Patient-reported outcomes in randomised controlled trials of gynaecological cancers: Investigating methodological quality and impact on clinical decision-making

AimThe aim for this study is to investigate the methodological quality and potential impact on clinical decision making of patient reported outcome (PRO) assessment in randomised controlled trials (RCTs) in the gynaecological cancer sites.MethodsA systematic review identified RCTs published between January 2004 and June 2012. Relevant studies were evaluated using a pre-determined extraction form which included: (1) Trial demographics and clinical and PRO characteristics; (2) level of PRO reporting and (3) bias, assessed using the Cochrane Risk of Bias tool. All studies were additionally analysed in relation to their relevance in supporting clinical decision making.ResultsFifty RCTs enrolling 24,991 patients were identified. In eight RCTs (16%) a PRO was the primary end-point. Twenty-one studies (42%) were carried out in a multi-national context. Where statistically significant PRO differences between treatments were found, it related in most cases to both symptoms and domains other than symptoms (n = 17, 57%). The majority of studies (n = 42, 84%) did not mention the mode of administration nor the methods of collecting PRO data. Statistical approaches for dealing with missing data were only explicitly mentioned in nine RCTs (18%). Sixteen RCTs (32%) were considered to be of high-quality and thus able to inform clinical decision making. Higher-quality PRO studies were generally associated with RCTs that were at a low risk of bias.ConclusionThis study showed that RCTs with PROs were generally well designed and conducted. In a third the information was very informative to fully understand the pros and cons of PROs treatment decision-making.     

Autoimmune pancreatitis type-1 associated with intraduct papillary mucinous neoplasm: Report of two cases

Chronic pancreatitis lesions usually embrace both intraduct papillary mucinous neoplasm (IPMN) and pancreatic ductal adenocarcinoma (PDAC). Patients at genetically-determined high risk of PDAC often harbor IPMN and/or chronic pancreatitis, suggesting IPMN, chronic pancreatitis and PDAC may share pathogenetic mechanisms. Chronic autoimmune pancreatitis (AIP) may also herald PDAC. Concurrent IPMN and AIP have been reported in few patients. Here we describe two patients with IPMN who developed type-1 AIP fulfilling the Honolulu and Boston diagnostic criteria. AIP diffusively affected the whole pancreas, as well as peripancreatic lymph nodes and the gallbladder. Previous pancreatic resection of focal IPMN did not show features of AIP. One of the patients carried a CFTR class-I mutation. Of notice, serum IgG4 levels gradually decreased to normal values after IPMN excision. Common risk factors to IPMN and AIP may facilitate its coincidental generation.     

Pain severity reduces life quality in chronic pancreatitis: Implications for design of future outcome trials

Background/objectivesChronic pancreatitis (CP) is a disabling disease characterised by abdominal pain, and various pancreatic and extra-pancreatic complications. We investigated the interactions between pain characteristics (i.e. pain severity and its pattern in time), complications, and quality of life (QOL) in patients with CP.MethodsThis was a cross-sectional study of 106 patients with CP conducted at two North European tertiary medical centres. Detailed information on clinical patient characteristics was obtained from interviews and through review of the individual patient records. Pain severity scores and pain pattern time profiles were extracted from the modified brief pain inventory short form and correlated to QOL as assessed by the EORTC QLQ-C30 questionnaire. Interactions with exocrine and endocrine pancreatic insufficiency, as well as pancreatic and extra-pancreatic complications were analysed using regression models.ResultsPain was the most prominent symptom in our cohort and its severity was significantly correlated with EORTC global health status (r = −0.46; P < 0.001) and most functional and symptom subscales. In contrast the patterns of pain in time were not associated with any of the life quality subscales. When controlling for interactions from exocrine and endocrine pancreatic insufficiency no effect modifications were evident (P = 0.72 and P = 0.85 respectively), while the presence of pancreatic and extra-pancreatic complications was associated with an almost 15% decrease in life quality (P = 0.004).ConclusionsPain severity and disease related complications significantly reduce life quality in patients with CP. This information is important in order to design more accurate and clinical meaningful endpoints in future outcome trials.     

Calcium,mitochondria and the initiation of acute pancreatitis

Acute pancreatitis is characterized by necrosis of its parenchymal cells and influx and activation of inflammatory cells that further promote injury and necrosis. This review is intended to discuss the central role of disorders of calcium metabolism and mitochondrial dysfunction in the mechanism of pancreatitis development. The disorders are placed in context of calcium and mitochondria in physiologic function of the pancreas. Moreover, we discuss potential therapeutics for preventing pathologic calcium signals that injure mitochondria and interventions that promote the removal of injured mitochondria and regenerate new and heathy populations of mitochondria.     

