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1.  Diagnostic and Prognostic Impact of Circulating YKL-40, IL-6, and CA 19.9 in Patients with Pancreatic Cancer 
PLoS ONE  2013;8(6):e67059.
Purpose
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.
Results
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).
Conclusions
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.
doi:10.1371/journal.pone.0067059
PMCID: PMC3694124  PMID: 23840582
2.  MicroRNA-199b-5p Impairs Cancer Stem Cells through Negative Regulation of HES1 in Medulloblastoma 
PLoS ONE  2009;4(3):e4998.
Background
Through negative regulation of gene expression, microRNAs (miRNAs) can function in cancers as oncosuppressors, and they can show altered expression in various tumor types. Here we have investigated medulloblastoma tumors (MBs), which arise from an early impairment of developmental processes in the cerebellum, where Notch signaling is involved in many cell-fate-determining stages. MBs occur bimodally, with the peak incidence seen between 3–4 years and 8–9 years of age, although it can also occur in adults. Notch regulates a subset of the MB cells that have stem-cell-like properties and can promote tumor growth. On the basis of this evidence, we hypothesized that miRNAs targeting the Notch pathway can regulated these phenomena, and can be used in anti-cancer therapies.
Methodology/Principal Findings
In a screening of MB cell lines, the miRNA miR-199b-5p was seen to be a regulator of the Notch pathway through its targeting of the transcription factor HES1. Down-regulation of HES1 expression by miR-199b-5p negatively regulates the proliferation rate and anchorage-independent growth of MB cells. MiR-199b-5p over-expression blocks expression of several cancer stem-cell genes, impairs the engrafting potential of MB cells in the cerebellum of athymic/nude mice, and of particular interest, decreases the MB stem-cell-like (CD133+) subpopulation of cells. In our analysis of 61 patients with MB, the expression of miR-199b-5p in the non-metastatic cases was significantly higher than in the metastatic cases (P = 0.001). Correlation with survival for these patients with high levels of miR-199b expression showed a positive trend to better overall survival than for the low-expressing patients. These data showing the down-regulation of miR-199b-5p in metastatic MBs suggest a potential silencing mechanism through epigenetic or genetic alterations. Upon induction of de-methylation using 5-aza-deoxycytidine, lower miR-199b-5p expression was seen in a panel of MB cell lines, supported an epigenetic mechanism of regulation. Furthermore, two cell lines (Med8a and UW228) showed significant up-regulation of miR-199b-5p upon treatment. Infection with MB cells in an induced xenograft model in the mouse cerebellum and the use of an adenovirus carrying miR-199b-5p indicate a clinical benefit through this negative influence of miR-199b-5p on tumor growth and on the subset of MB stem-cell-like cells, providing further proof of concept.
Conclusions/Significance
Despite advances in our understanding of the pathogenesis of MB, one-third of these patients remain incurable and current treatments can significantly damage long-term survivors. Here we show that miR-199b-5p expression correlates with metastasis spread, identifying a new molecular marker for a poor-risk class in patients with MB. We further show that in a xenograft model, MB tumor burden can be reduced, indicating the use of miR199b-5p as an adjuvant therapy after surgery, in combination with radiation and chemotherapy, for the improvement of anti-cancer MB therapies and patient quality of life. To date, this is the first report that expression of a miRNA can deplete the tumor stem cells, indicating an interesting therapeutic approach for the targeting of these cells in brain tumors.
doi:10.1371/journal.pone.0004998
PMCID: PMC2656623  PMID: 19308264
3.  Tumor Marker Evolution: Comparison with Imaging for Assessment of Response to Chemotherapy in Patients with Colorectal Liver Metastases 
Annals of Surgical Oncology  2010;17(4):1010-1023.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1245/s10434-009-0887-5
PMCID: PMC2840671  PMID: 20052553
4.  Differential diagnosis between chronic pancreatitis and pancreatic cancer: value of the detection of KRAS2 mutations in circulating DNA 
British Journal of Cancer  2002;87(5):551-554.
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
doi:10.1038/sj.bjc.6600475
PMCID: PMC2376157  PMID: 12189555
KRAS2 mutations; circulating DNA; pancreatic adenocarcinoma; chronic pancreatitis
5.  Combined detection tumor markers for diagnosis and prognosis of gallbladder cancer 
AIM: To clarify the value of combined use of markers for the diagnosis of gallbladder cancer and prediction of its prognosis.
METHODS: Serum cancer antigens (CA)199, CA242, carcinoembryonic antigen (CEA), and CA125 levels were measured in 78 patients with gallbladder cancer (GBC), 78 patients with benign gallbladder diseases, and 78 healthy controls using electrochemiluminescence. CA199, CA242, CEA, and CA125 levels and positive rates were analyzed and evaluated pre- and post-operatively. Receiver operator characteristic curves were used to determine diagnostic sensitivity and specificity of GBC. Survival time analysis, including survival curves, and multivariate survival analysis of a Cox proportional hazards model was performed to evaluate independent prognostic factors.
RESULTS: Serum CA242, CA125, and CA199 levels in the GBC group were significantly higher when compared with those in the benign gallbladder disease and healthy control groups (P < 0.01). With a single tumor marker for GBC diagnosis, the sensitivity of CA199 was the highest (71.7%), with the highest specificity being in CA242 (98.7%). Diagnostic accuracy was highest with a combination of CA199, CA242, and CA125 (69.2%). CA242 could be regarded as a tumor marker of GBC infiltration in the early stage. The sensitivity of CA199 and CA242 increased with progression of GBC and advanced lymph node metastasis (P < 0.05). The 78 GBC patients were followed up for 6-12 mo (mean: 8 mo), during which time serum CA199, CA125, and CA242 levels in the recurrence group were significantly higher than in patients without recurrence (P < 0.01). The post-operative serum CA199, CA125, and CA242 levels in the non-recurrence group were significantly lower than those in the GBC group (P < 0.01). Multivariate survival analysis using a Cox proportional hazards model showed that cancer of the gallbladder neck and CA199 expression level were independent prognostic factors.
CONCLUSION: CA242 is a marker of GBC infiltration in the early stage. CA199 and cancer of the gallbladder neck are therapeutic and prognostic markers.
doi:10.3748/wjg.v20.i14.4085
PMCID: PMC3983467  PMID: 24744600
Gallbladder cancer; Tumor marker; Combined detection; Diagnosis; Prognosis
6.  Analysis of new N-category on prognosis of oesophageal cancer with positive lymph nodes in a Chinese population 
Radiology and Oncology  2013;47(1):63-70.
