Miroslav Zavoral

Molecular biology of pancreatic cancer

In spite of continuous research efforts directed at early detection and treatment of pancreatic cancer, the outlook for patients affected by the disease remains dismal. With most cases still being diagnosed at advanced stages, no improvement in survival prognosis is achieved with current diagnostic imaging approaches. In the absence of a dominant precancerous condition, several risk factors have been identified including family history, chronic pancreatitis, smoking, diabetes mellitus, as well as certain genetic disorders such as hereditary pancreatitis, cystic fibrosis, familial atypical multiple mole melanoma, and Peutz-Jeghers and Lynch syndromes. Most pancreatic carcinomas, however, remain sporadic. Current progress in experimental molecular techniques has enabled detailed understanding of the molecular processes of pancreatic cancer development. According to the latest information, malignant pancreatic transformation involves multiple oncogenes and tumor-suppressor genes that are involved in a variety of signaling pathways. The most characteristic aberrations (somatic point mutations and allelic losses) affect oncogenes and tumor-suppressor genes within RAS, AKT and Wnt signaling, and have a key role in transcription and proliferation, as well as systems that regulate the cell cycle (SMAD/DPC, CDKN2A/p16) and apoptosis (TP53). Understanding of the underlying molecular mechanisms should promote development of new methodology for early diagnosis and facilitate improvement in current approaches for pancreatic cancer treatment.

Five-year analysis of the prevention of colorectal sporadic adenomatous polyps trial

OBJECTIVES:Subjects in the Prevention of Colorectal Sporadic Adenomatous Polyps (PreSAP) trial (PRESAP/NCT00141193/www.clinicaltrials.gov) were studied to determine efficacy and safety at a year 5 assessment.METHODS:In this randomized, placebo-controlled, double-blind trial, 1,561 subjects with diagnosed colorectal adenomas removed within 3 months of the studys initiation were assessed after ∼3 years on celecoxib followed by 2 years off. Studied in 107 primary and secondary care settings, subjects were stratified by cardioprotective aspirin use and randomized to receive orally 400 mg celecoxib (933 subjects) or placebo (628 subjects) once daily. Efficacy was measured by colonoscopy at years 1, 3, and 5, and safety was measured by investigators for the on-treatment period and collected by subject self-report over 2 years post-treatment.RESULTS:At year 5, the primary outcome measure was the rate of new adenomas measured cumulatively from baseline. This rate was statistically significantly lower in the celecoxib group (51.4%) than in the placebo group (57.5%; P<0.001). Similarly, the cumulative rate of new advanced adenomas was significantly lower in the celecoxib group (10.0%) than in the placebo group (13.8%; P=0.007). However, the year 5 interval measure, which was not cumulative and did not take the rates of previous years into account, showed that after 2 years off treatment, the celecoxib group (27.0%) was 1.66 times more likely to have new adenomas than the placebo group (16.3%; P<0.0001). Similarly, the percentage of patients with new advanced adenomas was significantly higher in the celecoxib group (5.0%) than in the placebo group (3.8%) (P=0.0072). The evaluation of safety from baseline through year 5 indicated that the risks of serious cardiac disorders (relative risk (RR) 1.66; 95% confidence interval (CI) 1.01–2.73), selected renal/hypertension events (RR 1.35; 95% CI 1.09–1.68), and general vascular (RR 1.34; 95% CI 1.08–1.68) and cardiac disorders (RR 1.59; 95% CI 1.12–2.26) were higher in those taking celecoxib than in those on placebo.CONCLUSIONS:The year 5 cumulative measures of the incidence of new and advanced adenomas were significantly lower in the celecoxib group than in the placebo group, but the year 5 interval rates of these measures were significantly lower in the placebo group than the celecoxib group, perhaps suggesting a release of cyclooxygenase-2 inhibition. Consistent with what has been previously reported, increased risk of renal/hypertension events and cardiac disorders associated with celecoxib therapy mandates caution in patient selection.

Colorectal cancer screening: 20 years of development and recent progress

Colorectal cancer (CRC) is the second most common cancer in Europe and its incidence is steadily increasing. This trend could be reversed through timely secondary prevention (screening). In the last twenty years, CRC screening programs across Europe have experienced considerable improvements (fecal occult blood testing; transition from opportunistic to population based program settings). The Czech Republic is a typical example of a country with a long history of nationwide CRC screening programs in the face of very high CRC incidence and mortality rates. Each year, approximately 8000 people are diagnosed with CRC and some 4000 die from this malignancy. Twenty years ago, the first pilot studies on CRC screening led to the introduction of the opportunistic Czech National Colorectal Cancer Screening Program in 2000. Originally, this program was based on the guaiac fecal occult blood test (FOBT) offered by general practitioners, followed by colonoscopy in cases of FOBT positivity. The program has continuously evolved, namely with the implementation of immunochemical FOBTs and screening colonoscopy, as well as the involvement of gynecologists. Since the establishment of the Czech CRC Screening Registry in 2006, 2405850 FOBTs have been performed and 104565 preventive colonoscopies recorded within the screening program. The overall program expanded to cover 25.0% of the target population by 2011. However, stagnation in the annual number of performed FOBTs lately has led to switching to the option of a population-based program with personal invitation, which is currently being prepared.

