High Expression of Plasminogen Activator Inhibitor-2 (PAI-2) is a Predictor of Improved Survival in Patients with Pancreatic Adenocarcinoma

Objective Recent findings suggest that the urokinase-type plasminogen activator (uPA), its receptor (uPAR), plasminogen activator inhibitor-1 (PAI-1), and -2 (PAI-2) play key roles in cancer invasion. Summary Background Data The prognostic value of components of this system is well established in breast cancer. However, little is known of its involvement in pancreatic cancer (PC). Methods Quantitative real-time polymerase chain reaction (Q-RT-PCR) was used on tissue-banked specimens and immunohistochemistry (IHC) on paraffin specimens was used to measure expression of uPA, uPAR, PAI-1, and PAI-2 proteins in 46 PC and 12 cystadenoma specimens. Results were related to survival using Cox’s proportional hazards testing. Results Increased expression of uPA, uPAR, and PAI-1 in PC tissue were independently associated with a higher Union Internationale Contre le Cancer [International Union Against Cancer (UICC)] tumor stage (P < 0.001) and were intercorrelated (P < 0.001). Overexpression of uPAR indicated reduced survival (P = 0.03). Conversely, PAI-2 messenger ribonucleic acid (mRNA) overexpression, which occurred in 21 of 46 tumors, negatively correlated with tumor size (P = 0.008) and survival (P < 0.007) but not with uPA, uPAR, or tumor stage. There was good agreement between PAI-2 mRNA value and IHC score (P < 0.001). Using Cox’s stepwise analysis, PAI-2 mRNA value (HR = 0.24; P = 0.001) and UICC tumor stage (HR = 2.014; P = 0.001) independently predicted survival. An IHC score for PAI-2 of 3+ or 4+ also independently predicted improved survival (HR = 2.72; P = 0.025). Conclusions The uPA/uPAR/PAI-1 system is activated in advanced pancreatic cancer and may account for the tumor’s aggressive behavior, whereas PAI-2 expression appears to be independent of uPA/uPAR/PAI-1 and is associated with improved prognosis. Because of its intercorrelation with mRNA expression, PAI-2 IHC may be used as an indicator of survival.     

Adverse Tumor Biology Associated with Mesenterico-Portal Vein Resection Influences Survival in Patients with Pancreatic Ductal Adenocarcinoma

Background

Although pancreatoduodenectomy (PD) with mesenterico-portal vein resection (VR) can be performed safely in patients with resectable pancreatic ductal adenocarcinoma (PDAC), the impact of this approach on long-term survival is controversial.

Patients and Methods

Analyses of a prospectively collected database revealed 122 consecutive patients with PDAC who underwent PD with (PD+VR) or without (PD?VR) VR between January 2004 and May 2012. Clinical data, operative results, and survival outcomes were analysed.

Results

Sixty-four (53 %) patients underwent PD+VR. The majority (84 %) of the venous reconstructions were performed with a primary end-to-end anastomosis. Demographic and postoperative outcomes were similar between the two groups. American Society of Anesthesiologists (ASA) score, duration of operation, intraoperative blood loss, and blood transfusion requirement were significantly greater in the PD+VR group compared with the PD?VR group. Furthermore, the tumor size was larger, and the rates of periuncinate neural invasion and positive resection margin were higher in the PD+VR group compared with the PD?VR group. Histological venous involvement occurred in 47 of 62 (76 %) patients in the PD+VR group. At a median follow-up of 29 months, the median overall survival (OS) was 18 months for the PD+VR group, and 31 months for the PD?VR group (p = 0.016). ASA score, lymph node metastasis, neurovascular invasion, and tumor differentiation were predictive of survival. The need for VR in itself was not prognostic of survival.

Conclusions

PD with VR has similar morbidity but worse OS compared with a PD?VR. Although VR is not predictive of survival, tumors requiring a PD+VR have more adverse biological features.     

Adjuvant Chemotherapy After Neoadjuvant Chemotherapy for Pancreatic Cancer is Associated with Improved Survival for Patients with Low-Risk Pathology

Annals of Surgical Oncology - With limited evidence, the benefit of adjuvant chemotherapy (AT) after completion of neoadjuvant chemotherapy (NT) and surgical resection for patients with pancreatic...     

