Aaron R. Sasson

En Bloc Resection for Locally Advanced Cancer of the Pancreas ☆: Is It Worthwhile?

The benefit of radical surgical resection of contiguously involved structures for locally advanced pancreatic cancer is unclear. The aim of this study was to examine patient outcome after extended pancreatic resection for locally advanced tumors and to determine if any subset of extended resection affected outcome. We retrospectively reviewed the records of 116 patients with adenocarcinoma of the pancreas, who underwent extirpative pancreatic surgery between 1987 and 2000. Of the 116 patients, 37 (32%) required resection of surrounding structures (group I), and 79 patients (68%) underwent standard pancreatic resections (group II). In all cases, all macroscopic disease was excised. In group I a total of 46 contiguously involved structures were resected: vascular in 25 patients (54%), mesocolon in 16 (35%) (colic vessels in 3, colon in 13), adrenal in three (7%), liver in one (2%), stomach in one (2%) (for a tumor in the tail of the pancreas), and multiple structures in four. Excision of regional blood vessels included the superior mesenteric vein and/or portal vein in 16, hepatic artery in five, and celiac axis in four. No differences between groups I and II were detected for any of the following parameters: age, sex, history of previous operation, estimated blood loss, or hospital stay. For the entire cohort the morbidity and mortality were 38% and 1.7%, respectively, and these rates were similar in the two groups. Adjuvant therapy was administered to more than 90% of patients in both groups. However, patients in group I were more likely to have received neoadjuvant therapy (76% vs. 42%, P = 0.001). Total pancreatectomy and distal pancreatectomy were more often performed in group I (P = 0.005). Additionally, the median operative time was longer (8.5 hours compared to 6.9 hours (P = 0.0004)). Both groups had similar rates of microscopically positive margins and involved lymph nodes, as well as total number of lymph nodes removed. The median survival was 26 months for patients in group I and 16 months for patients in group II (P = 0.08). The median disease-free survival for groups I and II was 16 months and 14 months, respectively (P = 0.88). In comparing patients in group I, who underwent vascular resection vs. mesocolon (colon or middle colic vessels) resection, the median survival was 26 months and 19 months, respectively (P = 0.12). We were unable to detect a difference in outcome for patients with locally advanced cancers requiring extended pancreatic resections compared to patients with standard resections. En bloc resection of involved surrounding structures, to completely extirpate all macroscopic disease, may be of benefit in selected patients with locally advanced disease, particularly when combined with preoperative chemoradiation therapy.

Effect of preoperative chemoradiotherapy on surgical margin status of resected adenocarcinoma of the head of the pancreas

We examined the effect of preoperative chemoradiotherapy on the ability to obtain pathologically negative resection margins in patients undergoing pancreaticoduodenectomy for adenocarcinoma of the head of the pancreas. Between 1987 and 2000, 100 patients underwent Whipple resection with curative intent for primary adenocarcinoma of the head of the pancreas. Pathologic assessment of six margins (proximal and distal superior mesenteric artery, proximal and distal superior mesenteric vein, pancreas, retroperkoneum, common bile duct, and hepatic artery) was undertaken by either frozen section (pancreas and common duct) or permanent section. A margin was considered positive if tumor was present less than 1 mm from the inked specimen. Margins noted to be positive on frozen section were resected when-ever possible. Of the 100 patients treated, 47 (47%) underwent postoperative radiation and chemotherapy (group I) and 53 (53%) received preoperative chemoradiotherapy (group II) with either 5-fluorouracil (32 patients) or gemcitabine (21 patients). Patient demographics and operative parameters were similar in the two groups, with the exception of preoperative tumor size (CT scan), which was greater in group II (P <0.001), and number of previous operations, which was greater in group II (P <0.0001). Statistical analysis of the number of negative surgical margins clear of tumor was performed using Fisher’s exact test. All patients (100%) had six margins assessed for microscopic involvement with tumor. In the preoperative therapy group, 5 (7.5%) of 53 patients had more than one positive margin, whereas 21 (44.7%) of 47 patients without preoperative therapy had more than one margin with disease extension (P < 0.001). Additionally, only 11 (25.6%) of the 47 patients without preoperative therapy had six negative margins vs. 27 (50.9%) of 53 in the group receiving preoperative therapy (P = 0.013). Survival analysis reveals a significant increase in survival in margin-negative patients (P = 0.02). Similarly, a strong trend toward improved disease-free and overall survival is seen in patients with a single positive margin vs. multiple margins. Overall, we find a negative impact on survival with an increasing number of positive margins (P = 0.025, hazard ratio 1.3). When stratified for individual margin status, survival was decreased in patients with positive superior mesenteric artery (P = 0.06) and vein (P = 0.04) margins. However, this has not yet resulted in a significant increase in disease-free or overall survival for patients receiving preoperative therapy (P = 0.07).

