Endoluminal radiofrequency ablation in patients with malignant biliary obstruction: a randomised trial.

BACKGROUND: Endoluminal radiofrequency ablation (RFA) has been promoted as palliative treatment for patients with cholangiocarcinoma (CCA) and pancreatic ductal adenocarcinoma (PDAC) in order to improve biliary drainage and eventually prolong survival. No high level evidence is, however, available on this technique. DESIGN: In this randomised controlled study, we compared endoluminal RFA plus stenting with stenting alone (control group) in patients with malignant biliary obstruction; metal stents were primarily placed. Primary outcome was overall survival; secondary outcomes were stent patency, quality of life and adverse events. In a superiority design, survival was assumed to be doubled by RFA as compared with 6.4 months in the control group (n=280). RESULTS: A total of 161 patients (male:female 90:71, mean age 71±9 years) were randomised before recruitment was terminated for futility after an interim analysis. Eighty-five patients had CCA (73 hilar, 12 distal) and 76 had pancreatic cancer. There was no difference in survival in both subgroups: for patients with CCA, median survival was 10.5 months (95% CI 6.7 to 18.3) in the RFA group vs 10.6 months (95% CI 9.0 to 24.8), p=0.58)) in the control group. In the subgroup with pancreatic cancer, median survival was 6.4 months (95% CI 4.3 to 9.7) for the RFA vs 7.7 months (95% CI 5.6 to 11.3), p=0.73) for the control group. No benefit was seen in the RFA group with regard to stent patency (at 12 months 40% vs 36% in CCA and 66% vs 65% in PDAC), and quality of life was unchanged by either treatment and comparable between the groups. Adverse events occurred in seven patients in each groups. CONCLUSION: A combination of endoluminal RFA and stenting was not superior to stenting alone in prolonging survival or improving stent patency in patients with malignant biliary obstruction. TRIAL REGISTRATION NUMBER: NCT03166436.

Periprocedural safety profile of peroral endoscopic myotomy (POEM)-a retrospective analysis of adverse events according to two different classifications.

BACKGROUND: Peroral endoscopic myotomy (POEM) is nowadays a standard method for treatment of achalasia; nevertheless, it remains an invasive intervention with corresponding risk of adverse events (AEs). The classification and grading of AEs are still a matter of discussion. The aim of our retrospective study was to assess the occurrence of all "undesirable" events and "true" adverse events in patients undergoing POEM and to compare the outcomes when either Clavien-Dindo classification (CDC) or American Society of Gastrointestinal Endoscopy (ASGE) lexicon classification applied. METHODS: This was a retrospective analysis of prospectively managed database of all patients who had undergone POEM between December 2012 and August 2018. We assessed the pre-, peri-, and early-postoperative (up to patient's discharge) undesirable events (including those not fulfilling criteria for AEs) and "true" AEs according the definition in either of the classifications. RESULTS: A total of 231 patients have successfully undergone 244 POEM procedures (13 × re-POEM). Twenty-nine procedures (11.9%) passed uneventfully, while in 215 procedures (88.1%), a total of 440 undesirable events occurred. The CDC identified 27 AEs (17 minor, 10 major) occurring in 23/244 (9.4%) procedures. The ASGE lexicon identified identical 27 AEs (21 mild or moderate, 6 severe or fatal) resulting in the severity distribution of AEs being the only difference between the two classifications. Only the absence of previous treatment was found to be a risk factor [p = 0.047, OR with 95% CI: 4.55 (1.02; 20.25)] in the combined logistic regression model. CONCLUSION: Undesirable events are common in patients undergoing POEM but the incidence of true AEs is low according to both classifications. Severe adverse events are infrequent irrespective of the classification applied. CDC may be more appropriate than ASGE lexicon for classifying POEM-related AEs given a surgical nature of this procedure.

Endoscopic pyloromyotomy for the treatment of severe and refractory gastroparesis: a pilot, randomised, sham-controlled trial.

