Circulating tumour DNA, a promising biomarker for the management of colorectal cancer

Publication date: Available online 16 December 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Shelize Khakoo, Alexandros Georgiou, Marco Gerlinger, David Cunningham, Naureen Starling
Circulating cell free tumour DNA (ctDNA) maintains the same genomic alterations that are present in the corresponding tumour, thereby allowing for quantitative and qualitative real-time evaluation in body fluids as an alternative to onerous repeat biopsies. Improvements in the sensitivity of techniques used to identify ctDNA has led to a surge of research investigating its role in the detection of: early disease, relapse, response to therapy and emerging drug resistance mechanisms. Following curative surgery, ctDNA detection is a promising marker of minimal residual disease and could better select patients for adjuvant chemotherapy. Longitudinal monitoring could help identify early relapse. In metastatic disease, ctDNA can predict response to chemotherapy prior to evidence of disease progression on imaging and investigate novel primary and acquired resistance mechanisms to targeted therapies. More experience in detecting, analysing and interpreting ctDNA within prospective trials, will better define its role for implementation into routine clinical practice.



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A SYSTEMATIC REVIEW OF THE SAFETY PROFILE OF THE DIFFERENT COMBINATIONS OF FLUOROPYRIMIDINES AND OXALIPLATIN IN THE TREATMENT OF COLORECTAL CANCER PATIENTS

Publication date: Available online 16 December 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Chiara Baratelli, Clizia Zichi, Massimo Di Maio, Maria Pia Brizzi, Cristina Sonetto, Giorgio Vittorio Scagliotti, Marco Tampellini
The available fluoropyrimidines and oxaliplatin combinations for colorectal cancer patients have different safety profiles. The aim of this systematic review was to compare their toxicities.The eligible studies were classified as: no bolus; 5-FU single bolus; 5-FU double bolus; capecitabine. We calculated the incidence of "any-grade" and "severe" toxicity for haematological and non-haematological adverse events of each group.We identified 184 treatment groups; compared to 5-FU double bolus, except for high-grade anaemia, all the groups showed reduced risk of haematological toxicities, with the most relevant advantages for single bolus regimens. Concerning non-haematological toxicities, compared to double bolus, the single bolus group showed a statistically significant reduced risk for many gastrointestinal toxicities and for pheripheral neuropathy.This is the first systematic review of the toxicity profile of different 5-FU or capecitabine and oxaliplatin regimens. Single 5-FU bolus is associated with a definitely favourable toxicity profile, both for haematological and non-haematological toxicity.



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Do the right thing: neural network mechanisms of memory formation, expression and update in Drosophila

Publication date: April 2018
Source:Current Opinion in Neurobiology, Volume 49
Author(s): Paola Cognigni, Johannes Felsenberg, Scott Waddell
When animals learn, plasticity in brain networks that respond to specific cues results in a change in the behavior that these cues elicit. Individual network components in the mushroom bodies of the fruit fly Drosophila melanogaster represent cues, learning signals and behavioral outcomes of learned experience. Recent findings have highlighted the importance of dopamine-driven plasticity and activity in feedback and feedforward connections, between various elements of the mushroom body neural network. These computational motifs have been shown to be crucial for long term olfactory memory consolidation, integration of internal states, re-evaluation and updating of learned information. The often recurrent circuit anatomy and a prolonged requirement for activity in parts of these underlying networks, suggest that self-sustained and precisely timed activity is a fundamental feature of network computations in the insect brain. Together these processes allow flies to continuously adjust the content of their learned knowledge and direct their behavior in a way that best represents learned expectations and serves their most pressing current needs.



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Morphological characteristics and variations of the human quadratus plantae muscle