Early diagnosis of pancreatic cancer: neutrophil gelatinase-associated lipocalin as a marker of pancreatic intraepithelial neoplasia.

Pancreatic cancer is a highly lethal malignancy with a dismal 5-year survival of less than 5%. The scarcity of early biomarkers has considerably hindered our ability to launch preventive measures for this malignancy in a timely manner. Neutrophil gelatinase-associated lipocalin (NGAL), a 24-kDa glycoprotein, was reported to be upregulated nearly 27-fold in pancreatic cancer cells compared to normal ductal cells in a microarray analysis. Given the need for biomarkers in the early diagnosis of pancreatic cancer, we investigated the expression of NGAL in tissues with the objective of examining if NGAL immunostaining could be used to identify foci of pancreatic intraepithelial neoplasia, premalignant lesions preceding invasive cancer. To examine a possible correlation between NGAL expression and the degree of differentiation, we also analysed NGAL levels in pancreatic cancer cell lines with varying grades of differentiation. Although NGAL expression was strongly upregulated in pancreatic cancer, and moderately in pancreatitis, only a weak expression could be detected in the healthy pancreas. The average composite score for adenocarcinoma (4.26±2.44) was significantly higher than that for the normal pancreas (1.0) or pancreatitis (1.0) (P<0.0001). Further, although both well- and moderately differentiated pancreatic cancer were positive for NGAL, poorly differentiated adenocarcinoma was uniformly negative. Importantly, NGAL expression was detected as early as the PanIN-1 stage, suggesting that it could be a marker of the earliest premalignant changes in the pancreas. Further, we examined NGAL levels in serum samples. Serum NGAL levels were above the cutoff for healthy individuals in 94% of pancreatic cancer and 62.5% each of acute and chronic pancreatitis samples. However, the difference between NGAL levels in pancreatitis and pancreatic cancer was not significant. A ROC curve analysis revealed that ELISA for NGAL is fairly accurate in distinguishing pancreatic cancer from non-cancer cases (area under curve=0.75). In conclusion, NGAL is highly expressed in early dysplastic lesions in the pancreas, suggesting a possible role as an early diagnostic marker for pancreatic cancer. Further, serum NGAL measurement could be investigated as a possible biomarker in pancreatitis and pancreatic adenocarcinoma.

Factors influencing survival after resection for periampullary neoplasms

BACKGROUND The purpose of this study was to determine predictors of survival after resection for periampullary neoplasms. METHODS Over a 15-year period, 208 patients underwent laparotomy for periampullary neoplasms. Data were analyzed to assess predictors of survival. RESULTS Pathologic examination showed pancreatic cancer (n = 136; 65%), ampullary cancer (n = 28; 13%), distal common bile duct cancer (n = 10; 5%), duodenal cancer (n = 4; 2%), neuroendocrine tumor (n = 11; 5%), cystadenocarcinoma (n = 4; 2%), cystadenoma (n = 5; 2%), and other (n = 10; 5%). A total of 129 patients underwent pancreatic resection (71 Whipples, 35 total pancreatectomies, 21 distal pancreatectomies, and 2 partial pancreatectomies) whereas 79 patients were found to be unresectable and underwent palliative bypass and/or biopsy. Median survival was 20.4 months for resectable patients versus 4.5 months for unresectable patients (P<0.001). Of the 129 resected patients, factors significantly (P<0.05) favoring long-term survival on univariate analysis included well-differentiated histology, common bile duct or ampullary adenocarcinoma, early stage, tumor diameter <2 cm, negative margins, and absence of lymph node metastases, perineural, or vascular invasion. Age, sex, race, and type of procedure had no influence on survival. On multivariate analysis, only tumor differentiation appeared independently related to survival. Using Kendalls tau analysis, tumor type and grade correlated significantly with all other predictors. CONCLUSIONS Of all variables studied, tumor type and poor tumor differentiation in periampullary neoplasms appear to be markers that predict a constellation of other adverse findings.