Background
The 7th edition of the new TNM classification system for oesophageal cancer (EC) has been published. N-category is now divided into N0, N1, N2 and N3. In this study, we aimed to validate the prognostic ability of the new N classification system in EC with positive lymph nodes in a Chinese population, and evaluate whether the new N classification system can help the decision-making for postoperative adjuvant therapy.
Patients and methods
From 2002 to 2008, thoracic EC who underwent oesophagectomy were retrospectively analysed. Patients pathological stage 6th edition of the American Joint Committee on Cancer / Union International Against Cancer (AJCC/UICC) TNM classification were switched to pathological stage 7th edition for this analysis. Patients with pathological stage T1-4N1-3M0 EC were selected. Kaplan-Meier method and Cox regression analysis were employed to compare overall survival (OS).
Results
A total of 545 patients met the inclusion criteria: 346 (63.5%) received oesophagectomy alone, 199 (36.5%) received oesophagectomy and adjuvant radiotherapy, and 36.1% (197/545) received oesophagectomy and adjuvant chemotherapy. Univariate analysis and multivariate analysis revealed significant difference in OS among patients at different postoperative pN-category (p<0.001). This was also present in patients receiving postoperative radiotherapy (p<0.001) and those undergoing postoperative chemotherapy (p<0.001). There was no marked difference in OS between patients receiving postoperative adjuvant therapy and surgery alone at the same postoperative pN-category, except that postoperative radiotherapy marginally improved OS in patients with pN2 and pN3 disease.
Conclusions
Our results validated the prognostic ability of new N classification system. The N-category is an independent prognostic factor in patients with resectable thoracic EC who were positive for lymph nodes in a Chinese population. Further studies are required to clarify the role of new N classification system in the decision-making for postoperative adjuvant therapy.
doi:10.2478/v10019-012-0039-6
PMCID: PMC3573836  PMID: 23450452
oesophageal cancer; prognostic factor; radiotherapy; oesophagectomy; chemotherapy
7.  A Six-Gene Signature Predicts Survival of Patients with Localized Pancreatic Ductal Adenocarcinoma 
PLoS Medicine  2010;7(7):e1000307.
Jen Jen Yeh and colleagues developed and validated a six-gene signature in patients with pancreatic ductal adenocarcinoma that may be used to better stage the disease in these patients and assist in treatment decisions.
Background
Pancreatic ductal adenocarcinoma (PDAC) remains a lethal disease. For patients with localized PDAC, surgery is the best option, but with a median survival of less than 2 years and a difficult and prolonged postoperative course for most, there is an urgent need to better identify patients who have the most aggressive disease.
Methods and Findings
We analyzed the gene expression profiles of primary tumors from patients with localized compared to metastatic disease and identified a six-gene signature associated with metastatic disease. We evaluated the prognostic potential of this signature in a training set of 34 patients with localized and resected PDAC and selected a cut-point associated with outcome using X-tile. We then applied this cut-point to an independent test set of 67 patients with localized and resected PDAC and found that our signature was independently predictive of survival and superior to established clinical prognostic factors such as grade, tumor size, and nodal status, with a hazard ratio of 4.1 (95% confidence interval [CI] 1.7–10.0). Patients defined to be high-risk patients by the six-gene signature had a 1-year survival rate of 55% compared to 91% in the low-risk group.
Conclusions
Our six-gene signature may be used to better stage PDAC patients and assist in the difficult treatment decisions of surgery and to select patients whose tumor biology may benefit most from neoadjuvant therapy. The use of this six-gene signature should be investigated in prospective patient cohorts, and if confirmed, in future PDAC clinical trials, its potential as a biomarker should be investigated. Genes in this signature, or the pathways that they fall into, may represent new therapeutic targets.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Pancreatic cancer kills nearly a quarter of a million people every year. It begins when a cell in the pancreas (an organ lying behind the stomach that produces digestive enzymes and hormones such as insulin, which controls blood sugar levels) acquires genetic changes that allow it to grow uncontrollably and to spread around the body (metastasize). Nearly all pancreatic cancers are “pancreatic ductal adenocarcinomas” (PDACs)—tumors that start in the cells that line the tubes in the pancreas that take digestive juices to the gut. Because PDAC rarely causes any symptoms early in its development, it has already metastasized in about half of patients before it is diagnosed. Consequently, the average survival time after a diagnosis of PDAC is only 5–8 months. At present, the only chance for cure is surgical removal (resection) of the tumor, part of the pancreas, and other nearby digestive organs. The operation that is needed for the majority of patients—the Whipple procedure—is only possible in the fifth of patients whose tumor is found when it is small enough to be resectable but even with postoperative chemotherapy, these patients only live for 23 months after surgery on average, possibly because they have micrometastases at the time of their operation.
Why Was This Study Done?
Despite this poor overall outcome, about a quarter of patients with resectable PDAC survive for more than 5 years after surgery. Might some patients, therefore, have a less aggressive form of PDAC determined by the biology of the primary (original) tumor? If this is the case, it would be useful to be able to stratify patients according to the aggressiveness of their disease so that patients with very aggressive disease could be given chemotherapy before surgery (neoadjuvant therapy) to kill any micrometastases. At present neoadjuvant therapy is given to patients with locally advanced, unresectable tumors. In this study, the researchers compare gene expression patterns in primary tumor samples collected from patients with localized PDAC and from patients with metastatic PDAC between 1999 and 2007 to try to identify molecular markers that distinguish between more and less aggressive PDACs.
What Did the Researchers Do and Find?
The researchers identified a six-gene signature that was associated with metastatic disease using a molecular biology approach called microarray hybridization and a statistical method called significance analysis of microarrays to analyze gene expression patterns in primary tumor samples from 15 patients with localized PDAC and 15 patients with metastatic disease. Next, they used a training set of tumor samples from another 34 patients with localized and resected PDAC, microarray hybridization, and a graphical method called X-tile to select a combination of expression levels of the six genes that discriminated optimally between high-risk (aggressive) and low-risk (less aggressive) tumors on the basis of patient survival (a “cut-point”). When the researchers applied this cut-point to an independent set of 67 tumor samples from patients with localized and resected PDAC, they found that 42 patients had high-risk tumors. These patients had an average survival time of 15 months; 55% of them were alive a year after surgery. The remaining 25 patients, who had low-risk tumors, had an average survival time of 49 months and 91% of them were alive a year after resection.
