The impact of elevated serum IgG4 levels in patients with primary sclerosing cholangitis

Background

Elevated IgG4 levels have been reported among patients with primary sclerosing cholangitis. Epidemiological data has only been provided from tertiary centres.

Aims

To investigate the prevalence of elevated IgG4 levels and to compare prognosis between patients with and without elevated IgG4 levels in serum in two European cohorts of patients with primary sclerosing cholangitis.

Methods

Serum IgG4-levels were measured in a consecutive series of patients from Berlin, and retrospectively collected in a population-based cohort from Sweden (total N = 345). Cox's proportional hazard analysis was used to calculate relative risks for liver-related death or liver transplantation and cholangiocarcinoma.

Results

Elevated IgG4 values were demonstrated in 10% of patients. A previous history of pancreatitis, combined intra- and extrahepatic biliary involvement and jaundice were independently associated with elevated IgG4 in multivariate analysis. IgG4 status was not associated with an increased risk for the combined endpoint liver-related death or liver transplantation or cholangiocarcinoma.

Conclusion

The prevalence of elevated IgG4 values among European patients with primary sclerosing cholangitis is similar to what previously has been reported from the United States. Elevated IgG4 was not associated with an increased risk of liver transplantation or liver-related death or cholangiocarcinoma.     

Incidental findings: the time is not yet ripe for a policy for biobanks

Incidental findings (IFs) are acknowledged to be among the most important ethical issues to consider in biobank research. Genome-wide association studies and disease-specific genetic research might reveal information about individual participants that are not related to the research purpose, but may be relevant to those participants'' future health. In this article, we provide a synopsis of arguments for and against the disclosure of IFs in biobank research. We argue that arguments that do not distinguish between communications about pathogenic conditions and complex genetic risk for diseases fail, as preferences and decisions may be far more complex in the latter case. The principle of beneficence, for example, often supports the communication of incidentally discovered diseases, but if communication of risk is different, the beneficence of such communication is not equally evident. By conflating the latter form of communication with the former, the application of ethical principles to IFs in biobank research sometimes becomes too easy and frictionless. Current empirical surveys of people''s desire to be informed about IFs do not provide sufficient guidance because they rely on the same notion of risk communication as a form of communication about actual health and disease. Differently designed empirical research and more reflection on biobank research and genetic risk information is required before ethical principles can be applied to support the adoption of a reasonable and comprehensive policy for handling IFs.A much discussed problem associated with biobank research is the return to participants of incidental findings (IFs): ‘a finding concerning an individual research participant that has a potential health or reproductive importance and is discovered in the course of conducting research but is beyond the aims of the study.''¹ How should such information be handled ethically responsibly in genome-wide association studies and disease-specific genetic research?In this paper, we argue that the discussion up until now has neglected a distinction that should be held in the forefront of the discussion, especially concerning genetic biobank research: the distinction between an incidentally discovered disease and an incidentally discovered increased genetic risk for disease of unclear predictive value. Biobank research and rapidly increasing studies in genomics, proteomics, and nutrigenomics continue to identify many genes and biomarkers associated with risk of disease. Genetic testing for monogenic disorders are well established in health services, but little is yet known of the best way to handle complex risk information associated with multifactorial disorders in which the predictive importance of individual elements – genetic, epigenetic, or environmental – will differ for different individuals. The value of being informed about an incidentally discovered genetic risk (be it inherited or caused by a virus) is therefore much more difficult to ascertain than that for an incidentally discovered pathogenic condition revealed, for example, in a brain imaging study.The aim of this paper is to exhibit the absence of a distinction between disease and complex genetic risk for disease in the discussion, and to show how the arguments therefore fail to address the more complex kinds of IFs that increasingly arise in biobank research. Further research should be conducted before the arguments can be considered conclusive.Disease risks can be discovered also in imaging studies, of course, a blood vessel with thin walls can imply an increased risk for stroke. Our focus in this paper, however, is on genetic biobank research, where IFs increasingly concern multifactorial risks for disease having both genetic and environmental dimensions, which we believe introduce complications that so far have not been addressed.     

predictors for failure of stent treatment for benign esophageal perforations- a single center 10-year experience

