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Background: A low-sodium diet and diuretics, although widely used, are not always the most satisfactory therapy for treatment of ascites in nonazotemic patients with liver cirrhosis. The objective of this investigation was to analyze various predictive factors influencing the therapeutic response to diuretic treatment of ascites in these patients. Methods: Twenty-seven patients with nonazotemic liver cirrhosis and ascites were initially treated with spironolactone, 200 mg/day. If no response was observed, furosemide was added at 40-120 mg/day. Before and during the diuretic therapy 30 clinical and laboratory variables were investigated as possible predictive factors influencing the therapeutic response to diuretics. The renal arterial resistive index (RI) (reflecting renal vascular resistance) was estimated with duplex Doppler ultrasonography. Results: Sixteen of the 27 patients (59%) responded to spironolactone alone, whereas 6 patients (22%) responded to combined diuretic therapy with spironolactone and furosemide. Five patients (19%) did not respond to diuretic treatment. Eight of the 30 variables analyzed were statistically significant as possible predictive factors influencing the diuretic response: previous episodes of ascites and gastrointestinal hemorrhage, the presence of peripheral edema, the amount of ascites, plasma renin activity, plasma aldosterone concentrations, urinary sodium excretion, and renal interlobar arterial RI. In all patients who had diuretic-resistant ascites, renal interlobar arterial RI was greater than 0.70. Only 9% of patients who responded satisfactorily to diuretic therapy had interlobar arterial RI greater than 0.70. Conclusions: According to our results, consideration for combining the clinical findings with noninvasively measured renal arterial RI using duplex Doppler ultrasonography would be mandatory in identifying a subgroup of cirrhotic patients with ascites who are at high risk for diuretic unresponsiveness. [ABSTRACT FROM AUTHOR]

The membrane EGFR (mEGFR) protein overexpression in the head and neck squamous cell carcinoma (SCC) is considered to cause increased EGFR activity which adds to tumorigenicity and therapy resistance. The mEGFR upon stimulation can translocate to the nucleus nuclear EGFR (nEGFR) where it has been associated with poor prognosis and worse survival in many cancers. The relevance of differentially located EGFR proteins in laryngeal lesions has not been studied enough and remains unclear. Aim of our study was to examine nEGFR and mEGFR protein expression as well as EGFR gene status and cell cycle proliferation markers in the laryngeal polyps, dysplasia, and SCC using immunohistochemistry and in situ hybridization. There was significantly higher frequency of strong nEGFR between SCC, dysplasia, and polyps (P<0.0001), and strong mEGFR in the SCC and laryngeal dysplasia comparing to polyps (P<0.0001). Gene amplification was confirmed only in relatively small number of SCC but not in non-neoplastic lesions. In dysplasia the statistically significant positive correlations between nEGFR, and Ki-67 (P=0.029), p53 (P=0.001), and cyclin D1 (P=0.031) were found. nEGFR and mEGFR expression showed statistically significant inverse correlation in the SCC (P=0.004) as well as nEGFR and cyclin D1 (P=0.032). Univariate statistical analysis showed statistically significant correlation between strong nEGFR protein expression and worse overall survival in laryngeal SCC, alone or in