Mutational landscape of combined hepatocellular-cholangiocarcinoma and its clinicopathological significance

Abstract

Backgrounds/Aims

Combined hepatocellular-cholangiocarcinoma (cHC-CC), which generally has a poor prognosis, comprises of hepatocellular carcinoma (HCC), cholangiocarcinoma (CC), and diverse components with intermediate features between HCC and CC. Histological subtypes with stem cell features (the SC subtype) have different clinicopathological significance in cHC-CC. The mutational status may reflect the clinicopathological subgroup of cHC-CC together with the histological subtype.

Methods

We examined the mutational statuses of KRAS, IDH1 or 2 (IDH1/2), ARID1A, the TERT promoter, and p53 and their relationships with clinicopathological features in 53 patients with cHC-CC. Background liver diseases were hepatitis B (n=9), hepatitis C (22), alcohol (5), nonalcoholic fatty liver disease (NAFLD) (8), and unknown (9).

Results

Mutations in KRAS, IDH1/2, ARID1A, the TERT promoter and p53 were detected in 4 (7.5%), 6 (11.8%) 7 (13.2%), 16 (31.3%), and 24 patients (45.3%), respectively. KRAS mutations correlated with higher histological diversity scores and a higher M-factor (p<0.05). ARID1A mutations correlated with alcohol, smaller tumor sizes, lower grade of co-existent HCC, and AFP-positivity and were associated with cholangiolocellular carcinoma subtype-predominant (p<0.05). TERT promoter mutations correlated with hepatitis B, an intermediate subtype-predominant histology, higher clinical stage, and higher N-factor (p<0.05) and were associated with gender (female-predominant) and previous therapy. p53 mutations correlated with AFP-positivity (p<0.05).

Conclusion

The results of the mutational analysis revealed that cHC-CC has diverse types of mutations and also that mutations in the TERT promoter and ARID1A may reflect etiological impact, different histological subtypes, histogenesis and tumor aggressiveness. These results suggest the potential efficacy of molecular-based subclassification of cHC-CC.

This article is protected by copyright. All rights reserved.

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Reply: How do we stage acellular mucin in lymph nodes of colorectal cancer specimens without neo-adjuvant therapy?

Abstract

Following our recently published correspondence on this subject¹, we have been made aware that the UICC/TNM have given a view on the staging of colorectal cancer in neo-adjuvant therapy-naïve colorectal cancer patients, whereby acellular mucin in lymph nodes has been detected. Like us, they view such a finding as representing lymph node disease positive for metastatic colorectal cancer².

This article is protected by copyright. All rights reserved.

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Effect of perioperative parecoxib sodium on postoperative pain control for transcatheter arterial chemoembolization for inoperable hepatocellular carcinoma: A prospective randomized trial

European Radiology

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Real-world effectiveness and safety of ombitasvir/paritaprevir/ritonavir ± dasabuvir ± ribavirin in hepatitis C: AMBER study

Alimentary Pharmacology and Therapeutics

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Right-sided diverticulitis requiring colectomy: an evolving demographic? A review of surgical outcomes from the national inpatient sample database

Journal of Gastrointestinal Surgery

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Similar efficacy of proton-pump inhibitors vs h2-receptor antagonists in reducing risk of upper gastrointestinal bleeding or ulcers in high-risk users of low-dose aspirin

Gastroenterology

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A systematic review of local excision after neoadjuvant therapy for rectal cancer: Are ypT0 tumors the limit?

Diseases of the Colon and Rectum

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Phase II trial of subcutaneous methylnaltrexone in the treatment of severe opioid-induced constipation (OIC) in cancer patients: an exploratory study

International Journal of Clinical Oncology

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Parametric response mapping of contrast-enhanced biphasic CT for evaluating tumour viability of hepatocellular carcinoma after TACE

European Radiology

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Effects of sex, drinking history, and omega-3 and omega-6 fatty acids dysregulation on the onset of liver injury in very heavy drinking alcohol-dependent patients

Alcoholism: Clinical and Experimental Research

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Prospective cohort study of laparoscopic and open hepatectomy for hepatocellular carcinoma

British Journal of Surgery

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Dietary advanced glycation end-products aggravate non-alcoholic fatty liver disease

World Journal of Gastroenterology

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Using experience-based design to improve the care experience for patients with pancreatic cancer

Journal of Oncology Practice

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The impact of directly acting antivirals on the enzymatic liver function of liver transplant recipients with recurrent hepatitis C

Transplant Infectious Disease

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Evolution of disease phenotype in pediatric-onset Crohn’s disease after more than 10 years follow-up-Cohort study

Digestive and Liver Diseases

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Pancreatic Safety of Sitagliptin in the TECOS Study

Diabetes Care

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Four-factor prothrombin complex concentrate for coagulopathy reversal in patients with liver disease

Clinical and Applied Thrombosis/Hemostasis

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‘Pre-endoscopy point of care test (Simtomax- IgA/IgG-Deamidated Gliadin Peptide) for coeliac disease in iron deficiency anaemia: Diagnostic accuracy and a cost saving economic model’

BMC Gastroenterology

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Factors influencing delayed hospital presentation in patients with appendicitis: The APPE survey

Journal of Surgical Research

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No evidence of firstly acquired acute hepatitis C virus infection outbreak among HIV-infected patients from Southern Spain: A multicentric retrospective study from 2000-2014

BMC Infectious Diseases

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Primary appendiceal lymphoma: clinical characteristics and outcomes of 116 patients

Journal of Surgical Research

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Preoperative Short Course Radiotherapy for Rectal Cancer Provides Excellent Disease Control and Toxicity: Results from a Single US Institution

Practical Radiation Oncology

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Vascular territories of the medial upper arm—an anatomic study of the vascular basis for individualized flap design

Abstract

Background

Fasciocutaneous flaps supplied by discrete perforator arteries can be raised in numerous parts of the human body and are routinely used in plastic surgery. The aim of this anatomical investigation was to provide a description of the vascular supply of the medial upper arm, to localize and measure the perforator arteries and to define potential perforator flap dimensions in pendency of individual anatomical conditions.

