Surveillance for pancreatic cancer in high-risk individuals.

Background: Surveillance of individuals at high risk of pancreatic ductal adenocarcinoma (PDAC) and its precursors might lead to better outcomes. The aim of this study was to determine the prevalence and outcomes of PDAC and high-risk neoplastic precursor lesions among such patients participating in surveillance programmes. Methods: A multicentre study was conducted through the International CAncer of the Pancreas Screening (CAPS) Consortium Registry to identify high-risk individuals who had undergone pancreatic resection or progressed to advanced PDAC while under surveillance. High-risk neoplastic precursor lesions were defined as: pancreatic intraepithelial neoplasia (PanIN) 3, intraductal papillary mucinous neoplasia (IPMN) with high-grade dysplasia, and pancreatic neuroendocrine tumours at least 2 cm in diameter. Results: Of 76 high-risk individuals identified in 11 surveillance programmes, 71 had undergone surgery and five had been diagnosed with inoperable PDAC. Of the 71 patients who underwent resection, 32 (45 per cent) had PDAC or a high-risk precursor (19 PDAC, 4 main-duct IPMN, 4 branch-duct IPMN, 5 PanIN-3); the other 39 patients had lesions thought to be associated with a lower risk of neoplastic progression. Age at least 65 years, female sex, carriage of a gene mutation and location of a lesion in the head/uncinate region were associated with high-risk precursor lesions or PDAC. The survival of high-risk individuals with low-risk neoplastic lesions did not differ from that in those with high-risk precursor lesions. Survival was worse among patients with PDAC. There was no surgery-related mortality. Conclusion: A high proportion of high-risk individuals who had surgical resection for screening- or surveillance-detected pancreatic lesions had a high-risk neoplastic precursor lesion or PDAC at the time of surgery. Survival was better in high-risk individuals who had either low- or high-risk neoplastic precursor lesions compared with that in patients who developed PDAC.

Antecedentes: Se podrían obtener mejores resultados con el seguimiento de individuos de alto riesgo para adenocarcinoma ductal pancreático (pancreatic ductal adenocarcinoma, PDAC) y lesiones precursoras. El objetivo de este estudio fue determinar la prevalencia y los resultados del PDAC y de las lesiones precursoras de alto riesgo neoplásico en pacientes que participaron en programas de seguimiento. Métodos: Se llevó a cabo un estudio multicéntrico a través del registro internacional del consorcio CAPS (Common Automotive Platform Standard) para identificar a las personas de alto riesgo que se habían sometido a una resección pancreática o habían progresado a PDAC avanzado mientras estaban en seguimiento. Se definieron como lesiones neoplásicas precursoras de alto riesgo la neoplasia intraepitelial pancreática de tipo 3 (PanIN­3), la neoplasia papilar mucinosa intraductal (intraductal papillary mucinous neoplasia, IPMN) con displasia de alto grado y los tumores neuroendocrinos pancreáticos (pancreatic neuroendocrine tumours, PanNET) de ≥ 2 cm de diámetro. Resultados: De 76 individuos con lesiones de alto riesgo identificados en 11 programas de seguimiento, 71 fueron tratados quirúrgicamente y 5 fueron diagnosticados de un PDAC inoperable. De las 71 resecciones, 32 (45%) tenían PDAC o una lesión precursora de alto riesgo (19 PDAC, 4 IPMN de conducto principal, 4 IPMN de rama secundaria y 5 PanIN­3). Los otros 39 pacientes tenían lesiones que se consideraron asociadas con un menor riesgo de progresión neoplásica. La edad ≥ 65 años, el sexo femenino, el ser portador de una mutación genética y la localización de la lesión en la cabeza/proceso uncinado fueron factores asociados a las lesiones precursoras de alto riesgo o al PDAC. No hubo diferencias en la supervivencia de individuos de alto riesgo con lesiones neoplásicas de bajo riesgo frente a aquellos que presentaron lesiones precursoras de alto riesgo. La supervivencia fue peor en los pacientes con PDAC. No hubo mortalidad relacionada con la cirugía. Conclusión: Un elevado porcentaje de individuos de alto riesgo que se sometieron a resección quirúrgica tras la detección de lesiones pancreáticas en el seguimiento tenían una lesión precursora neoplásica de alto riesgo o un PDAC. La supervivencia fue mejor en individuos de alto riesgo que tenían lesiones precursoras neoplásicas de bajo o alto riesgo en comparación con aquellos pacientes que habían desarrollado un PDAC.

