Reactivation of the insulin-like growth factor-Ⅱsignaling pathway in human hepatocellular carcinoma

Constitutive activation of the insulin-like growth factor (IGF)-signaling axis is frequently observed in human hepatocellular carcinoma(HCC).Especially the over- expression of the fetal growth factor IGF-Ⅱ,IGF-Ⅰ receptor(IGF-IR),and cytoplasmic downstream effectors such as insulin-receptor substrates(IRS)contribute to proliferation,anti-apoptosis,and invasive behavior. This review focuses on the relevant alterations in this signaling pathway and independent in vivo models that support the central role IGF-Ⅱsignaling during HCC development and progression.Since this pathway has become the center of interest as a target for potential anti-cancer therapy in many types of malignancies,various experimental strategies have been developed,including neutralizing antibodies and selective receptor kinase inhibitors,with respect to the specific and efficient reduction of oncogenic IGF-Ⅱ/IGF-IR-signaling.

Prospective evaluation of small bowel preparation with bisacodyl and sodium phosphate for capsule endoscopy

AIM： To determine the effect of Prepacol, a combination of sodium phosphate and bisacodyl, on transit and quality of capsule endoscopy （CE）. METHODS： Fivety two consecutive patients were included in this prospective study. CE was performed following a 12 h fasting period. Twenty six patients were randomized for additional preparation with Prepacol. The quality of CE was assessed separately for the proximal and the distal small bowel by 3 experienced endoscopists on the basis of a graduation which was initially developed with 20 previous CE. RESULTS： Preparation with Prepacol accelerated small bowel transit time （262 ± 55 rain vs 287 ± 97 min）, but had no effect on the quality of CE. Visibility was significantly reduced in the distal compared to the proximal small bowel. CONCLUSION： The significantly reduced visibility of CE in the distal small bowel allocates the need for a good preparation. Since Prepacol has no beneficial effect on CE the modality of preparation and the ideal time of application remains unclear. Further standardized examinations are necessary to identify sufficient preparation procedures and to determine the impact of the volume of the preparation solution.

Intestinal-borne dermatoses significantly improved by oral application of Escherichia coli Nissle 1917

AIM: To evaluate the effect of oral Escherichia coli (E. coli) Nissle application on the outcome of intestinal-borne dermatoses.METHODS: In a randomized, controlled, non-blinded prospective clinical trial 82 patients with intestinal-borne facial dermatoses characterized by an erythematous papular-pustular rash were screened. At the initiation visit 37 patients entered the experimental arm and 20 patients constituted the control arm. All 57 patients were treated with a vegetarian diet and conventional topical therapy of the dermatoses with ointments containing tetracycline, steroids and retinoids. In the experimental arm patients received a one month therapy with oral E. coli Nissle at a maintenance dose of 2 capsules daily. The experimental group was compared to a non-treatment group only receiving the diet and topical therapy. The primary outcome parameter was improvement of the dermatoses, secondary parameters included life quality and adverse events. In addition the immunological reaction profile (IgA, interleucin-8 and interferon-α) was determined. Furthermore the changes of stool consistency and the microbiota composition over the time of intervention were recorded.RESULTS: Eighty-nine percent of the patients with acne, papular-pustular rosacea and seborrhoic dermatitis responded to E. coli Nissle therapy with significant amelioration or complete recovery in contrast to 56% in the control arm (P < 0.01). Accordingly, in the E. coli Nissle treated patients life quality improved significantly (P < 0.01), and adverse events were not recorded. The clinical improvement was associated with a significant increase of IgA levels to normal values in serum as well as suppression of the proinflammatory cytokine IL-8 (P < 0.01 for both parameters). In the E. coli Nissle treated group a shift towards a protective microbiota with predominance of bifidobacteria and lactobacteria (> 107 CFU/g stool) was observed in 79% and 63% of the patients, respectively (P < 0.01), compared to no change in the control group without E. coli Nissle. Moreover, the detection rate of a pathogenic flora dropped from 73% to 14 % of the patients in the experimental arm (P < 0.01) with no significant change in the control arm (accounting 80% before and 70% after the observation period, P > 0.05). Accordingly, stool consistency, color and smell normalized in the E. coli Nissle treated patients.CONCLUSION: E. coli Nissle protects the mucus barrier by overgrowth of a favorable gut microbiota with less immunoreactive potential which finally leads to clinical improvement of intestinal borne dermatoses.

