Early detection of sporadic pancreatic cancer: time for change.

Sporadic pancreatic cancer amounts to ∼90% of all pancreatic cancers. It is a gloomy depressive disease and the most recalcitrant malignancy, with a very low 5-year survival (3-6%). At present, diagnostic methods are commonly applied, as used half a century ago, after the appearance of local and systemic symptoms (abdominal and back pain, cholestasis, painless jaundice, fatigue, anorexia, weight loss, anemia, peripheral phlebitis, and cachexia). Unfortunately, these symptoms are harbingers of an advanced disease. The subsequent imaging methods may offer additional information on the location, size, and morphology of the lesion, but they do not influence the prognosis. Radical surgery may be offered to 15-20% of patients. The relapses after surgery are frequent and chemotherapy may be palliative. Preventive programs represent the only possibility of improvement. We propose the first multistep and multidisciplinary preventive program for early detection of sporadic pancreatic cancer for the differential identification of average-risk patients who probably have the disease from those who do not.

Precursors of pancreatic cancer.

Pancreatic cancer (PC) behaves very differently in comparison with other malignancies. Its incidence has been increasing continuously; mortality has not decreased, the diagnosis is frequently late, radical surgery is performed only in 15-20% of patients, and chemotherapy is only palliative. PC occurs in three different forms. Sporadic PC accounts for 90% of all PCs. Its most frequent form is the pancreatic ductal adenocarcinoma. The remaining 10% constitute two minority groups: familial PC (7%) and PC as a manifestation of a genetic cancer syndrome (3%). PCs are preceded by a precancerous lesion (precursor). At present, six different precursors are known. They have different histomorphological characteristics and malignant potential. The recognition and correct interpretation of individual precursors influences adequate clinical decision-making. The publication surveys the present knowledge of individual precursors and their role in the early pancreatic carcinogenesis.

Lower plasma levels of glucose-dependent insulinotropic peptide (GIP) and pancreatic polypeptide (PP) in patients with ductal adenocarcinoma of the pancreas and their relation to the presence of impaired glucoregulation and weight loss.

BACKGROUND: The changes in gastrointestinal hormones associated with pancreatic ductal adenocarcinoma (PDAC) in patients with impaired glucoregulation have yet to be evaluated. The aim of this study was to determine plasma concentrations of selected gastrointestinal hormones in PDAC patients with and without diabetes and to compare them with levels found in Type 2 diabetic patients without cancer. METHODS: In this study we examined plasma concentrations of glucose-dependent insulinotropic peptide (GIP), glucagon-like peptide 1 (GLP-1), pancreatic polypeptide (PP), peptide YY (PYY) and neuropeptide Y (NPY), and cytokines leptin and adiponectin in 94 patients with histologically confirmed PDAC. Thirty-nine patients with Type 2 diabetes without PDAC and 29 healthy individuals with no evidence of acute or chronic diseases were examined as controls. RESULTS: Significantly lower plasma concentrations of GIP were found in PDAC patients with new-onset diabetes/prediabetes (n = 76), or in those with normal glucose regulation (n = 18), compared to patients with Type 2 diabetes without PDAC and controls (15.5 (3.7-64.5) or 6.5 (1.7-24.5) vs. 39.8 (15.1-104.7) and 28.8 (7.4-112.2) ng/L, p < 0.001); the same relationship was observed for PP (38.9 (10.2-147.9) or 28.1 (7.9-100.0) vs 89.1 (38.0-208.9) and 75.8 (30.1-190.6) ng/L, p < 0.01), respectively. The lowest levels of GIP and PP concentrations were found in PDAC patients with new-onset diabetes/prediabetes and weight loss > 2 kg (p < 0.001). CONCLUSIONS: We conclude that GIP and PP plasma concentrations are lower in pancreatic cancer irrespective of the degree of glucose intolerance as compared to Type 2 diabetic patients and healthy controls. In new onset diabetes especially if associated with weight loss, these changes may represent a new clue for the diagnosis of PDAC.

Early detection of pancreatic cancer: impact of high-resolution imaging methods and biomarkers.

High-resolution imaging methods (HRIMs) and biomarkers present the second step of pancreatic cancer (PC) diagnostics in at-risk individuals. These include patients with positive risk factors, early symptoms, nonresponders to the initial antidiabetic therapy, patients older than 50 years of age with new-onset unstable diabetes requiring insulin as well as patients with long-term insulin-non-dependent diabetes and recent (up to 6 months) failure of antidiabetic therapy. The procedures should be started without delay and the co-operation between the primary and tertiary medical centers is highly desirable. An early indication of HRIMs and biomarkers is a prerequisite for the diagnosis of a resectable PC. This publication reviews the recent contribution of HRIMs and biomarkers toward an early diagnosis of PC.

Increased tissue and circulating levels of dipeptidyl peptidase-IV enzymatic activity in patients with pancreatic ductal adenocarcinoma.