An Unexpected Etiology of Pancreatic Panniculitis: A Case Report.

BACKGROUND: Pancreatic panniculitis is a rare cause of subcutaneous fat necrosis secondary to elevated serum levels of pancreatic enzymes. It is most often associated with pancreatic acinar cell carcinoma, but has also been seen in patients with pancreatitis. CASE REPORT: We present a case of a 64 year old Caucasian man without symptoms of pancreatitis who presents with pancreatic panniculitis manifesting in multiple subcutaneous ulcerating nodules of the bilateral lower extremities, discovered to have a previously unreported etiology for this condition. He had no evidence of pancreatitis or malignancy, but instead a pancreatic-portal fistula resulting in panniculitis. CONCLUSION: Peripancreatic vascular lesions must also be considered in the differential diagnosis of pancreatic panniculitis. The diagnosis, pathology, and treatment of pancreatic panniculitis are reviewed herein.

Use and perceived effectiveness of non-analgesic medical therapies for chronic pancreatitis in the United States.

BACKGROUND: Effectiveness of medical therapies in chronic pancreatitis has been described in small studies of selected patients. AIM: To describe frequency and perceived effectiveness of non-analgesic medical therapies in chronic pancreatitis patients evaluated at US referral centres. METHODS: Using data on 516 chronic pancreatitis patients enrolled prospectively in the NAPS2 Study, we evaluated how often medical therapies [pancreatic enzyme replacement therapy (PERT), vitamins/antioxidants (AO), octreotide, coeliac plexus block (CPB)] were utilized and considered useful by physicians. RESULTS: Oral PERT was commonly used (70%), more frequently in the presence of exocrine insufficiency (EI) (88% vs. 61%, P < 0.001) and pain (74% vs. 59%, P < 0.002). On multivariable analyses, predictors of PERT usage were EI (OR 5.14, 95% CI 2.87-9.18), constant (OR 3.42, 95% CI 1.93-6.04) or intermittent pain (OR 1.98, 95% CI 1.14-3.45). Efficacy of PERT was predicted only by EI (OR 2.16, 95% CI 1.36-3.42). AO were tried less often (14%) and were more effective in idiopathic and obstructive vs. alcoholic chronic pancreatitis (25% vs. 4%, P = 0.03). Other therapies were infrequently used (CPB - 5%, octreotide - 7%) with efficacy generally <50%. CONCLUSIONS: Pancreatic enzyme replacement therapy is commonly utilized, but is considered useful in only subsets of chronic pancreatitis patients. Other medical therapies are used infrequently and have limited efficacy.

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.

Multiple roles of mucins in pancreatic cancer, a lethal and challenging malignancy.

Mucins are members of an expanding family of large multifunctional glycoproteins. Pancreatic mucins have important biological functions, including the protection, lubrication, and moisturisation of the surfaces of epithelial tissues lining ductal structures within the pancreas. Several lines of evidence support the notion that deregulated mucin production is a hallmark of inflammatory and neoplastic disorders of the pancreas. Herein, we discuss the factors that contribute to the lethality of pancreatic cancer as well as the key role played by mucins, particularly MUC1 and MUC4, in the development and progression of the disease. Aspects pertaining to the aberrant expression and glycosylation of mucins are discussed, with special emphasis on their potential impact on the design and implementation of adequate diagnostic and therapeutic strategies for combating this lethal malignancy.

Gastric myoelectrical activity and its relationship to the development of nausea and vomiting after intensive chemotherapy and autologous stem cell transplantation.