What Do These Findings Mean?
These and other findings identify a six-gene signature that can predict outcomes in patients with localized, resectable PDAC better than, and independently of, established clinical markers of outcome. If the predictive ability of this signature can be confirmed in additional patients, it could be used to help patients make decisions about their treatment. For example, a patient wondering whether to risk the Whipple procedure (2%–6% of patients die during this operation and more than 50% have serious postoperative complications), the knowledge that their tumor was low risk might help them decide to have the operation. Conversely, a patient in poor health with a high-risk tumor might decide to spare themselves the trauma of major surgery. The six-gene signature might also help clinicians decide which patients would benefit most from neoadjuvant therapy. Finally, the genes in this signature, or the biological pathways in which they participate, might represent new therapeutic targets for the treatment of PDAC.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000307.
The US National Cancer Institute provides information for patients and health professionals about all aspects of pancreatic cancer (in English and Spanish), including a booklet for patients
The American Cancer Society also provides detailed information about pancreatic cancer
The UK National Health Service and Cancer Research UK include information for patients on pancreatic cancer on their Web sites
MedlinePlus provides links to further resources on pancreatic cancer (in English and Spanish)
Cure Pancreatic Cancer provides information about scientific and medical research related to the diagnosis, treatment, cure, and prevention of pancreatic cancer
Pancreatic Cancer Action Network is a US organization that supports research, patient support, community outreach, and advocacy for a cure for pancreatic cancer
doi:10.1371/journal.pmed.1000307
PMCID: PMC2903589  PMID: 20644708
8.  Macrophage inhibitory cytokine 1 (MIC-1/GDF15) as a novel diagnostic serum biomarker in pancreatic ductal adenocarcinoma 
BMC Cancer  2014;14(1):578.
Background
Macrophage inhibitory cytokine 1 (MIC-1/GDF15) has been identified as a potential novel biomarker for detection of pancreatic cancer (PCa). However, the diagnostic value of serum MIC-1 for pancreatic ductal adenocarcinoma (PDAC), particularly for those at the early stage, and the value for treatment response monitoring have not yet been investigated.
Methods
MIC-1 expression in tumor tissue was analyzed by RT-PCR from 64 patients with PDAC. Serum MIC-1 levels were detected by ELISA in 1472 participants including PDAC, benign pancreas tumor, chronic pancreatitis and normal controls. The diagnostic performance of MIC-1 was assessed and compared with CA19.9, CEA and CA242, and the value of it as a predictive indicator for therapeutic response and tumor recurrence was also evaluated.
Results
MIC-1 levels were significantly elevated in PDAC tissues as well as serum samples. The sensitivity of serum MIC-1 for PDAC diagnosis was much higher than that of CA19.9 (65.8% vs. 53.3%) with similar specificities. Furthermore, serum MIC-1 detected 238 out of 377 (63.1%) CA19.9-negative PDAC. Moreover, receiver operating characteristic (ROC) curve analysis also showed that serum MIC-1 had a better performance compared with CA19.9 in distinguishing early-stage PDAC from normal serum with a higher sensitivity (62.5% vs. 25.0% respectively). Notably, serum MIC-1 level was significantly decreased in patients with PDAC after curative resection and returned to elevated levels when tumor relapse occurred.
Conclusions
Serum MIC-1 is significantly elevated in most PDAC, including those with negative CA19.9 and early stage disease, and thus may serve as a novel diagnostic marker in early diagnosis and postoperative monitoring of PDAC.
doi:10.1186/1471-2407-14-578
PMCID: PMC4133074  PMID: 25106741
9.  Prognosis of malignant intraductal papillary mucinous tumours of the pancreas after surgical resection. Comparison with pancreatic ductal adenocarcinoma 
Gut  2002;51(5):717-722.
Background: Although the prognosis in malignant resectable intraductal papillary mucinous tumours of the pancreas (IPMT) is often considered more favourable than for ordinary pancreatic ductal adenocarcinoma, the long term outcome remains ill defined.
Aims: To assess prognostic factors in patients with malignant IPMT after surgical resection, and to compare long term survival rates with those of patients surgically treated for ductal adenocarcinoma.
Methods: Seventy three patients underwent surgery for malignant IPMT in four French centres. Clinical, biochemical, and pathological features and follow up after resection were recorded. Patients with invasive malignant IPMT were matched with patients with pancreatic ductal adenocarcinoma, according to age and TNM stages; survival rates after resection were compared.
Results: Surgical treatment for IPMT were pancreaticoduodenectomy (n=46), distal (n=14), total (n=11), or segmentary (n=2) pancreatectomy. The operative mortality rate was 4%. IPMT corresponded to in situ (n=22) or invasive carcinoma (n=51). In the latter group, 17 had lymph node metastases. Overall median survival was 47 months. Five year survival rates in patients with in situ and invasive carcinoma were 88% and 36%, respectively. On univariate analysis, abdominal pain, preoperative high serum carbohydrate antigen 19.9 concentrations, caudal localisation, invasive carcinoma, lymph node metastases, peripancreatic extension, and malignant relapse were associated with a fatal outcome. Using multivariate analysis, lymph node metastases were the only prognostic factor (OR 7.5; 95% CI: 3.4 to 16.4). Overall five year survival rate was higher in patients with malignant invasive IPMT compared with those with pancreatic ductal carcinoma (36 v 21%, p=0.03), but was similar in the subset of stage II/III tumours.
Conclusions: The prognosis of patients with resected in situ/invasive stage I malignant IPMT is excellent. In contrast, prognosis of locally advanced forms is as poor as in patients with pancreatic ductal adenocarcinoma.
PMCID: PMC1773420  PMID: 12377813
pancreas; intraductal papillary mucinous tumours
10.  Is there a role for the quantification of RRM1 and ERCC1 expression in pancreatic ductal adenocarcinoma? 
BMC Cancer  2012;12:104.
Background
RRM1 and ERCC1 overexpression has been extensively investigated as potential predictive markers of tumor sensitivity to conventional chemotherapy agents, most thoroughly in lung cancer. However, data in pancreatic cancer are scarce.
