Perineural invasion (PNI) is a common feature in pancreatic ductal adenocarcinoma (PDAC) and correlates with an aggressive tumor behavior already at early stages of disease. PNI is currently considered as a "present vs. absent" feature, and a severity score system has not yet been established. The aim of the present study was thus to develop and validate a score system for PNI and to correlate it with other prognostic features. In this monocentric retrospective study, 356 consecutive PDAC patients (61.8% upfront surgery patients, 38.2% received neoadjuvant therapy) were analyzed. PNI was scored as follows: 0: absent; 1: the presence of neoplasia along nerves < 3 mm in caliber; and 2: neoplastic infiltration of nerve fibers ≥ 3 mm and/or massive perineural infiltration and/or the presence of necrosis of the infiltrated nerve bundle. For every PNI grade, the correlation with other pathological features, disease-free survival (DFS), and disease-specific survival (DSS) were analyzed. Uni- and multivariate analysis for DFS and DSS were also performed. PNI was found in 72.5% of the patients. Relevant trends between PNI score and tumor differentiation grade, lymph node metastases, vascular invasion, and surgical margins status were found. The latter was the only parameter statistically correlated with the proposed score. The agreement between pathologists was substantial (Cohen's K 0.61). PNI severity score significantly correlated also with decreased DFS and DSS at univariate analysis (p < 0.001). At multivariate analysis, only the presence of lymph node metastases was an independent predictor of DFS (HR 2.235 p < 0.001). Lymph node metastases (HR 2.902, p < 0.001) and tumor differentiation grade (HR 1.677, p = 0.002) were independent predictors of DSS. Our newly developed PNI score correlates with other features of PDAC aggressiveness and proved to have a prognostic role though less robust than lymph nodes metastases and tumor differentiation grade. A prospective validation is needed.

The survival impact of distal pancreatectomy (DP) with celiac axis resection for locally advanced pancreatic body/tail cancer remains unclear.

A total of 16 patients underwent DP with celiac axis resection, while 76 underwent standard DP for pancreatic body/tail cancer. The indications for DP with celiac axis resection included: (a) tumor invasion of either the celiac axis or common hepatic artery or both [CA/CHA (+)] and (b) tumor invasion of the root of the splenic artery, which is difficult to dissect without securing an adequate surgical margin [CA/CHA (-)].

DP with celiac axis resection presented longer operative time and greater amount of blood loss than DP. The median survival time was 17.5 months in the DP with celiac axis resection group and 43.1 months in the DP group (p = 0.040). Among the patients who underwent DP with celiac axis resection, the median survival time was 35.1 months in the CA/CHA (-) group and 13.2 months in the CA/CHA (+) group (p = 0.001). Comparing the patients undergoing standard DP and DP with celiac axis resection with a CA/CHA (-) status, there were no significant differences in either disease-free or overall survival times. The CA19-9 value, CA/CHA (+) status, and microscopic venous infiltration were revealed independent significant prognostic factors.

DP with celiac axis resection should therefore be indicated in patients with a CA/CHA (-) status. However, it is difficult to justify the use of DP with celiac axis resection in patients with CA/CHA (+) status due to the poor survival.

To show the advisability, satisfactory tolerance and good analgesic effect of surgery for pancreatic ductal carcinoma with celiac trunk invasion.

Distal subtotal pancreatectomy with resection of celiac trunk and common hepatic artery was made in 21 patients.

Early postoperative complications after distal subtotal pancreatectomy with celiac trunk resection occurred in 10 (47.6%) patients. There was no postoperative mortality. Resection edges including retroperitoneal space and pancreas did not contain tumor cells according to histological examination. Complete analgesic effect was obtained in 100% of patients after distal subtotal pancreatectomy with celiac trunk resection and neurodissection. 1- and 2-year survival was 59.1% and 21.5% respectively in patients with locally advanced pancreatic ductal carcinoma who underwent distal subtotal pancreatectomy with celiac trunk resection, median - 13 months, maximum lifetime - 57 months.

Distal subtotal pancreatectomy with resection of celiac trunk and common hepatic artery is safe, provides significant analgesic effect, increases resectability and expands the indications for pancreatectomy.

Positive surgical margin of extrapancreatic nerve plexus (ENP) is a major cause of non-curative resection during pancreaticoduodenectomy (PD) for periampullary carcinoma (PC), which is difficult to detect at the early stage of PD. We describe a novel surgical technique using an isolating tape (iTape)-oriented ENP-first dissection (IOEFD) during PD. The iTape is firstly passed through the retroperitoneal space between ENP and inferior vena cava. Then, the iTape is further extracted from major vessels such as the common hepatic and superior mesenteric artery. Consequently, the iTape encircles ENP alone. By tugging both ends of the iTape and vessel tapes to various directions from the caudal and cranial side of the pancreas, ENP is individually dissected without dividing any organ or tissue. Ten patients with periampullary carcinomas, consisting of one distal bile duct carcinoma, four ampullary carcinomas and five pancreatic head carcinomas underwent IOEFD during PD. Among these, nine underwent PDs after confirming negative surgical margin of ENP by IOEFD, while in the other case, PD was abandoned and converted to digestive bypass because of positive ENP margin during IOEFD. By final pathological diagnosis, R0 resection has been established in all nine patients who underwent PD with IOEFDs. Our pilot study indicated that inappropriate non-curative resection can be avoided by IOEFD during PD.