OBJECTIVES: Gastric motor dysfunction may be responsible, in some patients, for the nausea and emesis that occur after high-dose chemotherapy (HDT) and autologous stem cell transplantation (SCT). Because gastric myoelectrical abnormalities may result in nausea and vomiting in other contexts, we sought to define the prevalence of these abnormalities and their relationship to the development of nausea and vomiting in patients undergoing autologous HDT and SCT, and to determine whether electrogastrography (EGG) could serve to detect gastric motor dysfunction in this population. METHODS: We prospectively studied patients with a variety of malignancies who received standard transplantation doses of chemotherapeutic agents and antiemetics. Gastric emptying scintigraphy was performed before HDT. Gastric myoelectrical activity was assessed before HDT and on days 0, 7, 14, 21, and 28 from SCT using cutaneous EGG electrodes and a portable EGG recorder, and was analyzed by means of a dedicated software program after removal of motion artifact. Symptom assessment was obtained daily from initiation of HDT to 28 days after SCT. RESULTS: A total of 25 patients were studied: 13 women and 12 men, with a median age of 50 yr (range = 32-65 yr). Before HDT, gastric emptying scintigraphy was normal in all patients (median T(1/2) of 50 min [range = 22-75 min]) and only one patient had mild nausea and anorexia. Nausea, emesis, and anorexia occurred in all patients, peaked in severity at day +7 from SCT and, with the exception of anorexia, had returned toward baseline levels by day +28. Fasting dysrhythmias were present in 63% of the studies at baseline. Serial EGG recordings revealed significant slowing of the dominant frequency with a consequent decrease in tachygastria and increase in normogastria and bradygastria as the symptoms peaked in severity with a subsequent return to baseline values at the study's end. The only clinical variable that was predictive of symptom severity was gender. Women had a higher risk of developing anorexia (score > or = 2) at day +14 compared to men (odds ratio = 11.2; 95% CI = 1.7-76.9; p = 0.01). CONCLUSIONS: Baseline abnormalities in gastric myoelectrical activity occur frequently in patients who undergo HDT and autologous SCT despite normal gastric emptying scintigraphy and an absence of symptoms. Although slowing of the dominant frequency was seen as symptoms worsened, we failed to identify any EGG parameter at baseline that could predict the severity of nausea, vomiting or anorexia after transplantation.

Effects of low doses of erythromycin on the 13C Spirulina platensis gastric emptying breath test and electrogastrogram: a controlled study in healthy volunteers.

OBJECTIVE: Electrogastrography and stable isotope gastric emptying breath tests (GEBTs) are relatively simple, noninvasive tests of gastric motor function that may be useful in monitoring the effects of therapeutic interventions. It was our primary objective to examine the effects of low dose i.v. erythromycin on the results of the 13C Spirulina platensis GEBT and electrogastrography. We were also interested in evaluating the reproducibility of these tests. METHODS: In 10 healthy subjects (five female, ages 23-37 yr), we simultaneously performed the GEBT, using a prepackaged meal (340 kcal), and electrogastrography on each of four different occasions separated by at least 1 wk. After performance of baseline studies, they were repeated in random order after the infusion of 50 mg of erythromycin (Er50), 100 mg erythromycin (Er100), and a placebo (saline). Breath samples were obtained at baseline and at 75, 90, and 180 min after the meal and T1/2 and Tlag calculated. Electrogastrography recordings began 30 min before the test meal and continued for 2 h after the meal. RESULTS: Baseline and placebo T1/2 and Tlag were similar. Er50 resulted in a modest acceleration of gastric emptying (T1/2 Er50 vs baseline vs placebo = 104.0 vs 132.7 vs 125.5 min) and reduction in lag time (Tlag Er50 vs baseline vs placebo = 47.2 vs 61.5 vs 56.2 min). A similar decrease was seen in response to Er100. The baseline and placebo fasting and fed electrogastrography parameters were similar. After infusion of Er100, the percentage of normal slow waves in the first postprandial hour decreased relative to baseline and placebo (percent normogastria Er100 vs baseline vs placebo = 64.1+/-7.5 vs 82.4+/-6.4 vs 79.7+/-5.5). This corresponded with an increase in percent tachygastria during the same period and an overall decrease in the mean dominant frequency. Similar but less striking changes were seen after administration of Er50. Replicate GEBTs showed a high degree of reproducibility both within and between individuals for T1/2 and Tlag. In contrast, replicate electrogastrograms revealed moderate to high variability for all parameters except the dominant frequency. CONCLUSION: The stable isotope GEBT utilizing 13C S. platensis demonstrates responsiveness to the prokinetic effects of low dose i.v. erythromycin and good reproducibility.