Material and Methods

A total of 20 upper limbs from 11 fresh cadavers were examined. The brachial arteries were exposed and the medial perforator arteries selectively injected with methylene blue and india ink in an alternating sequence. The size of the angiosomes, the diameter and length of the perforators' pedicles and distances between the arteries and the medial epicondyle and apex of the axilla respectively were measured.

Results

On average, 4.55 ± 1.47 perforating arteries arose from the brachial artery and it's medial off branching arteries. Their mean diameter was 0.68 ± 0.27 mm and their pedicles had an average length of 3.62 ± 1.61 cm measured from suprafascial until arborisation. In 80% the first proximal perforator was present in an area of 4 cm radius at centre coordinates of (20/2). A constant distal perforator was found within a circle of 3 cm radius, of which the centre had the coordinates (8/1). The average size of the angiosomes was 121.1 ± 58.5 cm². Direct branches of the brachial artery feed circular shaped vascular territories, whereas superior ulnar collateral arteries (SUCAs) feed oblong shaped territories.

Conclusion

This anatomical study provides valuable data of the medial arm flap in order to be applied clinically. © 2016 Wiley Periodicals, Inc.

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Ectopic implantation of an avulsed scalp with a tissue expander on a forearm for combined total scalp avulsion and spine injuries: a case report

Abstract

Total scalp avulsion with severe cervical spine injury is a contraindication for emergency replantation of the scalp to its anatomical site. We describe a case involving the ectopic implantation of an avulsed scalp on the forearm. A 41-year-old woman presented with severe total scalp avulsion and tears in the intervertebral discs at the C4/5 and C5/6 levels. The avulsed scalp was ectopically implanted on the left forearm with a tissue expander to provide support. Two-stage replantation of the scalp at its anatomical site was performed 19 and 40 days later. Replantation was successful, and the avulsed tissue exhibited excellent viability. In conclusion, this case shows that the ectopic implantation of the avulsed scalp on the forearm may be an option for total scalp avulsion with cervical spine injury.

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Effect of fibrin sealant in positioning and stabilizing microvascular pedicle: A comparative study

Abstract

Introduction

Fibrin sealants have had applications in hemostasis, cohesion, and promotion of healing in plastic surgery. In this article, we review cases where fibrin sealant was used to stabilize microvascular pedicles and compared with previous free flaps performed without fibrin sealant.

Methods

Between 2008 and 2010, 62 consecutive patients underwent free tissue transfer for reconstruction; this involved 33 latissimus dorsi perforator flaps, 14 thoracodorsal artery perforator flaps, 9 latissimus dorsi myocutaneous flaps, 3 lateral thoracic artery perforator flaps, and 3 transverse rectus abdominis myocutaneous flaps, used in head and neck reconstruction, lower limb reconstructions, breast reconstructions, and facial palsy reconstruction. Following microvascular anastomosis, the microvascular pedicles were placed in the optimal position, and fibrin sealant was used to fix and stabilize them. The complications, such as venous thrombosis, arterial thrombosis, hematoma, and vascular pedicle kinking, were compared with that of 672 previous free flaps without fibrin sealant for stabilizing microvascular pedicles.

Results

Among the 62 free tissue transfers using fibrin sealant, there was only one complication involving flap failure (1.6%), in this case due to venous thrombosis. Analysis of 672 free flaps performed without application of fibrin sealant revealed 24 complications (3.6%), due to 3 venous thrombosis, 1 arterial thrombosis, 4 vascular pedicel compression due to hematoma, and 16 pedicle kinking. However, the comparison of complications between the free flap using fibrin sealant and the free flap without fibrin sealant were not statistically significant (P = 0.65).

Conclusions

Fibrin sealant can be used to prevent vascular kinking and to position anastomosed vessels after successful micro-anastomosis and allow the reconstructive surgeon to overcome challenging situations of vascular pedicle related complications

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A de novo mutation in the NALCN gene in an adult patient with cerebellar ataxia associated with intellectual disability and arthrogryposis

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IJMS, Vol. 17, Pages 1567: Advanced Glycation End-Products Induce Apoptosis of Vascular Smooth Muscle Cells: A Mechanism for Vascular Calcification