Publication date: March 2018
Source:Annals of Anatomy - Anatomischer Anzeiger, Volume 216
Author(s): Bettina Pretterklieber
The quadratus plantae (QP) is a highly variable structure. A number of partly inexact descriptions of this entity have been provided in textbooks of anatomy. Although several authors have examined the QP, its exact site of origin and type of insertion have hitherto not been specified. The aim of this study has been to provide detailed qualitative and quantitative data about the number of heads, points of origin, and type of insertion of the QP. The QP in both feet of 50 formalin-fixed specimens of body donors (25 men and women) were analyzed by gross anatomical dissection. It was composed of one (34%), two (57%) or three heads (9%). The latter condition was observed only in men. The lateral head was absent in 31 feet, and the medial head only in one right foot of a man. The medial head arose, amongst others, in 100% of the examined cases from the medial calcaneal surface, in 93% from the long plantar ligament and in 80% from the plantar calcaneocuboid ligament. The lateral head arose, amongst others, from the long plantar ligament in 90%, and from the lateral process of the calcaneal tuberosity in 64% of the examined feet. The type of insertion was always a mixture of at least two of three types; i.e. muscular (84%), tendinous (89%) and aponeurotic (45%). As additional findings, the flexor digitorum accessorius longus (FDAL) and the peroneocalcaneus internus (PCI) were observed in 12% of all individuals and in 20% of men. The present investigation revealed that the QP may be classified according to the number of heads, but no classification can be given for its points of origin or type of insertion. The present data are mandatory for anatomical and surgical practice and will hopefully lead to further imaging and biomechanical studies.



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Periodic acid-Schiff (PAS) reaction and plastination in whole body slices. A novel technique to identify fascial tissue structures

Publication date: March 2018
Source:Annals of Anatomy - Anatomischer Anzeiger, Volume 216
Author(s): Hanno Steinke, Dina Wiersbicki, Marie-Lynn Speckert, Claudia Merkwitz, Thomas Wolfskämpf, Benjamin Wolf
Since collagen rich fascial tissue is often very delicate and difficult to discern on native tissue slices, we have developed a method for staining full-body slices using the periodic acid-Schiff (PAS) reaction with subsequent plastination. Since the PAS reaction primarily stains carbohydrates, we could exploit the circumstance that different collagen types vary in carbohydrate content. Contrary to fasciae, tissues such as muscle, bone, nerves and blood vessels exhibit significantly less staining or remain unstained. We have validated the whole-body slice staining results in microscopic tissue slides which were stained with standard extracellular matrix stains such as Masson-Goldner trichrome stain and van-Gieson stain. Furthermore, we have performed immunofluorescence imaging to confirm the presence of collagen in the stained tissue. We achieved very good staining and plastination results and were able to clearly identify even very thin fascia in transversal body slices. This technique may prove useful in advancing our knowledge on the complex topography of fascial structures.



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Immunolocalization of connective tissue growth factor, transforming growth factor-beta1 and phosphorylated-SMAD2/3 during the postnatal tooth development and formation of junctional epithelium

Publication date: March 2018
Source:Annals of Anatomy - Anatomischer Anzeiger, Volume 216
Author(s): Shubo Li, Yihuai Pan
Connective tissue growth factor (CTGF) is a downstream mediator of transforming growth factor-beta 1 (TGF-β1) and TGF-β1-induced CTGF expression is regulated through SMAD pathway. However, there is no literature showing the expression of TGF-β1-SMAD2/3-CTGF signaling pathway during postnatal tooth development and the formation of junctional epithelium (JE). Hence, we aimed to analyze the localization of TGF-β1, CTGF and phosphorylated SMAD2/3 (p-SMAD2/3) in the developing postnatal rat molars. Wistar rats were killed at postnatal (PN) 0.5, 3.5, 7, 14 and 21days and the upper jaws were processed for immunohistochemistry. At PN0.5 and PN3.5, weak staining for TGF-β1 and CTGF was evident in preameloblasts (PA), while moderate to strong staining was seen in odontoblasts (OD), dental papilla (DPL), secretary ameloblasts (SA), preodontoblasts (PO) and polarized odontoblasts (PoO). There was no staining for p-SMAD2/3 in PA, SA, PO and PoO, although strong staining was localized in DPL. OD was initially moderately positive and then negative for p-SMAD2/3. At PN7, intense staining for TGF-β1 and CTGF was observed in SA, OD, dental pulp (DP) and predentin respectively. p-SMAD2/3 was strongly expressed in DP and moderately expressed in SA and OD. At PN14 and PN21, both reduced enamel epithelium (REE) and JE showed a strong reaction for TGF-β1 and CTGF. p-SMAD2/3 was intensely and weakly expressed in REE and JE respectively. These data demonstrate that the expression of CTGF, TGF-β1 and p-SNAD2/3 is tissue-specific and stage-specific, and indicate a regulatory role for a TGF-β1-SMAD2/3-CTGF signaling pathway in amelogenesis, dentinogenesis and formation of JE.