Methods
We investigated the mRNA and protein expression of ERCC1 and RRM1 by RT-PCR and immunohistochemistry (IHC) in formalin-fixed, paraffin-embedded pancreatic ductal carcinoma (PDA) tissues. The primary outcome investigated was the association between RRM1 and ERCC1 expression and overall survival (OS) or disease-free survival (DFS).
Results
A total of 94 patients with resected PDA were included in this study. Most of them (87%) received gemcitabine based chemotherapy. Data for OS analysis was available in all cases but only 68% had enough information to estimate DFS. IHC analysis revealed information for 99% (93/94) and 100% of the cases for RRM1 and ERCC1 expression respectively. However, PCR data interpretation was possible in only 49 (52%) and 79 (84%) cases respectively. There was no significant association between high or low expression of either RRM1 or ERCC1, detected by IHC and OS (14.4 vs. 19.9 months; P = 0.5 and 17.1 vs. 19.9; P = 0.83 respectively) or PCR and OS (48.0 vs. 24.1 months; P = 0.21 and 22.0 vs. 16.0 months; P = 0.39 respectively). Similar results were obtained for DFS.
Conclusions
RRM1 and ERCC1 expression does not seem to have a clear predictive or prognostic value in pancreatic cancer. Our data raise some questions regarding the real clinical and practical significance of analyzing these molecules as predictors of outcomes.
doi:10.1186/1471-2407-12-104
PMCID: PMC3364898  PMID: 22436573
11.  Preoperative/Neoadjuvant Therapy in Pancreatic Cancer: A Systematic Review and Meta-analysis of Response and Resection Percentages 
PLoS Medicine  2010;7(4):e1000267.
Jörg Kleef and colleagues systematically reviewed studies on neoadjuvant therapy and tumor response, toxicity, resection, and survival percentages in pancreatic cancer and suggest that patients with locally nonresectable tumors should be included in neoadjuvant protocols.
Background
Pancreatic cancer has an extremely poor prognosis and prolonged survival is achieved only by resection with macroscopic tumor clearance. There is a strong rationale for a neoadjuvant approach, since a relevant percentage of pancreatic cancer patients present with non-metastatic but locally advanced disease and microscopic incomplete resections are common. The objective of the present analysis was to systematically review studies concerning the effects of neoadjuvant therapy on tumor response, toxicity, resection, and survival percentages in pancreatic cancer.
Methods and Findings
Trials were identified by searching MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials from 1966 to December 2009 as well as through reference lists of articles and proceedings of major meetings. Retrospective and prospective studies analyzing neoadjuvant radiochemotherapy, radiotherapy, or chemotherapy of pancreatic cancer patients, followed by re-staging, and surgical exploration/resection were included. Two reviewers independently extracted data and assessed study quality. Pooled relative risks and 95% confidence intervals were calculated using random-effects models. Primary outcome measures were proportions of tumor response categories and percentages of exploration and resection. A total of 111 studies (n = 4,394) including 56 phase I–II trials were analyzed. A median of 31 (interquartile range [IQR] 19–46) patients per study were included. Studies were subdivided into surveys considering initially resectable tumors (group 1) and initially non-resectable (borderline resectable/unresectable) tumors (group 2). Neoadjuvant chemotherapy was given in 96.4% of the studies with the main agents gemcitabine, 5-FU (and oral analogues), mitomycin C, and platinum compounds. Neoadjuvant radiotherapy was applied in 93.7% of the studies with doses ranging from 24 to 63 Gy. Averaged complete/partial response probabilities were 3.6% (95% CI 2%–5.5%)/30.6% (95% CI 20.7%–41.4%) and 4.8% (95% CI 3.5%–6.4%)/30.2% (95% CI 24.5%–36.3%) for groups 1 and 2, respectively; whereas progressive disease fraction was estimated to 20.9% (95% CI 16.9%–25.3%) and 20.8% (95% CI 14.5%–27.8%). In group 1, resectability was estimated to 73.6% (95% CI 65.9%–80.6%) compared to 33.2% (95% CI 25.8%–41.1%) in group 2. Higher resection-associated morbidity and mortality rates were observed in group 2 versus group 1 (26.7%, 95% CI 20.7%–33.3% versus 39.1%, 95% CI 29.5%–49.1%; and 3.9%, 95% CI 2.2%–6% versus 7.1%, 95% CI 5.1%–9.5%). Combination chemotherapies resulted in higher estimated response and resection probabilities for patients with initially non-resectable tumors (“non-resectable tumor patients”) compared to monotherapy. Estimated median survival following resection was 23.3 (range 12–54) mo for group 1 and 20.5 (range 9–62) mo for group 2 patients.
Conclusions
In patients with initially resectable tumors (“resectable tumor patients”), resection frequencies and survival after neoadjuvant therapy are similar to those of patients with primarily resected tumors and adjuvant therapy. Approximately one-third of initially staged non-resectable tumor patients would be expected to have resectable tumors following neoadjuvant therapy, with comparable survival as initially resectable tumor patients. Thus, patients with locally non-resectable tumors should be included in neoadjuvant protocols and subsequently re-evaluated for resection.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Pancreatic cancer is the fourth leading cause of cancer-related deaths worldwide. It begins when a cell in the pancreas (an organ lying behind the stomach that produces digestive enzymes and hormones such as insulin that controls blood sugar levels) acquires genetic changes that allow it to grow uncontrollably and, sometimes, to spread around the body (metastasize). Because pancreatic cancer rarely causes any symptoms early in its development, it is locally advanced in more than a third of patients and has already metastasized in another half of patients by the time it is diagnosed. Consequently, on average, people die within 5–8 months of a diagnosis of pancreatic cancer. At present, the only chance for cure is surgical removal (resection) of the tumor, part of the pancreas, and other nearby digestive organs. This procedure—the Whipple procedure—is only possible in the fifth of patients whose tumor is found when it is small enough to be resectable, and even in these patients, the cure rate associated with surgery is less than 25%, although radiotherapy or chemotherapy after surgery (adjuvant therapy) can be beneficial.
Why Was This Study Done?
For patients whose tumor has metastasized, palliative chemotherapy to slow down tumor growth and to minimize pain is the only treatment option. But, for the many patients whose disease is locally advanced and unresectable at diagnosis, experts think that “neoadjuvant” therapy might be helpful. Neoadjuvant therapy—chemotherapy and/or radiotherapy given before surgery—aims to convert unresectable tumors into resectable tumors by shrinking the visible tumor and removing cancer cells that cannot be seen with the naked eye. Randomized phase III trials—studies in which groups of patients are randomly assigned to different interventions and specific outcomes measured—are the best way to determine whether an intervention has any clinical benefits, but no randomized phase III trials of neoadjuvant therapy for unresectable pancreatic cancer have been undertaken. Therefore, in this systematic review (a study that uses predefined criteria to identify all the research on a given topic) and meta-analysis (a statistical method for combining the results of several studies), the researchers analyze data from other types of studies to investigate whether neoadjuvant therapy for pancreatic cancer provides any clinical benefits.