Vascular calcification, especially medial artery calcification, is associated with cardiovascular death in patients with diabetes mellitus and chronic kidney disease (CKD). To determine the underlying mechanism of vascular calcification, we have demonstrated in our previous report that advanced glycation end-products (AGEs) stimulated calcium deposition in vascular smooth muscle cells (VSMCs) through excessive oxidative stress and phenotypic transition into osteoblastic cells. Since AGEs can induce apoptosis, in this study we investigated its role on VSMC apoptosis, focusing mainly on the underlying mechanisms. A rat VSMC line (A7r5) was cultured, and treated with glycolaldehyde-derived AGE-bovine serum albumin (AGE3-BSA). Apoptotic cells were identified by Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. To quantify apoptosis, an enzyme-linked immunosorbent assay (ELISA) for histone-complexed DNA fragments was employed. Real-time PCR was performed to determine the mRNA levels. Treatment of A7r5 cells with AGE3-BSA from 100 µg/mL concentration markedly increased apoptosis, which was suppressed by Nox inhibitors. AGE3-BSA significantly increased the mRNA expression of NAD(P)H oxidase components including Nox4 and p22phox, and these findings were confirmed by protein levels using immunofluorescence. Dihydroethidisum assay showed that compared with cBSA, AGE3-BSA increased reactive oxygen species level in A7r5 cells. Furthermore, AGE3-induced apoptosis was significantly inhibited by siRNA-mediated knockdown of Nox4 or p22phox. Double knockdown of Nox4 and p22phox showed a similar inhibitory effect on apoptosis as single gene silencing. Thus, our results demonstrated that NAD(P)H oxidase-derived oxidative stress are involved in AGEs-induced apoptosis of VSMCs. These findings might be important to understand the pathogenesis of vascular calcification in diabetes and CKD.

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IJMS, Vol. 17, Pages 1569: Molecular Characterization and Growth Association of Two Apolipoprotein A-Ib Genes in Common Carp (Cyprinus carpio)

Apolipoprotein A-I (ApoA-I) is functionally involved in the transportation and metabolism of lipids in vertebrates. In this study, two isoforms of apoA-Ib in common carp (Cyprinus carpio L.) were characterized. Sequence comparison and phylogenetic analysis showed that C. carpio ApoA-Ib is relatively conserved within cyprinid fishes. During embryonic development, C. carpio apoA-Ib was first expressed at the stage of multi-cells, and the highest mRNA level was observed at the stage of optic vesicle. A ubiquitous expression pattern was detected in various tissues with extreme predominance in the liver. Significantly different expression levels were observed between light and heavy body weight groups and also in the compensatory growth test. Seventeen and eight single-nucleotide polymorphisms (SNPs) were identified in matured mRNA of the C. carpio apoA-Ib.1 and apoA-Ib.2, respectively. Two of these SNPs (apoA-Ib.2-g.183A>T and apoA-Ib.2-g.1753C>T) were significantly associated with body weight and body length in two populations of common carp. These results indicate that apoA-Ib may play an important role in the modulation of growth and development in common carp.

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IJMS, Vol. 17, Pages 1565: Plant-to-Plant Variability in Root Metabolite Profiles of 19 Arabidopsis thaliana Accessions Is Substance-Class-Dependent

Natural variation of secondary metabolism between different accessions of Arabidopsis thaliana (A. thaliana) has been studied extensively. In this study, we extended the natural variation approach by including biological variability (plant-to-plant variability) and analysed root metabolic patterns as well as their variability between plants and naturally occurring accessions. To screen 19 accessions of A. thaliana, comprehensive non-targeted metabolite profiling of single plant root extracts was performed using ultra performance liquid chromatography/electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC/ESI-QTOF-MS) and gas chromatography/electron ionization quadrupole mass spectrometry (GC/EI-QMS). Linear mixed models were applied to dissect the total observed variance. All metabolic profiles pointed towards a larger plant-to-plant variability than natural variation between accessions and variance of experimental batches. Ratios of plant-to-plant to total variability were high and distinct for certain secondary metabolites. None of the investigated accessions displayed a specifically high or low biological variability for these substance classes. This study provides recommendations for future natural variation analyses of glucosinolates, flavonoids, and phenylpropanoids and also reference data for additional substance classes.

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Ultrastrong trapping of VEGF by graphene oxide: Anti-angiogenesis application

Publication date: December 2016
Source:Biomaterials, Volume 109
Author(s): Pei-Xin Lai, Chung-Wein Chen, Shih-Chun Wei, Tzu-Yu Lin, Hong-Jyuan Jian, Irving Po-Jung Lai, Ju-Yi Mao, Pang-Hung Hsu, Han-Jia Lin, Wen-Shyong Tzou, Shiow-Yi Chen, Scott G. Harroun, Jui-Yang Lai, Chih-Ching Huang
Angiogenesis is the process of formation of new blood vessels, which is essential to human biology, and also plays a crucial role in several pathologies such as tumor growth and metastasis, exudative age-related macular degeneration, and ischemia. Vascular endothelial growth factor (VEGF), in particular, VEGF-A165 is the most important pro-angiogenic factor for angiogenesis. Thus, blocking the interaction between VEGFs and their receptors is considered an effective anti-angiogenic strategy. We demonstrate for that first time that bovine serum albumin-capped graphene oxide (BSA−GO) exhibits high stability in physiological saline solution and possesses ultrastrong binding affinity towards VEGF-A165 [dissociation constant (Kd) ∼3 × 10⁻¹² M], which is at least five orders of magnitude stronger than that of high-abundant plasma proteins such as human serum albumin, fibrinogen, transferrin, and immunoglobulin G. Due to the surprising binding specificity of BSA−GO for VEGF-A165 in complex plasma fluid, we have also studied the anti-angiogenic effects in vitro and in vivo. Results show that BSA−GO not only effectively inhibits the proliferation, migration and tube formation of human umbilical vein endothelial cells, but also strongly disturbs the physiological process of angiogenesis in chick chorioallantoic membrane and blocks VEGF-A165-induced blood vessel formation in rabbit corneal neovascularization. Our findings indicate that GO nanomaterials can potentially act as therapeutic anti-angiogenic agents via ultrastrong VEGF adsorption and its activity suppression.

