Utility of a repeated EUS at a tertiary-referral center

BACKGROUND: The utility of a repeated EUS by experts is not known. OBJECTIVE: To define the utility of a repeated EUS for the same indication. DESIGN: A retrospective case series. SETTING: Tertiary-referral hospital in Indianapolis, Indiana. PATIENTS: Consecutive subjects, with and without cancer, who, between January 2000 and September 2006, underwent an initial EUS elsewhere within 6 and 12 weeks of a repeated EUS at our hospital. INTERVENTIONS: A repeated EUS. MAIN OUTCOME MEASUREMENTS: Clinical impact of a repeated EUS. RESULTS: Of 8936 EUS examinations, 73 repeated procedures (0.8%) were identified, and 24 were excluded. The 49 initial EUS procedures (26 men, median age 59 years) were done in Indiana (n = 44) or another state (n = 5) by one of 15 physicians in private practice (n = 48) or at a teaching hospital (n = 1). An EUS-guided FNA (EUS-FNA) was performed during an initial EUS in 21 patients (no biopsy diagnostic for cancer) and was not attempted in 14 patients. The principle indication for a repeated EUS (n = 35) was for an EUS-FNA after the initial tissue sampling was benign, nondiagnostic, or not done. A second EUS had no clinical impact in 18 patients (37%). In the remaining 31 patients (63%), a repeated EUS provided a new or changed clinical diagnosis (n = 12), the initial diagnosis of primary pancreatic cancer (n = 5) or GI stromal tumor (GIST) (n = 1) after a previous nondiagnostic biopsy; or the initial diagnosis of primary (n = 4) or metastatic (n = 2) pancreatic cancer, metastatic esophageal cancer (n = 1), hilar cholangiocarcinoma (n = 1), GIST (n = 1), or pancreatic neuroendocrine tumor (n = 1), or an initial aspiration of a pancreatic cyst (n = 3) after a previous EUS-FNA was not able to be performed. LIMITATIONS: A retrospective design; a small number of nonpancreatic indications. CONCLUSIONS: In this study, a repeated EUS at a tertiary-referral center had a clinical impact in 63% of patients when performed by experts for a similar clinical indication.     

Improving outcomes for operable pancreatic cancer: Is access to safer surgery the problem?

Despite advances in the understanding and treatment of pancreatic cancer in the last two decades, there is a persisting nihilistic attitude among clinicians. An alarmingly high rate of under-utilization of surgical management for operable pancreatic cancer was recently reported in the USA, where more than half of patients with stage 1 operable disease and no other contraindications were not offered surgery as therapy, denying this group of patients a 20% chance of long-term survival. These data indicate that a nihilistic attitude among clinicians may be a significant and reversible cause of the persisting high mortality of patients with pancreatic cancer. This article examines the modern management of pancreatic cancer, in particular, the advances in surgical care that have reduced the mortality of pancreatectomy to almost that of colonic resection, and outlines a strategy for improving outcomes for patients with pancreatic cancer now and in the future.     

Role of endoscopic ultrasound in pancreatic cancer

Pancreatic cancer (PC) is the fourth most common cause of cancer deaths in Western societies. It is an aggressive tumor with an overall 5-year survival rate of less than 5%. Surgical resection offers the only possibility of cure and long-term survival for patients suffering from PC; however, unfortunately, fewer than 20% of patients suffering from PC have disease that is amendable to surgical resection. Therefore, it is important to accurately diagnose and stage these patients to enable optimal treatment of their disease. The imaging modalities involved in the diagnosis and staging of PC include multidetector CT scanning, endoscopic ultrasound (EUS), endoscopic retrograde cholangiopancreaticography and MRI. The roles and relative importance of these imaging modalities have changed over the last few decades and continue to change owing to the rapid technological advances in medical imaging, but these investigations continue to be complementary. EUS was first introduced in the mid-1980s in Japan and Germany and has quickly gained acceptance. Its widespread use in the last decade has revolutionized the management of pancreatic disease as it simultaneously provides primary diagnostic and staging information, as well as enabling tissue biopsy. This article discusses the potential benefits and drawbacks of EUS in the primary diagnosis, staging and assessment of resectability, and EUS-guided fine-needle aspiration in PC. Difficult diagnostic scenarios and pitfalls are also discussed. A suggested management algorithm for patients with suspected PC is also presented.     

