Circulating Tumor Cells in Colorectal Cancer: Detection Systems and Clinical Utility.

Colorectal cancer (CRC) is the third most common cancer worldwide. The high mortality from CRC is mainly related to metastasis affecting distant organs and their function. Dissemination of tumor cells from the primary tumor and hematogeneous spread are considered crucial in the formation of tumor metastases. The analysis of circulating tumor cells (CTCs) and CTC clusters in the blood can be used for the early detection of invasive cancer. Moreover, CTCs have a prognostic significance in the monitoring of a malignant disease or the response to chemotherapy. This work presents an overview of the research conducted on CTCs with the aim of finding suitable detection systems and assessing the possibility of clinical applications in patients with CRC.

CHRONIC PSEUDO-OBSTRUCTION OF THE SIGMOID COLON: A CASE REPORT.

Chronic intestinal pseudo-obstruction (CIPO) is a rare syndrome characterized by signs of intestinal obstruction lasting for 6 months or more, in the absence of a definitive cause of obstruction. We report a case of CIPO in a 49-year-old female patient with a 6-month history of ongoing irregular bowel movements, manifested as constipation and diarrhea accompanied by abdominal pain and bloated feeling. Contrast-enhanced abdominal computed tomography and magnetic resonance enterography revealed focal thickening of a segment of the lienal flexure and intermittent areas of wider and narrower caliber along the sigmoid colon. No signs of a definitive cause of obstruction were found, but evidence for dolichosigma was revealed, which was later confirmed with colonoscopy. Due to persisting symptoms, the patient agreed to elective resection of the sigmoid colon. Following the procedure, symptoms regressed with a significant improvement in the quality of life. The patient has been regularly monitored in an outpatient setting and reports absence of the symptoms since the procedure. Pathophysiology of the resected section revealed more prominent lymphatic tissue, follicular arrangement, and reactively altered germinal centers, which can suggest CIPO.

Profiling Colorectal Cancer in the Landscape Personalized Testing-Advantages of Liquid Biopsy.

Drug-specific therapeutic approaches for colorectal cancer (CRC) have contributed to significant improvements in patient health. Nevertheless, there is still a great need to improve the personalization of treatments based on genetic and epigenetic tumor profiles to maximize the quality and efficacy while limiting cytotoxicity. Currently, CEA and CA 19-9 are the only validated blood biomarkers in clinical practice. For this reason, laboratories are trying to identify new specific prognostics and, more importantly, predictive biomarkers for CRC patient profiling. Thus, the unique landscape of personalized biomarker data should have a clinical impact on CRC treatment strategies and molecular genetic screening tests should become the standard method for diagnosing CRC. This review concentrates on recent molecular testing in CRC and discusses the potential modifications in CRC assay methodology with the upcoming clinical application of novel genomic approaches. While mechanisms for analyzing circulating tumor DNA have been proven too inaccurate, detecting and analyzing circulating tumor cells and protein analysis of exosomes represent more promising options. Blood liquid biopsy offers good prospects for the future if the results align with pathologists' tissue analyses. Overall, early detection, accurate diagnosis and treatment monitoring for CRC with specific markers and targeted molecular testing may benefit many patients.

A CROSS-SECTIONAL STUDY OF HEPATITIS B AND HEPATITIS C KNOWLEDGE AMONG DENTAL MEDICINE STUDENTS AT THE UNIVERSITY OF ZAGREB.

Dental health care workers, particularly dental medicine students (DMS), are at an increased risk of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. The aim of our study was to assess the level of knowledge on HBV and HCV, estimate needlestick injury (NSI) prevalence and reporting practice in DMS at the University of Zagreb, and analyze how enrolment in obligatory and supplemental courses affects knowledge and NSI reporting practice. The knowledge was assessed by our questionnaires based on the Centers for Disease Control general handouts. Additional information was collected to examine the prevalence and reporting practice of NSI. Data were analyzed by descriptive statistical analysis, independent-samples t-test, proportion analyses, and combined factor analyses of categorical and quantitative variables in SPSS and R. In total, 206 students participated in the survey. The overall level of HBV- and HCV-related knowledge was poor, with the mean scores of 61.90% and 51.35%, respectively. Moreover, students enrolled in the first year demonstrated significantly lower levels of knowledge in comparison with their older peers. Of all participants, 18.2% had sustained a NSI and the majority of them (78.95%) had never reported the injury. In conclusion, DMS have low levels of knowledge on important occupational pathogens and poor NSI reporting practice. Moreover, formal education in the current form has failed to significantly improve student competence and theoretical knowledge translates poorly into more conscientious injury reporting practice. We should look for a better way to increase student awareness and level of knowledge on this topic.