Graphical abstract

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Treatment of spinal cord injury by an advanced cell transplantation technology using brain-derived neurotrophic factor-transfected mesenchymal stem cell spheroids

Publication date: December 2016
Source:Biomaterials, Volume 109
Author(s): Satoshi Uchida, Kentaro Hayakawa, Toru Ogata, Sakae Tanaka, Kazunori Kataoka, Keiji Itaka
Curing spinal cord injury (SCI) is challenging because of the onset of multiple and irreversible pathological responses to such injury. To suppress the responses, we employed an advanced cell transplantation technology integrating three-dimensional spheroid cell transplantation with non-viral gene transfection using biodegradable polycations. Brain-derived neurotrophic factor (BDNF)-transfected mesenchymal stem cell (MSC) spheroids were transplanted at thoraces level (Th9) to SCI region in mice. BDNF-transfected MSC spheroid transplantation led to a significantly enhanced recovery of hindlimb motor function in acute phase of SCI with myelinated axons preserved at the SCI region, while use of either technology in isolation, BDNF transfection or spheroid culture, exerted only a limited therapeutic effect, demonstrating the importance of integrated approaches. Secretion of endogenous therapeutic proteins, such as anti-inflammatory factors, was greater in MSC spheroids than in monolayer culture MSCs, and these factors appeared to act synergistically alongside BDNF secretion in SCI treatment. This study forms a basis for cell therapy regulating complex pathophysiologic processes.



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Prenatal diagnosis of 17q12 deletion syndrome: from fetal hyperechogenic kidneys to high risk for autism

Abstract

Objective

The linkage between 17q12 microdeletions, renal anomalies and higher risk for neuro-developmental disorders is well described in the literature. The current study presents prenatal diagnosis of normal-sized hyperechogenic fetal kidneys leading to the diagnosis of 17q12 deletion syndrome and autistic spectrum disorder.

Methods:

Over a period of nine years in a single referral center, seven fetuses were diagnosed with hyperechogenic renal parenchyma and followed prospectively. Amniocentesis for molecular diagnosis was performed in all cases, and subsequently five fetuses were found to harbor a 17q12 deletion by chromosomal microarray analysis. Postnatal evaluation was carried out by a developmental neurologist.

Results

Five of the seven fetuses had molecular diagnosis of 17q12 deletion. One patient elected termination of pregnancy. On long term follow up all of the four children showed symptoms consistent with neurodevelopmental disorders.

The two fetuses with no deletion have a normal follow up with regression of the renal hyper-echogenicity.

Conclusions

We report a strikingly high correlation between prenatal hyperechogenic kidneys, 17q12 micro deletion and autistic spectrum disorder with the advantage of optimal prenatal counseling as well as early diagnosis and intervention.

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Commentary on ‘Monitoring of Foot Oxygenation with Near-infrared Spectroscopy in Patients with Critical Limb Ischemia Undergoing Percutaneous Transluminal Angioplasty: A Pilot Study’

Publication date: Available online 15 September 2016
Source:European Journal of Vascular and Endovascular Surgery
Author(s): N. De Luccia




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Starving cancer from the outside and inside: separate and combined effects of calorie restriction and autophagy inhibition on Ras-driven tumors

Abstract

Background

Calorie restriction (CR) prevents obesity and exerts anticancer effects in many preclinical models. CR is also increasingly being used in cancer patients as a sensitizing strategy prior to chemotherapy regimens. While the beneficial effects of CR are widely accepted, the mechanisms through which CR affects tumor growth are incompletely understood. In many cell types, CR and other nutrient stressors can induce autophagy, which provides energy and metabolic substrates critical for cancer cell survival. We hypothesized that limiting extracellular and intracellular substrate availability by combining CR with autophagy inhibition would reduce tumor growth more effectively than either treatment alone.

Results

A 30 % CR diet, relative to control diet, in nude mice resulted in significant decreases in body fat, blood glucose, and serum insulin, insulin-like growth factor-1, and leptin levels concurrent with increased adiponectin levels. In a xenograft model in nude mice involving H-Ras^G12V-transformed immortal baby mouse kidney epithelial cells with (Atg5 ^+/+ ) and without (Atg5 ^−/−) autophagic capacity, the CR diet (relative to control diet) genetically induced autophagy inhibition and their combination, each reduced tumor development and growth. Final tumor volume was greatest for Atg5 ^+/+ tumors in control-fed mice, intermediate for Atg5 ^+/+ tumors in CR-fed mice and Atg5 ^−/− tumors in control-fed mice, and lowest for Atg5 ^−/− tumors in CR mice. In Atg5 ^+/+ tumors, autophagic flux was increased in CR-fed relative to control-fed mice, suggesting that the prosurvival effects of autophagy induction may mitigate the tumor suppressive effects of CR. Metabolomic analyses of CR-fed, relative to control-fed, nude mice showed significant decreases in circulating glucose and amino acids and significant increases in ketones, indicating CR induced negative energy balance. Combining glucose deprivation with autophagy deficiency in Atg5 ^−/− cells resulted in significantly reduced in vitro colony formation relative to glucose deprivation or autophagy deficiency alone.