OBJECTIVE: Endoscopic pyloromyotomy (G-POEM) is a minimally invasive treatment option with promising uncontrolled outcome results in patients with gastroparesis. DESIGN: In this prospective randomised trial, we compared G-POEM with a sham procedure in patients with severe gastroparesis. The primary outcome was the proportion of patients with treatment success (defined as a decrease in the Gastroparesis Cardinal Symptom Index (GCSI) by at least 50%) at 6 months. Patients randomised to the sham group with persistent symptoms were offered cross-over G-POEM. RESULTS: The enrolment was stopped after the interim analysis by the Data and Safety Monitoring Board prior to reaching the planned sample of 86 patients. A total of 41 patients (17 diabetic, 13 postsurgical, 11 idiopathic; 46% male) were randomised (21 G-POEM, 20-sham). Treatment success rate was 71% (95% CI 50 to 86) after G-POEM versus 22% (8-47) after sham (p=0.005). Treatment success in patients with diabetic, postsurgical and idiopathic gastroparesis was 89% (95% CI 56 to 98), 50% (18-82) and 67% (30-90) after G-POEM; the corresponding rates in the sham group were 17% (3-57), 29% (7-67) and 20% (3-67).Median gastric retention at 4 hours decreased from 22% (95% CI 17 to 31) to 12% (5-22) after G-POEM and did not change after sham: 26% (18-39) versus 24% (11-35). Twelve patients crossed over to G-POEM with 9 of them (75%) achieving treatment success. CONCLUSION: In severe gastroparesis, G-POEM is superior to a sham procedure for improving both symptoms and gastric emptying 6 months after the procedure. These results are not entirely conclusive in patients with idiopathic and postsurgical aetiologies. TRIAL REGISTRATION NUMBER: NCT03356067; ClinicalTrials.gov.

Pancreatic cancer in patients with autoimmune pancreatitis: A scoping review.

BACKGROUND: Chronic pancreatitis is a known risk factor of pancreatic cancer (PDAC). A similar association has been suggested but not demonstrated for autoimmune pancreatitis (AIP). OBJECTIVE: The aim of our study was to identify and analyse all published cases of AIP and PDAC co-occurrence, focusing on the interval between the diagnoses and the cancer site within the pancreas. METHODS: Relevant studies were identified through automatic searches of the MEDLINE, EMBASE, Scopus, and Web of Science databases, and supplemented by manual checks of reference lists in all retrieved articles. Missing/unpublished data were obtained from the authors of relevant publications in the form of pre-prepared questionnaires. RESULTS: A total of 45 cases of PDAC in AIP patients were identified, of which 12 were excluded from the analysis due to suspicions of duplicity or lack of sufficient data. Thirty-one patients (94%) had type 1 AIP. Synchronous occurrence of PDAC and AIP was reported in 11 patients (33%), metachronous in 22 patients (67%). In the metachronous group, the median period between diagnoses was 66.5 months (2-186) and a majority of cancers (86%) occurred more than two years after AIP diagnosis. In most patients (70%), the cancer originated in the part of the pancreas affected by AIP. CONCLUSIONS: In the literature, there are reports on numerous cases of PDAC in AIP patients. PDAC is more frequent in AIP type 1 patients, typically metachronous in character, and generally found in the part of the pancreas affected by AIP.

Alpha-1 Antitrypsin and Hepatocellular Carcinoma in Liver Cirrhosis: SERPINA1 MZ or MS Genotype Carriage Decreases the Risk.

Heterozygotes for Z or S alleles of alpha-1-antrypsin (AAT) have low serum AAT levels. Our aim was to compare the risk of hepatocellular carcinoma (HCC) in patients with liver cirrhosis carrying the SERPINA1 MM, MZ and MS genotypes. The study groups consisted of 1119 patients with liver cirrhosis of various aetiologies, and 3240 healthy individuals served as population controls. The MZ genotype was significantly more frequent in the study group (55/1119 vs. 87/3240, p < 0.0001). The MS genotype frequency was comparable in controls (32/119 vs. 101/3240, p = 0.84). MZ and MS heterozygotes had lower serum AAT level than MM homozygotes (medians: 0.90 g/L; 1.40 g/L and 1.67 g/L; p < 0.001 for both). There were significantly fewer patients with HCC in the cirrhosis group among MZ and MS heterozygotes than in MM homozygotes (5/55 and 1/32 respectively, vs. 243/1022, p < 0.01 for both). The risk of HCC was lower in MZ and MS heterozygotes than in MM homozygotes (OR 0.3202; 95% CI 0.1361-0.7719 and OR 0.1522; 95% CI 0.02941-0.7882, respectively). Multivariate analysis of HCC risk factors identified MZ or MS genotype carriage as a protective factor, whereas age, male sex, BMI and viral aetiology of cirrhosis increased HCC risk.

Immunoglobulin G4-related disease in gastroenterology.