OPPORTUNISTIC SCREENING FOR COLORECTAL CANCER IN HIGH-RISK PATIENTS IN FAMILY MEDICINE PRACTICES IN THE REPUBLIC OF CROATIA.

Colorectal cancer is a malignant neoplasm which has an increasing incidence and represents a global public health problem. The majority of patients are diagnosed after the age of 50, and the risk of developing it over lifetime is 5%. Development of preventive, diagnostic and treatment methods has resulted in a significant reduction in mortality and other negative clinical outcomes. Precisely because of the efficient method of prevention and early detection of this disease, numerous countries, including Croatia, have organized national colorectal cancer screening and monitoring programs. However, these programs are primarily organized for the population with the usual, i.e. average risk of developing colorectal cancer. High-risk groups include persons with endoscopically detected and removed colon polyps, persons surgically treated for colon cancer, persons with a positive family history of colorectal cancer, persons with inflammatory bowel diseases, individuals and families with hereditary disorders or genetic mutations that increase the risk of this disease several fold, persons with acromegaly, and patients who have undergone ureterosigmoidostomy. Recommendations for the detection and monitoring of high-risk groups are often not defined clearly, and some of the existing ones are based mostly on scarce scientific evidence. It is commonly accepted that screening in high-risk groups should start at an earlier age, with shorter intervals between follow-ups. The basic diagnostic method for screening and monitoring in these patient groups is endoscopic monitoring, or colonoscopy. The aim of this review paper is to present the characteristics of the abovementioned risk groups and provide clear screening recommendations.

CROATIAN GUIDELINES FOR THE DIAGNOSIS AND TREATMENT OF NONALCOHOLIC FATTY LIVER DISEASE.

Nonalcoholic fatty liver disease (NAFLD) is a term describing excessive accumulation of fat in hepatocytes, and is associated with metabolic syndrome and insulin resistance. NAFLD prevalence is on increase and goes in parallel with the increasing prevalence of metabolic syndrome and its components. That is why Croatian guidelines have been developed, which cover the screening protocol for patients with NAFLD risk factors, and the recommended diagnostic work-up and treatment of NAFLD patients. NAFLD screening should be done in patients with type 2 diabetes mellitus, or persons with two or more risk factors as part of metabolic screening, and is carried out by noninvasive laboratory and imaging methods used to detect fibrosis. Patient work-up should exclude the existence of other causes of liver injury and determine the stage of fibrosis as the most important factor in disease prognosis. Patients with initial stages of fibrosis continue to be monitored at the primary healthcare level with the management of metabolic risk factors, dietary measures, and increased physical activity. Patients with advanced fibrosis should be referred to a gastroenterologist/hepatologist for further treatment, monitoring, and detection and management of complications.

Changes in metabolic hormones after bariatric surgery and their predictive impact on weight loss.

BACKGROUND: Although various metabolic hormones have been implicated in bariatric-related weight loss, their use as predictors of weight loss is unknown. Our study evaluates changes in metabolic hormones after bariatric surgery, and their role as predictors of weight loss. METHODS: This nonrandomized study included 51 patients, 21 underwent laporascopic adjustable gastric banding (LAGB), 15 laparoscopic sleeve gastrectomy (LSG) and 15 Roux-en Y gastric bypass (RYGB). Serum ghrelin, leptin, insulin, growth hormone, HOMA-IR and HOMA-ß was recorded at baseline and 1, 3, 6 and 12 months, and correlated with weight loss. Successful weight loss was defined as excess weight loss >50% at 12 months for all groups. RESULTS: Weight loss pattern was similar in all groups. Ghrelin increased only in the LAGB group (P = 0·016). However, baseline ghrelin concentrations >664·6 pg/mL in the LSG group predicted successful weight loss with 81·8% sensitivity and 100·0% specificity, and ghrelin >969·8 pg/mL in the 1st postoperative month predicted success with 83·3% sensitivity and 83·3% specificity in the LAGB group. Insulin and HOMA-IR decreased significantly in the LSG and RYGB group, HOMA-ß increased in the LAGB and LSG group. Serum leptin decreased and GH increased in all groups (P < 0·001 for all changes). Changes in insulin, leptin and growth hormone were not predictors, but a consequence of weight loss. CONCLUSIONS: LSG is the most effective procedure for improvement of beta-cell function. High baseline ghrelin in the LSG group and an adequate 1st month increase in the LAGB group are associated with greater weight loss. Validation studies are required to confirm the role of ghrelin in predicting weight loss after bariatric surgery, but also in selecting candidates for specific bariatric procedures.