The endoscopist’s role in the diagnosis and management of pancreatic cancer

Pancreatic cancer remains one of the most lethal malignancies with little improvement in survival over the past several decades in spite of advances in imaging, risk factor identification, surgical technique and chemotherapy. This disappointing outcome is mainly due to failures to make an early diagnosis. In fact, the majority of the patients present with inoperable advanced stages of the disease. Though some of the new tumor markers are promising, we are still in search of the one that has a high sensitivity and accuracy, yet is inexpensive and easy to obtain. The paradigm of management has shifted from up-front surgery followed by adjuvant chemotherapy to neoadjuvant chemoradiation followed by surgery, especially for borderline resectable cancers and even for some resectable cancers. In this article, we will critically assess the limitations of tumor markers and review the advancements in endoscopic techniques in the management of pancreatic cancer.     

Preoperative evaluation of pancreatic adenocarcinoma

The preoperative evaluation of resectability for pancreatic cancer fails to identify up to 25% of patients who are unfortunately found to be unresectable at surgical exploration. Inoperative findings in this circumstance is usually due to either small volume metastatic disease or regional tumor invasion. While advances in computed tomography (CT) technology has increased accuracy of local tumor extent, occult metastatic disease remains a common problem. Although 2-[¹⁸F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) has been demonstrated to be useful in the staging of many malignancies (e.g. esophageal cancer, recurrent colorectal cancer, lung cancer), it has not been found to significantly increase the accuracy of determining resectability preoperatively in pancreatic cancer, especially with regard to detection of small volume metastatic disease. There are a variety of pancreatic cancer-specific antigens which are being developed as a method for targeted molecular imaging; we provide preliminary data targeting the integrin α_vβ₆ to demonstrate the potential feasibility of this approach. Further developments may allow the accurate determination of patients with resectable pancreatic cancer, and more importantly, those with unresectable disease that may forego unnecessary surgery, the associated morbidity, and the subsequent delay of appropriate therapy.     

Borderline resectable pancreatic cancer: Definitions and management

Pancreatic cancer is the fourth leading cause of cancer death in the United States. While surgical resection remains the only curative option, more than 80% of patients present with unresectable disease. Unfortunately, even among those who undergo resection, the reported median survival is 15-23 mo, with a 5-year survival of approximately 20%. Disappointingly, over the past several decades, despite improvements in diagnostic imaging, surgical technique and chemotherapeutic options, only modest improvements in survival have been realized. Nevertheless, it remains clear that surgical resection is a prerequisite for achieving long-term survival and cure. There is now emerging consensus that a subgroup of patients, previously considered poor candidates for resection because of the relationship of their primary tumor to surrounding vasculature, may benefit from resection, particularly when preceded by neoadjuvant therapy. This stage of disease, termed borderline resectable pancreatic cancer, has become of increasing interest and is now the focus of a multi-institutional clinical trial. Here we outline the history, progress, current treatment recommendations, and future directions for research in borderline resectable pancreatic cancer.     

Pancreatic cancer: Can we screen? How should we stage?

Pancreatic cancer remains a deadly disease, with few patients surviving 5 years following diagnosis. Surgical resection remains the only treatment associated with the potential for cure; however, most patients have locally advanced or metastatic disease at presentation and thus are not surgical candidates. Advances in imaging technologies, biochemistry, and molecular genetics have raised hopes of improving the outcome for patients with pancreatic cancer through earlier and more accurate diagnosis. As our knowledge of the genetics of pancreatic cancer has increased, the possibility of screening to identify patients at risk to develop the disease also holds promise. This review focuses on the utility of current modalities to screen for pancreatic cancer as well as the most accurate and expedient methods to stage the disease.     

Endoscopic ultrasonography in the diagnosis and staging of pancreatic neoplasms

Summary Background. Pancreatic cancer is the fourth leading cause of death among Americans. Twenty-eight thousand cases of pancreatic cancer are diagnosed annually and about the same number of patients die of pancreatic cancer every year. Most patients with pancreatic cancer are diagnosed when the tumor is 3 cm or more in diameter. Most pancreatic cancers are metastatic at the time of diagnosis and the median survival is only 18–20 mo. Overall, actual 5-yr survival is about 10% and has not changed much over several decades. Curative surgical resection is currently believed to offer the only chance of long-term survival in these patients. Difficulty in the early diagnosis of pancreatic cancer remains a major obstacle in improving outcomes in these patients. Screening for pancreatic cancer is currently not recommended. However, recent developments in endoscopic ultrasound (EUS) and cytological EUS-guided fine-needle aspiration (FNA) allow early diagnosis of pancreatic cancer with histological confirmation. EUS-FNA in conjunction with helical CT also provides reliable preoperative staging of pancreatic tumors. EUS with FNA therefore appears to be a promising tool in the fight against pancreatic cancer.     

Pancreatic cancer: Can we screen? How should we stage?