Successful combination of direct antiviral agents in livertransplanted patients with recurrent hepatitis C virus

AIM To analyze the safety and efficiency of direct-actingantiviral(DAA) regimens in liver-transplanted patients with hepatitis C virus(HCV) reinfection.METHODS Between January 2014 and December 2016, 39 patients with HCV reinfection after liver transplantation were treated at our tertiary referral center with sofosbuvir(SOF)-based regimens, including various combinations with interferon(IFN), daclatasvir(DAC), simeprivir(SIM) and/or ledipasvir(LDV). Thirteen patients were treated with SOF + IFN ± RBV. Ten patients were treated with SOF + DAC ± RBV. Fiveteen patients were treated with fixed-dose combination of SOF + LDV ± RBV. One patient was treated with SOF + SIM + RBV. Three patients with relapse were retreated with SOF + LDV + RBV. The treatment duration was 12-24 wk in all cases. The decision about the HCV treatment was made by specialists at our transplant center, according to current available or recommended medications.RESULTS The majority of patients were IFN-experienced(29/39, 74.4%) and had a history of hepatocellular carcinoma(26/39, 66.7%) before liver transplantation. Sustained virological response at 12 wk(SVR12) was achieved in 10/13(76.9%) of patients treated with SOF + IFN ± RBV. All patients with relapse were treated with fixed-dose combination of SOF + LDV + RBV. Patients treated with SOF + DAC + RBV or SOF + LDV + RBV achieved 100% SVR12. SVR rates after combination treatment with inhibitors of the HCV nonstructural protein(NS)5 A and NS5 B for 24 wk were significantly higher, as compared to all other therapy regimens(P = 0.007). Liver function was stable or even improved in the majority of patients during treatment. All antiviral therapies were safe and well-tolerated, without need of discontinuation of treatment or dose adjustment of immunosuppression. No serious adverse events or any harm to the liver graft became overt. No patient experienced acute cellular rejection during the study period. CONCLUSION Our cohort of liver-transplanted patients achieved high rates of SVR12 after a 24-wk course of treatment, especially with combination of NS5 A and NS5 B inhibitors.

Enhanced expression of interleukin-18 in serum and pancreas of patients with chronic pancreatitis

AIM： To investigate interleukin-18 （IL-18） in patients with chronic panreatitis （CP）. METHODS： We studied 29 patients with CP and 30 healthy controls. Peripheral blood mononuclear cells （PBMC） were isolated and incubated with 50 mmol/L ethanol, lipopolysaccharide （LPS） （doses 25 g/L, 250 g/L, 2500 g/L） and both agents for 24 h. Levels of IL-18 in the supernatants, and levels of IL-18, IL-12, interferon （IFN）-T and soluble CD14 in the serum were analysed by EI_ISA technique. Expression of IL-18 in PBMC was investigated by reverse-transcription （RT）-PCR. IL-18 protein levels in CP tissue and in normal pancreas were studied by ELISA technique. IL-18 levels in PBMC and pancreatic tissue were determined by Westernblot. Immunohistochemistry for pancreatic IL-18 expression was performed.RESULTS： In patients, IL-18 serum levels were significantly enhanced by 76% （mean： 289.9 ± 167.7 ng/L） compared with controls （mean： 165.2 ± 43.6 ng/L; P 〈 0.0005）. IL-12 levels were enhanced by 25% in patients （18.3 ± 7.3 ng/L） compared with controls （14.7 ± 6.8 ng/L, P = 0.0576） although not reaching the statistical significance. IFN-γ, and soluble CD14 levels were not increased. In vitro, LPS stimulated significantly and dosedependently IL-18 secretion from PBMC. Incubation with ethanol reduced LPS-stimulated IL-18 secretion by about 50%. The mRNA expression of IL-18 in PBMC and the response of PBMC to ethanol and LPS was similar in CP patients and controls. In PBMC, no significant differences in IL-18 protein levels were detected between patients and controls. IL-18 protein levels were increased in CP tissues compared to normal pancreatic tissues. IL-18 was expressed by pancreatic acinar cells and by infiltrating inflammatory cells within the pancreas. CONCLUSION： IL-18 originates from the chronically inflammed pancreas and appears to be involved in the fibrotic destruction of the organ.

Magnetic resonance angiography for the primary diagnosis of pulmonary embolism: A review from the international workshop for pulmonary functional imaging

Pulmonary contrast enhanced magnetic resonance angiography(CE-MRA) is useful for the primary diagnosis of pulmonary embolism(PE). Many sites have chosen not to use CE-MRA as a first line of diagnostic tool for PE because of the speed and higher efficacy of computerized tomographic angiography(CTA). In this review, we discuss the strengths and weaknesses of CEMRA and the appropriate imaging scenarios for the primary diagnosis of PE derived from our unique multiinstitutional experience in this area. The optimal patient for this test has a low to intermediate suspicion for PE based on clinical decision rules. Patients in extremis are not candidates for this test. Younger women(< 35 years of age) and patients with iodinated contrast allergies are best served by using this modality We discuss the history of the use of this test, recent technical innovations, artifacts, direct and indirect findings for PE, ancillary findings, and the effectiveness(patient outcomes) of CE-MRA for the exclusion of PE. Current outcomes data shows that CE-MRA and NM V/Q scans are effective alternative tests to CTA for the primary diagnosis of PE.

