICC-Stage IIB, Grade2, R0, gemcitabine adjuvant), there was a significant difference in postoperative mean survival time (poor 21.0 months, better 58.1 months, P = 0.0067). Cancerous epithelial cells collected from FFPE tissue sections by laser micro-dissection (LMD) were processed for liquid chromatography-tandem mass spectrometry (LC-MS/MS). In total, 1099 unique proteins were identified and 6 proteins showed different expressions in the 2 groups by semi-quantitative comparison. Among these 6 proteins, we focused on Nm23/Nucleoside Diphosphate Kinase A (NDPK-A) and immunohistochemically confirmed its expression in the cohort of 96 cases. Kaplan-Meier analysis showed high Nm23/NDPK-A expression to correlate with significantly worse overall survival (P = 0.0103). Moreover, in the multivariate Cox regression model, Nm23/NDPK-A over-expression remained an independent predictor of poor survival with a hazard ratio of 1.97 (95% CI 1.16-3.56, P = 0.0110).
We identified 6 candidate prognostic markers for postoperative pancreatic cancer using FFPE tissues and immunohistochemically demonstrated high Nm23/NDPK-A expression to be a useful prognostic marker for pancreatic cancer.
Proteomics; Prognostic biomarker; Formalin-fixed paraffin-embedded (FFPE); Laser micro-dissection (LMD); Liquid chromatography-tandem mass spectrometry (LC-MS/MS); Nm23/Nucleoside Diphosphate Kinase A (NDPK-A)
CA 19.9 antigen is mainly secreted by biliary and pancreatic duct cells. Its metabolism could be modified in genetic haemochromatosis by iron accumulation within these cells. Therefore, CA 19.9 was assayed in the serum samples of 84 patients with genetic haemochromatosis before and after iron depletion and immunolocalised in the liver of 24 untreated genetic haemochromatosis cases. The study showed that serum CA 19.9 (N < 37 IU/l) was increased (SD) before treatment (41.2 (34)) when compared with after the venesection period (16 (12)), and correlated, before treatment, with the amount of iron excess, transaminases, fibrosis, and biliary iron deposits. Hepatic CA 19.9 was located within the cytoplasm of bile duct and cholangiolar cells. In conclusion, this study shows that a mild, reversible, and non-specific increase in serum CA 19.9 is common in genetic haemochromatosis patients and shows that this increase is related to iron excess, directly or through associated liver damage. The unexplained finding of a mild increase in serum CA 19.9 should lead, in a patient with no diagnosis, to the search for liver iron overload, and, in a patient with untreated genetic haemochromatosis, not to further diagnostic procedures unless this finding persists after completion of the venesection treatment.
Complete surgical resection still remains the only possibility of curing pancreatic cancer, however, only 10% of patients undergo curative surgery. Pancreatic resection currently remains the only method of curing patients, and has a 5-year overall survival rate between 7%-34% compared to a median survival of 3-11 mo for unresected cancer. Pancreatic surgery is a technically demanding procedure requiring highly standardized surgical techniques. Nevertheless, even in experienced hands, perioperative morbidity rates (delayed gastric emptying, pancreatic fistula etc.) are as high as 50%. Different strategies to reduce postoperative morbidity, such as different techniques of gastroenteric reconstruction (pancreatico-jejunostomy vs pancreatico-gastrostomy), intraoperative placement of a pancreatic main duct stent or temporary sealing of the main pancreatic duct with fibrin glue have not led to a significant improvement in clinical outcome. The perioperative application of somatostatin or its analogues may decrease the incidence of pancreatic fistulas in cases with soft pancreatic tissue and a small main pancreatic duct (< 3 mm). The positive effects of external pancreatic main duct drainage and antecolic gastrointestinal reconstruction have been observed to decrease the rate of pancreatic fistulas and delayed gastric emptying, respectively. Currently, the concept of extended radical lymphadenectomy has been found to be associated with higher perioperative morbidity, but without any positive impact on overall survival. However, there is growing evidence that portal vein resections can be performed with acceptable low perioperative morbidity and mortality but does not achieve a cure.
Pancreatic adenocarcinoma; Pancreatic fistula; Pancreatic surgery; Venous resection
The use of serial serum measurements of the carbohydrate antigen 19-9 (CA19-9) to guide treatment decisions and serve as a surrogate end point in clinical trial design requires further validation. We investigated whether CA19-9 decline represents an accurate surrogate for survival and time to treatment failure (TTF) in a cohort of 76 patients with advanced pancreatic cancer receiving fixed-dose rate gemcitabine in three separate studies. Statistically significant correlations between percentage CA19-9 decline and both overall survival and TTF were found, with median survival ranging from 12.0 months for patients with the greatest degree of biomarker decline (>75%) compared with 4.3 months in those whose CA19-9 did not decline during therapy (P<0.001). Using specific thresholds, patients with ⩾25% decline in CA19-9 during treatment had significantly better outcomes than those who did not (median survival and TTF of 9.6 and 4.6 months vs 4.4 and 1.5 months; P<0.001). Similar results were seen using both 50 and 75% as cutoff points. We conclude that serial CA19-9 measurements correlate well with clinical outcomes in this patient population, and that decline in this biomarker should be entertained for possible use as a surrogate end point in clinical trials for the selection of new treatments in this disease.
pancreatic cancer; CA19-9; gemcitabine; tumour marker; surrogate end point
Cancer-Testis Antigens (CTAs) are immunogenic proteins that are poor prognostic markers in non-small cell lung cancer (NSCLC). We investigated expression of CTAs in NSCLC and their association with response to chemotherapy, genetic mutations and survival.