Mucins in pancreatic cancer and its microenvironment.

Pancreatic cancer remains a lethal malignancy with poor prognosis owing to therapeutic resistance, frequent recurrence and the absence of treatment strategies that specifically target the tumour and its supporting stroma. Deregulated cell-surface proteins drive neoplastic transformations and are envisioned to mediate crosstalk between the tumour and its microenvironment. Emerging studies have elaborated on the role of mucins in diverse biological functions, including enhanced tumorigenicity, invasiveness, metastasis and drug resistance through their characteristic O-linked and N-linked oligosaccharides (glycans), extended structures and unique domains. Multiple mucin domains differentially interact and regulate different components of the tumour microenvironment. This Review discusses: the expression pattern of various mucins in the pancreas under healthy, inflammatory, and cancerous conditions; the context-dependent attributes of mucins that differ under healthy and pathological conditions; the contribution of the tumour microenvironment in pancreatic cancer development and/or progression; diagnostic and/or prognostic efficacy of mucins; and mucin-based therapeutic strategies. Overall, this information should help to delineate the intricacies of pancreatic cancer by exploring the family of mucins, which, through various mechanisms in both tumour cells and the microenvironment, worsen disease outcome.

Neoadjuvant chemoradiotherapy for adenocarcinoma of the pancreas: Analysis of histopathology and outcome

To examine the histopathologic effect of neoadjuvant therapy and its impact on survival in patients with carcinoma of the pancreas, we retrospectively reviewed the records of 116 patients who underwent resections for pancreatic cancer from 1987 to 2000. Median follow-up of surviving patients was 19 mo (range 4–150 mo). Preoperative chemotherapy was administered in 61 patients (53%) and consisted of 5-fluorouracil/mitomycin C in 35 patients and gemcitabine in 26 patients, given concurrently with external beam radiation (5040 cGy). All resections were performed with curative intent (98 Whipples, 11 total, 6 distal, and 1 central pancreatectomy). Histopathologic examination included an estimation of the amount of fibrosis present in the tumor specimen (expressed as the percentage of fibrosis identified relative to the amount of neoplastic cells present). The mean fibrosis level for the series was 56% (range 5% to 100%). The administration of neoadjuvant therapy resulted in greater fibrosis (73%) than no preoperative treatment (38%) (p=0.0001). Higher mean fibrosis levels were observed in patients with negative lymph nodes (p=0.0006) and negative margins (p=0.05). Factors associated with improved survival (log rank test) included: negative margins (p=0.001), negative lymph nodes (p=0.03), and use of neoadjuvant therapy (p=0.03). Median survival in the neoadjuvant group was 23 mo vs 16 mo without preoperative therapy (p=0.03). In conclusion, the use of neoadjuvant therapy resulted in a greater degree of fibrosis in the specimen. Patients with negative margins and negative lymph nodes had a greater amount of fibrosis present, and these were significant predictors of improved outcome. Although retrospective, this series suggests an improvement in survival in patients treated with neoadjuvant therapy.

Early diagnosis of pancreatic cancer: challenges and new developments.

Pancreatic cancer is a lethal malignancy with its incidence almost equivalent to mortality. The complex pathophysiology, absence of early diagnostic and prognostic markers and unresponsiveness to radiation and chemotherapies are major barriers against successful therapy. Poor performance of therapeutic agents, even in the initial stage of invasive cases, emphasizes the importance of early detection for improved survival. The present review discusses the challenges and advances in biomarkers including serological signatures, circulating tumor cells, autoantibodies, epigenetic markers and miRNAs that are being explored to detect this cancer at early stages. Considering the long time gap between the development of malignant lesions and full-blown primary and metastatic pancreatic cancer, unique opportunities are being contemplated for the development of potential diagnostic and prognostic markers.