AIM:To investigate possible predictors for failed selfexpandable metallic stent(SEMS)therapy in consecutive patients with benign esophageal perforationrupture(EPR).METHODS:All patients between 2003-2013 treated for EPR at the Karolinska University Hospital,a tertiary referral center,were studied with regard to initial management with SEMS.Patients with malignancy as an underlying cause and those with anastomotic leakages were excluded.Sealing of the perforation with a covered SEMS was the primary strategy whenever feasible.Stent therapy failure was defined as a radical change of treatment strategy due to uncontrolled mediastinitis,which in this setting consisted of emergency esophagectomy with end-esophagostomy or death as a consequence of the perforation and subsequent uncontrolled sepsis.Patient and lesion characteristics were analyzed and are presented as median and interquartile range.Possible predictors for failed stent therapy were analyzed with uni-variate logistic regression,while variables with P<0.2 were further analyzed with multi-variate logistic regression.RESULTS:Of the total number of 48 patients presenting with EPR,40 patients(83.3%)were treated with SEMS at the time of admission,with an intention to heal the perforation.Twenty-three patients had Boerhaave’s syndrome(58%),16 had an iatrogenic perforation(40%)and 1 had external trauma to the esophagus(3%).The total in-hospital mortality,including the cases that had other initial treatments(n=8),was10.4%and 7.5%among those who were subjected to the SEMS-based strategy.In 33 of the 40 patients(82.5%)who were treated with stent,the EPR healed without further change in treatment strategy.Patients classified as treatment success received a SEMS at a median time of 1(1-1)d after the actual EPR,compared to 3(1-10)d among those where the initial treatment failed,P=0.039 in uni-variate analysis and P=0.052 in multi-variate analysis.No other significant factors emerged,indicating an increased risk for failure.Six of 7 patients,where stent treatment of the defect failed,underwent an emergency esophagectomy with end esophagostomy and one patient died.CONCLUSION:SEMS as an upfront therapeutic strategy seems to be a successful concept,when applied to an unselected group of patients with EPR.     

SOX11 and TP53 add prognostic information to MIPI in a homogenously treated cohort of mantle cell lymphoma – a Nordic Lymphoma Group study

Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma, where survival has been remarkably improved by use of protocols including high dose cytarabine, rituximab and autologous stem cell transplantation, such as the Nordic MCL2/3 protocols. In 2008, a MCL international prognostic index (MIPI) was created to enable stratification of the clinical diverse MCL patients into three risk groups. So far, use of the MIPI in clinical routine has been limited, as it has been shown that it inadequately separates low and intermediate risk group patients. To improve outcome and minimize treatment‐related morbidity, additional parameters need to be evaluated to enable risk‐adapted treatment selection. We have investigated the individual prognostic role of the MIPI and molecular markers including SOX11, TP53 (p53), MKI67 (Ki‐67) and CCND1 (cyclin D1). Furthermore, we explored the possibility of creating an improved prognostic tool by combining the MIPI with information on molecular markers. SOX11 was shown to significantly add prognostic information to the MIPI, but in multivariate analysis TP53 was the only significant independent molecular marker. Based on these findings, we propose that TP53 and SOX11 should routinely be assessed and that a combined TP53/MIPI score may be used to guide treatment decisions.     

Asparaginase‐associated pancreatitis in children with acute lymphoblastic leukaemia in the NOPHO ALL2008 protocol

L‐asparaginase is an important drug in the treatment of childhood acute lymphoblastic leukaemia (ALL). Treatment is associated with several toxicities, including acute pancreatitis. Clinical course, presentation, re‐exposure to L‐asparginase after pancreatitis and risk of recurrent pancreatitis within an asparaginase‐intensive protocol has been poorly reported. Children (1–17 years) on the ongoing Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol with asparaginase‐associated pancreatitis (AAP) diagnosed between 2008 and 2012 were identified through the online NOPHO ALL toxicity registry. NOPHO ALL2008 includes eight or 15 doses of intramuscular pegylated L‐asparginase (PEG‐asparaginase) 1000 iu/m²/dose at 2–6 weeks intervals, with a total of 30 weeks of exposure to PEG‐asparaginase (clinicaltrials.gov no: NCT00819351). Of 786 children, 45 were diagnosed with AAP with a cumulative risk of AAP of 5·9%. AAP occurred after a median of five doses (range 1–13), and 11 d (median) from the latest administration of PEG‐Asparaginase. Thirteen patients developed pseudocysts (30%) and 11 patients developed necrosis (25%). One patient died from pancreatitis. Twelve AAP patients were re‐exposed to L‐asparginase, two of whom developed mild AAP once more, after four and six doses respectively. In conclusion, re‐exposure to PEG‐asparaginase in ALL patients with mild AAP seems safe.     

Nonlinear structured-illumination microscopy with a photoswitchable protein reveals cellular structures at 50-nm resolution

Using ultralow light intensities that are well suited for investigating biological samples, we demonstrate whole-cell superresolution imaging by nonlinear structured-illumination microscopy. Structured-illumination microscopy can increase the spatial resolution of a wide-field light microscope by a factor of two, with greater resolution extension possible if the emission rate of the sample responds nonlinearly to the illumination intensity. Saturating the fluorophore excited state is one such nonlinear response, and a realization of this idea, saturated structured-illumination microscopy, has achieved approximately 50-nm resolution on dye-filled polystyrene beads. Unfortunately, because saturation requires extremely high light intensities that are likely to accelerate photobleaching and damage even fixed tissue, this implementation is of limited use for studying biological samples. Here, reversible photoswitching of a fluorescent protein provides the required nonlinearity at light intensities six orders of magnitude lower than those needed for saturation. We experimentally demonstrate approximately 40-nm resolution on purified microtubules labeled with the fluorescent photoswitchable protein Dronpa, and we visualize cellular structures by imaging the mammalian nuclear pore and actin cytoskeleton. As a result, nonlinear structured-illumination microscopy is now a biologically compatible superresolution imaging method.