Role of miR-653 and miR-29c in downregulation of CYP1A2 expression in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a major contributor to the worldwide cancer burden. Recent studies on HCC have demonstrated dramatic alterations in expression of several cytochrome P450 (CYP) family members that play a crucial role in biotransformation of many drugs and other xenobiotics; however, the mechanisms responsible for their deregulation remain unclear. METHODS: We investigated a potential involvement of miRNAs in downregulation of expression of CYPs observed in HCC tumors. We compared miRNA expression profiles (TaqMan Array Human MicroRNA v3.0 TLDA qPCR) between HCC human patient tumors with strong (CYP-) and weak/no (CYP+) downregulation of drug-metabolizing CYPs. The role of significantly deregulated miRNAs in modulation of expression of the CYPs and associated xenobiotic receptors was then investigated in human liver HepaRG cells transfected with relevant miRNA mimics or inhibitors. RESULTS: We identified five differentially expressed miRNAs in CYP- versus CYP+ tumors, namely miR-29c, miR-125b1, miR-505, miR-653 and miR-675. The two most-upregulated miRNAs found in CYP- tumor samples, miR-29c and miR-653, were found to act as efficient suppressors of CYP1A2 or AHR expression. CONCLUSIONS: Our results revealed a novel role of miR-653 and miR-29c in regulation of expresion of CYPs involved in crucial biotransformation processes in liver, which are often deregulated during liver cancer progression.

Triple malignancy (NET, GIST and pheochromocytoma) as a first manifestation of neurofibromatosis type-1 in an adult patient.

BACKGROUND: Neurofibromatosis type-1 (NF1), also called von Recklinghausen disease, is a rare genetic disease which can lead to the development of benign or even malignant tumors. NF1 is mostly diagnosed in children or early adolescents who present with clinical symptoms. A curative therapy is still missing and the management of NF1 is based on careful surveillance. Concerning tumors which affect the gastrointestinal tract in patients with NF1, the most common is a gastrointestinal stromal tumor (GIST). CASE PRESENTATION: We present a case of a 58-year-old adult patient with dyspeptic symptoms who was incidentally diagnosed with triple malignancy (pheochromocytoma, multiple GISTs of small intestine and an ampullary NET) as a first manifestation of NF1. The patient underwent surgical treatment (adrenalectomy and pancreaticoduodenectomy) with no complications and after 2 years remains in oncological remission. CONCLUSION: NF1 is a rare genetic disease which can cause various benign or malignant tumors. The coincidence of GIST and NET is almost pathognomonic for NF1 and should raise a suspicion of this rare disorder in clinical practice.

Multiple neuroendocrine tumor of the small bowel: a case report and a review of literature.

Primary malignant tumors of small bowel constitute only about 1-2% of all gastrointestinal neoplasms. Although neuroendocrine tumors (NETs) are relatively rare, they still represent the second most common malignancy of the small bowel (after adenocarcinoma). Clinical manifestations include abdominal pain, bowel obstruction, diarrhea, weight loss and bleeding. The differential diagnosis of obscure gastrointestinal bleeding can sometimes be challenging for endoscopy as well as for radiology methods. We present the case of an 80-year-old man suffering from severe hypochromic anemia. Routine endoscopic methods did not show any appropriate pathology. Finally, a single ulcerative infiltration of the ileum was diagnosed by capsule endoscopy (CE). CT enterography did not reveal any other lesions. In accordance with a positive chromogranin A, endoscopic and radiologic methods, a suspicion of NET was expressed. During the surgery, 7 lesions were found and a resection of 120 cm of ileum was performed. The histology confirmed a diagnosis of NET grade 1, with a total number of 15 NET lesions in the specimen. The following octreotide scan did not show any residual infiltration. We present a patient with 15 NET lesions in the ileum diagnosed by CE and successfully cured by surgical resection of the ileum. Key words: capsule endoscopy - carcinoid syndrome - gastrointestinal carcinoids - neuroendocrine tumor - obscure gastrointestinal bleeding - small bowel - surgery.

The Use of Biomarkers in Early Diagnostics of Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid malignancies with increasing incidence. The poor prognosis is due to the aggressive nature of the tumor, late detection, and the resistance to chemotherapy and radiotherapy. A radical surgery procedure is the only treatment that has been shown to improve the 5-year survival rate to 20-25%. However, the majority of patients (80-85%) are diagnosed with locally advanced or metastatic disease and just 15-20% patients are diagnosed in an early stage allowing them to undergo the potentially curative surgical resection. The early detection of PDAC without the use of invasive methods is challenging and discovery of a cost-effective biomarker with high specificity and sensitivity could significantly improve the treatment and survival in these patients. In this review, we summarize current and newly examined biomarkers in early PDAC detection.