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Dissociation of mono- and co-culture spheroids into single cells for subsequent flow cytometric analysis

Publication date: March 2018
Source:Annals of Anatomy - Anatomischer Anzeiger, Volume 216
Author(s): Ute Grässer, Monika Bubel, Daniela Sossong, Martin Oberringer, Tim Pohlemann, Wolfgang Metzger
BackgroundSpheroids are considered to reflect the natural organization of cells better than 2D cell cultures, but their analysis by flow cytometry requires dissociation into single cells.MethodsWe established protocols for dissociation of mono- and co-culture spheroids consisting of human fibroblasts and human endothelial cells. Cell recovery rate and viability after dissociation were evaluated with hemocytometer and by flow cytometry. The diameter of cells and the amount of cell aggregates were quantified by Casy^®-technology and the cellular composition was analyzed by flow cytometry.ResultsOptimal dissociation conditions with low cell aggregation were determined by size, cultivation time and cellular composition of the spheroids. Smaller spheroids (10,000 cells) could be dissociated with Accutase^®, whereas larger spheroids (50,000 cells) required more stringent dissociation conditions. The size of the cells decreased with increasing cultivation time. Cell recovery rate was dependent upon cellular composition and spheroid size. The highest cell recovery rate was found for co-culture spheroids. The highest cell viability was detected for dissociated fibroblast spheroids. A quantitative analysis of the cellular composition of dissociated co-culture spheroids was possible.DiscussionSpheroids can be successfully dissociated into singular cells for subsequent flow cytometric analysis. Dissociation conditions as well as cell recovery rate and cell viability depend on size, cultivation time and cellular composition of the spheroids. The observed decrease in cell size in spheroids over time might be responsible for the well-known time-dependent decrease in spheroid size.



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Complications in the treatment of mandibular condylar fractures: Surgical versus conservative treatment

Publication date: March 2018
Source:Annals of Anatomy - Anatomischer Anzeiger, Volume 216
Author(s): Iván García-Guerrero, Juan M. Ramírez, Rafael Gómez de Diego, José M. Martínez-González, María S. Poblador, José L. Lancho
ObjectivesIn the present article, we aim to review the main intra- and post-operative complications associated with two different therapeutic approaches for treating mandibular condylar fractures: conservative (CTR) and surgical treatment (ORIF, Open Reduction and Internal Fixation).Material and methodsWe have carried out a retrospective, meta-analytic, observational study using literature review, covering the period between 2000- September 2017. The data obtained were processed using statistical software SPSS v.0.18 and R v.2.11.1. The chi-squared test was used for comparison of relative frequencies for independent samples.ResultsA total of 2458 patients with 2810 fractures were collected for study. Patients treated with CTR and ORIF were an average of 29 years old, of those treated with CTR, 72.37% and 27.63% were male or female respectively and, of those treated with ORIF, 70.36% and 29.64% were male or female respectively. The main complications suffered by CTR and ORIF patients were: asymmetry (10.2%/6.4%), residual pain (6.5%/5.6%), temporomandibular joint and articular imbalance (15.9%/10.3%) and malocclusion (11.1%/4.0%), respectively. We only found significant differences between CTR and ORIF in the number of cases of temporomandibular joint and articular imbalance and malocclusion.Facial nerve damage was found exclusively among ORIF patients (8.6%) of which 8.3% were temporary and 0.3% permanent.ConclusionsThe complications associated with either technique are minimal and infrequent, resulting in successful outcomes with minimal morbidity. CTR are associated with complications deriving from delayed mobilization leading to functional limitation, whereas the main complication associated with ORIF treatment was facial nerve damage.



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Effect of different resistance-training protocols on the extracellular matrix of the calcaneal tendon of rats