Limitations and opportunities of non-invasive liver stiffness measurement in children

Changes in liver structure are an important issue in chronic hepatopathies.Until the end of the 20 th century,these changes could only be determined by histological analyses of a liver specimen obtained via biopsy.The well-known limitations of this technique(i.e.,pain,bleeding and the need for sedation) have precluded its routine use in follow-up of patients with liver diseases.However,the introduction of non-invasive technologies,such as ultrasound and magnetic resonance imaging,for measurement of liver stiffness as an indirect marker of fibroses has changed this situation.Today,several noninvasive tools are available to physicians to estimate the degree of liver fibrosis by analysing liver stiffness.This review describes the currently available tools for liver stiffness determination that are applicable to follow-up of liver fibrosis/cirrhosis with established clinical use in children,and discusses their features in comparison to the "historical" tools.

Extrapulmonary sarcoidosis of liver and pancreas: A case report and review of literature

Sarcoidosis is a chronic multisystemic granulomatous disease of unknown origin, which can involve nearly all organs. In the case of an infrequent gastrointestinal tract involvement in systemic sarcoidosis, granulomas of the liver are most commonly described while isolated pancreatic sarcoid lesions are rarely seen. We report a case of systemic sarcoidosis with exclusive extrapulmonal involvement of the liver and the pancreas in a 71-year- old white man. The diagnosis of liver involvement was confirmed by biopsy. Pancreatic surgery was needed because preoperative evaluation could not exclude pancreatic cancer and for biliary decompression. An extensive literature review of systemic sarcoidosis, focusing on reported cases with unusual presentation of sarcoidosis in the liver and the pancreas, its diagnosis, treatment, and prognosis was made.

Complications of dexamethasone implants:risk factors,prevention,and clinical management

AIM:To evaluate major complications after intravitreal injection of dexamethasone implants(Ozurdex)and their clinical management.METHODS:In a retrospective observational study between 2014 and 2016 at two university hospitals,we reviewed the clinical records of 1241 consecutive macular edema patients treated with the dexamethasone implant,and separated severe adverse events in the injection procedure from those that were post-injection complications.We evaluated the cause and the outcomes in each case.RESULTS:In twenty-one procedures(1.69%)we noticed significant complications during and after intravitreal injection of the dexamethasone implant.Complications related to the injection procedure were in one case,that a second implant was injected by mistake in the same eye on the same day.In another case,the implant lodged in the sclera during retraction of the injector needle.Leaking scleral tunnel at the injection site led to hypotony in another case.There were 10 cases of post-injection displacement of the implant into the anterior chamber and one case with a migrated and trapped device between the intraocular lens and an artificial iris.Displacement typically occurred in patients with preexisting risk factors:eyes with complicated intraocular lens implantation,iris reconstruction or iris defects or pseudophakic eyes after vitrectomy were prone to develop this complication.Displacement led to secondary corneal decompensation with pseudohypopyon.One case developed an endophthalmitis,and we observed four cases of retinal detachment.Two eyes presented with long-lasting hypotony due to ciliary insufficiency.CONCLUSION:Treatment with the dexamethasone implant may cause various expected or unexpected complications that may have serious consequences for the patient and require further surgery.To reduce complications,clinicians should evaluate certain risk factors before scheduling patients for dexamethasone implant treatment and use proper injection techniques.

冠状动脉药物洗脱支架晚发支架内急性血栓形成分析

目的分析近期临床应用冠脉药物洗脱支架（drug-eludng stent，DES）术后，晚发的支架内急性血栓形成病例的发生特点及可能影响因素。方法应用关键词：coronary artery、sirolimus、paclitaxil、drug-eluting stent、thrombosis，anuerysm、malapposition等，应用美国国立医学图书馆的PubMed系统和德国海德堡大学的电子期刊系统对临床医学核心期刊进行系统检索。对检索出的12个病例及本中心3例冠状动脉内置入DES后晚发支架内急性血栓形成病例汇总分析。结朵共有15例患者，在DES（simlimus和paclitaxel支架）术后出现晚发的支架内急性血栓形成和（或）同时合并冠脉瘤样扩张、支架与血管壁贴合不良（malapposition）。急性血栓发生时间：120～540天。9例患者在停用阿司匹林、氯吡格雷后4—15天发生；3例患者在DES置入部位出现明显冠脉瘤样扩张和（或）瘤腔内血栓形成；4倒患者在DES发生急性血栓时、同时置入的6枚普通金属支架完全通畅。结论晚发的DES内急性血栓形成（≥6个月）、支架与血管壁贴合不良、明显的冠脉管壁瘤样扩张造成再次严重的心肌缺血或梗死。