What Did the Researchers Do and Find?
In their systematic review, the researchers identified 111 studies involving 4,394 patients in which the effects of neoadjuvant chemotherapy and/or radiotherapy on tumor response, tumor resectability, and patient survival had been investigated. They subdivided the studies into two groups: group 1 studies included patients whose tumors were considered resectable on preoperative examination, and group 2 studies included patients whose tumors were borderline resectable or unresectable. In their meta-analysis, the researchers found that similar percentages of the tumors in both groups responded to neoadjuvant therapy by shrinking or regressing and that about a fifth of the tumors in each group grew larger or metastasized during neoadjuvant therapy. In the group 1 studies, three-quarters of the tumors were resectable after neoadjuvant therapy (a decrease in the proportion of tumors that could be treated surgically) whereas in the group 2 studies, a third of the tumors were resectable after neoadjuvant therapy (an increase in the proportion of tumors that could be treated surgically). After resection, the average survival time for group 1 patients was 23.3 months, a similar survival time to that seen in patients treated with surgery and adjuvant therapy. The average survival time for group 2 patients after resection was 20.5 months.
What Do These Findings Mean?
The finding that the average survival time after neoadjuvant therapy and surgery in patients whose tumor was judged resectable before neoadjuvant therapy was similar to that of patients treated with chemotherapy and/or radiotherapy after surgery suggests that for patients with resectable tumors, neoadjuvant therapy will not provide any clinical benefit. By contrast, the finding that a third of patients initially judged unresectable were able to undergo resection after neoadjuvant therapy and then had a similar survival rate to patients judged resectable before neoadjuvant treatment strongly suggests that patients presenting with locally advanced/unresectable tumors should be offered neoadjuvant therapy and then re-evaluated for resection. Randomized trials are now needed to confirm this finding and to determine the optimum neoadjuvant therapy for this group of patients.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000267.
The US National Cancer Institute provides information for patients and health professionals about all aspects of pancreatic cancer (in English and Spanish), including a booklet for patients
The American Cancer Society also provides detailed information about pancreatic cancer
The UK National Health Service and Cancer Research UK include information for patients on pancreatic cancer on their Web sites
MedlinePlus provides links to further resources on pancreatic cancer (in English and Spanish)
Pancreatica.org, PancreaticDuct.org, and the Pancreatic Cancer Action Network give more information to pancreatic cancer patients, their families, and caregivers
doi:10.1371/journal.pmed.1000267
PMCID: PMC2857873  PMID: 20422030
12.  Serum CA 19-9 as a Biomarker for Pancreatic Cancer—A Comprehensive Review 
Pancreatic cancer is an aggressive tumor with a dismal prognosis, biomarkers that can detect tumor in its early stages when it may be amenable to curative resection may improve prognosis. At present, serum CA 19-9 is the only validated tumor marker in widespread clinical use, but precise knowledge of its role in pancreatic cancer diagnosis, staging, determining resectability, response to chemotherapy and prognosis remains limited. A comprehensive search was performed using PubMed 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 studied and clinically useful biomarker for pancreatic cancer. Unfortunately, CA 19-9 serum level evaluation in pancreatic cancer patients is limited by poor sensitivity, false negative results in Lewis negative phenotype (5–10%) and increased false positivity in the presence of obstructive jaundice (10–60%). Serum CA 19-9 level has no role in screening asymptomatic populations, and has a sensitivity and specificity of 79–81% and 82–90% respectively for the diagnosis of pancreatic cancer in symptomatic patients. Pre-operative CA 19-9 serum level provide useful prognostic information as patients with normal CA 19-9 serum levels (<37 U/ml) have a prolonged median survival (32–36 months) compared to patients with elevated CA 19-9 serum 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 may 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. Carbohydrate antigen (CA 19-9) is the most extensively studied and validated serum biomarker for the diagnosis of pancreatic cancer in symptomatic patients. The CA 19-9 serum level can provide important information with regards to prognosis, overall survival, and response to chemotherapy as well as predict post-operative recurrence. 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.
doi:10.1007/s13193-011-0042-1
PMCID: PMC3244191  PMID: 22693400
Pancreatic cancer; Tumor markers; CA 19-9; Diagnosis; Screening; Prognosis; Resectability; Recurrence
13.  Predictors for resectability and survival in locally advanced pancreatic cancer after gemcitabine-based neoadjuvant therapy 
BMC Surgery  2014;14:72.
Background
To evaluate the predictors for resectability and survival of patients with locally advanced pancreatic cancer (LAPC) treated with gemcitabine-based neoadjuvant therapy (GBNAT).
Methods
Between May 2003 and Dec 2009, 41 tissue-proved LAPC were treated with GBNAT. The location of pancreatic cancer in the head, body and tail was 17, 18 and 6 patients respectively. The treatment response was evaluated by RECIST criteria. Surgical exploration was based on the response and the clear plan between tumor and celiac artery/superior mesentery artery. Kaplan–Meier analysis and Cox Model were used to calculate the resectability and survival rates.
Results
Finally, 25 patients received chemotherapy (CT) and 16 patients received concurrent chemoradiation therapy (CRT). The response rate was 51% (21 patients), 2 CR (1 in CT and 1 in CRT) and 19 PR (10 in CT and 9 in CRT). 20 patients (48.8%) were assessed as surgically resectable, in which 17 (41.5%) underwent successful resection with a 17.6% positive-margin rate and 3 failed explorations were pancreatic head cancer for dense adhesion. Two pancreatic neck cancer turned fibrosis only. Patients with surgical intervention had significant actuarial overall survival. Tumor location and post-GBNAT CA199 < 152 were predictors for resectability. Post-GBNAT CA-199 < 152 and post-GBNAT CA-125 < 32.8 were predictors for longer disease progression-free survival. Pre-GBNAT CA-199 < 294, post-GBNAT CA-125 < 32.8, and post-op CEA < 6 were predictors for longer overall survival.