We studied 199 patients with pathological N2 NSCLC treated with neoadjuvant chemotherapy (NAC; n = 94), post-operative observation (n = 49), adjuvant chemotherapy (n = 47) or unknown (n = 9). Immunohistochemistry for NY-ESO-1, MAGE-A and MAGE-C1 was performed. Clinicopathological features, response to neoadjuvant treatment and overall survival were correlated. DNA mutations were characterized using the Sequenom Oncocarta panel v1.0. Affymetrix data from the JBR.10 adjuvant chemotherapy study were obtained from a public repository, normalised and mapped for CTAs.
NY-ESO-1 was expressed in 50/199 (25%) samples. Expression of NY-ESO-1 in the NAC cohort was associated with significantly increased response rates (P = 0.03), but not overall survival. In the post-operative cohort, multivariate analyses identified NY-ESO-1 as an independent poor prognostic marker for those not treated with chemotherapy (HR 2.61, 95% CI 1.28–5.33; P = 0.008), whereas treatment with chemotherapy and expression of NY-ESO-1 was an independent predictor of improved survival (HR 0.267, 95% CI 0.07–0.980; P = 0.046). Similar findings for MAGE-A were seen, but did not meet statistical significance. Independent gene expression data from the JBR.10 dataset support these findings but were underpowered to demonstrate significant differences. There was no association between oncogenic mutations and CTA expression.
NY-ESO-1 was predictive of increased response to neoadjuvant chemotherapy and benefit from adjuvant chemotherapy. Further studies investigating the relationship between these findings and immune mechanisms are warranted.
Various multigene predictors of breast cancer clinical outcome have been commercialized, but proved to be prognostic only for hormone receptor (HR) subsets overexpressing estrogen or progesterone receptors. Hormone receptor negative (HRneg) breast cancers, particularly those lacking HER2/ErbB2 overexpression and known as triple-negative (Tneg) cases, are heterogeneous and generally aggressive breast cancer subsets in need of prognostic subclassification, since most early stage HRneg and Tneg breast cancer patients are cured with conservative treatment yet invariably receive aggressive adjuvant chemotherapy.
An unbiased search for genes predictive of distant metastatic relapse was undertaken using a training cohort of 199 node-negative, adjuvant treatment naïve HRneg (including 154 Tneg) breast cancer cases curated from three public microarray datasets. Prognostic gene candidates were subsequently validated using a different cohort of 75 node-negative, adjuvant naïve HRneg cases curated from three additional datasets. The HRneg/Tneg gene signature was prognostically compared with eight other previously reported gene signatures, and evaluated for cancer network associations by two commercial pathway analysis programs.
A novel set of 14 prognostic gene candidates was identified as outcome predictors: CXCL13, CLIC5, RGS4, RPS28, RFX7, EXOC7, HAPLN1, ZNF3, SSX3, HRBL, PRRG3, ABO, PRTN3, MATN1. A composite HRneg/Tneg gene signature index proved more accurate than any individual candidate gene or other reported multigene predictors in identifying cases likely to remain free of metastatic relapse. Significant positive correlations between the HRneg/Tneg index and three independent immune-related signatures (STAT1, IFN, and IR) were observed, as were consistent negative associations between the three immune-related signatures and five other proliferation module-containing signatures (MS-14, ONCO-RS, GGI, CSR/wound and NKI-70). Network analysis identified 8 genes within the HRneg/Tneg signature as being functionally linked to immune/inflammatory chemokine regulation.
A multigene HRneg/Tneg signature linked to immune/inflammatory cytokine regulation was identified from pooled expression microarray data and shown to be superior to other reported gene signatures in predicting the metastatic outcome of early stage and conservatively managed HRneg and Tneg breast cancer. Further validation of this prognostic signature may lead to new therapeutic insights and spare many newly diagnosed breast cancer patients the need for aggressive adjuvant chemotherapy.
Pancreatic cancer is still associated with a poor prognosis and remains—as the fourth leading cause of cancer related mortality—a therapeutic challenge. Overall long-term survival is about 1–5%, and in only 10–20% of pancreatic cancer patients is potentially curative surgery possible, increasing five-year survival rates to approximately 20–25%. Pancreatic surgery is a technically challenging procedure and has significantly changed during the past decades with regard to technical aspects as well as perioperative care. Standardized resections can be carried out with low morbidity and mortality below 5% in high volume institutions. Furthermore, there is growing evidence that also more extended resections including multivisceral approaches, vessel reconstructions or surgery for tumor recurrence can be carried out safely with favorable outcomes. The impact of adjuvant treatment, especially chemotherapy, has increased dramatically within recent years, leading to significantly improved postoperative survival, making pancreatic cancer therapy an interdisciplinary approach to achieve best results.
pancreatic cancer; surgery; standard resection; extended approach