Publication date: March 2018
Source:Annals of Anatomy - Anatomischer Anzeiger, Volume 216
Author(s): Josete Mazon, Andrea Aparecida de Aro, Priscyla Waleska Simões, Edson Rosa Pimentel
The calcaneal tendon extracellular matrix (ECM) is composed of collagen, non-collagenous glycoproteins and proteoglycans, and able to adapt to various biomechanical stimuli. The objective of this study was to analyze the response of different resistance-training protocols, such as hypertrophy, strength and resistance, on the organization of the calcaneal tendon after training. Wistar rats were divided into four groups: untrained (UT), resistance training (RT), hypertrophy training (HT), and strength training (ST). The protocol in a vertical climbing platform was performed thrice per week over twelve weeks. For biochemical study, the tendons of each group were minced and analyzed for gelatinases, quantification of non-collagenous proteins, sulfated glycosaminoglycans, and hydroxyproline. For morphological analysis, sections were stained with HE and toluidine blue. Non-stained sections were used for birefringence analysis under polarization microscopy. The highest hydroxyproline concentrations were found in HT (154.8±14.2) and RT (173.6±25.2) compared with UT (122.4±27.0). A higher concentration of non-collagenous proteins was detected in the RT group (14.98mg/g) compared with the other groups. In polarization microscopy, major birefringence was observed in HT and the lowest in ST compared with UT, indicating higher organization of collagen bundles in HT. In analysis for zymography, the presence of latent MMP-9 was more prominent in the ST group and the active MMP-9 more prominent in the HT group. For MMP-2, significant differences in the latent isoform between the HT (184,867±6765) and UT (173,018±9696) groups were found. In sections stained with toluidine blue (TB), higher metachromasia was observed in the tendon's distal region in HT and RT groups, indicating a greater amount of proteoglycans. We conclude that the different training protocols produced different responses in the ECM. The remarkable presence of MMP-2 and -9 in the hypertrophy training group may be related to the highest organization of collagen bundles and possibly a more efficient remodeling process, observed in that group, as demonstrated by images and measurements of birefringence.



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Editorial Board

Publication date: January 2018
Source:Annals of Anatomy - Anatomischer Anzeiger, Volume 215





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OBC

Publication date: January 2018
Source:Annals of Anatomy - Anatomischer Anzeiger, Volume 215





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Ultrasound assessment of soft tissue augmentation around implants in the aesthetic zone using a connective tissue graft and xenogeneic collagen matrix - 1-year randomised follow-up

Publication date: Available online 15 December 2017
Source:Annals of Anatomy - Anatomischer Anzeiger
Author(s): Monika Puzio, Artur Błaszczyszyn, Jakub Hadzik, Marzena Dominiak
PurposeA comparative, ultrasound evaluation of the thickness of keratinized mucosa (TKT) around implants one year after gingival augmentation (GA) by means of a connective tissue graft (CTG) and the xenogeneic collagen matrix (CMX).Materials and methodsA total of 75 bone level tapered implants (Conelog^® Camlog) were inserted in 57 patients in the aesthetic area of both jaws. The patients were divided into 3 groups: control group I- without GA; group II- GA 3 months before implantation, and group III- GA 3 months after implantation. Groups II and III were divided into two subgroups depends on type of material used for GA: a) CMX (Mucograft^®, Geistlich Pharma AG) and b) CTG. The patients underwent a clinical and ultrasound examination before, then after 3 and 12 months following GA respectively to evaluate TKT at two points using ultrasound equipment (Pirop^®, Echoson). Point 1 was considered to be in the middle of the line connecting the cemento-enamel junction (CEJ) to the adjacent teeth, and point 2 on the mucogingival junction (MGJ).ResultsThree months after GA, the highest increase in gingival thickness was noted in group IIIb (point 1-0.95mm, 2- 1.01mm). However, 12 months after GA the highest gingival thickness was observed in group IIb (point 1- 1.76mm, 2- 1.36m) and next IIIb (point 1- 1.52mm, 2- 1.15mm).ConclusionsBoth CTG and Geistlich Mucograft^® increased TKT, but higher values were noted using CTG augmentation before implantation. An ultrasonic device can be used as a non-invasive, reliable, and reproducible method for evaluating TKT.



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Distribution and neurochemistry of porcine urinary bladder-projecting sensory neurons in subdomains of the dorsal root ganglia: a quantitative analysis