This review summarizes current knowledge of the biology, pathology and clinical understanding of lymphatic invasion and metastasis in pancreatic cancer. We discuss the clinical and biological consequences of lymphatic invasion and metastasis, including paraneoplastic effects on immune responses and consider the possible benefit of therapies to treat tumors that are localized to lymphatics. A review of current techniques and methods to study interactions between tumors and lymphatics is presented.

Perineural invasion (PNI) has been reported as one of the sources of locoregional recurrence in resected pancreatic cancer (PC). However the impact of PNI in resected pancreatic cancer remains controversial. The purpose of this study was to determine the association between PNI status and clinical outcomes.

Publications were identified which assessed prognostic significance of PNI status in resected pancreatic cancer up to February 2013. A meta-analysis was performed to clarify the association between PNI status and clinical outcomes.

A total of 21 studies met the inclusion criteria, covering 4,459 cases. Analysis of these data showed that intrapancreatic PNI was correlated with reduced overall survival only in resected pancreatic ductal adenocarcinoma (PDAC) patients (HR=1.982, 95%CI: 1.526-2.574, p=0.000). Extrapancreatic PNI was correlated with reduced overall survival in all resected pancreatic cancer patients (HR=1.748, 95%CI: 1.372- 2.228, p=0.000). Moreover, intrapancreatic PNI status may be associated with tumor recurrence in all resected pancreatic cancer patients (HR=2.714, 95%CI: 1.885-3.906, p=0.000).

PNI was an independent and poor prognostic factor in resected PDAC patients. Moreover, intrapancreatic PNI status may be associated with tumor recurrence.

Borderline resectable (BR) pancreatic head carcinoma (PhC) is an advanced disease, presenting with infiltration of major vessels. Major vascular resection (VR), particularly arterial resection, to achieve microscopic no residual tumor (R0) is a controversial approach, due to the potential complications. In this study, we aimed to clarify the benefit of en bloc R0 resection with VR for PhC by retrospectively evaluating 78 PhC patients who underwent pancreatoduodenectomy at our institute. The patients were divided into 4 groups as follows: R, resectable (n=20); BR-V, BR involving the superior mesenteric vein or portal vein (PV) (n=28); BR-SMA, BR involving the superior mesenteric artery (n=21); and BR-HA, BR involving the hepatic artery (n=9). In total, 65 patients underwent VR, with 63, 21 and 9 patients undergoing PV, SMA and HA resection, respectively. The R0 rates were as follows: R group, 85%; BR-V, 82%; BR-SMA, 71%; and BR-HA, 33%. The median survival time and 5-year survival rate for R0 resection were 31 months and 25% in the R group, 22 months and 28% in the BR-V group, 17 months and 27% in the BR-SMA group and 10 months and 0% in the BR-HA group, respectively. The prognosis was comparable among the BR-V, BR-SMA and R groups, but was significantly poorer in the BR-HA group. In total, 5 patients (6.4%) died perioperatively (4 from postoperative hemorrhage and 1 from suffocation due to failure of expectoration, without pneumonia or asthma). Of the 4 patients who succumbed to hemorrhage, 3 had undergone arterial resection. Therefore, en bloc resection with major VR for R0 may be suitable for BR-V and BR-SMA PhC patients.

Pancreatic cancer is one of the most fatal human malignancies. Though a relatively rare malignancy, it remains one of the deadliest tumors, with an extremely high mortality rate. The prognosis of patients with pancreatic cancer remains poor; only patients with small tumors and complete resection have a chance of a complete cure. Pancreatic cancer responds poorly to conventional therapies, including chemotherapy and irradiation. Tumor-specific targeted therapy is a relatively recent addition to the arsenal of anti-cancer therapies. It is important to find novel targets to distinguish tumor cells from their normal counterparts in therapeutic approaches. In the past few decades, studies have revealed the molecular mechanisms of pancreatic tumorigenesis, growth, invasion and metastasis. The proteins that participate in the pathophysiological processes of pancreatic cancer might be potential targets for therapy. This review describes the main players in perineural invasion, hypoxia and desmoplasia and the molecular mechanisms of these pathophysiological processes.

Interaction of cancer cells with diverse cell types in the tumor stroma is today recognized to have a fate-determining role for the progression and outcome of human cancers. Despite the well-described interactions of cancer cells with several stromal components, i.e., inflammatory cells, cancer-associated fibroblasts, endothelial cells, and pericytes, the investigation of their peculiar relationship with neural cells is still at its first footsteps. Pancreatic cancer (PCa) with its abundant stroma represents one of the best-studied examples of a malignant tumor with a mutually trophic interaction between cancer cells and the intratumoral nerves embedded in the desmoplastic stroma. Nerves in PCa are a rich source of neurotrophic factors like nerve growth factor (NGF), glial-cell-derived neurotrophic factor (GDNF), artemin; of neuronal chemokines like fractalkine; and of autonomic neurotransmitters like norepinephrine which can all enhance the invasiveness of PCa cells via matrix-metalloproteinase (MMP) upregulation, trigger neural invasion (NI), and activate pro-survival signaling pathways. Similarly, PCa cells themselves provide intrapancreatic nerves with abundant trophic agents which entail a remarkable neuroplasticity, leading to emergence of more routes for NI and cancer spread, to augmented local neuro-surveillance, neural sensitization, and neuropathic pain. The strong correlation of NI with PCa-associated desmoplasia suggests the potential presence of a triangular relationship between nerves, PCa cells, and other stromal partners like myofibroblasts and pancreatic stellate cells which generate tumor desmoplasia. Hence, although not a classical hallmark of human cancers, nerve-cancer interactions can be considered as an indispensable sub-class of cancer-stroma interactions in PCa. The present article provides an overview of the so far known nerve-cancer interactions in PCa and illustrates their ominous role in the stromal biology of human PCa.