Metformin Use Is Associated with Improved Survival in Patients Undergoing Resection for Pancreatic Cancer

Preclinical evidence has demonstrated anti-tumorigenic effects of metformin. The effects of metformin following pancreatic cancer, however, remain undefined. We sought to assess the association between metformin use and survival using a large, nationally representative sample of patients undergoing surgery for pancreatic cancer. Patients undergoing a pancreatic resection between January 01, 2010, and December 31, 2012, were identified using the Truven Health MarketScan database. Clinical data, including history of metformin use, as well as operative details and information on long-term outcomes were collected. Multivariable Cox proportional hazards regression analysis was performed to assess the effect of metformin use on overall survival (OS). A total of 3393 patients were identified. The mean age of patients was 54.2 years (SD?=?9.1 years). Roughly one half of patients were female (n?=?1735, 51.1 %); 49.1 % (n?=?1665) presented with a Charlson comorbidity index of 3 or greater (CCI ≥3); and 19.6 % (n?=?664) had diabetes. At the time of surgery, 60.0 % (n?=?2034) of patients underwent a pancreaticoduodenectomy, 35.7 % (n?=?1212) a partial/distal pancreatectomy, while 4.3 % (n?=?147) had a total pancreatectomy. On pathology, 1057 (31.2 %) had lymph node metastasis. Metformin use was identified in 456 patients (13.4 %) and was more commonly administered among patients without locally advanced disease (14.3 vs. 11.6 %, p?=?0.038). While OS was comparable between patients within the first year of surgery (OS at 1 year 65.4 % [95 % confidence interval (CI) 63.4–67.3 %] vs. 69.2 % [95 % CI 64.2–73.4 %]), patients who received metformin demonstrated an improved OS beginning at 18 months following surgery. On multivariable analysis adjusting for patient and clinicopathologic characteristics, metformin use was independently associated with a decreased risk of mortality (hazard ratio [HR]?=?0.79, 95 % CI 0.67–0.93, p?=?0.005). Metformin use was associated with an improved overall survival among patients undergoing pancreatic surgery for pancreatic cancer. Further work is necessary to better understand its role in modifying cancer-specific and overall health outcomes.     

Perioperative Blood Transfusion Is Associated with Decreased Survival in Patients Undergoing Pancreaticoduodenectomy for Pancreatic Adenocarcinoma: a Multi-institutional Study

Introduction

In this multi-institutional study of patients undergoing pancreaticoduodenectomy for pancreatic adenocarcinoma, we sought to identify factors associated with perioperative transfusion requirement as well as the association between blood transfusion and perioperative and oncologic outcomes.

Methods

The surgical databases across six high-volume institutions were analyzed to identify patients who underwent pancreaticoduodenectomy for pancreatic adenocarcinoma from 2005 to 2010. For statistical analyses, patients were then stratified by transfusion volume according to whether they received 0, 1–2, or >2 units of packed red blood cells.

Results

Among 697 patients identified, 42 % required blood transfusion. Twenty-three percent received 1–2 units, and 19 % received >2 units. Factors associated with an increased transfusion requirement included older age, heart disease, diabetes, longer operative time, higher blood loss, tumor size, and non-R0 margin status (all p?p?=?0.02) and overall survival (14.0 vs. 21.0 months, p?2 units (hazard ratio, 1.92, p?=?0.009) and postoperative transfusions as independent factors associated with decreased disease-free survival.

Conclusions

This multi-institutional study represents the largest series to date analyzing the effects of perioperative blood transfusion on patient outcomes following pancreaticoduodenectomy for pancreatic adenocarcinoma. While blood transfusion was not associated with increased rate of infectious complications, allogeneic blood transfusion did confer a negative impact on disease-free and overall survival.     

Pancreatic Ductal Adenocarcinoma is Associated with a Distinct Urinary Metabolomic Signature

Background

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with poor prognosis in part due to the lack of early detection and screening methods. Metabolomics provides a means for noninvasive screening of tumor-associated perturbations in cellular metabolism.

Methods

Urine samples of PDAC patients (n = 32), healthy age and gender-matched controls (n = 32), and patients with benign pancreatic conditions (n = 25) were examined using ¹H-NMR spectroscopy. Targeted profiling of spectra permitted quantification of 66 metabolites. Unsupervised (principal component analysis, PCA) and supervised (orthogonal partial-least squares discriminant analysis, OPLS-DA) multivariate pattern recognition techniques were applied to discriminate between sample spectra using SIMCA-P⁺ (version 12, Umetrics, Sweden).