Pancreatic cancer remains a deadly disease, with few patients surviving 5 years following diagnosis. Surgical resection remains the only treatment associated with the potential for cure; however, most patients have locally advanced or metastatic disease at presentation and thus are not surgical candidates. Advances in imaging technologies, biochemistry, and molecular genetics have raised hopes of improving the outcome for patients with pancreatic cancer through earlier and more accurate diagnosis. As our knowledge of the genetics of pancreatic cancer has increased, the possibility of screening to identify patients at risk to develop the disease also holds promise. This review focuses on the utility of current modalities to screen for pancreatic cancer as well as the most accurate and expedient methods to stage the disease.     

Development of chemotherapy and significance of conversion surgery after chemotherapy in unresectable pancreatic cancer

While surgery currently remains the only potentially curative treatment available for pancreatic cancer, only 20% to 30% of patients have resectable disease at diagnosis. Recently, with the introduction of intensive chemotherapy regimens such as oxaliplatin, irinotecan, fluorouracil plus leucovorin (FOLFIRINOX) and gemcitabine plus nab‐paclitaxel, for the treatment of unresectable pancreatic cancer, the antitumor activity and overall survival in patients with pancreatic cancer have dramatically improved. These advances in intensive chemotherapy have led to the possibility of conversion of unresectable disease to resectable disease, and it has been reported that more than 20% of pancreatic cancer patients with unresectable locally advanced disease at diagnosis undergo successful conversion surgery after FOLFIRINOX therapy. In metastatic pancreatic cancer, resection for the primary lesion of pancreatic cancer may show some benefits for some patients with complete resolution of metastases by chemotherapy. Furthermore, surgical resection in some patients with only a few metastases, so‐called oligometastases, have also been reported. Conversion surgery is becoming increasingly possible with the introduction of intensive chemotherapies, however, the actual clinical benefits of resection in such cases has not yet been sufficiently investigated. The long‐term safety, feasibility and outcomes still need to be investigated in well‐designed, multi‐institutional studies on a large number of patients.     

Retroperitoneal dissection followed by translateral retroperitoneal approach for pancreatic cancer

To improve the surgical results for pancreatic cancer, extended surgery has been performed at our institution since 1973. The translateral retroperitoneal approach was developed as one of these extended procedures in 1976. With this procedure, the lymph nodes around the pancreas, the superior mesenteric artery, and the abdominal, aorta are removed and a combined resection of the portal vein is performed. This approach has been employed in 54 patients with pancreatic cancer. Of these 54, 9 have survived for 5 years or more. Here we describe the technique, focusing in particular on the dissection of the retroperitoneum and the region around the superior mesenteric artery.     

Treatment of locally advanced pancreatic cancer: should we resect when resectable?

While the outcome of surgery for locally advanced pancreatic cancer is still quite poor, over the past 2 decades, surgical outcomes have gradually improved in Japan. Because the advantages of surgery over radiochemotherapy have not yet been confirmed by randomized, controlled trials, it has long been discussed whether surgical resection could be indicated for locally advanced pancreatic cancer. We recently performed a multicenter, randomized, controlled trial comparing surgical resection and radiochemotherapy for locally advanced pancreatic cancer. Twenty patients were assigned to the surgery group, and 22 to the radiochemotherapy group. Although there was 1 operative death, surgery offered significantly better results than radiochemotherapy, as measured by 1-year survival (62% vs. 32%, P = 0.05), mean survival time (>17 vs. 11 months, P < 0.03), and hazard ratio (0.46, P = 0.04). There was no significant difference in the quality of life score or laboratory data, apart from increased diarrhea after surgery. In this article, the results of our trial are reviewed in brief, and our opinion on surgical treatment of locally advanced pancreatic cancer is discussed.     

Involvement of eicosanoids in the pathogenesis of pancreatic cancer: The roles of cyclooxygenase-2 and 5-lipoxygenase

The interplay between inflammation and cancer progression is a growing area of research. A combination of clinical, epidemiological, and basic science investigations indicate that there is a relationship between inflammatory changes in the pancreas and neoplastic progression. Diets high in ω-6 polyunsaturated fatty acids provide increased substrate for arachidonic acid metabolism by cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) to form eicosanoids. These eicosanoids directly contribute to pancreatic cancer cell proliferation. Both COX-2 and 5-LOX are upregulated in multiple cancer types, including pancreatic cancer. In vitro studies using pancreatic cancer cell lines have demonstrated upregulation of COX-2 and 5-LOX at both the mRNA and protein levels. When COX-2 and 5-LOX are blocked via a variety of mechanisms, cancer cell proliferation is abrogated both in vitro and in vivo. The mechanism of COX-2 has been shown to include effects on apoptosis as well as angiogenesis. 5-LOX has been implicated in apoptosis. The use of COX-2 and 5-LOX inhibitors in clinical studies in patients with pancreatic cancer has been limited. Patient enrollment has been restricted to those with advanced disease which makes evaluation of these drugs as chemopreventive agents difficult. COX-2 and 5-LOX expression have been shown to be present during the early neoplastic changes of pancreatic cancer, well before progression to invasive disease. This indicates that the ideal role for these interventions is early in the disease process as preventive agents, perhaps in patients with chronic pancreatitis or hereditary pancreatitis.     