Perineural invasion (PNI) is the initial infiltration of tumor cells into the retroperitoneal nerve plexus and along the nerves. It precludes curative resection, is thought to be the major cause of local recurrence following resection, and is a special metastatic route in pancreatic cancer. Glial cell line-derived neurotrophic factor (GDNF) was recently recognized as a key player in the PNI process. This review covers the most recently published studies on the role of GDNF in pancreatic cancer. We introduce the players in PNI, summarize the distribution of GDNF and its receptors in pancreatic cancer, and discuss the effects and underlying mechanism of GDNF in the PNI process. Finally, we also review some potential inhibitors for GDNF-targeted therapy.

Pancreatic carcinoma is an extremely high-grade malignant tumor with fast development and high mortality. The incidence of pancreatic carcinoma continues to increase. Peripancreatic invasion and metastasis are the main characteristics and important prognostic factors in pancreatic carcinoma, especially invasion into the nervous system; pancreatic nerve innervation includes the intrapancreatic and extrapancreatic nerves. A strong grasp of pancreatic nerve innervation may contribute to our understanding of pancreatic pain modalities and the metastatic routes for pancreatic carcinomas. Computed tomography (CT) and magnetic resonance imaging (MRI) are helpful techniques for depicting the anatomy of extrapancreatic nerve innervation. The purpose of the present work is to show and describe the anatomy of the extrapancreatic neural plexus and to elucidate its characteristics using CT and MRI, drawing on our own previous work and the research findings of others.

Computed tomography (CT) and magnetic resonance imaging (MRI) are excellent modalities which have the ability to detect, depict and stage the nerve invasion associated with pancreatic carcinoma. The aim of this article is to review the CT and MR patterns of pancreatic carcinoma invading the extrapancreatic neural plexus and thus provide useful information which could help the choice of treatment methods. Pancreatic carcinoma is a common malignant neoplasm with a high mortality rate. There are many factors influencing the prognosis and treatment options for those patients suffering from pancreatic carcinoma, such as lymphatic metastasis, adjacent organs or tissue invasion, etc. Among these factors, extrapancreatic neural plexus invasion is recognized as an important factor when considering the management of the patients.

The Italian Group of Gastrointestinal Pathologists has named a committee to develop recommendations concerning the surgical pathology report for pancreatic cancer. The committee, formed by individuals with special expertise, wrote the recommendations, which were reviewed and approved by council of the Group. The recommendations are divided into several areas including an informative gross description, gross specimen handling, histopathologic diagnosis, immunohistochemistry, molecular findings, and a checklist. The purpose of these recommendations is to provide a fully informative report for the clinician.

Our objective is to study the characteristics of extrapancreatic neural plexus invasion by pancreatic carcinoma on MR imaging.

20 patients with both pancreatic carcinoma and extrapancreatic neural plexus invasion confirmed by pathology were recruited in this study. MR imaging was performed within 1 month before surgery. On MR images, signal intensity at the site of potential extrapancreatic neural plexus invasion, lymph nodes and tumor size were noted. The relationship of extrapancreatic neural plexus invasion to these findings was analyzed.

Signs of extrapancreatic neural plexus invasion were depicted on MR imaging in 80% of patients, which included streaky and strand-like signal intensity structure in fat tissue in 50% of patients and irregular masses adjacent to tumor in 30%. Signal intensity at invasion site was similar to that of pancreatic carcinoma. The frequencies of patients with vascular invasion and with lymph nodes larger than 5 mm were, respectively, 50% and 55%. Tumor diameter was 24 +/- 7 mm on MR imaging. Extrapancreatic neural plexus invasion was correlated with vascular invasion (r = 0.58, P < 0.005), slightly related with lymphadenopathy (r = 0.35, 0.1 > P > 0.05), but not related with tumor size.

MR imaging is useful to depict extrapancreatic neural plexus invasion by pancreatic carcinoma.

Perineural invasion (PNI) is one of the most common routes of invasion in pancreatic cancer and the exact mechanism is still not clear. The aim of the present study was to investigate the effect of nerve growth factor (NGF) and tyrosine kinase receptor A (TrkA) on PNI and to clarify the possible mechanism of PNI in pancreatic cancer.

Expressions of NGF/TrkA were examined in 51 human primary pancreatic cancer using immunohistochemistry (IHC) and reverse transcription polymerase chain reaction (RT-PCR). The molecular findings were correlated with PNI, clinicopathological parameters and expression of Ki-67.