Update on familial pancreatic cancer.

Approximately 5% to 10% of patients with pancreatic cancer have one or more first-degree relatives with this disease. A subset of these individuals have a hereditary form of pancreatic cancer designated by association with such hereditary disorders as familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, hereditary pancreatitis, or familial atypical multiple mole melanoma (FAMMM) syndrome. A subset of those FAMMM kindred with the CDKN2A (p16) germline mutation that expresses both pancreatic cancer and malignant melanoma may constitute a new hereditary pancreatic cancer-prone syndrome.

Hereditary pancreatic cancer.

Hereditary pancreatic cancer (PC) appears to be exceedingly heterogeneous, as evidenced by its association with a variety of integrally associated diverse cancers and/or differing mendelian inherited cancer syndromes, which include the Lynch syndrome II variant of hereditary nonpolyposis colorectal cancer, hereditary breast-ovarian cancer syndrome in families with the BRCA2 mutation, hereditary pancreatitis, Peutz-Jeghers polyposis and the familial atypical multiple-mole melanoma syndrome in families with the CDKN2A (p16) germline mutation. Because of this heterogeneity, we provide a conservative estimate that about 5% (1,460) of PC cases in the US annually are hereditary. Although this number is relatively small, members of hereditary PC families serve as excellent models for studying the etiology, natural history, biomarkers, pathogenesis, potential carcinogenic exposures and their perturbation of underlying genetic events, and treatment of PC. These individuals would benefit greatly from method(s) capable of detecting cancer at an early stage, and such knowledge would also be useful for improving the diagnosis of the much more common 'sporadic' form of PC.

Genetic counseling and testing for germline p16 mutations in two pancreatic cancer-prone families.

The mortality from pancreatic cancer coincides closely with its incidence, indicating a dismal outlook. Hereditary factors probably account for approximately 5%-10% of the pancreatic cancer burden. The molecular genetic etiology of pancreatic cancer is only beginning to be identified. We describe our genetic counseling experience with 2 large families prone to pancreatic cancer-malignant melanoma in which p16 (CDKN2) germline mutations had been identified. Members of each family underwent intensive counseling before and at the time of disclosure of p16 germline mutation findings. Two non-cancer-affected siblings from each of the 2 families had p16 mutations identified in DNA from their peripheral blood lymphocytes. In each case, a parent affected with pancreatic cancer also harbored the p16 mutation identified in DNA from their respective tumor blocks. The sibling pairs stated that they would seriously consider prophylactic pancreatectomy if biomarkers or imaging findings suggested a precancerous state. Our experience highlights limited options for managing these families and emphasizes the need for better tools to diagnose pancreatic cancer at a curable stage.

Hereditary pancreatic adenocarcinoma. A clinical perspective.

Although the total number of patients in these various high-risk groups is relatively small, they nevertheless provide excellent models for studying the cause, natural history, pathogenesis, and treatment of pancreatic cancer. These patients would also benefit greatly from procedures capable of detecting cancer at an early stage. This knowledge would be useful for the much commoner sporadic form of pancreatic cancer, in which diagnosis is almost always late and prognosis fatal. With early diagnosis, surgical resection before the cancer's extension beyond the organ's anatomic confines could be curative. The establishment of a National Familial Pancreatic Cancer Registry is essential and would increase the availability of these invaluable families for medical research.

Imaging techniques in the evaluation of adenocarcinoma of the pancreas.