Conclusions

Combined restriction of extracellular (via CR in vivo or glucose deprivation in vitro) and intracellular (via autophagy inhibition) sources of energy and nutrients suppresses Ras-driven tumor growth more effectively than either CR or autophagy deficiency alone. Interventions targeting both systemic energy balance and tumor-cell intrinsic autophagy may represent a novel and effective anticancer strategy.

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Effect of Tulsi ( Ocimum sanctum Linn.) Supplementation on Metabolic Parameters and Liver Enzymes in Young Overweight and Obese Subjects

Abstract

Ocimum sanctum Linn. (also known as Tulsi) is a sacred Indian plant, the beneficial role of which, in obesity and diabetes is described traditionally. This is a randomized, parallel group, open label pilot study to investigate the effect of O. sanctum on metabolic and biochemical parameters in thirty overweight/obese subjects, divided into two groups A and B. Group A (n = 16) received one 250 mg capsule of Tulsi (O. sanctum) extract twice daily in empty stomach for 8 weeks and group B (n = 14) received no intervention. Statistically significant improvements in the values of serum triglycerides (p = 0.019); low density lipoprotein (p = 0.001); high density lipoprotein (p = 0.001); very low density lipoprotein (p = 0.019); Body Mass Index, BMI (p = 0.005); plasma insulin (p = 0.021) and insulin resistance (p = 0.049) were observed after 8 weeks in the O. sanctum intervention group. The improvement in HDL-C in the intervention group when compared to the control group was also statistically significant (p = 0.037). There was no significant alteration of the liver enzymes SGOT and SGPT in both the intervention (p = 0.141; p = 0.074) and control arms (p = 0.102; p = 0.055) respectively. These observations clearly indicate the beneficial effects of O. sanctum on various biochemical parameters in young overweight/obese subjects.

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Chimpanzees ( Pan troglodytes ) Flexibly Use Introduced Species for Nesting and Bark Feeding in a Human-Dominated Habitat

Abstract

As habitat loss and fragmentation place growing pressure on endangered nonhuman primate populations, researchers find increasing evidence for novel responses in behavior. In western Uganda between the Budongo and Bugoma Forests, chimpanzees (Pan troglodytes schweinfurthii) inhabit a mosaic landscape comprising forest fragments, human settlements, and agricultural land. We recorded nests and feeding evidence of unhabituated chimpanzees in this region over a 12-mo period. We found extensive evidence of nesting in introduced tree species, including eucalyptus (Eucalyptus grandis), guava (Psidium guajava), cocoa (Theobroma cacao), and Caribbean pine (Pinus caribaea). In addition, we found instances of ground nesting, nest reuse, and composite nests constructed from branches of multiple trees. This evidence may indicate a lack of suitable nesting trees or attempts by chimpanzees to nest in areas of riparian forest that allow them to avoid human detection. We also found new evidence for eucalyptus bark feeding by chimpanzees. Such evidence suggests chimpanzees respond flexibly to mitigate anthropogenic pressures in human-dominated landscapes. The limits of such flexibility remain unknown. Further research is needed to examine systematically the factors influencing the use of such resources and to understand better the extent to which chimpanzees can persist while relying on them.

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Impact of Measuring Patient-Reported Outcomes in Dermatology Drug Development

Abstract

Although some symptoms of dermatologic diseases, such as pruritus and pain, can be subjectively assessed only by patients, the most commonly used endpoints in dermatology drug research traditionally have been clinician-reported outcomes. Research has found that patient-reported outcomes (PROs) were included in only one-quarter of 125 trials conducted between 1994 and 2001. Our objective was to characterize the impact of PROs in dermatology drug development from the patient, prescriber, regulator, payer, and manufacturer perspectives using a case study approach. We conducted a structured literature review for pivotal clinical trials using PROs for six dermatologic products (MAS063DP, onabotulinumtoxinA, calcipotriene hydrate plus betamethasone dipropionate, pimecrolimus, tacrolimus, and ustekinumab). We also searched regulatory websites to identify product labeling and the UK National Institute for Health and Care Excellence website to identify submissions for the products of interest. A total of 32 articles illustrating the various perspectives were selected for inclusion. Clinical trials that include PROs allow patients to differentiate among treatments based on the experience of other patients participating in trials and enable prescribers to understand the benefit–risk profile of new treatments. The inclusion of PROs enables regulators to evaluate product benefits with a patient-centered perspective; five of the products of interest obtained eight total product labeling statements. PRO data supported manufacturers' dissemination of product benefits in the form of publications and PRO labeling for the product. For payers, PRO data were used in an analysis of cost effectiveness of new treatments. Inclusion of PROs in dermatology drug development programs benefits patients, prescribers, regulators, manufacturers, and payers.

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Role of Fluorouracil, Doxorubicin, and Streptozocin Therapy in the Preoperative Treatment of Localized Pancreatic Neuroendocrine Tumors

Abstract

Introduction

5-Fluorouracil, doxorubicin, and streptozocin (FAS) leads to a 39 % response rate in advanced pancreatic neuroendocrine tumors (pNETs). We sought to validate our hypothesis that preoperative FAS may facilitate resection of locoregionally advanced pNETs by reducing the anatomic extent of the primary tumor.