Training on an ex vivo animal model improves endoscopic skills: a randomized, single-blind study

BACKGROUND Animal models are used for training of different endoscopic procedures. Whether this really improves endoscopic skills remains controversial. OBJECTIVE To assess the effectiveness of training by using an ex vivo animal gastric model on the performance of two therapeutic procedures-hemostasis and treatment of perforation. DESIGN A randomized, single-blind study. SETTING An experimental endoscopy center in a university hospital. PARTICIPANTS Thirty-one gastroenterology fellows with comparable endoscopic experience. METHODS Participants were randomized into two groups: with (T, n = 16) and without (S, n = 15) training. All fellows continued with standard endoscopic practice. Baseline skills were assessed at enrollment. All physicians in group T underwent 2 full days of a hands-on course over a 3-month period, in addition to their standard endoscopic practice. Both groups then underwent a blinded, final evaluation. Endoscopic skills were scored from 1 (best) to 5 (poorest) by two expert, blinded tutors. Outcomes of clinical hemostatic procedures also were analyzed. MAIN OUTCOME MEASUREMENTS Successful hemostasis and successful perforation closure. RESULTS Thirty physicians completed the study. Hemostasis results (n = 15): The number of physicians who carried out a successful hemostasis procedure increased significantly in the group with training (27% vs 73%; P = .009) but did not change in the group without training (20% vs 20%). The mean scores of injection and clipping technique improved significantly only after training. The number of clips used decreased significantly only in the group with training; the time of clipping did not change significantly in either group. Perforation results (n = 15): The number of physicians with a successful and complete perforation closure increased nearly significantly in the group with training (40% vs 73%, P = .06) as opposed to the group without training (27% vs 47%; P = .27). The procedure time decreased significantly in the group with training only. In clinical practice, fellows in group T had a significantly higher success rate with respect to hemostatic procedures (83.2%, range 67-100 vs 63.6%, range 25-100; P = .0447). The majority of participants (93%) agreed that such courses should be compulsory in gastroenterological credentials. LIMITATIONS A retrospective analysis of clinical outcomes. Clinical outcome data were based on self-reporting of the participants. CONCLUSION Hands-on training by using an animal ex vivo model improves endoscopic skills in both hemostasis and perforation closure. In clinical practice, the training improves the outcome of hemostatic procedures.

Colorectal cancer prevention in the Czech Republic: time trends in performance indicators and current situation after 10 years of screening

The incidence and mortality of colorectal cancer (CRC) in the Czech Republic is significant. The National CRC Screening Program started in 2000 and was further enhanced in 2009. In 2010, the European Guidelines were introduced. The aim of the present trend study was to evaluate the quality of the Czech National Colorectal Cancer Screening Program using early performance and long-term impact indicators. The screening program has been assessed using data from three sources: the Czech National Cancer Registry, the Czech National Reference Centre, and the Czech CRC Screening Registry. The data were compared with a set of recommended quality control indicators. Between 2006 and 2010, a total of 1 881 299 fecal occult blood tests were performed, of which 87 397 were positive (4.6%). Until 2011, a total of 68 527 fecal occult blood test follow-up colonoscopies were performed. In addition, between 2009 and 2011, a total of 10 309 screening colonoscopies were performed. As a result, a total of 25 255 adenomas (32.0% rate) and 3379 CRCs (4.3% rate) were detected. A trend of cancer detection in earlier stages has been observed. The overall program coverage has increased to 22.7% of the target population in 2010. The majority of European guidelines’ quality indicators for nonpopulation-based programs were implemented in the Czech National CRC Screening program. An improvement in program management was accompanied by an increase in coverage as well as other performance indicators.

Single loop-and-clips technique (king closure) for gastrotomy closure after transgastric ovariectomy: a survival experiment

Introduction A safe closure technique of transluminal access is essential for the widespread application of natural orifice transluminal endoscopic surgery (NOTES). Aim To evaluate the feasibility and effectiveness of a novel single loop-and-clips closure technique (KING closure). Material and methods An experimental survival study using female laboratory pigs was performed. A gastrotomy was performed using a standard percutaneous endoscopic gastrostomy technique. A peritoneoscopy with an ovariectomy was then performed with a double-channel endoscope, on a total of 14 pigs. Two different techniques of gastrotomy closure were analysed: a loop-and-clips closure technique (n = 7) and a standard closure using endoclips (n = 7). After a follow-up period of 30 days, the animals were euthanized for post-mortem examination. Results In the “loop-and-clip” closure group, the correct placement of an endoloop and clips was achieved in all animals. At necropsy, no animal showed signs of an abscess or peritonitis. Histological examination demonstrated a patent full-thickness gastric wall closure without evidence of local complications in all instances. In the “clips” group, the gastrotomy closure was assessed as probably unsafe in three animals. At necropsy 3 (42.9%) abscesses and 1 (14.3%) case of peritonitis were found. Conclusions A single loop-and-clips closure technique (KING closure) represents a feasible, simple and effective method of gastric incision closure. It appears to be superior to the standard endoscopic closure technique using clips.