Conclusion
Tumor location and post-GBNAT CA199 < 152 are predictors for resectability while pre-GBNAT CA-199 < 294, post-GBNAT CA-125 < 32.8, post-GBNAT CA-199 < 152 and post-op CEA < 6 are survival predictors in LAPC patients with GBNAT.
doi:10.1186/1471-2482-14-72
PMCID: PMC4182443  PMID: 25258022
Locally advanced pancreatic cancer (LAPC); Neoadjuvant therapy; Concurrent chemoradiation therapy (CCRT)
14.  Optimal Timing of Systemic Therapy in Resectable Colorectal Liver Metastases 
The American surgeon  2013;79(4):414-421.
Perioperative chemotherapy has been shown to improve disease-free survival compared with surgery alone for resectable colorectal liver metastases (CLM). We examined our experience with systemic chemotherapy in this clinical setting. A prospectively collected liver surgery database identified 210 patients treated for resectable CLM from 1996 to 2010. Results were correlated to four treatment groups: posthepatectomy adjuvant only, prehepatectomy preoperative only, perioperative (preoperative and adjuvant), and surgery only. Seventy-nine (37.6%) patients received posthepatectomy adjuvant only treatment, 33 (15.7%) received prehepatectomy preoperative only treatment, 46 (21.9%) received perioperative (preoperative and adjuvant) treatment, whereas 52 (24.8%) received surgery alone. Preoperative and adjuvant systemic chemotherapy regimens were as follows: 23 (29.1%) and 18 (14.4%) received a 5-fluorouracil monotherapy regimen, 19 (24.1%) and 31 (24.8%) received an irinotecan-based regimen, and 28 (35.4%) and 37 (29.6%) received an oxaliplatin-based regimen. Nine (11.4%) and 12 (9.6%) received some other unknown combination. Treatment groups showed no difference in gender, mean tumor size, number of tumors, margin status, or postoperative complications with the only difference being a higher incidence of metachronous tumors in the preoperative only and perioperative groups (P = 0.01). Median follow-up and overall survival were 25 and 41 months, respectively. The adjuvant, preoperative, perioperative, and surgery only groups had a median survival time of 48, 35, 39, and 29 months, respectively (log-rank P = 0.04). Independent predictors of overall survival on multivariate analysis included treatment algorithm used and postoperative complication status. Adjuvant only systemic therapy was associated with an improved survival in resectable CLM. Prospective randomized trials are needed to confirm these findings.
PMCID: PMC3888812  PMID: 23574853
15.  Fixed-Dose-Rate Gemcitabine: A Viable First-Line Treatment Option for Advanced Pancreatic and Biliary Tract Cancer 
The Oncologist  2010;15(2):e1-e4.
Background.
We have already reported on fixed-dose-rate gemcitabine (FDR-Gem) in advanced, inoperable pancreatic ductal adenocarcinoma (PDAC) and biliary tract cancer (BTC) in the context of a formal phase II study; building on that experience, we have now expanded the study to reach a cumulative accrual of 106 patients.
Methods.
One hundred six patients (PDAC/BTC, 75/31) were treated with weekly FDR-Gem (1,000 mg/m2 infused at 10 mg/m2 per minute). Patient characteristics included: male-to-female ratio, 0.83; median age, 63 years (range, 28–82); metastatic disease in 66% of patients; and an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0–1 in 81% of patients.
Results.
The median and total number of treatment weeks delivered were 8 (range, 2–22) and 1,154, respectively. Thirteen percent of patients achieved an objective response, 42% experienced a positive clinical benefit response, and 54% achieved a >50% reduction in serum cancer antigen (CA)19.9 levels. The median progression-free survival (PFS) and overall survival (OS) times for the entire population were 4.4 months (95% confidence interval [CI], 3.5–5.1 months) and 7.7 months (95% CI, 6.3–8.8 months), respectively, with 20% of patients alive at 1 year. On multivariate analysis, a CA19.9 reduction >50% and baseline ECOG PS score of 0 were the only independent predictors of PFS and OS, respectively. Treatment was well tolerated, with grade 3–4 neutropenia in 47 of 1,154 treatment weeks (4.1%), and grade 3 anemia and thrombocytopenia in 8 of 1,154 (0.7%) and 16 of 1,154 (1.4%) treatment weeks, respectively.
Conclusions.
Currently available evidence, including this updated analysis, supports the use of FDR-Gem as a first-line option in advanced PDAC, and possibly in BTC, patients and prompts the continued evaluation of this approach in combination regimens.
doi:10.1634/theoncologist.2008-0135
PMCID: PMC3227937  PMID: 20189980
Gemcitabine; Pancreatic cancer; Fixed dose-rate; First-line treatment
16.  The clinical utility of serum CA 19-9 in the diagnosis, prognosis and management of pancreatic adenocarcinoma: An evidence based appraisal 
Background
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.
Methods
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.
Results
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%).
Conclusions
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.
doi:10.3978/j.issn.2078-6891.2011.021
PMCID: PMC3397644  PMID: 22811878
Pancreatic cancer; tumor markers; CA 19-9; diagnosis; screening; prognosis; resectability; recurrence
17.  Resectable pancreatic small cell carcinoma 
Rare Tumors  2011;3(1):e5.
Primary pancreatic small cell carcinoma (SCC) is rare, with just over 30 cases reported in the literature. Only 7 of these patients underwent surgical resection with a median survival of 6 months. Prognosis of SCC is therefore considered to be poor, and the role of adjuvant therapy is uncertain. Here we report two institutions' experience with resectable pancreatic SCC. Six patients with pancreatic SCC treated at the Johns Hopkins Hospital (4 patients) and the Mayo Clinic (2 patients) were identified from prospectively collected pancreatic cancer databases and re-reviewed by pathology. All six patients underwent a pancreaticoduodenectomy. Clinicopathologic data were analyzed, and the literature on pancreatic SCC was reviewed. Median age at diagnosis was 50 years (range 27–60). All six tumors arose in the head of the pancreas. Median tumor size was 3 cm, and all cases had positive lymph nodes except for one patient who only had five nodes sampled. There were no perioperative deaths and three patients had at least one postoperative complication. All six patients received adjuvant therapy, five of whom were given combined modality treatment with radiation, cisplatin, and etoposide. Median survival was 20 months with a range of 9–173 months. The patient who lived for 9 months received chemotherapy only, while the patient who lived for 173 months was given chemoradiation with cisplatin and etoposide and represents the longest reported survival time from pancreatic SCC to date. Pancreatic SCC is an extremely rare form of cancer with a poor prognosis. Patients in this surgical series showed favorable survival rates when compared to prior reports of both resected and unresectable SCC. Cisplatin and etoposide appears to be the preferred chemotherapy regimen, although its efficacy remains uncertain, as does the role of combined modality treatment with radiation.
doi:10.4081/rt.2011.e5
PMCID: PMC3070453  PMID: 21464878
pancreas; small cell; carcinoma; resectable.