Patients

All patients who received FAS between 2000 and 2012 as initial therapy for a localized pNET were reviewed. Tumor size and vascular relationships were compared on pretreatment and posttreatment imaging studies to quantify treatment response.

Results

Twenty-nine patients received a median 4 cycles of FAS (range 2–15). Rates of RECIST progressive disease (PD), stable disease (SD), and partial response (PR) were 3, 90, and 7 %, respectively. An interface was observed between the tumor and a major mesenteric artery and/or vein in 19 (66 %) and 24 (83 %) patients, respectively; after therapy with FAS, 17 (59 %) and 22 (76 %) had persistent interface with artery and/or vein. Fourteen (48 %) patients underwent pancreatectomy, 7 (50 %) required vascular management, and 9 (64 %) operations were R0. The median overall survival of unresected and resected patients was 41 months (95 % CI, 16–66) and 112 months (95 % CI, 104–120) (P = 0.04).

Conclusions

Although patients receiving FAS for locoregionally advanced pNETs are unlikely to progress during systemic therapy, significant "downstaging" appears uncommon.

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Is Modern Medical Management Changing Ultimate Patient Outcomes in Inflammatory Bowel Disease?

Abstract

Background

The impact of modern medical management of inflammatory bowel disease (IBD) on surgical necessity and outcomes remains unclear. We hypothesized that surgery rates have decreased while outcomes have worsened due to operating on "sicker" patients since the introduction of biologic medications.

Methods

The Nationwide Inpatient Sample and ICD-9-CM codes were used to identify inpatient admissions for Crohn's disease and ulcerative colitis. Trends in IBD nutrition, surgeries, and postoperative complications were determined.

Results

There were 191,743 admissions for IBD during the study period. Surgery rates were largely unchanged over the study period, ranging from 9 to 12 % of admissions in both Crohn's disease and ulcerative colitis. The rate of poor nutrition increased by 67 % in ulcerative colitis and by 83 % in Crohn's disease. Rates of postoperative anastomotic leak (10.2–13.9 %) were unchanged over the years. Postoperative infection rates decreased by 17 % in Crohn's disease (18 % in 2003 to 15 % in 2012; P < 0.001) but did not show a trend in any direction in ulcerative colitis.

Conclusions

Rates of IBD surgery have remained stable while postoperative infectious complications have remained stable or decreased since the implementation of biologic therapies. We identified an increase in poor nutrition in surgical patients.

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Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Cardiovascular disease is the leading cause of death and complications in patients with type 2 diabetes. Recently, trials evaluating a sodium–glucose cotransporter 2 inhibitor (empagliflozin) and a glucagon-like peptide 1 (GLP-1) analogue (liraglutide) have shown improved cardiovascular outcomes…

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Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Cardiovascular disease is the leading cause of death and complications in patients with type 2 diabetes. Recently, trials evaluating a sodium–glucose cotransporter 2 inhibitor (empagliflozin) and a glucagon-like peptide 1 (GLP-1) analogue (liraglutide) have shown improved cardiovascular outcomes…

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Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Cardiovascular disease is the leading cause of death and complications in patients with type 2 diabetes. Recently, trials evaluating a sodium–glucose cotransporter 2 inhibitor (empagliflozin) and a glucagon-like peptide 1 (GLP-1) analogue (liraglutide) have shown improved cardiovascular outcomes…

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The role of microRNAs in the pathogenesis of autoimmune diseases

Publication date: Available online 15 September 2016
Source:Autoimmunity Reviews
Author(s): Ji-Qing Chen, Gábor Papp, Péter Szodoray, Margit Zeher
MicroRNAs (miRNAs) are single-stranded, endogenous non-coding small RNAs, ranging from 18 to 25 nucleotides in length. Growing evidence suggests that miRNAs are essential in regulating gene expression, cell development, differentiation and function. Autoimmune diseases are a family of chronic systemic inflammatory diseases. Recent findings on miRNA expression profiles have been suggesting their role as biomarkers in autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis and Sjögren's syndrome. In this review, we summarize the characteristics of miRNAs and their functional role in the immune system and autoimmune diseases including systemic lupus erythematosus, primary Sjögren's syndrome, rheumatoid arthritis, systemic sclerosis, multiple sclerosis and psoriasis; moreover, we depict the advantages of miRNAs in modern diagnostics.



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Dry eye disease and uveitis: a closer look at immune mechanisms in animal models of two ocular autoimmune diseases

Publication date: Available online 15 September 2016
Source:Autoimmunity Reviews
Author(s): Tanima Bose, Maria Diedrichs-Moehring, Gerhild Wildner
Understanding the immunopathogenesis of autoimmune and inflammatory diseases is a prerequisite for specific and effective therapeutical intervention. This review focuses on animal models of two common ocular inflammatory diseases, dry eye disease (DED), affecting the ocular surface, and uveitis with inflammation of the inner eye. In both diseases autoimmunity plays an important role, in idiopathic uveitis immune reactivity to intraocular autoantigens is pivotal, while in dry eye disease autoimmunity seems to play a role in one subtype of disease, Sjögren's syndrome (SjS). Comparing the immune mechanisms underlying both eye diseases reveals similarities, and significant differences. Studies have shown genetic predispositions, T and B cell involvement, cytokine and chemokine signatures and signaling pathways as well as environmental influences in both DED and uveitis. Uveitis and DED are heterogeneous diseases and there is no single animal model, which adequately represents both diseases. However, there is evidence to suggest that certain T cell-targeting therapies can be used to treat both, dry eye disease and uveitis. Animal models are essential to autoimmunity research, from the basic understanding of immune mechanisms to the pre-clinical testing of potential new therapies.