Early diagnosis of pancreatic adenocarcinoma: role of stroma, surface proteases, and glucose-homeostatic agents.

Objectives New-onset diabetes in pancreatic adenocarcinoma is due to a combination of insulin resistance and decreased &bgr;-cell function. Its differentiation from the common type 2 diabetes is the prerequisite for early diagnosis of pancreatic adenocarcinoma. Little attention has been paid to pancreatic stroma and surface proteases. Methods The activated fibroblasts selectively express fibroblast activation protein &agr;, a structural homolog of the ubiquitously expressed dipeptidyl peptidase 4. Their role in pancreatic carcinogenesis is reviewed. Results Homodimers and heterodimers of both enzymes display high specificity for peptides and proteins with penultimate proline or alanine. Most glucose-homeostatic agents are candidate substrates of these enzymes. The biological activity of truncated substrates is decreased or absent. Conclusions The interactions of surface proteases with glucose-homeostatic agents may adequately explain the evolution of diabetes associated with pancreatic adenocarcinoma and differentiate it from the common type 2 diabetes. Abbreviations BMI - body mass index FGF2 - fibroblast growth factor 2 IL-1 - interleukin-1 IL-6 - interleukin-6 PDGF - platelet-derived growth factor TGF-&bgr;1 - transforming growth factor-beta 1

Improvements in colorectal cancer screening programmes – quantitative immunochemical faecal occult blood testing – how to set the cut-off for a particular population

OBJECTIVE The aim of the study was to determine the optimum cut-off value of the quantitative immunochemical test (q-FIT) OC-Sensor for colorectal cancer and advanced adenomatous polyps in a particular population. METHODS 815 patients were referred for colonoscopy and were offered two q-FIT examinations at two different colonoscopy centers. The patients were classified according to the colonoscopic findings. Test sensitivity, specificity, and accuracy were statistically evaluated using one test and two tests at the levels of 50, 75, 100, 125, and 150 ng/mL of faecal hemoglobin in those patients with advanced polyps and colorectal cancer. The optimum cut-off test level for clinically significant neoplasia was determined using one test. RESULTS The optimum cut-off value of q-FIT OC-Sensor for the detection of clinically significant neoplasia in our particular population was determined as 75 ng/mL using one test. This value provides an optimum proportion of 73% sensitivity (±95% CI 60.3% - 83.4%) and 90% specificity (±95% CI 86.8% - 92.8%), PPV and NPV were determined as 54.76% and 95.43% respectively. CONCLUSIONS The first step in the implementation of q-FIT test in the screening program in our country is to determine the optimum cut-off level for a population, and to estimate the number of tests performed with respect to the optimum cost effectiveness and economical climate. Using one test, the optimum level of q-FIT OC-Sensor® in the Czech Republic was determined as 75 ng/mL. This study could serve as a model for further studies in other countries, where screening does not yet exist.

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.

How significant is the association between metabolic syndrome and prevalence of colorectal neoplasia

The incidence and prevalence of metabolic syndrome (MS) and colorectal cancer (CRC) has been rising in developed countries. The association between these two diseases has been widely studied and reported. Less evidence is available about the relationship between MS and CRC precancerous lesions (adenomatous polyps, adenomas). The aim of this paper is to present an overview of our scientific understanding of that topic and its implication in clinical practice. One of the principal goals of current CRC secondary prevention efforts is to detect and remove the precancerous lesions in individuals with an average CRC risk to prevent the development of invasive cancer. MS is not currently considered a high-risk CRC factor and is therefore not included in the guidelines of organized screening programs. However, in light of growing scientific evidence, the approach to patients with MS should be changed. Metabolic risk factors for the development of adenomas and cancers are the same - obesity, impaired glucose tolerance, dyslipidemia, hypertension, cardiovascular diseases and diabetes mellitus type 2. Therefore, the key issue in the near future is the development of a simple scoring system, easy to use in clinical practice, which would identify individuals with high metabolic risk of colorectal neoplasia and would be used for individual CRC secondary prevention strategies. Currently, such scoring systems have been published based on Asian (Asia-Pacific Colorectal Screening Score; APCS) and Polish populations.