Glasgow Blatchford, pre-endoscopic Rockall and AIMS65 scores show no difference in predicting rebleeding rate and mortality in variceal bleeding.

OBJECTIVE: To compare the performance of the Glasgow Blatchford score (GBS), pre-endoscopic Rockall score (PRS) and AIMS65 score in predicting specific clinical endpoints following variceal upper gastrointestinal hemorrhage (UGIH). MATERIAL AND METHODS: Between January 2008 and December 2013, we retrospectively analyzed 225 consecutive hospitalized patients managed for endoscopically confirmed UGIH. RESULTS: A total of 225 patients (mean age 61.3 years), mostly diagnosed with alcoholic cirrhosis (195/86.7%), presented with variceal UGIH during the study period. Rebleeding occurred in 22 (9.8%) patients and 30-day mortality was 39 (17.3%). Initial hemostasis was achieved with N-butyl cyanoacrylate (151/79.1%) and endoscopic variceal ligation (40/20.9%), while secondary rebleeding prophylaxis in 110 (48.9%) patients was accomplished using endoscopic variceal ligation (92%). The majority of patients died from the underlying disease, while 12 (30.8%) died from bleeding. Median hospital stay was 6 (1-35) days. There was no statistically significant difference among AIMS65, GBS and PRS in predicting mortality (AUROC 0.70 vs. 0.64 vs. 0.66) or rebleeding rates (AUROC 0.74 vs. 0.60 vs. 0.67). The GBS was superior in predicting the need for blood transfusion compared to AIMS65 score (AUROC 0.75 vs. 0.61, p = 0.01) and PRS (AUROC 0.75 vs. 0.58, p = 0.009). CONCLUSIONS: The AIMS65, GBS and PRS scores are comparable but not useful for predicting outcome in patients with variceal UGIH because of poor discriminative ability. The GBS is superior in predicting the need for transfusion compared to AIMS65 score and PRS.

Mortality in high-risk patients with bleeding Mallory-Weiss syndrome is similar to that of peptic ulcer bleeding. Results of a prospective database study.

OBJECTIVE: The aim of this study was to identify the predictive factors influencing mortality in patients with bleeding Mallory-Weiss syndrome in comparison with peptic ulcer bleeding. MATERIAL AND METHODS: Between January 2005 and December 2009, 281 patients with endoscopically confirmed Mallory-Weiss syndrome and 1530 patients with peptic ulcer bleeding were consecutively evaluated. The 30-day mortality and clinical outcome were related to the patients' demographic data, endoscopic, and clinical characteristics. RESULTS: The one-year cumulative incidence for bleeding Mallory-Weiss syndrome was 7.3 cases/100,000 people and for peptic ulcer bleeding 40.4 cases/100,000 people. The age-standardized incidence for both bleeding Mallory-Weiss syndrome and peptic ulcer bleeding remained unchanged during the observational five-year period. The majority of patients with bleeding Mallory-Weiss syndrome were male patients with significant overall comorbidities (ASA class 3-4). Overall 30-day mortality rate was 5.3% for patients with bleeding Mallory-Weiss syndrome and 4.6% for patients with peptic ulcer bleeding (p = 0.578). In both patients with bleeding Mallory-Weiss syndrome and peptic ulcer bleeding, mortality was significantly higher in patients over 65 years of age and those with significant overall comorbidities (ASA class 3-4). CONCLUSION: The incidence of bleeding Mallory-Weiss syndrome and peptic ulcer bleeding has not changed over a five-year observational period. The overall 30-day mortality was almost equal for both bleeding Mallory-Weiss syndrome and peptic ulcer bleeding and was positively correlated to older age and underlying comorbid illnesses.