Immunohistochemical analysis indicated that the presence and kind of PNI are prognostic parameters (P = 0.002,, P = 0.004). Tumors with high NGF expression exhibited more frequent presence of PNI (P = 0.033). NGF expression was significantly correlated with metastasis of lymph nodes and involvement of surgical margins (P = 0.006, 0.015). TrkA expression was significantly correlated with degree of PNI (P = 0.017). Negative correlations were found between expression of NGF/TrkA and Ki-67. As shown by RT-PCR, mRNA levels of NGF/TrkA with PNI were significantly higher than that without PNI.

In pancreatic cancer, overexpression of NGF may contribute to PNI by prompting the hyperplasia of nerves, restraining the apoptosis of tumor cells and specifically combining NGF and TrkA.

Although extrapancreatic nerve plexus (PLX) invasion is an important prognostic factor in pancreatic carcinoma, the spreading patterns of carcinoma via PLX have not been carefully explored because of the complex anatomical structures around the pancreas.

Fifty-eight patients underwent pancreaticoduodenectomy for carcinoma of the head of the pancreas. The patterns of PLX invasion were evaluated by careful pathological examination. The relationship between tumor location considering the embryological structure of the pancreas and the site of PLX invasion was investigated with an immunohistochemical study using pancreatic polypeptide.

Forty-six patients (79%) had PLX invasion. The typical patterns of PLX invasion were detected by pathological examination. Patients with carcinoma in ventral pancreas frequently had pancreatic head plexus 1, pancreatic head plexus 2, and superior mesenteric arterial plexus invasion. Patients with carcinoma in dorsal pancreas had invasion into common hepatic artery plexus and plexus within the hepatoduodenal ligament. A significant correlation between tumor location and the site of PLX invasion was observed.

Extrapancreatic nerve plexus invasion by carcinoma of the head of the pancreas could be divided into 2 patterns based on an embryological structure of the pancreas and the location of the tumor. These results about PLX invasion may provide important information to determine surgical strategy for carcinoma of the head of the pancreas.

The delineation of pancreatic nerve innervation during fetal life may contribute to our understanding of pancreatic pain modalities after birth. The aim of this study was to characterize the spatial and temporal distribution of nerve structures in the human pancreas throughout gestation. Computer-based image morphometry with piecewise polynomial interpolation analysis was performed to quantify nervous structures in the head, body and tail of the pancreas. Nerve structures were detected by automatic immunostaining techniques using a polyclonal antibody against two S-100 proteins that reacts strongly with human S100A and B that are detected in Schwann cells. Immunoreactivity was found in the parenchyma of head, body and tail of the pancreas with the relative density being head>body>tail. In addition to this extensive set of nerve fibers terminating in the pancreas there were large bundles of en passant nerve fibers in the dorsal region of the pancreas that were 3D reconstructed and were associated with the superior mesenteric plexus. If at first glance, the perimeter and the width of the nerve fibers seem to increase at a continuous rate up to term in all three regions of the pancreas, spatial and temporal co-analysis identified that the head of the pancreas shows a two-peak growth increase at 14 and 22 weeks of gestation with regard to the area, perimeter and width of the nerve structures, while the body and tail regions show a unique peak at 20 weeks. A developmental deceleration was found between the 22nd and the 36th week of gestation for the head region only. This is the first systematic study of nerve innervation of the human pancreas throughout gestation. The developmental dynamics of the pancreas nerve innervation corresponds approximately to the remodeling of the intrahepatic biliary system. Understanding the factors and disease states that may alter the distribution of nerve structures can be of significance for the development of therapies in pancreatic disorders of child- and adulthood.

The indications for a pancreatectomy with a partial resection of the portal or superior mesenteric vein for pancreatic cancer, when the vein is involved by the tumor, remain controversial. It can be assumed that when such involvement is not extensive, resection of the tumor and the involved venous segment, followed by venous reconstruction will extend the potential benefits of this resection to a larger number of patients. The further hypothesis of this study is that whenever involvement of the vein by the tumor does not exceed 2 cm in length, this involvement is more likely due to the location of the tumor being close to the vein rather than because of its aggressive biological behavior. Consequently, in these instances a pancreatectomy with a resection of the involved segment of portal or superior mesenteric vein for pancreatic cancer is indicated, as it will yield results that are superposable to those of a pancreatectomy for cancer without vascular involvement.

Twenty-nine patients with carcinoma of the pancreas involving the portal or superior mesenteric vein over a length of 2 cm or less underwent a macroscopically curative resection of the pancreas en bloc with the involved segment of the vein. The venous reconstruction procedures included a tangential resection/lateral suture in 15 cases, a resection/end-to-end anastomosis in 11, and a resection/patch closure in 3.

Postoperative mortality was 3.4%; morbidity was 21%. Local recurrence was 14%. Cumulative (standard error) survival rate was 17% (9%) at 3 years.

A pancreatectomy combined with a resection of the portal or superior mesenteric vein for cancer with venous involvement not exceeding 2 cm is indicated in order to extend the potential benefits of a curative resection.

Cancers of the pancreas are identified in 11 800 to 13 500 patients each year in Germany. Epidemiological studies prove smoking and chronic alcohol consumption as causes of about 30% of pancreatic cancers.

Selective literature review.