IgG4-related disease is a recently defined clinical entity that can manifest itself in any organ. The most common gastrointestinal manifestations are diseases of the pancreas (autoimmune pancreatitis type 1) and biliary tree (IgG4-associated cholangitis); involvement of liver parenchyma is uncommon and the affection of tubular organs is very rare. IgG4-related pancreatitis and cholangitis can mimic malignancies in their clinical presentation. Diagnosis is often difficult and requires careful evaluation of the combination of symptoms, serology and imaging findings, while adhering to the established diagnostic criteria. The first line of treatment is the administration of corticoids and the remission is achieved in the vast majority of patients. In case of contraindication, intolerance or failure of corticotherapy, patients should receive B cell depletion therapy (rituximab). Based on the available knowledge, monotherapy with other immunosuppressants is not considered to be sufficiently effective. Some patients may benefit from maintenance treatment to prevent relapse, which is otherwise common in both IgG4-related pancreatitis and cholangitis. Recognized IgG4-related disease has a good prognosis, but some patients develop irreversible fibrotic changes in the affected organ with consequent dysfunction; the possible association of the disease with a higher risk of malignancy has not yet been reliably elucidated.

Spironolactone-furosemide combination therapy and acid-base disorders in liver cirrhosis patients
.

OBJECTIVE: Respiratory alkalosis (RA) and dilutional hyperchloremic acidosis (DHA) are the most common acid-base balance (ABB) disorders in patients with liver cirrhosis. The aims of this study were to clarify whether RA develops in relation to DHA via respiratory compensation of metabolic acidosis and whether spironolactone in combination with low-dose furosemide - diuretics known to ameliorate DHA - positively affects RA in liver cirrhosis patients. MATERIALS AND METHODS: 59 patients with advanced cirrhosis were divided into two groups. Group D consisted of individuals (urine sodium concentration (UNa+) > 20 mmol/L) who responded to combination therapy consisting of spironolactone and low-dose furosemide. The non-D group consisted of individuals (UNa+ ≤ 20 mmol/L) who either did not respond to the treatment or who were not administered it. In both groups, we examined serum and urine concentrations of electrolytes and ABB parameters, including SNa+-SCl- and SNa+/SCl- values. RESULTS: In group D, we found a statistically significant relationship between pCO2 and SHCO3-: r = 0.756 (p < 0.001) and between pCO2 and SNa+-SCl-: r = 0.522 (p = 0.001). Neither Salb nor the corrected anion gap were associated with changes in SHCO3- or pCO2 values. Although SHCO3- values were normal, abnormal pCO2 values were observed in one third of group D patients. Based on multivariable analysis, SHCO3- proved to be a statistically significant influencing factor on pCO2 values. CONCLUSION: DHA contributes to the development of RA in individuals with liver cirrhosis. Reducing DHA by means of effective diuretic therapy comprising spironolactone and furosemide has a beneficial effect on RA in such patients.

IL28B rs12979860 T allele protects against CMV disease in liver transplant recipients in the post-prophylaxis and late period.

BACKGROUND: Cytomegalovirus (CMV) disease represents a serious complication in liver transplant (OLT) recipients. CMV prophylaxis reduces incidence of CMV disease in the early post-transplant period (on-prophylaxis disease, OPD) but may postpone its manifestation after the completion of prophylaxis. Post-prophylaxis disease (PPD) incidence after prophylaxis cessation may be modified by genetic factors. METHODS: We analyzed impact of IL28B rs1297986 variants on CMV disease incidence in 743 adult OLT recipients receiving universal prophylaxis. RESULTS: One hundred and forty-four (19.4%) patients had at least one CMV disease episode. One hundred and two of them (70.8%) had at least one OPD and 36 (25%) patients had PPD, six (4.2%) patients had both. The rate of IL28B T allele carriers was lower in PPD group (38.9%) in comparison with OPD group (66.7%, P = 0.005) and group without CMV disease (61.4%, P = 0.009). The impact of IL28B genotype on the risk of CMV OPD was significant neither in the allelic (TT + CT vs CC, P = 0.32) nor in the recessive model (TT vs CT + CC, P = 0.79). Contrarily, in the PPD group, T allele (TT + CT vs CC) had a protective effect, OR 0.4 (95% CI 0.2-0.8, P = 0.008). Further risk factors of PPD were age <55 years and valganciclovir prophylaxis, whereas the risk factors of OPD were age <55 years, cyclosporine A therapy and pre-transplant CMV serostatus (donor +/recipient -). CONCLUSIONS: IL28B rs12979860 T allele carriers had a lower risk of CMV PPD.

Expression profile of miR-17/92 cluster is predictive of treatment response in rectal cancer.