Results

Clear distinction between PDAC and controls was noted when using OPLS-DA. Significant differences in metabolite concentrations between cancers and controls (p < 0.001) were noted. Model parameters for both goodness of fit, and predictive capability were high (R ² = 0.85; Q ² = 0.59, respectively). Internal validation methods were used to confirm model validity. Sensitivity and specificity of the multivariate OPLS-DA model were summarized using a receiver operating characteristics (ROC) curve, with an area under the curve (AUROC) = 0.988, indicating strong predictive power. Preliminary analysis revealed an AUROC = 0.958 for the model of benign pancreatic disease compared with PDAC, and suggest that the cancer-associated metabolomic signature dissipates following RO resection.

Conclusions

Urinary metabolomics detected distinct differences in the metabolic profiles of pancreatic cancer compared with healthy controls and benign pancreatic disease. These preliminary results suggest that metabolomic approaches may facilitate discovery of novel pancreatic cancer biomarkers.

     

Pancreatic Ductal Adenocarcinoma is Associated with a Distinct Urinary Metabolomic Signature

Background

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with poor prognosis in part due to the lack of early detection and screening methods. Metabolomics provides a means for noninvasive screening of tumor-associated perturbations in cellular metabolism.

Methods

Urine samples of PDAC patients (n = 32), healthy age and gender-matched controls (n = 32), and patients with benign pancreatic conditions (n = 25) were examined using ¹H-NMR spectroscopy. Targeted profiling of spectra permitted quantification of 66 metabolites. Unsupervised (principal component analysis, PCA) and supervised (orthogonal partial-least squares discriminant analysis, OPLS-DA) multivariate pattern recognition techniques were applied to discriminate between sample spectra using SIMCA-P⁺ (version 12, Umetrics, Sweden).

Results

Clear distinction between PDAC and controls was noted when using OPLS-DA. Significant differences in metabolite concentrations between cancers and controls (p < 0.001) were noted. Model parameters for both goodness of fit, and predictive capability were high (R ² = 0.85; Q ² = 0.59, respectively). Internal validation methods were used to confirm model validity. Sensitivity and specificity of the multivariate OPLS-DA model were summarized using a receiver operating characteristics (ROC) curve, with an area under the curve (AUROC) = 0.988, indicating strong predictive power. Preliminary analysis revealed an AUROC = 0.958 for the model of benign pancreatic disease compared with PDAC, and suggest that the cancer-associated metabolomic signature dissipates following RO resection.

Conclusions

Urinary metabolomics detected distinct differences in the metabolic profiles of pancreatic cancer compared with healthy controls and benign pancreatic disease. These preliminary results suggest that metabolomic approaches may facilitate discovery of novel pancreatic cancer biomarkers.

     

Undetectable Preoperative Levels of Serum CA 19-9 Correlate with Improved Survival for Patients with Resectable Pancreatic Adenocarcinoma

Background: Serum levels of CA19-9 have been shown to correlate with both recurrence and survival in patients with pancreatic cancer. However, little is known about the prognosis for patients with undetectable levels of serum CA19-9.Methods :One hundred twenty-nine patients with pancreatic cancer who underwent preoperative assessment of serum CA19-9 followed by resection with curative intent between 1990 and 2002 were retrospectively analyzed. Data collected included preoperative serum CA19-9 level (U/mL), age, pathologic staging, and survival. Data were analyzed with the SAS system according to four distinct preoperative serum CA19-9 levels: undetectable, normal (<37), 38–200, and 200 U/mL.Results: Serum CA19-9 levels ranged from undetectable to 16,300 U/mL. Stage III/IV disease accounted for 86%, 67%, 59%, and 53% of patients in the four CA19-9 groups. The overall median and 5-year survivals were 19 months and 11%, respectively. Survival was similar between nonsecretors and those with normal CA 19-9 levels. However, both groups had statistically significant prolonged survival compared with the two groups with elevated CA 19-9 levels (P = .003). The only factors that were significant on univariate and multivariate analysis for overall survival were lymph node positivity (P = .015 and .002) and CA 19-9 grouping (P = .003 and P < .0001). Although this group of patients presented with predominately advanced-stage disease, their overall survival was superior.Conclusions: These findings suggest that patients who present with undetectable preoperative CA19-9 levels and potentially resectable pancreatic cancer, regardless of advanced stage, should be considered candidates for aggressive therapy.the 56th Annual Cancer Symposium of the Society of Surgical Oncology, Los Angeles, California, March 5–9, 2003.     