Imaging diagnosis of pancreatic cancer:A state-of-the-art review

Pancreatic cancer(PC)remains one of the deadliest cancers worldwide,and has a poor,five-year survival rate of 5%.Although complete surgical resection is the only curative therapy for pancreatic cancer,less than20%of newly-diagnosed patients undergo surgical resection with a curative intent.Due to the lack of early symptoms and the tendency of pancreatic adenocarcinoma to invade adjacent structures or to metastasize at an early stage,many patients with pancreatic cancer already have advanced disease at the time of their diagnosis and,therefore,there is a high mortality rate.To improve the patient survival rate,early detection of PC is critical.The diagnosis of PC relies on computed tomography(CT)and/or magnetic resonance imaging(MRI)with magnetic resonance cholangiopancreatography(MRCP),or biopsy or fine-needle aspiration using endoscopic ultrasound(EUS).Although multi-detector row computed tomography currently has a major role in the evaluation of PC,MRI with MRCP facilitates better detection of tumors at an early stage by allowing a comprehensive analysis of the morphological changes of the pancreas parenchyma and pancreatic duct.The diagnosis could be improved using positron emission tomography techniques in special conditions in which CT and EUS are not completely diagnostic.It is essential for clinicians to understand the advantages and disadvantages of the various pancreatic imaging modalities in order to be able to make optimal treatment and management decisions.Our study investigates the current role and innovative techniques of pancreatic imaging focused on the detection of pancreatic cancer.     

Current management of locally advanced pancreatic cancer

Almost 30% of patients with pancreatic cancer present with large, locally advanced tumors in the absence of distant metastases. Because surgical resection is frequently contraindicated by vascular invasion, locally advanced pancreatic cancer has a dismal prognosis with a 6-10-month median survival. Recent advances in the multimodality treatment of other gastrointestinal malignancies have not altered the management of patients with locally advanced pancreatic cancer, a clinical dilemma reflected by the number of nonrandomized trials and anecdotal reports addressing this difficult disease. Our review summarizes the current status of aggressive surgical resection and neoadjuvant chemoradiation for locally advanced pancreatic cancer and suggests a treatment algorithm for patients with this disease based upon published clinical evidence.     

Pancreatic cancer: Advances in treatment

Pancreatic cancer is a leading cause of cancer mortality and the incidence of this disease is expected to continue increasing. While patients with pancreatic cancer have traditionally faced a dismal prognosis, over the past several years various advances in diagnosis and treatment have begun to positively impact this disease. Identification of effective combinations of existing chemotherapeutic agents, such as the FOLFIRINOX and the gemcitabine + nab-paclitaxel regimen, has improved survival for selected patients although concerns regarding their toxicity profiles remain. A better understanding of pancreatic carcinogenesis has identified several pre-malignant precursor lesions, such as pancreatic intraepithelial neoplasias, intraductal papillary mucinous neoplasms, and cystic neoplasms. Imaging technology has also evolved dramatically so as to allow early detection of these lesions and thereby facilitate earlier management. Surgery remains a cornerstone of treatment for patients with resectable pancreatic tumors, and advances in surgical technique have allowed patients to undergo resection with decreasing perioperative morbidity and mortality. Surgery has also become feasible in selected patients with borderline resectable tumors as a result of neoadjuvant therapy. Furthermore, pancreatectomy involving vascular reconstruction and pancreatectomy with minimally invasive techniques have demonstrated safety without significantly compromising oncologic outcomes. Lastly, a deeper understanding of molecular aberrations contributing to the development of pancreatic cancer shows promise for future development of more targeted and safe therapeutic agents.     