Diagnostic criteria for acute liver failure due to Wilson disease

AIM： To describe the diagnostic criteria for acute liver failure due to Wilson disease （WD）, which is an uncommon cause of acute liver failure （ALF）. METHODS： We compared findings of patients presenting with ALF due to WD to those with ALF of other etiologies. RESULTS： Previously described criteria, such as low alkaline phosphatase activity, ratio of low alkaline phosphatase to total bilirubin or ratio of high aspartate arninotransferase （AST） to alanine arninotransferase （ALT）, failed to identify patients with ALF due to WD. There were significant differences in low ALT and AST activities （53 ± 43 vs 1982 ± 938, P 〈 0.0001 and 87 ± 44 vs 2756 ± 2941, P = 0.037, respectively）, low choline esterase activity （1.79 ± 1.2 vs 4.30 ± 1.2, P = 0.009）, high urine copper concentrations （93.4 ± 144.0 vs 3.5 ± 1.8, P = 0.001） and low hemoglobin （7.0 ± 2.2 vs 12.6 ± 1.8, P 〈 0.0001） in patients with ALF caused by WD as compared with other etiologies. Interestingly, 4 of 7 patients with ALF due to WD survived without liver transplantation. CONCLUSION： In ALF, these criteria can help establish a diagnosis of WD. Where applicable, slitlamp examination for presence of Kayser-Fleischer rings and liver biopsy for determination of hepatic copper concentration still remain important for the diagnosis of ALF due to WD. The need for liver transplantation should be evaluated carefully as the prognosis is not necessarily fatal.

Cancer-related microangiopathic hemolytic anemia in patients with advanced gastric cancer: A retrospective single-center analysis

BACKGROUND Microangiopathic hemolytic anemia(MAHA) with thrombocytopenia and organ failure caused by tumor-associated thrombotic microangiopathy(TMA) is a lifethreatening oncological emergency. Rapid diagnosis and precise distinction from other forms of TMA is crucial for appropriate therapy, which aims at treating the underlying malignancy. However, the prognosis of patients with cancer-related(CR)-MAHA is limited. To date, less than 50 patients with gastric cancer and CRMAHA have been reported, mainly as single case reports, and detailed information on treatment strategies and outcome are scarce. We analyzed the characteristics and outcomes data of CR-MAHA patients with gastric cancer treated at our center between 2012 and 2019.AIM To gain knowledge about CR-MAHA and the course of disease.METHODS We retrospectively analyzed patients using an institutional prospectively maintained database. Patients who had CR-MAHA but other cancer types or cancer of unknown primary were excluded. The basic requirements for inclusion were: Histologically proven gastric adenocarcinoma;and clinical diagnosis of hemolytic anemia with schistocytes with or without thrombocytopenia. The observation period for each patient started with the first day of documented symptoms. The follow-up period for this analysis ended on February 1, 2020.RESULTS We identified eight patients with a median age of 54 years. Histologically, all patients had(partial) diffuse subtypes of gastric adenocarcinoma with partial or complete signet cell morphology. All patients had metastatic disease and one patient had a microsatellite instability-high(MSI-H) tumor. In three patients, clinical signs of MAHA preceded the diagnosis of cancer, and in two patients, CRMAHA indicated recurrent disease. All patients had severe hemolytic anemia and thrombocytopenia. Six patients experienced severe bone pain, and five patients had dyspnea. Systemic, 5-fluorouracil-based combination chemotherapy was initiated in six patients, which resulted in rapid initial response with significant improvement of clinical symptoms and blood values. Progression-free survival(PFS) of the whole cohort was 1.9 wk and median overall survival(OS) was 1.9 wk. For patients with chemotherapy, PFS was 9.0 wk and OS was 10.3 wk. The patient with the MSI-H tumor has been undergoing immunotherapy for more than 3 years.CONCLUSION The benefit of chemotherapy in CR-MAHA patients is limited. Immunotherapy for patients with MSI-H tumors may lead to long-term tumor control even in CRMAHA patients.