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Psoriasis and autoimmunity

Publication date: Available online 15 September 2016
Source:Autoimmunity Reviews
Author(s): Michael Sticherling
Psoriasis is one of the most common chronic inflammatory human skin diseases. Though clinically well characterized, the exact etiological and pathogenic mechanisms are still not known in detail. Current knowledge indicates distinct overlap to other inflammatory as well as autoimmune disorders. However, the one or more relevant autoantigens could not be characterized so-far. On the other side, several autoimmune diseases were shown to be associated with psoriasis. In addition, serological autoimmune phenomena, namely diverse circulating specific autoantibodies could be demonstrated in the past. A matter of current debate is if psoriasis is a primary autoimmune disease or secondarily evolving into autoimmunity as seen in other chronic inflammatory diseases. Related to this aspect is the concept of autoinflammation versus autoimmunity where psoriasis shares mechanisms of both entities. Though T-cells remain among the most important cellular players in the pathogenesis of psoriasis and current therapeutic strategies successfully target these cells or their products irrespective of these concepts, autoimmunity if relevant will add to the treatment armamentarium by using protective and prophylactic antigen-specific modalities.



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Cognitive Disorders and Antiphospholipid Antibodies

Publication date: Available online 15 September 2016
Source:Autoimmunity Reviews
Author(s): Cécile M. Yelnik, Elizabeth Kozora, Simone Appenzeller
Cognitive disorders have frequently been described in the field of antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE). Nevertheless, the relationship between those disorders and antiphospholipid antibodies (aPL) remains unclear and seems to involve various mechanisms. Overlap with systemic lupus erythematosus, the small sample size of studies, and discrepancies in antiphospholipid antibodies and cognitive impairment determinations complicate analyzes of the literature data. In this paper, we summarize current knowledge on epidemiologic, clinical data, imaging findings and treatment of cognitive dysfunction associated with aPL. We analyzed separately data on aPL-positive carriers without history of clinical feature of APS; APS patients without overlaps autoimmune disease; and SLE associated aPL patients.



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Steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT): Characteristics, treatment and outcome in 251 cases from the literature

Publication date: Available online 15 September 2016
Source:Autoimmunity Reviews
Author(s): Charlotte Laurent, Jean Capron, Bluenn Quillerou, Guy Thomas, Sonia Alamowitch, Olivier Fain, Arsène Mekinian
BackgroundSteroid-responsive encephalopathy and associated autoimmune thyroiditis (SREAT) is characterized by encephalopathy and the presence of antithyroid antibodies. We describe the clinical presentation, outcome and treatments for SREAT by a systematic review of the literature.MethodsMEDLINE via PubMed, Web of Science and the Cochrane Library were searched for articles published until 2015. Inclusion criteria were unexplained encephalopathy with antithyroid antibodies.ResultsWe found reports of 251 patients (median age 52years [range 18–86], 73% females, 80 [32%] with preexisting thyroiditis). Patients presented encephalitis signs with convulsions (n=117; 47%), confusion (n=115, 46%), speech disorder (n=91, 37%), memory impairment (n=107, 43%), gait disturbance (n=67, 27%) and persecutory delusions (n=61, 25%). Twenty-eight patients (11%) presented progressive memory impairment and 26 (10%) isolated psychiatric disorders. In serum, 34% of patients were positive for anti-thyroid peroxidase (TPO) antibodies, 7% for anti-thyroglobulin (TG) antibodies, and 69% both. Thyroid-stimulating hormone levels were usually normal, at 2 UI/ml [0.001–205]. Cerebrospinal fluid from 10/53 patients (19%) was positive for anti-TPO antibodies, 2/53 (4%) anti-TG antibodies and 28 (53%) both. Electroencephalography findings were abnormal for 82% of patients, showing diffuse slowing consistent with encephalopathy (70%) or epileptic activity (14%). The first-line treatment was steroids in 193 patients and other immunosuppressive drugs in 10 cases. At a median follow-up of 12months [range 0.2–110], 91% of patients showed complete or partial neurological response, with anti-TPO and -TG antibody titers at 347 UI/ml [0–825000] and 110 UI/ml [0–50892], respectively. During follow-up, 40 patients (16%) experienced at least one relapse. Relapse was more frequent in patients with initial coma (26% vs 13%, p=0.08).ConclusionThe diagnosis of SREAT should be suspected in case of encephalopathy without obvious cause, to quickly start corticosteroid treatment. The exact modalities of treatment must be defined.