North vs south differences in acute peptic ulcer hemorrhage in Croatia: hospitalization incidence trends, clinical features, and 30-day case fatality.

AIM: To assess the seven-year trends of hospitalization incidence due to acute peptic ulcer hemorrhage (APUH) and associated risk factors, and examine the differences in these trends between two regions in Croatia. METHODS: The study collected sociodemographic, clinical, and endoscopic data on 2204 patients with endoscopically confirmed APUH who were admitted to the Clinical Hospital Center "Sestre Milosrdnice," Zagreb and Clinical Hospital Center Split between January 1, 2005 and December 31, 2011. We determined hospitalization incidence rates, 30-day case fatality rate, clinical outcomes, and incidence-associated factors. RESULTS: No differences were observed in APUH hospitalization incidence rates between the regions. Age-standardized one-year cumulative APUH hospitalization incidence rate calculated using the European Standard Population was significantly higher in Zagreb than in Split region (43.2/100 000 vs 29.2/100,000). A significantly higher APUH hospitalization incidence rates were observed in the above 65 years age group. Overall 30-day case fatality rate was 4.9%. CONCLUSION: The hospitalization incidence of APUH in two populations did not change over the observational period and it was significantly higher in the Zagreb region. The incidence of acute duodenal ulcer hemorrhage also remained unchanged, whereas the incidence of acute gastric ulcer hemorrhage increased. The results of this study allow us to monitor epidemiological indicators of APUH and compare data with other countries.

A first case of endoscopical removal of an eroded adjustable gastric band in Croatia.

Laparoscopic gastric banding (LAGB) is one of the most common surgical procedures in the treatment of morbid obesity since it provides good long-term outcomes in weight loss and decrease of comorbidities associated with obesity. Although the procedure has low morbidity and almost none-existing mortality, certain complications can occur. Erosion of the band into the gastric wall is one of the rare complications in LAGB. The reported incidence varies from 1 to 11%, however the largest study reported an incidence of 1.6%. This is in accordance with the incidence in our Centre for obesity, where only one case of erosion occurred among 112 operative procedures. The aim of this paper is to present a patient with gastric band erosion and it's removal by using the endoscopic techniques as a minimally invasive management method.

Antibiotics Prescribing Pattern and Quality of Prescribing in Croatian Dental Practices-5-Year National Study.

PURPOSE: Antibiotic resistance is one of the biggest threats to global health today. The aim of this study was to analyze antibiotic prescribing patterns and quality of prescribing in Croatian dental practices over a 5-year period. METHODS: This is a retrospective observational study based on the analysis of the electronic prescriptions (medicines in ATC groups J01 and P01) from dental practices in Croatia prescribed from 1 January 2015 to 31 December 2019. Prescriptions were retrieved from the Croatian Health Insurance Fund (HZZO). The analyses included the number of prescriptions, type and quantity of prescribed drugs, indication, and the patient's and prescriber's characteristics. RESULTS: The consumption increased from 1.98 DID in 2015, to 2.10 DID in 2019. The most prescribed antibiotic was Amoxicillin with clavulanic acid followed by Amoxicillin, Clindamycin, Metronidazole and Cefalexin. The analyses showed that 29.79% of antibiotics were not prescribed in accordance with the contemporary guidelines for the proper use of antibiotics. Additionally, 22% of antibiotics were prescribed in inconclusive indications. CONCLUSION: The research showed an increase in antibiotic consumption over five years along with unnecessary prescribing of antibiotics in cases with no indications for its use. The development of national guidelines for antibiotic use is necessary.

Pharmacokinetic Analysis of Ethanol in a Human Study: New Modification of Mathematic Model.