coexpression with strong cyclin D1 and high Ki-67 (P=0.025, P=0.046, P=0.043, respectively). Our data show that nEGFR cellular localization might influence biology of the laryngeal carcinogenesis and is indicator of poor survival., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: The aim of the study was to perform a pathohistological and immunohistochemical analysis of squamous cell (SC) carcinogenesis markers on epithelial linings of vocal cord polyps. The vocal box, being a heavily burdened organ with intensive cell renewal and regenerative processes, is therefore a favourable environment for constant epithelial growth and hyperplasia. In our ongoing projects on laryngeal carcinogenesis and research on laryngeal tissue, we encountered atypia on diagnosed nodules and polyps that are usually considered as benign formations, resulting from the above-mentioned cell renewal and regeneration, which lead to further investigation. The purpose was to see if changes in molecular markers of SC carcinogenesis follow, or, may appear in immunohistochemical (IHC) analysis, before histological atypia in standard haematoxylin-eosin (HE) staining, and contribute in early diagnosis of potentially suspect polyps., Methods: After classical pathohistological (PH) analysis on HE slides, IHC analysis of EGFR, cyclin D1, p53, Ki-67, and IMP3 was performed on tissue microarrays of laryngeal tissue (50 samples), ranging from normal to hyperplastic lesions with no atypia (34 samples), low-grade atypia (11 samples), and high-grade atypia (5 samples)., Results: This study established an increase and correlation of EGFR, cyclin D1, p53, Ki-67 and IMP3 IHC expressions with pathohistological findings of dysplasia in glottic polypoid lesions. Low and high-grade dysplasia had statistically higher percentages of EGFR-positive cells than normal epithelium and simple hyperplasia (SH) (low vs. normal/SH P = 0.007; high vs. normal/SH P = 0.001). High-grade dysplasia had statistically more positive cells than low-grade dysplasia (P = 0.004), and low-grade dysplasia had statistically more positive cells than specimens without atypia (P = 0.007). The percentage of positive cells was statistically higher for cyclin D1, p53 and Ki-67 in high-grade dysplasia versus low-grade dysplasia (cyclin D1 P = 0.011, p53 P = 0.002; Ki-67 P = 0.026; respectively) and versus normal epithelium and SH (cyclin D1 P = 0.003; p53 P = 0.001; Ki-67 P = 0.002; respectively). An increase of IMP3-positive cells with an increase of atypical changes in the laryngeal epithelium, from superficial towards basal layers was noticed, contrary to the usually seen positivity pattern of SC carcinogenesis markers from basal to superficial layers. A statistically significant difference of IMP3 IHC staining between the pathohistological groups (P = 0.003) was recorded., Conclusion: Only polyps that present with simple hyperplasia as the greatest mucosal change can be considered as benign formations. Pathohistologically detected atypia in polypoid changes of vocal cords, confirmed by molecular atypia with an increase of SC carcinogenesis markers, suggest their inclusion in studies of laryngeal carcinogenesis. Our results suggest that in problematic cases IHC analysis could be of interest in detection of biological aggressiveness in polypoid laryngeal tissue and beneficiary for polyp patients' follow-up. Further research of laryngeal carcinogenesis markers and their meaning in fibrovascular polyps is of interest., (Copyright © 2018. Published by Elsevier GmbH.)