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Catastrophic antiphospholipid syndrome (CAPS): Descriptive analysis of 500 patients from the International CAPS Registry

Publication date: Available online 15 September 2016
Source:Autoimmunity Reviews
Author(s): Ignasi Rodríguez-Pínto, Marta Moutinho, Irene Santacreu, Yehuda Shoenfeld, Doruk Erkan, Gerard Espinosa, Ricard Cervera
ObjectiveTo analyze the clinical and immunologic manifestations of patients with catastrophic antiphospholipid syndrome (CAPS) from the "CAPS Registry".MethodsThe demographic, clinical and serological features of 500 patients included in the website-based "CAPS Registry" were analyzed. Frequency distribution and measures of central tendency were used to describe the cohort. Comparison between groups regarding qualitative variables was undertaken by chi-square or Fisher exact test while T-test for independent variables was used to compare groups regarding continuous variables.Results500 patients (female: 343 [69%]; mean age 38±17) accounting for 522 episodes of CAPS where included in the analysis. Forty percent of patients had an associated autoimmune disease, mainly systemic lupus erythematosus (SLE) (75%). The majority of CAPS episodes were triggered by a precipitating factor (65%), mostly infections (49%). Clinically, CAPS was characterized by several organ involvement affecting kidneys (73%), lungs (60%), brain (56%), heart (50%), and skin (47%). Lupus anticoagulant, IgG anticardiolipin and IgG anti-β2-glycprotein antibodies were the most often implicated antiphospholipid antibodies (83%, 81% and 78% respectively). Mortality accounted for 37% of episodes of CAPS.Several clinical differences could be observed based on the age of presentation and its association to SLE. Those cases triggered by a malignancy tended to occur in older patients, while CAPS episodes in young patients were associated with an infectious trigger and peripheral vessels involvement. Additionally, CAPS associated with SLE were more likely to have severe cardiac and brain involvement leading to a higher mortality (48%).ConclusionAlthough the presentation of CAPS is characterized by multiorgan thrombosis and failure, clinical differences among patients exist based on age and underlying chronic diseases, e.g. malignancy, SLE.



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The association of other autoimmune diseases in patients with autoimmune thyroiditis: Review of the literature and report of a large series of patients

Publication date: Available online 15 September 2016
Source:Autoimmunity Reviews
Author(s): Poupak Fallahi, Silvia Martina Ferrari, Ilaria Ruffilli, Giusy Elia, Marco Biricotti, Roberto Vita, Salvatore Benvenga, Alessandro Antonelli
We have evaluated prospectively the prevalence of other autoimmune disorders in outpatient clinic in 3069 consecutive patients with diagnosed chronic autoimmune thyroiditis (AT), with respect to two age- and sex-matched control groups: a) a control group of 1023 subjects, extracted from a random sample of the general population without thyroid disorders; b) 1023 patients with non-toxic multinodular goiter extracted from the same random sample of the general population, with similar odine intake. The results of our study demonstrate a significant increase of the prevalence of autoimmune disorders in AT patients (with respect to both controls), for the following diseases: chronic autoimmune gastritis (CAG), vitiligo (Vit), rheumatoid arthritis, polymialgia rheumatica (Polym), celiac disease, diabetes, sjogren disease, multiple sclerosis, systemic lupus erythematosus, sarcoidosis, alopecia, psoriathic arthritis, systemic sclerosis, HCV-related cryoglobulinemia. While the statistical analysis reached near the significance for Addison's disease and ulcerative colitis. Interestingly, the association of three autoimmune disorders was observed almost exclusively in AT patients, and the most frequent associations were AT+CAG+Vit and AT+CAG+Polym.We suggest that patients with AT who remain unwell, or who develop new not specific symptoms (despite adequate treatment) should be screened for other autoimmune disorders, avoiding the delay in the diagnosis of these disorders.



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Prevalence and predictors of valvular heart disease in patients with systemic lupus erythematosus

Publication date: Available online 15 September 2016
Source:Autoimmunity Reviews
Author(s): Florencia Vivero, Cristina Gonzalez-Echavarri, Beatriz Ruiz, Irene Maderuelo, Guillermo Ruiz-Irastorza
ObjectivesWe aimed to study the frequency, severity and predictors of valvular heart disease (VHD) in our lupus cohort.Material and Methods211 patients were included. A transthoracic echocardiogram was used for this study. Significant valvular lesions were classified into two groups: valvular thickening and valvular dysfunction. Univariate logistic regression was performed in order to find associations with valvular thickening and dysfunction. Those variables with a p value ≤0.1 in the univariate analysis were subsequently included in multiple logistic regression models.ResultsSignificant valve lesions were found in 53 patients (25%). The independent predictors of valvular thickening were the age at the time of the echocardiogram (OR 1.05, 95% CI 1.02–1.7), lymphopenia (OR 3.6, 95%CI 1.4–9.5), thrombocytopenia (OR 2.65, 95%CI 1.24–5.72), and anti-Sm antibodies (OR 3.28, 95%CI 1.44–7.33). The independent predictors of valvular dysfunction were age at the time of the echocardiogram (OR 1.045, 95%CI 1.009–1.083), thrombocytopenia (OR 5, 95%CI 1.66–14.86), hypertension (OR 6.2, 95%CI 2.1–18.4) and aPL (OR 6.2, 95%CI 2.1–18.4). Regarding the latter, the independent relation with valvular dysfunction was only seen for the double positivity aCL/LA, (OR 13.2, 95%CI 3.8–45.2, p<0.0001).ConclusionsOur study confirms the high prevalence of significant VHD in SLE patients. Clinical variables related with persistent inflammatory activity were associated with VHD. The association between VHD and aPL positivity was confirmed. Double-positive aCL/LA patients were most likely to suffer from valvular dysfunction.



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