Positive Expression of L1-CAM is Associated with Perineural Invasion and Poor Outcome in Pancreatic Ductal Adenocarcinoma

Background  

Pancreatic ductal adenocarcinoma (PDAC) frequently invades and migrates along neural tissue, which results in local tumor recurrences, distant metastases, and poor prognosis. We evaluated whether L1 cell adhesion molecule (L1-CAM) and glial cell line-derived neurotrophic factor (GDNF) expression in PDAC correlated with neural invasion and overall survival on a large cohort of previously untreated patients.     

Collapsin Response Mediator Protein 4 Expression is Associated with Liver Metastasis and Poor Survival in Pancreatic Cancer

Background

Pancreatic cancer is an aggressive malignancy with one of the worst mortality rates of all cancers. Recently, collapsin response mediator proteins (CRMPs) were reported to be associated with proliferation, apoptosis, differentiation, and invasion in several cancers. However, CRMP expression and their role in pancreatic cancer have not been investigated. This study aimed to clarify the clinical significance of CRMPs in pancreatic cancer.

Methods

Expression of crmp genes in 11 pairs of pancreatic cancer and corresponding noncancerous pancreas tissues were examined by real-time RT-PCR. Knockdown of CRMP4 expression using siRNA was examined in pancreatic cancer cell lines to determine whether CRMP4 regulates cell proliferation and invasion in vitro. Furthermore, CRMP4 protein levels in primary tumors of pancreatic cancer (n = 53) were examined by immunohistochemistry and compared with the clinicopathological features of the tumors.

Results

Of all the CRMPs, only CRMP4 was differentially expressed in pancreatic cancer tissues (p = 0.008). CRMP4 knockdown using siRNA reduced cellular invasion, but did not affect proliferation. The expression of CRMP4 was detected immunohistochemically in 34 (64.2 %) of the 53 pancreatic cancer samples, and CRMP4 expression was correlated with severe venous invasion (p = 0.044), stage (p = 0.019), and liver metastasis (p = 0.021). Multivariate analyses suggested that venous invasion and CRMP4 overexpression were prognostic factors for survival.

Conclusions

Our results suggested that CRMP4 is significantly associated with poor prognosis by promoting liver metastasis and can serve as a novel therapeutic target for pancreatic cancer.

     

Collapsin Response Mediator Protein 4 Expression is Associated with Liver Metastasis and Poor Survival in Pancreatic Cancer

Background

Pancreatic cancer is an aggressive malignancy with one of the worst mortality rates of all cancers. Recently, collapsin response mediator proteins (CRMPs) were reported to be associated with proliferation, apoptosis, differentiation, and invasion in several cancers. However, CRMP expression and their role in pancreatic cancer have not been investigated. This study aimed to clarify the clinical significance of CRMPs in pancreatic cancer.

Methods

Expression of crmp genes in 11 pairs of pancreatic cancer and corresponding noncancerous pancreas tissues were examined by real-time RT-PCR. Knockdown of CRMP4 expression using siRNA was examined in pancreatic cancer cell lines to determine whether CRMP4 regulates cell proliferation and invasion in vitro. Furthermore, CRMP4 protein levels in primary tumors of pancreatic cancer (n = 53) were examined by immunohistochemistry and compared with the clinicopathological features of the tumors.

Results

Of all the CRMPs, only CRMP4 was differentially expressed in pancreatic cancer tissues (p = 0.008). CRMP4 knockdown using siRNA reduced cellular invasion, but did not affect proliferation. The expression of CRMP4 was detected immunohistochemically in 34 (64.2 %) of the 53 pancreatic cancer samples, and CRMP4 expression was correlated with severe venous invasion (p = 0.044), stage (p = 0.019), and liver metastasis (p = 0.021). Multivariate analyses suggested that venous invasion and CRMP4 overexpression were prognostic factors for survival.

Conclusions

Our results suggested that CRMP4 is significantly associated with poor prognosis by promoting liver metastasis and can serve as a novel therapeutic target for pancreatic cancer.

     

High Expression of CHRNA1 is Associated with Reduced Survival in Early Stage Lung Adenocarcinoma after Complete Resection

Background

Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths around the world, and a high recurrence rate after complete resection is an important issue reducing the cure rate and survival of patients with early stage NSCLC. Several pathologic biomarkers are associated with recurrence in early stage lung cancer after complete resection.

Methods

We evaluated the expression and prognostic value of the α1 subunit of the nicotinic acetylcholine receptor (CHRNA1) as well as other pathologic features of tumor tissues resected from patients with stage I adenocarcinoma of the lung.