CD40-mediated immune cell activation enhances response to anti-PD-1 in murine intrahepatic cholangiocarcinoma

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A comparison of the diagnostic efficacy in type 1 autoimmune pancreatitis based on biopsy specimens from various organs

BackgroundComprehensive immunostaining evaluation of the biopsy specimens from various organs with type 1 autoimmune pancreatitis (AIP) has not been elucidated. Our aim was to clarify which of these biopsy specimens and counting method could be a useful tool for supporting the diagnosis of AIP.MethodsWe retrospectively evaluated biopsy specimens from pancreas (n = 19), stomach (n = 28), duodenum (n = 27), duodenal papilla (n = 25), colon (n = 19), liver (n = 11), bile duct (n = 24), and minor salivary gland (n = 13) in 36 patients with AIP. Positive IgG4 immunostaining (>10 plasma cells/high-power field [HPF]) and positive IgG4/IgG ratio (>40%) of biopsy specimens from 8 sites of 6 organs in one HPF and an average from 3 HPFs were compared between AIP and controls.ResultsThe sensitivity of IgG4 immunostaining for AIP in one HPF were 16% in pancreas, 14% in stomach, 15% in duodenum, 52% in duodenal papilla, 11% in colon, 27% in liver, 21% in bile duct and 8% in minor salivary gland, respectively. The positive IgG4 immunostaining of the duodenal papilla in one HPF showed the highest sensitivity (52%) and accuracy (73%) among the 8 sites. It also showed the highest sensitivity among 4 different counting methods (IgG4 immunostaining in one HPF and 3 HPFs, both IgG4 immunostaining and IgG/IgG4 ratio in one HPF and 3 HPFs), but there were no significant differences with respect to specificity and accuracy.ConclusionsIgG4 immunostaining of swollen duodenal papilla with more than 10 IgG4-positive plasma cells in at least one HPF is useful for supporting the diagnosis of AIP.     

The Inherited Genetic Component of Sporadic Pancreatic Adenocarcinoma

Pancreatic cancer, like many other complex diseases, has genetic and environmental components to its etiology. It is likely that relatively common genetic variants with modest effects on pancreatic cancer risk play an important role in both familial and sporadic forms of the disease, either individually or in interaction with environmental factors. The relatively highfrequencyofsuch variants meansthattheycould potentially explain a substantial portion of disease risk. Here we summarize the findings published to date from genetic association studies¹. In general, very few low-penetrance variants have been identified and those that have require replication in independent studies. Possible gene-environment interactions arising from these studies also require replication. More comprehensive approaches are needed to make progress, including global analyses of biologically sound pathways and genome-wide association studies. Large samplesizesare required to do thisappropriatelyand multi-study consortia make this possible. A number of consortia of preexisting studies have already been formed, and these will facilitate the identification of further low-penetrance variants and gene-environment interaction. However, these approaches do not substitute for the design of novel, sufficiently powered studies that apply uniform criteria to case selection, the acquisition of environmental exposure information, and to biological sample collection.     

Immune monitoring of anti cytomegalovirus antibodies and risk of cytomegalovirus disease in heart transplantation

We sought to determine whether quantitative assessment of anti-cytomegalovirus (CMV) antibodies could be useful to identify patients at risk of cytomegalovirus (CMV) disease after heart transplantation (HT). 75 patients who underwent HT at a single health care center were prospectively studied. Induction therapy included 2 doses of daclizumab and maintenance tacrolimus (n=42) or cyclosporine (n=29), mycophenolate mofetil and prednisone. All patients received prophylaxis with gancyclovir or valganciclovir. Anti-CMV intravenous immunoglobulin (CMV-IG) was added in high risk patients (CMV D+/R- serostatus). Serial determinations of anti-CMV antibodies, immunoglobulins (IgG, IgA, IgM) and IgG-subclasses were analysed. CMV infection was based on detection of the virus by antigenemia. CMV disease consisted of detection of signs or symptoms attributable to this microorganism. Ten patients (13.3%) developed CMV disease. Mean time of development of CMV disease was 3.4+/-1.6 months. In Cox regression analysis, patients with low baseline anti-CMV titers (<4.26 natural logarithm of titer, RH: 8.1, 95%CI: 1.93-34.1, p=0.004) and recipients with 1-month post-HT IgG hypogammaglobulinemia (IgG<500 mg/dl, RH: 4.49, 95%CI: 1.26-15.94, p=0.02) were at higher risk of having CMV disease. Despite use of prophylactic CMV-IG, D+/R- patients showed significantly lower titers of anti-CMV antibodies at 7 d, 30 d and 90 d post HT as compared with HT recipients without infections. Four out of 6 of these patients developed late CMV disease. Monitoring of specific anti-CMV antibodies on the bedside warrants further evaluation as a potential tool to identify heart transplant recipients at higher risk of CMV disease.