Publication date: Available online 21 November 2017
Source:Annals of Anatomy - Anatomischer Anzeiger
Author(s): Anna Kozłowska, Anita Mikołajczyk, Mariusz Majewski
The aim of the present study has been to verify the inter- and intraganglionic distribution pattern of porcine urinary bladder-projecting (UBP) neurons localized in the sacral dorsal root ganglia (DRGs). The morphology and chemical phenotype of these cells have also been investigated. These neurons were visualized using the fluorescent tracer Fast Blue (FB) which was injected bilaterally into the urinary bladder wall of five juvenile female pigs. The intraganglionic distribution showed that small- and medium-sized FB+ perikarya were mainly located in the central (S3-S4) and periphero-central (S2) region of the ganglia, while large cells were heterogeneously distributed. Immunohistochemistry revealed that the most frequently observed markers in small and medium-sized UBP perikarya were: neurofilament 200, lectin from Bandeiraea simplicifolia (Griffonia simplicifolia) isolectin B4, substance P, calcitonin gene-related peptide, pituitary adenylate cyclase-activating polypeptide and transient receptor potential vanilloid 1. Moreover, UBP neurons containing these substances were also mainly observed in the central and periphero-central region of the ganglion. Differences in the percentage of traced cells and their neuropeptide content were observed between the S2, S3 and S4 DRGs. In conclusion, the present study, for the first time, describes the arrangement of UBP DRGs neurons within particular subdomains of sacral ganglia, taking into account their size and chemical phenotype.



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Evaluation of patients' compliance in different age groups: preventive methodology.

Related Articles

Evaluation of patients' compliance in different age groups: preventive methodology.

Minerva Stomatol. 2017 Dec 14;:

Authors: Maspero C, Galbiati G, Giannini L, Zanoni F, Farronato M, Esposito L

Abstract
BACKGROUND: The aim of this work is to evaluate the effectiveness of the SSRD Department of University of Milan PREVENTION PROGRAM between subjects of different sex and ages.
METHODS: PREVENTION PROGRAM is divided into six stages, in which specific and standardized procedures are effected on patient; then checkups are planned after three months. 90 patients (48 females, 42 males) were included. Subjects were divided into three ages groups: 6-9, 10- 12 and over 12 years old. Plaque Index, Bleeding Index, and quantitative and qualitative variations of bacterial plaque were considered.
RESULTS: Remarkable results were obtained regarding both the effective reduction of bacterial oral flora and patient's compliance and learning, especially in the group of patients older than 10 years. The new values of parameters recorded at the end of the study showed that all the subjects included in the sample had an improvement of compliance in oral hygiene, in particular: - P.I. level 3, 10-12 age, sex; - B.I. level 4, males over 10, female 6-9 age; - quantitative and qualitative variations of bacterial plaque, level 4, all groups.
CONCLUSIONS: Patient instruction and motivation allow to obtain optimal results in particular in patients aged more than 10 years.

PMID: 29243447 [PubMed - as supplied by publisher]

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Prevalence of dental caries among schoolchildren from North-Eastern Italian population.

Related Articles

Prevalence of dental caries among schoolchildren from North-Eastern Italian population.

Minerva Stomatol. 2017 Dec 14;:

Authors: Dobbiani A, Berton F, Perinetti G, Costantinides F, DI Lenarda R

Abstract
OBJECTIVE: The longitudinal aspect of dental caries has not been previously reported for the Italian population. The primary object of the present study is to collect information of the prevalence of dental decay among the schoolchildren of primary school of Gradisca d'Isonzo (GO) and to analyse the tendency of caries among the students followed since the first year of school.
METHODS: Subsequent examinations hold from 2011 to 2015 has been conducted by two calibrated examiners. Oral hygiene instruction and motivation followed the visits. According to WHO principals DMFT and dmft were recorded. The children in the survey were divided into five groups according to their ages (6, 7, 8 and 9 years), and these groups were considered separately. Descriptive and statistical analysis of the data were conducted.
RESULTS: More than 400 pupils were recruited, resulting in almost 900 examinations during five years. Overall, the %dft ≥ 1 children range from 18.9% (10 years, 2013) to 53.5% (8 years, 2011) across the different age groups. Overall, the %DFT ≥ 1 children range from 8.3% (6 years, 2011) to 44.1% (10 years, 2012) across the different age groups.
CONCLUSIONS: Within the limits of the present study, the WHO goals are still not met, among the population in exam. Our results show a trend of decay diminution that enhances in the cohort of 10-aged children suggesting the importance of dental education. Furthermore, the lack of paediatric initiatives of oral hygiene may be overcome by a national intensive educational program, supported by further scientific evidence.