[Liver rupture with hemoperitoneum as rare complication of cardiopulmonary resuscitation in young patient with acute myocardial infarction]. / Ruptura jater s hemoperitoneem jako vzácná komplikace kardiopulmonální resuscitace u mladé pacientky s akutním infarktem myokardu.

Rupture of the liver is a rare but a very serious complication of cardiopulmonary resuscitation. The presented case report describes a young patient with acute myocardial infarction with ST segment elevation treated by primary PCI. Just during admission to the hospital she had ventricular fibrillation with prolonged resuscitation. Subsequently due to a decrease of hemoglobine a liver rupture with hemoperitoneum was diagnosed by ultrasonography and computed tomography (CT). Conservative therapy with repeated ultrasonography and CT examinations was successful even without discontinuation dual antiplatelet therapy. Frequency of this rare complication, diagnostics and therapeutic options are discussed.

Apoptosis inhibitor 5 (API-5; AAC-11; FIF) is upregulated in human carcinomas in vivo.

Apoptosis inhibitor 5 (API-5) is a 55 kDa nuclear protein with potent anti-apoptotic signaling in tumor cells in vitro. In this study, we analyzed the expression of the API-5 protein in vivo in a broad spectrum of human carcinomas, including those of the colon, lung, liver, kidney, pancreas, stomach and esophagus using tumor tissues obtained during tumor resection. The results showed significant upregulation of API-5 expression in biopsies of lung (23%, n=13) and colorectal tumors (33%, n=27) in comparison with biopsies from the adjacent normal tissue. Colon cancer biopsies were used to study the cell populations with an upregulated level of expression of API-5 more closely. Using a magnetic bead-based selection for the epithelial cell marker EpCAM, we purified epithelial cells from the tumor and control tissues and analyzed these cells for API-5 expression by western immunoblotting. We observed that EpCAM-positive tumor cells expressed API-5 in all three colorectal cancer cases tested, in contrast to the control EpCAM-positive and EpCAM-negative cells isolated from the control or tumor tissues. These data suggest that the expression of the API-5 protein is upregulated in tumor epithelial cells and may serve as a prognostic marker in colorectal cancer.

[Utilization of the knowledge of antibiotic pharmacokinetics in the treatment of thoracic empyema]. / Vyuzití znalostí farmakokinetiky antibiotik pri lécbe empyemu hrudníku.

AIM OF THE STUDY: To confirm whether respecting the pharmacokinetics of beta-lactam antibiotics in the treatment of thoracic empyema substantially influences the lengths of antibiotic therapy, thoracic drainage and hospital stay. MATERIAL AND METHODS: During a 30-month period, we compared two groups of patients treated for empyema, one with the standard administration of antibiotics, i.e. a 30-minute bolus, the other with the administration infusion time prolonged to 2 to 3 hours. We observed how rapidly inflammatory markers decreased (C-reactive protein, leukocytes), the lengths of thoracic drainage, antibiotic administration and hospital stay. The results were statistically compared. RESULTS: The study involved 58 patients with the average age of 57 years, the majority of whom were men (50). The empyema aetiology was mostly parapneumonic. The results of primary cultivation were dominated by Gram-positive cocci and anaerobes. Gram-negative bacteria, as well as fungi, were mainly cultured as secondary hospital microflora. Both groups were comparable as to the size, age distribution, male to female ratio and microbiological spectrum of the cultured pathogens. Already the fourth postoperative day, statistically significant difference occurred in the C-reactive protein level and white cell count. The lengths of chest drainage, administration of antibiotics and hospital stay were 1 to 2 days shorter in the latter group. However, the decrease was not statistically significant. CONCLUSION: The prolongation of antibiotic administration infusion time contributed to faster inflammation regression, shorter antibiotic therapy and thus shorter hospital stay without increased costs. Although the aforementioned parameters were not statistically significant, we consider any shortening of antibiotic administration time and hospital stay to be beneficial for patients. The approach should be recommended for clinical practice, especially in the treatment of severe infections.

A shift in the diagnostics of the small intestine tumors.