BACKGROUND/OBJECTIVES: Pancreatic ductal adenocarcinoma (PDAC) is frequently heralded by an impairment of glucose homeostasis. Dipeptidyl peptidase-IV (DPP-IV) and fibroblast activation protein alpha (FAP) are aminopeptidases that regulate several bioactive peptides involved in glucoregulation, and are frequently dysregulated in cancer. The present study analyzes blood plasma levels and the quantity and localization of DPP-IV and FAP in PDAC tissues. METHODS: DPP-IV and FAP concentration and enzymatic activity were evaluated in the plasma from 93 PDAC, 39 type 2 diabetes mellitus (T2DM) and 29 control subjects, and in matched paired non-tumorous and tumor tissues from 48 PDAC patients. The localization of DPP-IV and FAP was determined using immunohistochemistry and catalytic histochemistry. RESULTS: The enzymatic activity and concentration of DPP-IV was higher in PDAC tumor tissues compared to non-tumorous pancreas. DPP-IV was expressed in cancer cells and in the fibrotic stroma by activated (myo)fibroblasts including DPP-IV(+)FAP(+) cells. FAP was expressed in stromal cells and in some cancer cells and its expression was increased in the tumors. Plasmatic DPP-IV enzymatic activity, and in particular the ratio between DPP-IV enzymatic activity and concentration in PDAC with recent onset DM was higher compared to T2DM. In contrast, the plasmatic FAP enzymatic activity was lower in PDAC compared to T2DM and controls and rose after tumor removal. CONCLUSIONS: DPP-IV-like enzymatic activity is upregulated in PDAC tissues. PDAC patients with recent onset diabetes or prediabetes have increased plasmatic DPP-IV enzymatic activity. These changes may contribute to the frequently observed association of PDAC and recent onset impairment of glucoregulation.

Early pancreatic carcinogenesis - risk factors, early symptoms, and the impact of antidiabetic drugs.

Risk factors (long-term diabetes, obesity) and early symptoms (new-onset diabetes, loss of weight, or persistent low body mass) are the initial symptoms of pancreatic carcinogenesis. They may be influenced by antidiabetic drugs and their correct evaluation is a prerequisite for early diagnosis of pancreatic cancer (PC). We review the risk factors, early symptoms, and the impact of antidiabetic drugs on early pancreatic carcinogenesis. The main source of data was the database Medline/PubMed and abstracts of international congresses (DDW, UEGW). The risk factors and early symptoms are integral components of the familial PC surveillance and sporadic PC screening. Preventive programs should always be include multistep and multidisciplinary procedures. The correct evaluation of antidiabetic drugs and their interactions with other components of pancreatic carcinogenesis may influence the early diagnosis of PC.

[Early detection of sporadic pancreatic cancer]. / Casná detekce sporadického karcinomu pankreatu.

Pancreatic cancer (PC) behaves very differently in comparison with other malignancies. Its prevalence continuously increases, mortality does not decrease, diagnosis is frequently late, radical surgery is limited to 15-20 % of patients, postoperative relapses are frequent, and chemotherapy has a palliative character. Preventive programs are the only possibility of improvement. In familial pancreatic cancer (FPC) the knowledge of the genetic mutation enables earlier entry of specialists into the surveillance program. The repeated use of high resolution imaging methods (including endoscopy and pancreatic cytology) may be followed by more frequent detection of the precursors and earlier stages of FPC. The identification of sporadic pancreatic cancer (SPC) depends fully on the construction of a multi-step and multi-disciplinary preventive program.

[KRAS mutation assay on EUS-FNA specimens from pacients with pancreatic mass]. / Vysetrení mutace KRAS v EUS-FNA preparátech pacientu s tumorem pankreatu.

Differential diagnosis of solid pancreatic masses using EUS FNA is in 1015 % of cases still challenging. Promising method, which helps to distinguish between chronic pancreatitis and cancer, is point mutations of the proto-oncogene KRAS test. This method is not established in routine clinical practice yet.Objectives were the determination of the sensitivity of the KRAS assay using various kinds of samples of patients with pancreatic mass and testing the effect of the presence of KRAS mutations on the prognosis of survival. 147 patients underwent EUS-FNA examination of pancreatic mass, accompanied by blood sampling with subsequent separation of plasma for the detection of circulating tumor DNA. Part of biopsy sample was left native in a stabilizing solution and part as cytological smear. Samples (native aspirates, cytological smears, plasma) were examined for the presence of KRAS mutation by heteroduplex analysis, denaturing capillary electrophoresis.Among 147 patients with pancreatic masses, 118 were diagnosed as a cancer, 26 chronic pancreatitis, 3 neuroendocrine tumor. In total 147 native aspirates, 118 cytological smears and 94 plasma samples were examined. The highest sensitivity of KRAS mutation was reached in the group of pancreatic cancer patients using cytology, in which 90 % of KRAS mutation was detected (106/118 of the samples). When using the native cellular aspirates, mutation was detected in 78 % (92/118 samples), and examination of plasma was positive in 27 % (24/90 samples). In four patients with chronic pancreatitis KRAS mutations was detected, although none has been cytologically confirmed as a cancer. Two of these four patients were confirmed in the course of the disease as a cancer, one patient died because of alcoholic delirium and the last one was indicated for surgery recently.Examination of KRAS mutations can be performed in all patients undergoing EUS-FNA, with the cytology being the most reliable type of sample for genetic tests. KRAS examination would be reasonable to introduce into routine clinical practice in a group of patients with unclear differential diagnosis of chronic pancreatitis, especially in those with suspicion of cancer in inflammatory terrain.Kexwords: pancreatic cancer, chronic pancreatitis, KRAS mutation , EUS-FNA.