18.  Carcinoma of the ampulla of Vater: prognostic factors after curative surgery: a series of 45 cases. 
Gut  1997;40(3):350-355.
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).
PMCID: PMC1027085  PMID: 9135524
19.  Value of Carbohydrate Antigen 19-9 in Predicting Response and Therapy Control in Patients with Metastatic Pancreatic Cancer Undergoing First-Line Therapy 
Frontiers in Oncology  2013;3:155.
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.
doi:10.3389/fonc.2013.00155
PMCID: PMC3682131  PMID: 23785668
pancreatic neoplasms; CA 19-9; response; therapy control; prediction
20.  Adjuvant gemcitabine versus NEOadjuvant gemcitabine/oxaliplatin plus adjuvant gemcitabine in resectable pancreatic cancer: a randomized multicenter phase III study (NEOPAC study) 
BMC Cancer  2011;11:346.
Background
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.
Methods/Design
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.
Discussion
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.
Trial registration
clinicalTrials.gov NCT01314027
doi:10.1186/1471-2407-11-346
PMCID: PMC3176241  PMID: 21831266
21.  Prognostic potential of ERCC1 protein expression and clinicopathologic factors in stage III/N2 non-small cell lung cancer 
Background
Pathological stage III/N2 non-small cell lung cancer (NSCLC) is heterogeneous, and the optimal prognostic marker for survival remains unclear in Chinese patients. The aim of the present study was to assess the prognostic value of the clinicopathologic features and excision repair cross-complementing group-1 (ERCC1) in resected p-stage III/N2 NSCLC patients that received cisplatin-based adjuvant chemotherapy.
Methods
Clinical data concerning 115 patients with histopathologically confirmed stage III/N2 NSCLC who underwent a complete resection were reviewed retrospectively. All patients received cisplatin-based adjuvant chemotherapy. The protein expression levels for ERCC1 were immunohistochemically examined in 115 patients. The relationship between the ERCC1 protein expression level and the clinical outcomes of the patients was then observed.
Results
The 5-year survival rate and median survival time of patients with pathological stage III/N2 NSCLC after surgery and postoperative chemotherapy was 27.0% and 28.0 months, respectively. Survival of patients with ERCC1 negative tumors was significantly longer than those with ERCC1 positive tumors (p = 0.004). However, it was not entirely clear whether adjuvant chemotherapy with cisplatin-based agents was beneficial for ERCC1-negative patients with p-stage III/N2. A multivariate analysis of survival in patients with stage III/N2 NSCLC showed that surgical procedure (pneumonectomy vs. lobectomy; p = 0.001), number of involved lymph nodes (≤5 vs. >5; p = 0.001) and ERCC1 protein expression (negative vs. positive; p = 0.012) were significant prognostic factors. In addition, the prognosis of patients with skip mediastinal lymph node metastasis showed a tendency for improved survival, but this was no significant (p = 0.432).
Conclusions
Findings from this retrospective study suggested that the number of involved lymph nodes and the type of pulmonary resection are significant and independent prognosis factors in patients with p-stage III/N2 NSCLC. In addition, it was found that ERCC1 protein expression might play an important role in the prognosis of p-stage III/N2 NSCLC patients treated with cisplatin-based adjuvant chemotherapy.
doi:10.1186/1749-8090-8-149
PMCID: PMC3681661  PMID: 23759026
Excision repair cross complementation 1; Non-small lung cancer; Number of involved lymph nodes; Prognosis; Skip metastasis
22.  Carbohydrate 19.9 Antigen Serum Levels in Liver Disease 
BioMed Research International  2013;2013:531640.
Background. Carbohydrate 19.9 antigen (CA19.9) has been used in the diagnosis and followup of gastrointestinal tumours. The aim of this prospective longitudinal study was the evaluation of CA19.9 levels in patients with chronic hepatitis and hepatic cirrhosis hepatitis C virus and B virus correlated. Materials and Methods. 180 patients were enrolled, 116 with HCV-related chronic liver disease (48% chronic hepatitis, 52% cirrhosis) and 64 with HBV-related chronic liver disease (86% chronic hepatitis, 14% cirrhosis). Patients with high levels of CA19.9 underwent abdominal ecography, gastroendoscopy, colonoscopy, and abdominal CT scan. Results. 51.7% of patients with HCV-related chronic liver disease and 48.4% of those with HBV-related chronic liver disease presented high levels of CA19.9. None was affected by pancreatic or intestinal neoplasia, cholestatic jaundice, or other diseases potentially able to induce Ca19.9 elevations. CA19.9 levels were elevated in 43.3% of HCV chronic hepatitis, in 56.3% of HCV cirrhosis, in 45.1% of HBV chronic hepatitis, and in 58% of HBV cirrhosis. Conclusions. CA19.9 commonly increases in the serum of patients with chronic viral hepatitis. Elevation of CA 19.9 is not specific for neoplastic disease and is related to the severity of fibrosis and to the viral aetiology of hepatitis.
doi:10.1155/2013/531640
PMCID: PMC3824822  PMID: 24282817
23.  First-line erlotinib and fixed dose-rate gemcitabine for advanced pancreatic cancer 
AIM: To investigate activity, toxicity, and prognostic factors for survival of erlotinib and fixed dose-rate gemcitabine (FDR-Gem) in advanced pancreatic cancer.
METHODS: We designed a single-arm prospective, multicentre, open-label phase II study to evaluate the combination of erlotinib (100 mg/d, orally) and weekly FDR-Gem (1000 mg/m2, infused at 10 mg/m2 per minute) in a population of previously untreated patients with locally advanced, inoperable, or metastatic pancreatic cancer. Primary endpoint was the rate of progression-free survival at 6 mo (PFS-6); secondary endpoints were overall response rate (ORR), response duration, tolerability, overall survival (OS), and clinical benefit. Treatment was not considered to be of further interest if the PFS-6 was < 20% (p0 = 20%), while a PFS-6 > 40% would be of considerable interest (p1 = 40%); with a 5% rejection error (α = 5%) and a power of 80%, 35 fully evaluable patients with metastatic disease were required to be enrolled in order to complete the study. Analysis of prognostic factors for survival was also carried out.