PMID: 29243446 [PubMed - as supplied by publisher]

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Ewing’s Sarcoma of the Maxillofacial Region In Greek Children: Report of 6 Cases and Literature Review

Ewing's sarcoma (ES) is the second most common primary bone tumor in children and adolescents after osteosarcoma, initially described by Ewing in 1921 as an undifferentiated tumor involving the diaphysis of long bones that, unlike osteosarcoma, was radiation sensitive (Thorn et al. 2016). It accounts for approximately 3% of pediatric cancers and is most commonly diagnosed during the second decade of life, with a male to female ratio of 1.3:1 (Bernstein et al. 2006; Grevener et al. 2016). It usually affects the pelvis and long bones; extraskeletal tumors are rare in children (Osborn et al.

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“Three-dimensional Analysis of Cranial Base Morphology in Patients with Hemifacial Microsomia.”

Many researchers have studied the relationship between facial asymmetry and cranial base morphology, but they have failed to reach a consensus. In this study, we aimed to verify whether the cranial base is involved in hemifacial microsomia (HFM).

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IgE promotes type 2 innate lymphoid cells in murine food allergy

Abstract

Background

Mast cells serve an important sentinel function at mucosal barriers and have been implicated as key early inducers of Type 2 immune responses in food allergy. The generation of Th2 and IgE following food allergen ingestion is inhibited in the absence of mast cells. Group 2 innate lymphoid cells are also thought to play an important early role in nascent allergic responses.

Objective

To test whether IgE-mediated mast cell activation promotes intestinal ILC2 responses following ingestion of food allergens and whether ILC2 amplify food allergy.

Methods

Two different mouse models of food allergy, one using intraperitoneally ovalbumin (OVA) primed BALB/c animals and the other using enterally peanut-sensitized inherently atopic IL4raF709 mice, were applied to test the contributions of IgE antibodies and mast cells to ILC2 responses. The effect of ILC2 on mast cell activation and on anaphylaxis was tested.

Results

ILC2 responses were significantly impaired in both models of food allergy in Igh7^-/- mice harboring a targeted deletion of the gene encoding IgE. A similar reduction in food allergen-induced ILC2 was observed in mast cell deficient Il4raF709 Kit^W-sh mice and this was partially corrected by reconstituting these animals using cultured bone marrow mast cells. Mast cells activated ILC2 for IL-13 production in an IL-4Rα-dependent manner. Activated ILC2 amplified systemic anaphylaxis by increasing target tissue sensitivity to mast cell mediators.

Conclusions & clinical relevance

These findings support an important role for IgE-activated mast cells in driving intestinal ILC2 expansion in food allergy and reveal that ILC2, in turn, can enhance responsiveness to the mediators of anaphylaxis produced by mast cells. Strategies designed to inhibit IgE signaling or mast cell activation are likely to inhibit both Type 2 immunity and immediate hypersensitivity in food allergy.

This article is protected by copyright. All rights reserved.

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Typical sensory organization test findings and clinical implication in acute vestibular neuritis

Sensory organization test (SOT) is used to evaluate postural instability. We wanted to characterize the SOT findings in patients with acute vestibular neuritis (VN).

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Clinicopathologic and Immunohistochemical Study of Combined Small Cell Carcinoma and Urothelial Carcinoma Molecular Subtype

Abstract

Muscle invasive bladder cancer, an aggressive disease with heterogeneous molecular profiles, has recently been subclassified into three major molecular subtypes -basal, luminal and "p53-like" urothelial carcinomas (UCas), which bear prognostic and therapeutic implication. Similar to breast cancer, basal and luminal subtype UCas are designated by basal (CK5/14) and luminal (CK20) markers. The "p53-like" subtype presents with wild-type p53 gene with upregulated p53 pathways and is implicated in chemoresistance. Urinary bladder is one of the most common primary sites of extrapulmonary small cell carcinoma (SmCC). Bladder SmCC frequently coexists with UCa; however, the relation of SmCC with specific UCa molecular subtypes has not been studied. The aim of this study is to investigate the clinicopathology and immunophenotypes of the combined SmCC and UCa molecular subtypes. A total of 22 combined SmCC and UCa cases were studied for the clinicopathology and immunohistochemical (IHC) profiles by luminal and basal cell markers as well as Her2/Neu and p53. Our results demonstrated that all the urinary bladder SmCCs were associated with high grade UCas. They were more commonly seen in older male patients with a smoking history and had a poor prognosis. Based on the reported molecular subtyping, the UCas could be immunohistochemically subclassified into luminal, basal, dual and null types, which showed different clinicopathologic and IHC features. Compared to non-SmCC associated UCa, the subtypes of UCa in the combined SmCCs and UCas were characterized by: 1) Although overall luminal type was still relatively more common in men, basal marker-expressing subtypes were significantly increased in incidence and were more common in women. 2) Her2/Neu overexpression was more commonly observed in luminal than basal cell marker-expressing UCas. 3) IHC overexpression of p53 was common in all the subtypes, with UCas and SmCCs sharing the same p53 expression pattern. Although limited by relatively a small number of cases, the results of this study will enhance our understanding of the combined SmCC and UCa entity and potentially lead to a future therapeutic management.