The surgical management of pancreatic cancer

There have been significant advances made over the years in the areas of critical care, anesthesia, and surgical technique, which have led to improved mortality rates and survival after resection for pancreatic cancer. The standard of care is currently PD or PPPD for pancreatic cancers of the head, uncinate process, or neck and DP for pancreatic cancers of the body or tail. Resections are performed with the goals of negative margins and minimal blood loss, and referral to high-volume centers and surgeons is encouraged. However, 5-year survival rate after curative resection still remains at less than 20%. In an effort to improve survival and extend the limits of resectability, many centers have attempted extended lymphadenectomy and portal venous and even arterial resection and reconstruction. Extended lymphadenectomy has not led to improved survival for these patients. Portal vein resection has increased the number of patients amenable to resection, with equivalent survival rates compared with those of standard resections. Portal vein invasion is thus no longer considered a contraindication to resection at many large centers. Resection and reconstruction of involved arteries have been rarely performed and are currently not considerations for most patients. It is likely that future improvements in survival lie in the realm of adjuvant therapy. As chemotherapeutic and other tumor-directed agents continue to evolve and advance, this will hopefully lead to improved survival for patients undergoing surgical resection for pancreatic cancer.     

Pancreatic cancer

Substantial progress has been made in our understanding of the biology of pancreatic cancer, and advances in patients' management have also taken place. Evidence is beginning to show that screening first-degree relatives of individuals with several family members affected by pancreatic cancer can identify non-invasive precursors of this malignant disease. The incidence of and number of deaths caused by pancreatic tumours have been gradually rising, even as incidence and mortality of other common cancers have been declining. Despite developments in detection and management of pancreatic cancer, only about 4% of patients will live 5 years after diagnosis. Survival is better for those with malignant disease localised to the pancreas, because surgical resection at present offers the only chance of cure. Unfortunately, 80-85% of patients present with advanced unresectable disease. Furthermore, pancreatic cancer responds poorly to most chemotherapeutic agents. Hence, we need to understand the biological mechanisms that contribute to development and progression of pancreatic tumours. In this Seminar we will discuss the most common and deadly form of pancreatic cancer, pancreatic ductal adenocarcinoma.     

Rare long-term survivors of pancreatic adenocarcinoma without curative resection

Long-term outcome data in pancreatic adenocarcinoma are predominantly based on surgical series, as resection is currently considered essential for long-term survival. In contrast, five-year survival in non-resected patients has rarely been reported. In this report, we examined the incidence and natural history of ≥ 5-year survivors with non-resected pancreatic adenocarcinoma. All patients with pancreatic adenocarcinoma who received oncologic therapy alone without surgery at our institution between 1995 and 2009 were identified. Non-resected ≥ 5-year survivors represented 2% (11/544) of all non-resected patients undergoing treatment for pancreatic adenocarcinoma, and 11% (11/98) of ≥ 5-year survivors. Nine patients had localized tumor and 2 metastatic disease at initial diagnosis. Disease progression occurred in 6 patients, and the local tumor bed was the most common site of progression. Six patients suffered from significant morbidities including recurrent cholangitis, second malignancy, malnutrition and bowel perforation. A rare subset of patients with pancreatic cancer achieve long-term survival without resection. Despite prolonged survival, morbidities unrelated to the primary cancer were frequently encountered and a close follow-up is warranted in these patients. Factors such as tumor biology and host immunity may play a key role in disease progression and survival.     

Pancreatic cancer proteome: the proteins that underlie invasion, metastasis, and immunologic escape

BACKGROUND & AIMS: Pancreatic cancer is a highly lethal disease that has seen little headway in diagnosis and treatment for the past few decades. The effective treatment of pancreatic cancer is critically relying on the diagnosis of the disease at an early stage, which still remains challenging. New experimental approaches, such as quantitative proteomics, have shown great potential for the study of cancer and have opened new opportunities to investigate crucial events underlying pancreatic tumorigenesis and to exploit this knowledge for early detection and better intervention. METHODS: To systematically study protein expression in pancreatic cancer, we used isotope-coded affinity tag technology and tandem mass spectrometry to perform quantitative proteomic profiling of pancreatic cancer tissues and normal pancreas. RESULTS: A total of 656 proteins were identified and quantified in 2 pancreatic cancer samples, of which 151 were differentially expressed in cancer by at least 2-fold. This study revealed numerous proteins that are newly discovered to be associated with pancreatic cancer, providing candidates for future early diagnosis biomarkers and targets for therapy. Several differentially expressed proteins were further validated by tissue microarray immunohistochemistry. Many of the differentially expressed proteins identified are involved in protein-driven interactions between the ductal epithelium and the extracellular matrix that orchestrate tumor growth, migration, angiogenesis, invasion, metastasis, and immunologic escape. CONCLUSIONS: Our study is the first application of isotope-coded affinity tag technology for proteomic analysis of human cancer tissue and has shown the value of this technology in identifying differentially expressed proteins in cancer.