MicroRNA (miRNA) profiling represents a promising source of cancer-related biomarkers. miRNA signatures are specific for each cancer type and subgroups of patients with diverse treatment sensitivity. Yet this miRNA potential has not been satisfactorily explored in rectal cancer (RC). The aim of the study was to identify the specific miRNA signature with clinical and therapeutic relevance for RC. Expressions of 2555 miRNA were examined in 20 pairs of rectal tumors and matched non-malignant tissues by 3D-Gene Toray microarray. Candidate miRNAs were validated in an independent cohort of 100 paired rectal tissues and in whole plasma and exosomes of 100 RC patients. To study the association of miRNA profile with therapeutic outcomes, plasma samples were taken repeatedly over a time period of 1 year reflecting thus patients' treatment responses. Finally, the most prominent miRNAs were investigated in vitro for their involvement in cell growth. We identified RC-specific miRNA signature that distinguishes responders from non-responders to adjuvant chemotherapy. A predominant part of identified miRNAs was represented by the members of miR-17/92 cluster. Upregulation of miRNA-17, -18a, -18b, -19a, -19b, -20a, -20b and -106a in tumor was associated with higher risk of tumor relapse and their overexpression in RC cell lines stimulated cellular proliferation. Examination of these miRNAs in plasma exosomes showed that their levels differed between RC patients and healthy controls and correlated with patient's treatment response. miRNAs from miR-17/92 cluster represent a non-invasive biomarker to predict posttreatment prognosis in RC patients.

Gentamicin submucosal lavage during peroral endoscopic myotomy (POEM): a retrospective analysis.

BACKGROUND AND AIMS: Peroral endoscopic myotomy (POEM) is an evolving therapeutic modality for achalasia. According to the original Inoue's technique, a submucosal lavage with gentamicin has been practiced due to the fear of infection. This single-tertiary center study was intended to assess the clinical significance of the topical antibiotic lavage during POEM. METHODS: A retrospective analysis of prospectively collected data was conducted. The outcomes of patients who received the gentamicin lavage (group A) during POEM were compared to those who did not (group B). The main outcome variables were infectious adverse events, post-POEM fever, and markers of systemic inflammatory response. One day before and after POEM, all patients received systemic antibiotic prophylaxis with ceftriaxone. RESULTS: Of 124 consecutive patients having undergone POEM, 60 patients received a lavage with 80 mg of gentamicin into the submucosal tunnel before starting the myotomy, while 64 patients did not. The overall treatment success at 3 months did not differ between the two groups (group A 94.7 vs. 97.5% group B). We did not experience any significant infectious adverse events in either group. CRP and WBC levels were lower in patients with lavage versus those without [CRP: median 52.7 (IQR 34.9) vs. 69.5 (54.1); p = 0.01; WBCs: median 10.9 (IQR 3.3) vs. 12.6 (3.9); p < 0.01]. Post-procedural fever was present in 10% of patients in either group. CONCLUSIONS: During POEM, the submucosal lavage with gentamicin prior to the myotomy does not play a role in the prevention of clinically significant infectious adverse events, although the systemic inflammatory response may be decreased.

Erratum to: Per-oral endoscopic myotomy (POEM): mid-term efficacy and safety.

The Given Names and Family Names were all inadvertently inverted. The correct order is: Jan Martinek, Hana Svecova, Zuzana Vackova, Radek Dolezel, Ondrej Ngo, Jana Krajciova, Eva Kieslichova, Radim Janousek, Alexander Pazdro, Tomas Harustiak, Lucie Zdrhova, Pavla Loudova, Petr Stirand, Julius Spicak. The original article was corrected.

Per-oral endoscopic myotomy (POEM): mid-term efficacy and safety.

BACKGROUND AND AIMS: Per-oral endoscopic myotomy (POEM) is becoming a standard treatment for achalasia. Long-term efficacy and the rate of post-POEM reflux should be further investigated. The main aim of this study was to analyze safety and mid-term (12 and 24 months) clinical outcomes of POEM. METHODS: Data on single tertiary center procedures were collected prospectively. The primary outcome was treatment success defined as an Eckardt score < 3 at 12 and 24 months. A total of 155 consecutive patients with achalasia underwent POEM; 133 patients were included into the analysis (22 patients will be analyzed separately as part of a multicenter randomized clinical trial). RESULTS: POEM was successfully completed in 132 (99.2%) patients, and the mean length of the procedure was 69.8 min (range 31-136). One patient underwent a drainage for pleural effusion; no other serious adverse events occurred. Treatment success at 3, 12, and 24 months was observed in 95.5% (CI 89.6-98.1), 93.4% (86.5-96.8), and 84.0% (71.4-91.4) of patients, respectively. A total of 11 patients (8.3%) reported initial treatment failure (n = 5) or later recurrence (n = 6). The majority of relapses occurred in patients with achalasia type I (16.7 vs. 1.1% achalasia type II vs. 0% achalasia type III; p<0.05). At 12 months, post-POEM reflux symptoms were present in 29.7% of patients. At 3 months, mild reflux esophagitis was diagnosed in 37.6% of patients, and pathological gastroesophageal reflux was detected in 41.5% of patients. A total of 37.8% of patients had been treated with a proton pump inhibitor. CONCLUSION: POEM resulted in greater than 90% treatment success at 12 months which tends to decrease to 84% after 2 years. More than one-third of the patients had mild reflux symptoms and/or mild esophagitis.