Transcriptional profiling of peripheral blood mononuclear cells in pancreatic cancer patients identifies novel genes with potential diagnostic utility

Background It is well known that many malignancies, including pancreatic cancer (PC), possess the ability to evade the immune system by indirectly downregulating the mononuclear cell machinery necessary to launch an effective immune response. This knowledge, in conjunction with the fact that the trancriptome of peripheral blood mononuclear cells has been shown to be altered in the context of many diseases, including renal cell carcinoma, lead us to study if any such alteration in gene expression exists in PC as it may have diagnostic utility. Methods and Findings PBMC samples from 26 PC patients and 33 matched healthy controls were analyzed by whole genome cDNA microarray. Three hundred eighty-three genes were found to be significantly different between PC and healthy controls, with 65 having at least a 1.5 fold change in expression. Pathway analysis revealed that many of these genes fell into pathways responsible for hematopoietic differentiation, cytokine signaling, and natural killer (NK) cell and CD8+ T-cell cytotoxic response. Unsupervised hierarchical clustering analysis identified an eight-gene predictor set, consisting of SSBP2, Ube2b-rs1, CA5B, F5, TBC1D8, ANXA3, ARG1, and ADAMTS20, that could distinguish PC patients from healthy controls with an accuracy of 79% in a blinded subset of samples from treatment naïve patients, giving a sensitivity of 83% and a specificity of 75%. Conclusions In summary, we report the first in-depth comparison of global gene expression profiles of PBMCs between PC patients and healthy controls. We have also identified a gene predictor set that can potentially be developed further for use in diagnostic algorithms in PC. Future directions of this research should include analysis of PBMC expression profiles in patients with chronic pancreatitis as well as increasing the number of early-stage patients to assess the utility of PBMCs in the early diagnosis of PC.

Preoperative Nomogram to Predict Risk of Perioperative Mortality Following Pancreatic Resections for Malignancy

IntroductionThe majority of pancreatic resections for malignancy are performed in older patients with major comorbidities. The aim of this study was to develop a preoperative nomogram based on the presence of comorbidities to predict risk of perioperative mortality.Materials and MethodsThe National Inpatient Sample database was queried to identify patients that underwent pancreatectomy for malignancy. The preoperative comorbidities identified as predictors were used, and a nomogram was created. Sample A (2000–2004) was utilized to develop the model, and sample B (2005) was utilized to validate this model.ResultsThe overall actual observed perioperative mortality rate for samples A and B was 6.3% and 5.2%, respectively. The mean total points calculated for sample A by the nomogram was 131.7 that translates to a nomogram-predicted mortality rate of 4.9%, which is similar to the actual mortality. The mean total points for sample B was 128.1, which translates to a nomogram-predicted mortality rate of 4.6%. The similarity of mortality rates as predicted by the nomogram and a concordance index of 0.76 shows good agreement between the data and the nomogram.ConclusionThis preoperative nomogram has been shown to accurately predict the risk of perioperative mortality following pancreatectomy for malignancy.

Pancreatic incidentalomas: clinical and pathologic spectrum

BACKGROUND Incidental abnormalities are increasingly being detected. The pathology and clinical outcome of patients with pancreatic incidentalomas have not been well characterized. METHODS We reviewed the records of 356 patients with pancreatic abnormalities from August 2001 to June 2007. Clinical and pathologic data were collected for a cohort of patients who had incidental pancreatic lesions detected by imaging modalities. RESULTS Fifty-seven pancreatic incidentalomas were identified. Ninety percent of them were detected by computed axial tomography (CT). The most frequent indications for imaging were genitourinary symptoms and cancer surveillance. Sixty percent of the lesions were solid, and 40% were cystic. Surgical resection was performed in 33 patients. Locally advanced disease was found in six patients, and metastatic disease was found in 9 patients. The most frequent diagnoses were ductal adenocarcinoma, neuroendocrine tumors, and serous cystadenoma. CONCLUSIONS Patients with pancreatic incidentalomas account for a significant patient subgroup. Incidental pancreatic lesions occur frequently and require prompt surgical evaluation.