Only patients within TNM stage I and II have after oncologic tumor extirpation a chance for long term survival. Controlled prospective clinical trials demonstrated adjuvant chemotherapy yielding an additional significant survival benefit. The 3- and 5-year-survival after R0-resection and adjuvant chemotherapy are about 30% and below 15% respectively. Using the criteria of observed 5-year-survival less than 2% of all pancreatic cancer patients are alive. After R0-resection the median survival time is between 17 and 28 months, after R1/2-resection between 8 and 22 months.

Pancreatic cancer is even today for more than 95% of the patients incurable. Strategies to prevent pancreatic cancer are intended to stop smoking and chronic alcohol consumption and early surgical extirpation of cystic neoplastic lesions. For patients with established pancreatic cancer risk a follow-up protocol is discussed.

Neural invasion is one of the most important modes of tumor extension in pancreatobiliary tract cancer. However, the precise pattern of neural invasion and the relationship between neural invasion and nodal involvement are unknown.

Using 8 surgical specimens from patients with pancreatic cancer, 4973 sections were created and examined histopathologically. A total of 961 sections of VX2 tumor grown in the retroperitoneum of rabbits also were examined histologically. The precise mechanism by which neural invasion occurs and the relationship between nerve fascicle and lymph node involvement were determined by histological examination of serial sections.

Histological evaluation of the surgical specimens revealed continuity between the cancer cells between the inside and the outside of the perineurium. Tumor cells grew mainly in a continuous fashion along the branches of nerves. An advancing tip of the tumor cells was identified. The pattern of tumor spread in the experimental study was similar to that in the clinical study. Continuity was found between the cancer cells inside some lymph nodes and the cancer cells within the perineural space. This finding suggests that neural invasion might be a pathway to lymphatic involvement.

Neural invasion is a common, but not a specific, feature of pancreatic cancer. Tumor cells in the perineural space grow in a continuous fashion and may be responsible for some cases of lymphatic spread.

New understanding of the dynamic of acute pancreatitis, the clinical impact of local pathology in chronic pancreatitis and cystic neoplastic lesions bearing high potential for malignant transformation has changed the management of pancreatic diseases.

In acute pancreatitis, risk factors independently determining outcome in severe acute pancreatitis are early and persistent multiorgan failure, infected necrosis and extended sterile necrosis. The management of severe acute pancreatitis is based on early intensive-care treatment and late surgical debridement. In chronic pancreatitis, recent data from randomized controlled clinical trials have demonstrated duodenum-preserving pancreatic head resection with an inflammatory mass of the head as superior to pylorus-preserving Whipple resection. Cystic neoplasms are local lesions of the pancreas with high malignant potential. Local organ-preserving resection techniques have been applied with low morbidity and mortality, replacing a Whipple-type resection. Resection of pancreatic cancer is ineffective to cure patients. After an R0-resection, a significant survival benefit has been achieved when adjuvant chemotherapy has additionally been applied.

New knowledge about the nature of inflammatory diseases, cystic neoplastic lesions and malignant pancreatic tumours has changed the indication for surgical treatment and the application of organ-preserving surgical techniques.

The aim of this study was to determine the computed tomographic (CT) criteria for diagnosing the second portion of the extrapancreatic neural plexus (PLX-II) invasion by carcinoma of the pancreatic head region on thin-section helical CT.

A total of 41 patients with carcinoma of the pancreatic head region (17 in the pancreas, 24 in the lower common bile duct) underwent three-phase helical CT (collimation 5 mm; reconstruction 2.5 mm) before surgery. Two criteria were established for the assessment of the PLX-II running between the superior mesenteric artery (SMA) and the medial margin of the uncinate process: criterion A: assessment of the area around the SMA and inferior pancreaticoduodenal artery; criterion B: assessment of the jejunal trunk.

PLX-II invasion was pathologically confirmed in 19 patients with pancreatobiliary carcinoma. For criterion A, all 19 patients with positive PLX-II invasion and 20 of the 22 with negative PLX-II invasion were correctly diagnosed (sensitivity 100%; specificity 91%; accuracy 95%). For criterion B, 3 of the 17 patients with positive PLX-II invasion and all 20 with negative PLX-II invasion were correctly diagnosed (sensitivity 18%; specificity 100%; accuracy 62%). The two false-positive cases using criterion A were correctly diagnosed using criterion B.

Thin-section helical CT provides sufficient diagnostic ability regarding PLX-II invasion by carcinoma of the pancreatic head region.

The extrapancreatic nerve plexus (PL) invasion is a common feature of pancreatic cancer and affects the outcome of the patients after surgical resection. IPEUS with high-resolution probes can visualize the PL invasion with high overall accuracy rate. The aim of this study is to evaluate the clinical significance of the PL invasion diagnosed intraoperatively by intraportal endovascular ultrasonography (IPEUS).

IPEUS was performed in 64 patients who underwent the pancreatic resection. Several clinicopathological factors were studied in patients with or without PL invasion.

There were 18 cases in which PL invasion was confirmed pathologically. IPEUS showed 94% sensitivity, 98% specificity and 97% accuracy for the diagnosis of the PL invasion with the false-positive rate of 5.6%. The 1-, 2- and 3-year survival in 18 patients with PL invasion was 30, 6 and 0% in comparison to 52, 32 and 18% in those 46 patients without PL invasion and the difference was statistically significant (p = 0.008). A significant correlation was found between PL invasion and the portal vein invasion, invasion of the margins or pTNM stage.