RESULTS: From May 2007 to September 2009, 46 patients were enrolled (male/female: 25/21; median age: 64 years; median baseline carbohydrate antigen 19-9 (CA 19-9): 897 U/mL; locally advanced/metastatic disease: 5/41). PFS-6 and median PFS were 30.4% and 14 wk (95%CI: 10-19), respectively; 1-year and median OS were 20.2% and 26 wk (95%CI: 8-43). Five patients achieved an objective response (ORR: 10.9%, 95%CI: 1.9-19.9); disease control rate was 56.5% (95%CI: 42.2-70.8); clinical benefit rate was 43.5% (95%CI: 29.1-57.8). CA 19-9 serum levels were decreased by > 25% as compared to baseline in 14/23 evaluable patients (63.6%). Treatment was well-tolerated, with skin rash being the most powerful predictor of both longer PFS (P < 0.0001) and OS (P = 0.01) at multivariate analysis (median OS for patients with or without rash: 42 wk vs 15 wk, respectively, Log-rank P = 0.03). Additional predictors of better outcome were: CA 19-9 reduction, female sex (for PFS), and good performance status (for OS).
CONCLUSION: Primary study endpoint was not met. However, skin rash strongly predicted erlotinib efficacy, suggesting that a pharmacodynamic-based strategy for patient selection deserves further investigation.
doi:10.3748/wjg.v19.i28.4511
PMCID: PMC3725375  PMID: 23901226
Pancreatic cancer; Gemcitabine; Fixed dose-rate; Erlotinib; Prognostic factors; Cutaneous rash; Phase II trial
24.  Early Recurrence of Pancreatic Cancer after Resection and During Adjuvant Chemotherapy 
Background/Aim:
Adjuvant chemotherapy for 6 months is the current standard of care after potentially curative resection of pancreatic cancer and yields an overall survival of 15–20 months. Early tumor recurrence before or during adjuvant chemotherapy has not been evaluated so far. These patients may not benefit from adjuvant treatment.
Patients and Methods:
Thirty-five patients with resection of ductal pancreatic carcinoma and adjuvant chemotherapy with gemcitabine were analyzed between 2005 and 2007. All patients had a computed tomography (CT) scan before and during adjuvant chemotherapy after 2–3 months, 12/35 patients had a histologically confirmed R1 resection. Recurrence of pancreatic cancer was determined by CT scan and the clinical course.
Results:
Median survival of 35 patients with resected pancreatic cancer was 19.7 months, and the 2-year survival was 44%. Thirteen (37%) of the 35 patients analyzed with a CT scan showed tumor recurrence during adjuvant chemotherapy. Overall survival of patients with tumor recurrence was 9.3 months with a 2-year survival rate of 13%, whereas median overall survival of patients without early relapse was 26.3 months (P<0.001). Local recurrence of pancreatic cancer occurred in 38% (5/13); 46% (6/13) of patients developed distant metastasis, and 38% (5/13) developed lymph node metastasis. Early tumor recurrence during or adjuvant chemotherapy did not correlate with R status (R1 vs R0, P=0.69), whereas histologically confirmed lymph node invasion (pN0 vs pN1) and grading showed a statistically significant correlation with early relapse (P<0.05).
Conclusion:
A significant fraction of patients with resected pancreatic cancer have early relapse during adjuvant chemotherapy, especially those with lymph node metastasis. Radiologic examinations prior to and during adjuvant chemotherapy will help to identify patients with tumor recurrence who are unlikely to benefit from adjuvant treatment and will need individualized palliative chemotherapy.
doi:10.4103/1319-3767.93815
PMCID: PMC3326972  PMID: 22421717
Adjuvant chemotherapy; pancreatic cancer; recurrence
25.  Sequential chemotherapy and intensity-modulated radiation therapy in the management of locoregionally advanced nasopharyngeal carcinoma: Experience of 370 consecutive cases 
BMC Cancer  2010;10:39.
Introduction
To investigate the outcome of locoregionally advanced nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy (IMRT) after induction chemotherapy, with or without concomitant chemotherapy.
Methods
Between August 2003 and March 2007, 370 patients with locoregionally advanced NPC were treated with IMRT. Presenting stages were stage IIB in 62, stage III in 197, and stage IVA/B in 111 patients. All patients except for 36 patients with cervical lymphadenopathy of 4 cm or less in diameter received 2 cycles of cisplatin-based neoadjuvant chemotherapy. Forty-eight patients received cisplatin-based concurrent chemotherapy as well.
Results
With a median follow-up time of 31 months (range 5 to 61 months), the 3-year local control, regional control, metastasis-free survival (MFS), disease-free survival (DFS) and overall survival (OS) rates were 95%, 97%, 86%, 81% and 89%, respectively. Multivariate analyses revealed that both age (≤ 60 vs. >60) and N-classification are significant prognosticators for OS (P = 0.001, hazard ratio [HR] 2.395, 95% confidence interval [CI] 1.432-4.003; P = 0.012, hazard ratio [HR] 2.614, 95% confidence interval [CI] 1.235-5.533); And N-classification is the only significant predicative factor for MFS (P = 0.002, [HR] 1.99, 95% CI 1.279-3.098). T-classification and concurrent chemotherapy were not significant prognostic factors for local/regional control, MFS, DFS, or OS. Subgroup analysis revealed that concurrent chemotherapy provided no significant benefit to IMRT in locoregionally advanced NPC, but was responsible for higher rates of grade 3 or 4 acute toxicities (50% vs. 29.8%, P < 0.005). No grade 3 or 4 late toxicity including xerostomia was observed. However, two patients treated with IMRT and neoadjuvant but without concurrent and adjuvant chemotherapy died of treatment related complications.
Conclusion
IMRT following neoadjuvant chemotherapy produced a superb outcome in terms of local control, regional control, MFS, DFS, and OS rates in patients with stage IIB to IVB NPC. Effective treatment strategy is urgently needed for distant control in patients diagnosed with locoregionally advanced NPC.
doi:10.1186/1471-2407-10-39
PMCID: PMC2836300  PMID: 20146823

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