The aim of the study was to explore predictive value of the ALBI, PALBI and MELD scores on survival in patients resected for hepatocellular carcinoma with compensated liver cirrhosis and no macrovascular infiltration. In this retrospective study, longitudinal survival analysis was performed. We analyzed patient/tumor characteristics and MELD, ALBI and PALBI scores as liver function tests for predicting survival outcome. Survival was analyzed from the date of liver resection until death, liver transplantation, or end of follow-up. Patients were stratified for age, cirrhosis etiology, presence of esophageal varices, hepatocellular carcinoma stage, microvascular invasion, histologic differentiation, and resection margins. We identified 38 patients (alcoholic cirrhosis in 84.2% of patients) resected over an 8-year period. Median preoperative MELD score was 8, ALBI score -2.63, and PALBI score -2.38. During the follow-up period, 24 patients died. Estimated median survival time was 36 months. Microvascular invasion was observed in 33 patients. Higher ALBI score was associated with 23.1% higher relative risk of death. PALBI score was associated with 12.1% higher relative risk of death, whereas MELD score was not associated with the risk of death. In conclusion, ALBI score demonstrated significant predictive capabilities for survival in patients with compensated cirrhosis resected for hepatocellular carcinoma.

Introduction Despite some new treatment possibilities, the improvement in survival rate for hepatocellular carcinoma (HCC) patients is still poor due to late diagnosis. The aim of this study was to investigate the diagnostic sensitivity and specificity of protein induced by vitamin K absence or antagonist-II (PIVKAII), Glypican-3 (GP3), Cystatin B (CSTB), squamous cell carcinoma antigen 1 (SCCA1) and hepatocyte growth factor (HGF) as potential tumour markers for HCC in patients with alcoholic liver cirrhosis (ALC) using imaging techniques (MSCT and MRI) as reference standards. Patients and methods Eighty-three participants were included: 20 healthy volunteers, 31 patients with ALC and 32 patients with HCC. Peripheral blood sampling was performed for each participant, and serum concentrations of PIVKAII, GP3, CSTB, SCCA1 and HGF were determined using commercial ELISA kits. Results Only serum concentrations of PIVKAII were significantly higher in HCC patients as compared with ALC and healthy controls (cut-off: 2.06  µg/L; AUC: 0.903), whereas individual diagnostic performance of other individual compounds was inadequate. The 'best' combination of tumour markers in our study includes all tested markers with AUC of 0.967. Conclusion While novel diagnostic tumour markers are urgently needed, the examined potential tumour markers, with the exception of PIVKAII seem to be inadequate for diagnosing HCC in ALC. Furthermore, probably the future is in finding the best optimal combination of tumour markers for diagnosing HCC based on cost-effectiveness.

Aim: Primary: to evaluate predictivity of liver stiffness (LS), spleen stiffness (SS), and their ratio assessed by real-time 2D shear wave elastography (RT-2D-SWE) for adverse outcomes (hepatic decompensation, hepatocellular carcinoma or death; "event") in compensated liver cirrhosis (LC) patients. Secondary: to evaluate ability of these measures to discriminate between cirrhotic patients with/without esophageal varices (EV)., Methods: Predictivity of LS, SS, and LS/SS was assessed in a retrospectively analyzed cohort of compensated LC patients (follow-up cohort) and through comparison with incident patients with decompensated cirrhosis (DC) (cross-sectional cohort). Both cohorts were used to evaluate diagnostic properties regarding EV., Results: In the follow-up cohort (n=44) 18 patients (40.9%) experienced an "event" over a median period of 28 months. LS≥21.5 kPa at baseline was independently associated with 3.4-fold (95% confidence interval [CI] 1.16-10.4, P=0.026) higher risk of event. Association between SS and outcomes was weaker (P=0.056), while there was no association between LS/SS ratio and outcomes. Patients with DC (n=43) had higher LS (35.3 vs 18.3 kPa, adjusted difference 65%, 95% CI 43%-90%; P<0.001) than compensated patients at baseline. Adjusted odds of EV increased by 13% (95% CI 7.0%-20.0%; Plt;0.001) with 1 kPa increase in LS. At cut-offs of 19.7 and 30.3 kPa, LS and SS had 90% and 86.6% negative predictive value, respectively, to exclude EV in compensated patients., Conclusion: This is the first evaluation of RT-2D-SWE as a prognostic tool in LC. Although preliminary and gathered in a limited sample, our data emphasize the potential of LS to be a reliable predictor of clinical outcomes and the presence of EV in LC patients.

Diagnosis of esophageal varices (EV) is based upon endoscopic examination, which is a rather unpleasant method that carries a certain risk of complications. For that reason, efforts have been made to develop noninvasive methods for characterization of EV. The aim of this study was to explore the value of platelet count to spleen size ratio (PSR) for noninvasive prediction and characterization of EV in patients with alcoholic liver cirrhosis (ALC). One hundred and seventeen patients (20 females and 97 males, mean age 60.7) with ALC were included in our research. All patients underwent endoscopic examination upon which the EV were classified as small (< 5 mm), large (> 5 mm), or absent. Spleen size (bipolar diameter in mm) was assessed by ultrasound. Platelet count to spleen diameter ratio was calculated and the values obtained were compared to the presence, size and risk of bleeding from EV as defined by endoscopy. No significant difference in PSR could be found between patients without and with EV (1.341 ± 0.725 vs. 1.053 ± 0.636, respectively; p = 0.06). The PSR was significantly different between the patients with small and large EV (1.103 ± 0.689 vs. 0.876 ± 0.314; p < 0.05) with a cut-off value of 1.141 (sensitivity 94.7%, specificity 38.2%, AUROC = 0.656; p = 0.042). The value of PSR below 1.182 pointed to patients at risk from variceal bleeding with 91.7% sensitivity and 38.5% specificity (AUROC = 0.625, p = 0.035). Based on our results, it is not possible to recommend the use of PSR as the exclusive noninvasive indicator for the presence, size and bleeding risk from EV due to its low specificity for these categories in patients with ALC.