Adenocarcinoma of the pancreas is a highly malignant neoplasm that presents late and carries a dismal prognosis. Despite technical advances, the various imaging modalities used to evaluate and stage a pancreatic adenocarcinoma have not had a significant impact on survival rates. This article describes the various imaging modalities used to image and stage an adenocarcinoma of the pancreas and reviews their relative accuracy and limitations in diagnosing and staging this carcinoma. We conclude that for appropriate staging of adenocarcinoma of the pancreas, the combination of a computed axial tomography scan and an endoscopic ultrasound represents an efficient and cost-effective approach.

Pancreatic cancer.

Despite the many advances reported during the past year, pancreatic cancer remains a profound therapeutic challenge. Helical CT has become the preferred staging study at many institutions. The role of chemoradiation therapy in a preoperative and postoperative setting is being defined. Gemcitabine has become first-line therapy for patients with advanced pancreatic adenocarcinoma. It is hoped that the increasing knowledge of the molecular biology of pancreatic carcinoma will lead to improvements in diagnosing, staging, and treating pancreatic adenocarcinoma.

Staple occlusion of the infrarenal aorta: a videoscopic retroperitoneal approach.

PURPOSE: The purposes of this study were to determine whether available laparoscopic stapling devices could be used to interrupt the diseased human aorta, and to develop a videoscopic technique for retroperitoneal exposure and control of the infrarenal aorta in pigs. Our long-term goal is to develop a minimally invasive approach to the treatment of abdominal aortic aneurysms by exclusion and extraanatomic bypass. METHODS: Ten diseased, formalin-preserved human cadaver aortas underwent stapling using a laparoscopic stapling device. The aortas were then pressurized to superphysiologic levels to assess the integrity of the staple line. Ten swine underwent retroperitoneal video-assisted exploration with control and staple occlusion of the aorta and iliac artery. RESULTS: The staple line was complete and remained intact after pressurization in nine of 10 cadaver aortas, despite the presence of complex calcified disease. One aorta had a 2-mm opening through the staple line. Through the left retroperitoneal approach, the infrarenal aorta and left iliac artery could be dissected and controlled. A modified pledgeted technique used for stapling resulted in hemostasis of the staple line and exclusion of flow without injury to adjacent structures. CONCLUSIONS: The diseased human aorta can be occluded using available laparoscopic staplers. These swine experiments demonstrate the feasibility of the retroperitoneal approach for exclusion of infrarenal aortic aneurysms.

The 5S ribosomal RNA gene clusters in Tetrahymena thermophila: strain differences, chromosomal localization, and loss during micronuclear ageing.

The organization of the 5S genes in the genome of Tetrahymena thermophila was examined in various strains, with germinal ageing, and the 5S gene clusters were mapped to the MIC chromosomes. When MIC or MAC DNA is cut with the restriction enzyme EcoRI, electrophoresed, blotted, and probed with a 5S rDNA probe, the banding patterns represent the clusters of the 5S rRNA genes as well as flanking regions. The use of long gels and 60 h of electrophoresis at 10 mA permitted resolution of some 30-35 5S gene clusters on fragments ranging in size from 30-2 kb (bottom of gel). The majority of the 5S gene clusters were found in both MIC and MAC genomes, a few being MIC limited and a few MAC limited. The relative copy number of 5S genes in each cluster was determined by integrating densitometric tracings made from autoradiograms. The total number of copies in the MAC was found to be 33% greater than in the MIC. When different inbred strains were examined, the majority of the 5S gene clusters were found to be conserved, with a few strain-specific clusters observed. Nine nullisomic strains missing both copies of one or more MIC chromosomes were used to map the 5S gene clusters. The clusters were distributed non-randomly to four of the five MIC chromosomes, with 17 of them localized to chromosome 1. A deletion map of chromosome 1 was constructed using various deletion strains. Some of these deletion strains included B strain clones which had been in continuous culture for 15 years. Losses of 5S gene clusters in these ageing MIC could be attributed to deletions of particular chromosomes. The chromosomal distribution of the 5S gene clusters in Tetrahymena is unlike that found for the well-studied eukaryotes, Drosophila and Xenopus.