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Extracellular vesicles as drivers of epithelial-mesenchymal transition and carcinogenic characteristics in normal prostate cells

ABSTRACT

There is increasing evidence that cancer dissemination and metastasis establishment may not only be due to the movement of tumor cells. Content of extracellular vesicles (EVs) secreted by tumor cells may also reflect the origin of these cells. Some molecules that constitute these EVs have already been used as targets for detection of specific tumors. However, to the best of our knowledge, EVs from biopsies and plasma have not yet been compared nor thoroughly investigated as triggers of malignant transformation and metastatic niche formation. To evaluate the role of EVs in the cellular microenvironment, we have treated the normal epithelial prostate cell lines, RWPE-1 and PNT-2, with a pool of EVs from biopsies of prostate primary tumors (bEVs), biopsies of benign prostate hyperplasia (hEVs), plasma of prostate cancer (PCa) patients (pEVs) or plasma of healthy individuals (pnEVs). Each of the four pools consisted of isolated EVs from several subjects, of which PCa patients were in different stages of cancer. Migration and proliferation profiles, cytokine release, and a panel of PCa-associated genes' expression of epithelial-mesenchymal transition in the cell lines were evaluated after 24 h incubation with EVs. When compared to the control groups, cells treated with the pool of EVs isolated from tumor biopsies and plasma of PCa patients showed greater migration and proliferation, significant alterations in gene expression, and high levels of IL-8, factors that are associated with cancer development. Specifically, isolated bEVs and pEVs may induce malignant features in non-tumor cells by activating several cellular events associated with cancer progression, suggesting that future PCa therapy may target multiple elements found in tumor-derived EVs. This article is protected by copyright. All rights reserved

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A systematic review of validated sinus surgery simulators

Abstract

Background

Simulation provides a safe and effective opportunity to develop surgical skills. A variety of endoscopic sinus surgery (ESS) simulators have been described in the literature. Validation of these simulators allows for effective utilisation in training.

Objective of review

To conduct a systematic review of the published literature to analyse the evidence for validated ESS simulation.

Search strategy

Pubmed, Embase, Cochrane and Cinahl were searched from inception of the databases to January 11^th, 2017.

Evaluation method

12,516 articles were retrieved of which 10,112 were screened following the removal of duplicates. 38 full text articles were reviewed after meeting the search criteria. Evidence of face, content, construct, discriminant and predictive validity was extracted.

Results

20 articles were included in the analysis describing 12 ESS simulators. 11 of these simulators had undergone validation; 3 virtual reality, 7 physical bench models and 1 cadaveric simulator. 7 of the simulators were shown to have face validity, 7 had construct validity and 1 had predictive validity. None of the simulators demonstrated discriminate validity.

Conclusion

This systematic review demonstrates that a number of ESS simulators have been comprehensively validated. Many of the validation processes, however, lack standardisation in outcome reporting, thus limiting a meta-analysis comparison between simulators.

This article is protected by copyright. All rights reserved.

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Factors associated with possible complicated grief and major depressive disorders

Abstract

Objective

Complicated grief (CG) is considered a distinctive symptom from other bereavement-related mental impairments such as major depressive disorder (MDD). CG and MDD may appear independently or co-morbidly; however, the factors associated with each situation are unclear.

Methods

We conducted a nationwide cross-sectional questionnaire survey involving bereaved family members of cancer patients in 175 institutions. The following items were included in the questionnaires to assess the prevalence of CG and MDD, and the following associated factors: demographic characteristics; bereaved family depression (Patient Health Questionnaire-9) and grief status (Brief Grief Questionnaire); structure and process of care (Care Evaluation Scale); overall care satisfaction; and achievement of a good death (Good Death Inventory).