UNLABELLED: Primary, secondary, benign or malignant tumorous diseases of the small intestine are rare. They are very often diagnosed by accident or as a cause of acute abdomen. This work should answer the question, whether there is a method of making the diagnosis earlier when the disease is limited and easy to cure. METHODOLOGY: A retrospective study comprising 96 patients having undergone surgery for a small intestine tumor in our hospital from 1996 to 2005 is presented. An analysis of first symptoms, diagnostic methods and number of patients admitted during the years was made. In the year 1998 we changed our philosophy in trying to directly detect the small intestine pathology and not making the diagnosis by the exclusion only. Intestinal ultrasound was performed on the Ultramark 3000 HDI device with autofocussable convex 5 MHz and linear 7.5 MHz probes or nowadays ATL 5000 HDI, 7-12 MHz linear probe. No contrast enhancement was used. Abdominal CT engaged Somatom Plus appliance by Siemens, single detector with our conventional abdominal CT protocol. Enteroclysis was done with Micropaque suspension diluted 1:1 with HP-7000 300 ml with its application rate of 75 ml/min followed by HP-7000 solution 2000 ml, application rate of 120 ml/min. RESULTS: We treated surgically 96 patients with the small intestine tumor. A shift in the diagnostic algorithm was noticed in the bowel ultrasound now taking the lead. An enlarged portion of patients diagnosed by means of capsule endoscopy was also seen. An increase of surgically treated patients after 1998 was recorded and the majority of them could be offered an elective laparoscopic surgery in contrast to before 1998 when the majority of them had undergone surgery for an acute abdomen. CONCLUSION: The small bowel ultrasound can be recommended as the first choice method. All patients with even very moderate abdominal symptoms ought to be examined for the small intestine pathology. As a result one can get higher rate of elective surgery, if possible laparoscopic and higher number of R0 resections accompanied by longer survival.

Amyloidosis of the small intestine.

UNLABELLED: Amyloidosis is a rare disease characterized by forming pathological protein deposits - amyloid - in many organs and tissues. This decreases their functionality. The aim of this small study was to determine, whether the radiological picture of the small intestine involvement in amyloidosis is in some sense specific as sometimes described in literature giving rise to high suspicion for the disease in symptomatic patients. MATERIAL AND METHODS: The prospective study comprising seven patients hospitalized in surgical department is presented together with a survey on the disease, its appearance in radiological imaging. All patients underwent abdominal ultrasound (ATL 5000 HDI, 7-12MHz linear probe, no contrast enhancement, supine position), abdominal CT (Somatom Plus, Siemens, single detector, conventional abdominal CT protocol) and enteroclysis (Micropaque suspension 300ml, application rate of 75ml/min, dilution with HP-7000 being 1:1 and HP-7000 solution 2000ml, application rate of 120ml/min.). RESULTS: The amyloid deposits in the small intestine could be visualized in five of seven patients with the disease. Enteroclysis revealed a diffuse slowed down intestinal motility with an obstruction-like picture in all of our seven patients. The intestinal secretion was normal, plicae were getting polyp-like shape in five of them forming so called "thumb printing" picture. CT showed thickening of the intestinal wall due to deposits with poor blood supply and contrast retention in five of seven patients. Ultrasound visualized thickened, hypoechoic nodular plicae and slowed down motility in these five patients. The most striking finding was the pathological deposits in the intestinal wall were highly hypo-vascular. However, this picture is very similar to that of ischemic enteritis. All seven patients had proven amyloid deposits from bioptic specimens. CONCLUSION: The diagnosis of amyloidosis must be supported by bioptic examination as it has no pathognomic radiological picture. Nevertheless, it allows usually to rise a high suspicion for this and sometimes even guess the type of the pathological protein involved. This can start a search for the primary reason of possible amyloidosis and thus perhaps spear the patients quality of life.

Brachytherapy and percutaneous stenting in the treatment of cholangiocarcinoma: a prospective randomised study.

PURPOSE: To evaluate the effect of radiation therapy including intraluminal brachytherapy with iridium-192 on survival of patients with malignant biliary strictures (cholangiocarcinoma, histologically improved) treated with metallic stent in a prospective randomised study. METHOD AND MATERIALS: In the prospective randomised study, 21 patients with cholangiocarcinoma were treated with implantation of percutaneous stents followed with intraluminal Ir-192 brachytherapy (mean dose 30 Gy) and external radiotherapy (mean dose 50 Gy) and 21 patients were treated only with stents insertion. We did not find any statistically significant differences in age and tumor localization between these two groups of patients. RESULTS: All the patients died. In the group of patients treated with brachytherapy and with stent implantation, the mean survival time was 387.9 days. In the group of patients treated only with stent insertion the mean survival was 298 days. In effort to eliminate possible effect of external radiotherapy we treated the control group of eight patients with cholangiocarcinoma by stent insertion and brachytherapy only. CONCLUSION: Our results show that combined radiation therapy could extend the survival in the patients with cholangiocarcinoma obstruction.