Although enhanced epidermal growth factor receptor (EGFR) signaling has been connected with glottic cancerogenesis, the precise mechanisms of its activation still remain unclear. The aim of the present study was to examine EGFR on protein level, confronting cellular pattern of expression and EGFR gene amplification in glottic carcinomas. Tissue microarray technology was applied for uniformity of results. Biopsy specimens of patients with glottic squamous cell carcinoma and simple hyperplasia (control samples) were immunostained for EGFR. Immunohistochemical EGFR reaction was analyzed as membrane and cytoplasm positive and compared with the presence of gene amplification obtained by fluorescent in situ hybridization (FISH) analysis, obtained previously on a large group of patients. The cytoplasmic distribution of the EGFR staining appeared as a primary property of some squamous carcinoma cells; different from the membranous reaction, the reactions were mutually exclusive. Significantly higher scores of cytoplasmic EGFR staining were found in carcinomas with gene amplification when the cell reaction was examined in the basal and suprabasal layer. Our results suggest that EGFR expression in squamous cell carcinoma is different with regard to tumor cell position in carcinoma with ERGF gene amplification, which could be a new indicator of differently driven EGFR signaling in glottic cancer. Such results with cellular pattern distribution of EGFR protein are worthy of further research.

Aim: To study the epidemiologic indicators of uptake and characteristic colonoscopic findings in the Croatian National Colorectal Cancer Screening Program., Methods: Colorectal cancer (CRC) was the second leading cause of cancer mortality in men (n = 1063, 49.77/100,000), as well as women (n = 803, 34.89/100,000) in Croatia in 2009. The Croatian National CRC Screening Program was established by the Ministry of Health and Social Welfare, and its implementation started in September, 2007. The coordinators were recruited in each county institute of public health with an obligation to provide fecal occult blood testing (FOBT) to the participants, followed by colonoscopy in all positive cases. The FOBT was performed by hypersensitive guaiac-based Hemognost card test (Biognost, Zagreb). The test and short questionnaire were delivered to the home addresses of all citizens aged 50-74 years consecutively during a 3-year period. Each participant was required to complete the questionnaire and send it together with the stool specimen on three test cards back to the institute for further analysis. About 4% FOBT positive cases are expected in normal risk populations. A descriptive analysis was performed., Results: A total of 1,056,694 individuals (born between 1933-1945 and 1952-1957) were invited to screening by the end of September 2011. In total, 210,239 (19.9%) persons returned the envelope with a completed questionnaire, and 181,102 of them returned it with a correctly placed stool specimen on FOBT cards. Until now, 12,477 (6.9%), FOBT-positive patients have been found, which is at the upper limit of the expected values in European Guidelines for Quality Assurance in CRC Screening and Diagnosis [European Union (EU) Guidelines]. Colonoscopy was performed in 8541 cases (uptake 66%). Screening has identified CRC in 472 patients (5.5% of colonoscopied, 3.8% of FOBT-positive, and 0.26% of all screened individuals). This is also in the expected range according to EU Guidelines. Polyps were found and removed in 3329 (39% of colonoscopied) patients. The largest number of polyps were found in the left half of the colon: 64% (19%, 37% and 8% in the rectum, sigma, and descendens, respectively). The other 36% were detected in the proximal part (17% in the transverse colon and 19% in ceco-ascending colon). Small polyps in the rectum (5-10 mm in diameter), sigmoid and descending colon were histologically found to be tubular adenomas in 60% of cases, with a low degree of dysplasia, and 40% were classified as hyperplastic. Polyps of this size in the transverse or ceco-ascending colon in almost 20% had a histologically villous component, but still had a low degree of dysplasia. Polyps sized 10-20 mm in diameter were in 43% cases tubulovillous, and among them, 32% had areas with a high degree of dysplasia, especially those polyps in the ceco-ascending or transverse part. The characteristics of the Croatian CRC Screening National Program in the first 3 years were as follows: relatively low percentage of returned FOBT, higher number of FOBT-positive persons but still in the range for population-based programs, and higher number of pathologic findings (polyps and cancers)., Conclusion: These results suggest a need for intervention strategies that include organizational changes and educational activities to improve awareness of CRC screening usefulness and increase participation rates.