According to current results, the prognosis of the cases with PL invasion is very poor and indication for resection is doubtful. We conclude that the cases in which PL invasion is diagnosed by IPEUS are not indicated for extended resection and correct diagnosis of PL invasion is important not only to predict the outcome but also to decide the surgical procedure for obtaining negative margins while improving the quality of life after surgery.

Pancreaticoduodenectomy is often avoided in patients with portal or superior mesenteric venous involvement due to the perception that venous resection is complex, morbid, and carries a poor long-term survival. Our recent experience using state-of-the-art imaging and strict resection criteria show that venous reconstruction increases operative time, transfusion requirements, intensive care unit stay, and total hospital length of stay, but has no significant impact on operative morbidity rates, mortality rates, or the incidence of positive histologic margins. Kalpan-Meier life table analysis shows similar survival curves when compared to a contemporary cohort of patients who do not undergo venous reconstruction.

Adenocarcinoma of the pancreas is associated with the worst survival of any form of gastrointestinal malignancy. In spite of the progress in surgical treatment, resulting in increasing resection rates and a decrease in treatment-related morbidity and mortality, the true figures of cure are even today below 3%. The dissemination of pancreatic cancer behind the local tissue compartments restricts the short-term (< 3 years) and long-term outcome for patients who have undergone resection. By histological evaluation, less than 15% of the patients undergoing R(0) resection have a pN(0) status, more than 60% suffer from lymph angiosis carcinomatosa, and more than 50% suffer extrapancreatic nerve plexus infiltration. Hematoxylin and eosin-negative lymph nodes were found to be cancer positive when reverse transcriptase polymerase chain reaction (RT- PCR) or immunostaining was applied to the HE-negative lymph nodes. Cancer of the uncinate process has a very poor prognosis because there are no early symptoms; vessel wall involvement occurs early and frequently; a high association of liver metastasis exists as well. Surgery offers a low success rate, but it provides the only chance of cure. Ductal pancreatic cancer is diagnosed in more than 95% of the cases in an advanced stage; potentially curative resection can be performed only in about 10%-15% of these patients. Major contributions of surgery to improved treatment results are the reduction of surgical morbidity--e.g., early postoperative local and systemic complications--and a decrease of hospital mortality below 3%-5%. In most recently published prospective trials, R(0) resection has been reported to result in an increase in short-term survival beyond that recorded for patients with residual tumor. However, R(0) resection fails to improve long-term survival. In many published R(0) series, standard tissue resection of pancreatic head cancer with the Kausch-Whipple procedure failed to include remote cancer cell-positive tissues in the operative specimen; e.g., N(2)-lymph nodes, nerve plexus, and perivascular extrapancreatic and retropancreatic tissues were not excised. Cancer recurrence after so-called R(0) resection with curative intent is frequently the consequence of cancer left behind. Thus, long-term survival (> 5 years) is observed in a very small group of patients, contradicting the published 5-year actuarial survival rates of 20%-45% for resected patients. The assessment of clinical benefit from surgical or medical cancer treatment should therefore be based on several end points, not only on actuarial survival. Publication of actuarial survival figures must include the number of observed (actual) survivals, the definition of the subset of patients followed after resection, and the total number of patients in the study group; anything less is misleading. In reporting pancreatic cancer treatment trial results after oncological resections, more convincing primary end points to evaluate treatment efficacy are median survival (in months), actual survival at 1-5 years, and progression-free survival (in months). In series with multimodality treatment, clinical benefit response as well as quality of life measurements using the EORTC Quality of Life index C30 (QLQ-C30) are of importance in evaluating survival data. Adjuvant treatment improves survival after oncological resection; however, the short-term and long-term benefit after adjuvant chemotherapy in R(0) as well as in R(1)-(2) resected patients has not yet been underscored by data from controlled clinical trials. The survival benefit (median survival time) of adjuvant chemotherapy or radiochemotherapy has been demonstrated to be 6-10 months. Therefore, after oncological resection of pancreatic cancer each patient should be offered adjuvant treatment. A neoadjuvant treatment protocol for pancreatic cancer, however, has not been established.

The purpose of this study was to evaluate and clarify the clinical significance of CT scans of the inferior peripancreatic veins.

Forty-three patients with suspected pancreatic disease underwent three-phase helical CT (collimation, 5 mm; reconstruction, 2.5 mm; scan delay, 30, 60, and 150 sec). The frequency of visualization on CT of the anterior and posterior inferior pancreaticoduodenal veins, inferior pancreaticoduodenal vein, and first jejunal trunk was assessed and correlated with angiographic and pathologic findings.