Crohn's disease at the small bowel imaging by the ultrasound-enteroclysis.

UNLABELLED: Crohn's disease is more likely a systemic disease governed by a shift in the immune response, thus affecting the whole MALT system. Its treatment should be as conservative as possible and surgery is usually taking place after complications like indolent fistulations, stenoses, bleeding, or bowel perforation started. Standard radiological methods to check the extent of the disease are loaded either with certain radiation exposure (enteroclysis, CT) or lack standardization (ultrasound). The aim of this small study was to evaluate the worth of ultrasound-enteroclysis in detecting the extent and complications of the Crohn's disease in surgically treated patients. MATERIAL AND METHODS: Since 1997, when we started with the ultrasound-enteroclysis, 246 surgical performances were involved into our study. Out of them, 181 had conventional abdominal intestinal ultrasound as well as conventional enteroclysis within 1 week. Remaining 65 cases were diagnosed by the ultrasound-enteroclysis. Intestinal ultrasound was performed on the Ultramark 3000 HDI device with autofocussable convex 5 MHz and linear 7.5 MHz probes or nowadays ATL 5000 HDI, 7-12 MHz linear probe. No contrast enhancement was used. Enteroclysis was done with the Micropaque suspension diluted 1:1 with HP-7000 300 ml with its application rate up to 75 ml/min followed by HP-7000 solution 2000 ml, application rate of 120 ml/min. The patients with ultrasound-enteroclysis were applied HP 7000 solution only (2000 ml, rate 100ml/s) via an enteroclysis catheter. All investigations were video-recorded. RESULTS: Consent with the per-operative finding was reached in 162 from 181 enteroclyses and in 169 of 181 ultrasounds. Ultrasound-enteroclysis was precise in 61 cases from 65. Among these, 60 patients had the recurrence during the treatment proved by clinical and laboratory results. This re-activation was clearly revealed in 38 from 43 cases by enteroclysis, 41 from 43 by US and in 16 from 17 by ultrasound-enteroclysis. From 30 patients that developed acute complication non-responding to the conservative therapy (abscesses, fistulas and intestinal obstructions) there were 18 from 20 accurately diagnosed by enteroclysis, only 12 from 20 by US and 9 from 10 by US-enteroclysis. The differences were either statistically non-significant or there were too small numbers to give sensible statistical results, but low sensitivity of ultrasound in complications (p=0.05). CONCLUSION: US-enteroclysis seems to became the standard examination of patients with Crohn's disease mainly in those with unclear conventional ultrasound. The most important fact is that this examination significantly decreases the radiation load when maintaining high sensitivity. This is very important namely in patients with Crohn's disease that require life-long observation and repeated examinations. This examination is much more easy to standardize than the conventional US.

Biliary tree and cholecyst: post surgery imaging.

Recently, with improvements in surgical techniques there has been a substantial reduction in the incidence of biliary complications of hepatobiliary surgery. Nevertheless, bile duct injuries and other post-cholecystectomy complications are a serious problem and a major cause of morbidity and mortality. Early complications may include bile duct injury caused by mistakenly placed clips, erroneous cutting of bile ducts based on misinterpretation of biliary anatomy, periductal bile leakage that causes edema, fibrosis and secondary stricturing, and ischemia due to injury to the right hepatic artery. Bile duct strictures are the most common of the late complications and can develop a few months or many years after surgery. Early detection and accurate diagnosis have a fundamental importance for the successful treatment of these complications. Therefore, early and meaningful application of the imaging methods immediately after detection of the first symptoms is essential. Peroperative ultrasound and direct iodine contrast application into the biliary tree (operative cholangiography) are highly important for immediate visualization of the complications during surgery. Ultrasound can be used to aid in identification of ductal structures and the cholangiogram should be obtained to document the anatomy. Plain abdominal film could be made in the patients in poor clinical conditions after biliary surgery. Oral cholecystography has largely been replaced by ultrasonography (US) for evaluation of cholelithiasis and complications like post-cholecystectomy fluid collections. The same methodology replaced the conventional intravenous cholangiography. Nowadays computed tomography (CT), endoscopic retrograde cholangiopancreatography (ERCP), magnetic resonance cholangiography (MRCP) and ultrasound (US) have essential roles as primary imaging modalities after biliary tree and gallbladder surgery in the evaluation of associated complications and residual biliary stones. We review the role of the imaging in complications after biliary tree and gallbladder surgery.