Results

A high ratio (173/185) of CHRNA1 expression (93.5 %) was found in stage I lung adenocarcinoma. In the multivariate survival analysis, tumor necrosis, angiolymphatic invasion, perineural invasion, and CHRNA1 expression were independent poor prognostic factors for both recurrence-free and overall survival (OS). Patients expressing CHRNA1 had worse median recurrence-free survival (60.6 vs. 77.9 months, P = 0.03) and OS (65.1 vs. 77.9 months, P = 0.04) compared with CHRNA1-negative patients.

Conclusions

CHRNA1 expression could be directly tested from the tumor after complete resection. In early stage NSCLC, it could be a useful prognostic factor for recurrence and survival.     

Resolution of New-Onset Diabetes After Radical Pancreatic Resection Predicts Long-term Survival in Patients with Pancreatic Ductal Cell Adenocarcinoma

Purpose

To demonstrate the effect of diabetes mellitus (DM) (stratified by long-term/new-onset presurgical diabetes, resolved/unresolved postsurgical diabetes) on prognosis for pancreatic ductal cell adenocarcinoma (PDAC) after radical resection.

Methods

One hundred ninety-nine patients who underwent radical resection for PDAC between 2007 and 2011 at Ruijin Hospital (Shanghai, China) were retrospectively analyzed. Clinical and pathologic characteristics, surgical and adjuvant chemotherapy related outcomes, disease-free survival (DFS), and postoperative survival were compared among patients with long-term (≥2 years)/new-onset (<2 years) presurgical diabetes and resolved/unresolved postsurgical diabetes. Univariate and multivariable analysis was performed to determine factors associated with DFS and overall survival (OS).

Results

Of 199 patients, 90 (44.7 %) had DM, 64 of which were new onset and 26 of which were long-standing. Resolution of DM after radical pancreatic resection was observed in 65 % (42 of 64) in the new-onset group, but in none of the long-standing group. Resolved new-onset DM patients had larger, well-differentiated tumors compared to patients with unresolved new-onset DM. Patients with long-standing DM had shorter postoperative DFS and OS than nondiabetic/new-onset DM, whereas postoperative resolved new-onset DM is associated with longer DFS and OS than unresolved DM. Morbidity was higher and postoperative hospital stay was longer in patients with new-onset DM compared with patients with long-standing DM and patients without DM. There was no difference in the adjuvant chemotherapy toxicity rate among patients with long-standing or new-onset DM and those without DM.

Conclusions

Different status of DM has different effects on outcome after resection for PDAC. Long-standing DM is related to progression of disease, whereas postsurgical resolved new-onset DM is a favorable prognostic factor.     

Impact of Margin Status on Survival in Patients with Pancreatic Ductal Adenocarcinoma Receiving Neoadjuvant Chemotherapy

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Clinical and Pathologic Features Influencing Survival in Patients Undergoing Pancreaticoduodenectomy for Pancreatic Adenocarcinoma

Objective

The aim of the study was to determine the clinicopathological features that influence survival in patients with resected pancreatic ductal adenocarcinoma (PDA).

Methods

The study used a single institution retrospective review of patients undergoing pancreaticoduodenectomy (PD) for PDA from 1993 to 2010.

Results

Two hundred forty-six consecutive cases of resected PDA were identified: 128 males (52 %), median age 68 years. Median hospital length of stay was 8 days and 30-day mortality rate was 2.4 %. There were 101 (41.1 %) postoperative complications, 77 % of which were Dindo–Clavien Grade 3 or less. Overall survival was 85, 63, 25, and 15 % at 6 months, 1 year, 3 years, and 5 years, respectively, with a median survival of 17 months. Multivariate Cox proportional hazard modeling demonstrated lymph node ratio was negatively correlated with survival at all time points. Preoperative hypertension was a poor prognostic factor at 6 months, 3 years, and 5 years. The absence of postoperative complications was protective at 6 months whereas pancreatic leaks were associated with worse survival at 6 months. Abdominal pain on presentation, operative time, and estimated blood loss were also associated with decreased survival at various time points.

Conclusion

The strongest prognostic variable for short- and long-term survival after PD for PDA is lymph node ratio. Short-term survival is influenced by the postoperative course.     

Differential Expression of ERCC1 in Pancreas Adenocarcinoma: High Tumor Expression is Associated with Earlier Recurrence and Shortened Survival after Resection

Background  

Increased tumor expression of excision repair cross-complementing gene-1 (ERCC1) is associated with decreased survival in patients with various cancers. Its effect in pancreatic adenocarcinoma (PAC) is not defined.