The frequency of visualization of normal inferior peripancreatic veins in patients (n = 22) with a normal portomesenteric vein was 36% for the anteroinferior pancreaticoduodenal vein, 36% for the posteroinferior pancreaticoduodenal vein, 59% for the inferior pancreaticoduodenal vein, and 100% for the first jejunal trunk. The smaller inferior peripancreatic veins were frequently not visualized when normal. In patients (n = 13) with pancreatic carcinoma involving the portosuperior mesenteric vein, all of the inferior peripancreatic veins were dilated and easily recognizable. When the tumor did not involve the portosuperior mesenteric vein but did involve the anteroinferior pancreaticoduodenal, posteroinferior pancreaticoduodenal, and inferior pancreaticoduodenal veins (n = 8), some of the other peripancreatic veins (first jejunal trunk, anterior and posterior superior pancreaticoduodenal veins, and gastrocolic trunk) were dilated. Dilatation indicated tumor extension to the third portion of the duodenum. In patients (n = 7) with involvement of the inferior pancreaticoduodenal vein, the first jejunal trunk, or both without the involvement of the portosuperior mesenteric vein, dilatation of the other peripancreatic veins (anteroinferior pancreaticoduodenal vein, posteroinferior pancreaticoduodenal vein, anterosuperior pancreaticoduodenal vein, posterosuperior pancreaticoduodenal vein, and gastrocolic trunk) indicated tumor invasion of only the second portion of the extrapancreatic nerve plexus (n = 4) and tumor invasion of both the second portion of the extrapancreatic nerve and the mesenteric root (n = 3).

Dilatation of peripancreatic veins with nonvisualization of inferior peripancreatic veins suggests tumor invasion of peripancreatic tissue.

To determine the pattern of middle (Bm) and distal (Bi) bile duct cancers in an attempt to optimize surgical treatment.

Lymph node involvement and neural plexus invasion are the prognostic factors most amenable to surgery in Bm and Bi disease. However, a detailed analysis of these factors has not been conducted.

Fifty patients with Bm and Bi disease (Bm 14 patients, Bi 36 patients) were examined histopathologically. A precise determination was made of lymph node involvement and neural plexus invasion. Important prognostic factors were examined by clinicopathologic study to apply these findings to surgical management.

Frequencies of nodal involvement for Bm and Bi disease were 57% and 71%, respectively. The inferior periductal and superior pancreaticoduodenal lymph nodes were most commonly involved. Neural plexus invasion occurred in 20% of patients, particularly involving the plexus in the hepatoduodenal ligament and pancreatic head. Tumor was present at the surgical margin in 50% and 14% of patients with Bm and Bi disease, respectively. Five-year survival rates were 65% in the absence of nodal metastasis and 21% with nodal metastasis. A significant correlation existed between absence of tumor at the surgical margin and survival. A Cox proportional hazard model projected absence of tumor at the surgical margin, followed by nodal involvement, as the strongest prognostic variables.

Absence of tumor at the surgical margin and nodal involvement are important independent prognostic factors in Bm and Bi disease. Skeletonization of the hepatoduodenal ligament, including portal vein resection, is necessary for patients with Bm disease, and a wide nodal dissection is essential in all patients.

The intraportal endovascular ultrasonography (IPEUS) could diagnose the second portion of the extrapancreatic nerve plexus invasion and provide precise information in operative strategy. But, the first portion was not visualized clearly owing to poor tissue penetration of the ultrasound beam, which may have reduced diagnostic accuracy. Improvement of the scanning area is expected to make intraportal endovascular US even more useful.

Pancreatic cancer easily invades the retroperitoneal tissue, especially the extrapancreatic nerve plexus. We evaluated the extrapancreatic nerve plexus invasion of the pancreatic cancer with IPEUS. IPEUS was performed intraoperatively in 20 consecutive resected cases with carcinoma of the head of the pancreas.

IPEUS was performed with an 8-French, 20 MHz intravascular ultrasound catheter. IPEUS visualized the inferior pancreaticoduodenal artery (IPDA) in the extrapancreatic nerve plexus. The high-echoic area around the IPDA corresponds to the second portion of the extrapancreatic nerve plexus. The sonographic criterion for detection of the extrapancreatic nerve plexus invasion is low-echoic infiltration around the IPDA.

Extrapancreatic nerve plexus invasion was confirmed with resected specimens in 10 patients. The IPDA could not be visualized in two patients. In 18 patients, the diagnostic accuracy of invasion was evaluated. For diagnosis of extrapancreatic nerve plexus invasion with intraportal endovascular US, the sensitivity, specificity, and overall accuracy were 87.5, 90, and 88.7%, respectively.

Tumor invasion of the superior mesenteric-portal vein (SMPV) confluence is often considered a contraindication to pancreaticoduodenectomy for patients with malignant tumors of the pancreas or periampullary region. The authors sought to determine whether pancreaticoduodenectomy with en bloc resection of the SMPV confluence could be safely performed and whether tumors involving the SMPV confluence were associated with pathologic parameters suggesting poor prognosis.

Several centers have reported high rates of retroperitoneal margin positivity after pancreaticoduodenectomy for tumors of the pancreatic head and periampullary region. Positive-margin or incomplete resection is associated with early tumor recurrence and no survival benefit compared with palliative therapy. Tumor adherence to the lateral of posterior wall of the SMPV confluence often represents the only barrier to complete tumor resection at the time of pancreaticoduodenectomy.

Data on all patients undergoing pancreaticoduodenectomy for adenocarcinoma of the pancreas or periampullary region over a 3.5-year period were entered prospectively in a pancreatic tumor database. To be considered for surgery, patients were required to fulfill the following computed tomography criteria for resectability: 1) the absence of extrapancreatic disease, 2) no tumor encasement of the superior mesenteric artery or celiac axis, and 3) a patent SMPV confluence. Tumor adherence to the superior mesenteric vein or SMPV confluence was assessed intraoperatively, and en bloc venous resection was performed when necessary to achieve complete tumor extirpation. Data on operative characteristics, morbidity, mortality, tumor size, nodal metastases, margin positivity, perineural invasion, and tumor DNA content were compared for patients who did and did not receive venous resection.