Cardiac diagnostics before oral propranolol therapy in infantile hemangioma: retrospective evaluation of 234 infants

Background The indication and extent of cardiac screening before oral propranolol therapy (OPT) in patients with infantile hemangioma (IH) has been challenged. In this study, we evaluated pre-OPT cardiac diagnostics in a pediatric IH cohort in our department. Methods Retrospective chart review of infants ≤ 12 months old with IH undergoing OPT. The diagnostics prior to OPT, occurrence of complications, and outcome were recorded. Results A total of 234 patients were evaluated. The mean age at the onset of OPT was 4.2 ± 0.3 months, the average dura-tion of OPT was 6.1 ± 0.1 months, and the average follow-up was 12.3 ± 0.7 months. Echocardiograms and electrocardio-grams were performed prior to OPT in all patients. One hundred and three (44.0%) echocardiograms revealed pathological findings, 19 (8.1%) of which were minor (including atrial septal defects, pulmonary stenosis, and patent ductus arteriosus). Pathological findings were observed in 17 (7.3%) of electrocardiograms, only one (0.4%) of which was minor (suspected cardiac arrhythmia, subsequently excluded by long-term electrocardiogram analysis). These findings did not contraindicate OPT and no severe adverse events associated with OPT occurred during the follow-up period. Conclusions Routine cardiac screening by electrocardiogram and echocardiogram before OPT is debatable and not routinely indicated in children with IH. Further studies are necessary to draw definite conclusions on the reasonable indication and extent of this diagnostic approach.

Combined non-alcoholic fatty liver disease and type 2 diabetes in severely obese patients-medium term effects of sleeve gastrectomy versus Roux-en-Y-gastric bypass on disease markers

Background:We aimed to evaluate the medium-term efficacy of sleeve gastrectomy(SG)vs.Roux-en-Y gastric bypass(RYGB)on remission of non-alcoholic fatty liver disease(NAFLD)in patients with type 2 diabetes mellitus(T2DM).Methods:We identified severely obese patients[body mass index(BMI)>35 kg/m^(2)]with NAFLD(as defined by the Longitudinal Assessment of Bariatric Surgery Study)and T2DM(as defined by the American Association of Clinical Endocrinologists and the American College of Endocrinology)who underwent SG or RYGB in a single university surgical centre.The cohorts were match-paired and data were analysed after at least 3 years of follow up.The key outcomes measured were:(I)the improvement of liver function tests and NAFLD markers;(II)glycemic control and insulin resistance.Results:Ninety-six patients were investigated;44(45.8%)were women.The mean pre-operative BMI was 45.2 kg/m2 in the SG and 42.0 kg/m^(2) in the RYGB group.SG and RYGB both significantly reduced serum liver enzyme concentrations.NAFLD markers resolved 2 years after SG in all patients.In contrast,only 78%and 80%of patients achieved remission of NAFLD 2 and 3 years after RYBG respectively.Both procedures resulted in comparable rates of remission of T2DM.Conclusions:Bariatric surgery with SG may be preferable to RYGB for obese patients with NAFLD and T2DM based on the rates of remission of markers of these co-morbidities.However,our results need to be confirmed in prospective trials.Understanding the metabolic effects of specific bariatric surgical procedures may facilitate the development of a personalised approach to weight-loss surgery.

Quantification of Acupuncture Effects on Peripheral Neuropathy of Unknown and Diabetic Cause by Nerve Conduction Studies

Objective： To evaluate the effect of acupuncture on peripheral neuropathy （PN） as measured by changes in nerve conduction studies （NCS）. Methods： 192 patients with PN were evaluated over a period of 1 year. In 17 patients diabetic neuropathy was found. 3 of these patients received acupuncture therapy according to classical Chinese medicine as defined by the Heidelberg model of TCM and all improved in NCS. Of the 14 non-specifically treated patients, 3 （21.4%） presented with improved NCS and 11 （78.6%） aggravated in NCS （P〈0.03）. An overall of 47 patients met the criteria for PN of undefined aetiology, 21 patients received acupuncture therapy, while 26 patients received no specific treatment. All groups were examined by NCS before treatment and 4 months later. Results： 1） Diabetic neuropathy, in the control-group 3 patients improved and 11 showed an aggravation. Comparison of groups was significantly different. 2） PN, 16 patients （76.2%） in the acupuncture group improved, while only 4 patients in the control group （15.4%） did so. 3 patients in the acupuncture group （14.3%） showed no change and 2 patients an aggravation （9.5%）, whereas in the control group 7 patients showed no change （26.9%） and 15 an aggravation （57.7%）.Comparison of the groups was significantly different. Conclusion： There is a positive effect of acupuncture on PN, as measured by objective parameters （NCS）.