In the pharmacokinetic analysis of ethanol after oral administration, only single- or two-compartment models are used, but their precision in estimating pharmacokinetic parameters might be insufficient. In a recent study, pharmacokinetic analysis using a modified Norberg three-compartment model was performed after oral administration of differently sweetened alcoholic solutions and compared to pharmacokinetic analysis using the classic Widmark model. On three occasions, eight male volunteers consumed differently sweetened alcoholic solutions: non-sweetened, sweetened with sucrose, and sweetened with steviol glycoside. Blood ethanol concentration was determined from samples obtained at t = 15, 30, 60, 90, 120, 180 min after consumption. Pharmacokinetic analysis was performed model independently, using the classic Widmarks model and using the modified Norberg model. Results showed that estimated pharmacokinetic parameters depend on the type of model used. The classic Widmark model in particular overestimated the fraction of absorbed ethanol from the gastrointestinal system to systemic circulation. Furthermore, the type of sweetener also affected pharmacokinetic parameters, although the difference was not statistically significant. In conclusion, the novel pharmacokinetic model, while being more physiological, fits experimental data better and hence is more suitable for modelling real-life alcohol consumption. In addition, the effect of natural non-caloric sweetener steviol glycoside on ethanol pharmacokinetics, analysed for the first time in the current research, might be different when compared to the common-used sweetener sucrose.

The influence of etiologic factors on clinical outcome in patients with peptic ulcer bleeding.

BACKGROUND: Peptic ulcer bleeding remains an important cause of morbidity and mortality. AIM: The aim of this study was to evaluate the prevalence of non-steroidal anti-inflammatory drugs (NSAID) use, Helicobacter pylori infection and non-H. pylori-non-NSAIDs causes of peptic ulcer bleeding and to identify the predictive factors influencing the rebleeding rate and in-hospital mortality in patients with bleeding peptic ulcer. METHODS: A total of 1,530 patients with endoscopically confirmed peptic ulcer bleeding were evaluated consecutively between January 2005 and December 2009. The 30-day mortality and clinical outcome were related to patient's demographic data, endoscopic and clinical characteristics. RESULTS: The age-standardized 1-year cumulative incidence for peptic ulcer bleeding was 40.4 cases/100,000 people. The proportion of patients over 65 years increased from 45.7 % in 2005 to 61.4 % in 2009 (p = 0.007). Overall 30-day mortality rate was 4.6 %, not significantly different for conservatively and surgically treated patients (4.9 vs. 4.1 %, p = 0.87). Mortality was significantly higher in patients over 65 years of age and those with in-hospital bleeding recurrence. Patients with non-H. pylori-non-NSAID idiopathic ulcers had significantly higher 30-day mortality rate than those with H. pylori ulcers and NSAID-H. pylori ulcers (7.1 vs. 0 vs. 0.8 %, p = 0.001 and p = 0.007, respectively). There was no statistically significant difference between patients with NSAID ulcers and non-H. pylori-non-NSAID idiopathic ulcers in terms of 30-day mortality rate (5.3 vs. 7.1 %, p = 0.445). CONCLUSION: The incidence of peptic ulcer bleeding has not changed over a 5-year observational period. The overall 30-day mortality was positively correlated to older age, underlying comorbid illnesses, in-hospital bleeding recurrence and the absence of H. pylori infection.

Nutritional screening model in tertiary medical unit in Croatia.

BACKGROUND/AIMS: Malnutrition of hospitalized patients is often undetected and untreated due to poor awareness and insufficient knowledge of the attending hospital staff. Nutritional screening has not been part of the daily routine in Croatian hospitals. Our aim was to implement nutritional screening as part of the routine medical examination and to assess the nutritional risk at admission for all hospitalized patients. METHODS: All patients hospitalized in departments of internal medicine in tertiary hospitals in Croatia were screened at entry using the Nutrition Risk Screening 2002 (NRS 2002). RESULTS: Between October and December 2010, 1,696 patients were screened and analyzed (948 males and 748 females). 329 (19.4%) had an NRS 2002 score ≥3 and were considered to be at nutritional risk. An NRS 2002 score ≥3 was identified as a significant predictor of the length of hospital stay (beta coefficient = 0.06, p = 0.027) and fatal outcome (OR = 6.18, p < 0.001). Only 32.8% of malnourished patients received some nutritional support. CONCLUSIONS: Every fifth patient hospitalized in a general medical department in Croatia is at nutritional risk and the majority of them does not receive nutritional support. More effort is needed to implement nutritional standards in daily clinical practice.