Fifty-nine patients underwent pancreaticoduodenectomy, 36 without venous resection and 23 with en bloc resection of the SMPV confluence. No differences in median hospital stay, morbidity, mortality, tumor size, margin positivity, nodal positivity, or tumor DNA content were observed between groups.

When necessary, segmental resection of the SMPV confluence may be performed safely during pancreaticoduodenectomy for periampullary malignant tumors. Tumors invading the SMPV confluence are not associated with histologic parameters suggesting a poor prognosis. Our data suggest that venous involvement is a function of tumor location rather than an indicator of aggressive tumor biology.

The available data suggest that lymph node involvement is an important prognostic factor in patients with carcinoma of the head of the pancreas. Lymph node metastases occur in as many as 50% of the cases of even the smallest pancreatic cancers now being diagnosed and resected (i.e., those < 2 cm in diameter). There is some evidence, especially from clinical experience in Japan, that wider lymphatic dissections (i.e., wider than those commonly done with the standard Whipple resection) may prolong survival. Unfortunately, many of the available data around the world are retrospective and are not randomized between the standard and the radical operation. Moreover, the pathologic material has not been staged uniformly according to accepted criteria. Thus the various series are not comparable. Comparisons between series require standardization with respect to stage of disease, pathologic classification, and treatment protocols. Before any modification of the standard pancreaticoduodenectomy is adopted, an appropriately designed study should be performed to test its efficacy. This study would also require a more comprehensive analysis of the pathologic material than is commonly performed today in the United States and Europe.

The anatomy and topography of tissue surrounding the superior mesenteric artery were examined histopathologically, and the structure surrounding the superior mesenteric artery (SMA) was reconstructed with data from histologic examination and three-dimensional analyses. Specimens were obtained from three autopsy cases without abnormalities, two surgically resected cases of cancer of the pancreatic head, and one autopsy case of cancer of the pancreatic head. The endothelium or basal membrane of blood and lymph vessels were identified immunohistochemically, and the distribution of lymph nodes, blood vessels, lymph vessels, and collagen fibers was determined. The superior mesenteric plexus was found to be a relatively dense structure with a thickness of about 2 mm, composed of collagen fibers and connective tissue, which concentrically enveloped the small arteries, the superior mesenteric artery, nerve bundles, and capillaries. Lymph vessels larger than a few micrometers in diameter were often found outside of the plexus, and this plexus contained no lymph nodes in any sections. The three-dimensional study of the modes of spread along the superior mesenteric artery of pancreatic cancer revealed two types of spread: the tumor extends mainly by neural invasion, and the tumor extends mainly by lymph node metastases. These morphologic features suggest that lymphatic flow in the vicinity of the superior mesenteric artery passes primarily outside of the plexus, and complete excision of lymph nodes close to the superior mesenteric artery with preservation of the superior mesenteric plexus is feasible if there is no neural invasion into retropancreatic tissues.

To clarify the pattern of lymph node metastasis in carcinoma of the pancreas, lymph node involvement was examined in forty-two patients who underwent extensive nodal dissections, including the paraaortic lymph nodes. The correlation between the spread of the tumor and lymph node involvement was evaluated: The most common site of involved lymph nodes was the retropancreatic region. The prevalence of nodal metastases was 78.6%. Metastases to the paraaortic region were present in seven patients, among whom metastases in the paraaortic region were most common in the median region from the celiac artery to the inferior mesenteric artery and in the space between the aorta and the vena cava. The risk of lymph node metastases tended to increase with tumor size, except in the paraaortic region, where the correlation between the frequency of metastasis and tumor size was poor. The probability of lymph node metastases increased with the degree of lymphatic invasion (ly) and the growth pattern of the tumor (INF) and was high in patients with invasion into the retropancreatic tissue and in tumors with scirrhous histology. These results indicate that even in small cancers, lymph nodes of the paraaortic region frequently harbor metastases and should be dissected en block during radical resections of pancreatic cancer.

We enumerated the number of Ag-NORs in normal pancreatic ducts and exocrine pancreatic tumors to assess their cellular activity. Our results indicate that the mean number of Ag-NOR counts increased stepwise in the following order: normal pancreatic duct (1.26), serous cystadenoma (1.27), mucinous cystadenoma (1.65), mucinous cystadenocarcinoma (2.29), noninvasive intraductal variant of mucin-producing papillary adenocarcinoma (3.16), and a common type of invasive duct cell adenocarcinoma (3.78). These results suggest that cellular proliferative activity is low in normal pancreatic ducts and serous cystadenoma, intermediate in mucinous cystadenoma, and high in mucinous cystadenocarcinoma and duct cell adenocarcinoma. In addition, mucinous cystadenocarcinoma has significantly lower Ag-NOR counts than duct cell adenocarcinoma. We conclude that a clear quantitative difference between the Ag-NOR content of tumor cells of serous cystadenoma, mucinous cystadenoma, mucinous cystadenocarcinoma, and duct cell adenocarcinoma reflects the underlying different biologic behavior (chiefly, grade of malignancy) of these lesions.