Diverticular disease: diagnosis and treatment.

Diverticular disease is one of the most common gastroenterological diseases. Its morphological basis are diverticula, whose prevalence in adults nears 50 %, with 25% clinical symptomatology and 5% occurrence of complications. It is a disease of older age, however its incidence is also rising in younger individuals, where it takes a more severe course. Its incidence is ascribed to a diet with a relatively low fibre content, however studies do not yield such clear results. Further risk factors include smoking, use of opiates and corticoids, obesity, alcoholism and smoking, hypertension, polycystosis, immunosuppression and use of non-steroid antiflogistics. Patients with diverticular disease also present with abnormal intestinal motility, intestinal dysbiosis and other physiological and morphological abnormalities. The most types of diverticulosis occur in the sigmoid colon, though especially in Asia the colon ascendens is more frequently affected. There are several classification schemes among which an individual assessment of complications is gaining in importance. The diagnosis includes clinical data, routine laboratory tests for inflammation, calprotectin in stool, coloscopy, ultrasound, CT and magnetic resonance. The basis for the treatment of symptomatic uncomplicated diverticular disease consists of drugs bringing symptomatic relief, fibre, probiotics, mesalazine and non-absorbable antibiotics, nonetheless the results of a number of studies are not fully convincing. The recommended treatment should be initiated with dietary fibre and probiotics, in the case of lasting problems add a non-absorbable antibiotic rifaximine with cyclic administration. Mild diverticulitis should essentially be treated by means of hydration and adjustments in the dietary regimen, antibiotics are not necessary when its course is uncomplicated and improvement is achieved, however the decision is individual and risk factors such as immunosuppression, diabetes, old age, pregnancy etc. Antibiotics are reserved for the treatment of severe or repeated diverticulitis, sepsis and complications. As prevention of further attacks, again probiotics, mesalazine and cyclically non-absorbable antibiotics are used, e,g. for a period of 10 days at monthly intervals. The proportion of surgeries is decreasing also where acute conditions are concerned and the efficiency of conservative treatment of diverticulitis is on the increase. Abscess should primarily be treated via non-surgical drainage. Even perforation and peritonitis can be treated via laparoscopic drainage without subsequent surgery being necessary, of course considering an overall condition an individual decision needs to be made. Generalized and fecal peritonitis are treated by open surgery. Earlier, elective resection was recommended after 2 attacks of diverticulitis, currently an individual approach is emphasized with respect to age, comorbidities and a character of the complaint and it is only indicated exceptionally. The proportion of laparoscopic resections is growing. The results are basically identical for Hartmann's procedure as well as primary resection. Key words: calprotecin - diverticular disease - dietary fibre - diverticulosis - mesalazine - non-absorbable antibiotics - probiotics.

[Disorders of water and electrolyte metabolism and changes in acid-base balance in patients with ascitic liver cirrhosis]. / Poruchy vodního a elektrolytového metabolismu a zmeny acidobazické rovnováhy u pacientu s ascitickou cirhózou jater.

In patients with advanced cirrhosis with ascites disorders of water and electrolyte metabolism are often present and they are associated with changes in acid-base balance. These changes can be very complicated, their diagnosis and treatment difficult. Dilutional hyponatremia is the most common disorder. Hyponatremia in these patients is associated with increased morbidity and mortality before and after liver transplantation. Other common disorders include hyperchloremic acidosis, hypokalemia, metabolic alkalosis, lactic acidosis, respiratory alkalosis. If renal impairment occurs (for example hepatorenal syndrome), metabolic acidosis and retention of acid metabolites may develop. The pathogenesis of these conditions applies primarily hemodynamic changes. Activation of renin-angiotensin-aldosterone system and non-osmotic stimulation of antidiuretic hormone trigger serious changes in water and natrium-chloride metabolism. This activation is clinically expressed like oedema, ascites, hydrothorax, low to zero natrium concentration in urine and increased urinary osmolality, which is higher than serum osmolality. In practice, the evaluation can be significantly modified by the ongoing diuretic therapy. Closer monitoring of water and electrolyte metabolism together with acid-base balance in patients with ascitic liver cirrhosis is important, not only in terms of diagnosis but especially in terms of therapy.