New insight into the role of NT-proBNP in alcoholic liver cirrhosis as a noninvasive marker of esophageal varices.

AIM: To investigate the association between plasma concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and formation of esophageal varices. METHODS: Thirty-five patients with alcoholic cirrhosis were divided into three groups according to the Child-Pugh classification: grade A (n=11, 32%), B (n=12, 34%), and C (n=12, 34%). System hemodynamic parameters were measured using sphygmomanometry, electrocardiography, and echocardiography. NT-proBNP was analyzed by using an electrochemiluminiscence sandwich immunoassay. RESULTS: The presence of esophageal varices was associated with a higher serum NT-proBNP level, with a cut-off value of <101 pg/mL (sensitivity, 87.60% and specificity, 72.73%; P<0.001). CONCLUSIONS: NT-proBNP was found to be a marker of the presence of esophageal varices, but not a marker of progression of liver cirrhosis. In cirrhotic patients, NT-proBNP value <101 pg/mL was shown to be a valuable noninvasive parameter in predicting the presence of varices.

[Croatian guidelines for the management of pancreatic exocrine insufficiency]. / Hrvatske smjernice za lijecenje egzokrine pankreasne insuficijencije.

Pancreatic exocrine insufficiency is a major consequence of pancreatic diseases (e. g. chronic pancreatitis and cystic fibrosis), extrapancreatic diseases like celiac disease and Crohn's disease, and gastrointestinal and pancreatic surgical resections. Recognition of this entity is highly relevant to avoid malnutrition-related morbidity and mortality. The main clinical consequence of PEI is fat maldigestion and malabsorption, resulting in steatorrhoea. Pancreatic exocrine function should be assessed by measuring levels of faecal elastase-1. Pancreatic enzyme replacement therapy is the mainstay of treatment for PEI. Administration of enzymes in form of enteric-coated minimicrospheres avoids acid-mediated lipase inactivation and ensures gastric emptying of enzymes in parallel with nutrients. In adults, the initial recommended dose of pancreatic enzymes is 25.000 units of lipase per meal, titrating up to a maximum of 80000 units of lipase per meal. Large meals require 25.000 - 80.000 units of lipase per meal while snacks require 10.000 - 40.000 units of lipase per meal. Oral pancreatic enzymes should be taken with meals to ensure adequate mixing with the chyme. Adjunct therapy with acid-suppressing agents may be useful in patients who continue to experience symptoms of PEI despite high-dose enzyme therapy. Patients with PEI should be encouraged to consume small, frequent meals and to abstain from alcohol. Dietary fat restriction is not recommended for patients with PEI.

Liver regeneration as treatment target for severe alcoholic hepatitis.

Severe alcoholic hepatitis (AH) is a distinct entity in the spectrum of alcohol-related liver disease, with limited treatment options and high mortality. Supportive medical care with corticosteroids in selected patients is the only currently available treatment option, often with poor outcomes. Based on the insights into the pathogenetic mechanisms of AH, which are mostly obtained from animal studies, several new treatment options are being explored. Studies have implicated impaired and deranged liver regeneration processes as one of the culprit mechanisms and a potential therapeutic target. Acknowledging evidence for the beneficial effects of granulocyte colony-stimulating factor (G-CSF) on liver regeneration and immunomodulation in animal models, several human studies investigated its role in the treatment of advanced alcohol-related liver disease and AH. Contrary to the previously published studies suggesting benefits of G-CSF in the outcomes of patients with severe AH, these effects were not confirmed by a recently published multicenter randomized trial, suggesting that other options should rather be pursued. Stem cell transplantation represents another option for improving liver regeneration, but evidence for its efficacy in patients with severe AH and advanced alcohol-related liver disease is still very scarce and unconvincing, with established lack of efficacy in patients with compensated cirrhosis. In this review, we summarize the current knowledge on the pathogenesis and experimental therapies targeting liver regeneration. The lack of high-quality studies and evidence is a major obstacle in further treatment development. New insights into the pathogenesis of not only liver injury, but also liver regeneration processes are mandatory for the development of new treatment options. A reliable experimental model of the pathogenesis of AH and processes involved in liver recovery is still missing, and data obtained from animal studies are essential for future research.