Results

A total of 9,123 questionnaires were returned. The prevalence of CG and MDD was 14% and 17%, respectively. Additionally, 58% of the possible CG participants showed co-morbid symptoms. Common factors that showed significant association with either independent or co-morbid symptoms of CG and MDD were pre=existing mental impairment; belief in the survival of the soul after physical death; unpreparedness for the death; poor physical or psychological health status; and the belief that the deceased felt themselves as a burden to others (all p <0.05). The duration of bereavement did not remain significant after multivariate analysis.

Conclusions

While there were many common factors associated with both CG and MDD independently, few participants exhibited associations to both CG and MDD. Therefore, CG and MDD can be considered as distinctive symptoms, which frequently appear co-morbidly.

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Interventions developed with the Intervention Mapping protocol in the field of cancer: a systematic review.

Abstract

Objectives

The Intervention Mapping (IM) protocol provides a structured framework to develop, implement and evaluate complex interventions. The main objective of this review was to identify and describe the content of the interventions developed in the field of cancer with the IM protocol. Secondary objectives were to assess their fidelity to the IM protocol and to review their theoretical frameworks.

Methods

Medline, Web of Science, PsycINFO, Pascal, Francis, and BDSP databases were searched. All titles and abstracts were reviewed. A standardized extraction form was developed. All included studies were reviewed by two reviewers blinded to each other.

Results

Sixteen studies were identified, and these reported 15 interventions. The objectives were to increase cancer screening participation (n=7), early consultation (n=1) and aftercare / quality of life among cancer survivors (n=7). Six reported a complete participatory planning group and seven described a complete logic model of the problem. Ten studies described a complete logic model of change. The main theoretical frameworks used were the theory of planned behaviour (n=8), the transtheoretical model (n=6), the health belief model (n=6) and the social cognitive theory (n=6). The environment was rarely integrated in the interventions (n=4). Five interventions were reported as effective.

Conclusions

Culturally relevant interventions were developed with the IM protocol that were effective to increase cancer screening and reduce social disparities, particularly when they were developed through a participative approach and integrated the environment. Stakeholders' involvement and the role of the environment were heterogeneously integrated in the interventions.

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Predictors of adherence to exercise interventions during and after cancer treatment: a systematic review

Abstract

Objective

Exercise interventions benefit cancer patients. However, only low numbers of patients adhere to these interventions. This review aimed to identify predictors of exercise intervention adherence in patients with cancer, during and after multimodality cancer treatment.

Methods

A literature search was performed using electronic databases (Pubmed, Embase and Cochrane) to identify relevant papers published before February 1st 2017. Papers reporting randomized controlled trials, conducted in adult cancer patients who participated in an exercise intervention during and/or after multimodality cancer treatment, providing outcome of factors predicting exercise adherence were included. Papers were assessed for methodological quality by using the Physiotherapy Evidence Database scale.

Results

The search identified 720 potentially relevant papers, of which 15 fulfilled the eligibility criteria. In these 15 studies, 2,279 patients were included and 1,383 of these patients were randomized to an exercise intervention. During cancer treatment the factors predicting exercise adherence: location of the rehabilitation center, extensive exercise history, high motivation for exercise and fewer exercise limitations. After cancer treatment, factors that predicted adherence were: less extensive surgery, low alcohol consumption, high previous exercise adherence, family support, feedback by trainers and knowledge and skills of exercise. Methodological quality of the included papers was rated 'high'.

Conclusions

The most prominent predictors of adherence to exercise interventions were location of the rehabilitation center, extensive exercise history, high motivation for exercise and fewer exercise limitations. To increase the number of cancer patients that benefit, these results should be considered into the development and implementation of future exercise interventions.

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Development of an esophageal stimulation method to elicit swallowing reflex in humans

Abstract

Swallowing reflex is known to be evoked by gastroesophageal regurgitation or esophageal stimulation in animal studies. However, details regarding the stimulating material, bolus size, and stimulation area remain unclear for the stimulation-induced type of swallowing reflex in human. Here, we evaluated the effects of different kinds of stimulation via water and air injection of the esophagus on the initiation of the swallowing reflex. Nine healthy individuals participated in this study. A fiberoptic endoscope was passed transnasally and a thin catheter for injection was passed through the other side. The tip of the catheter was placed at the upper, upper middle, lower middle, or lower region of the esophagus and the rate of injection was controlled at 0.2 mL/s. Swallowing-reflex latency was calculated as the time from injection via air or thin/thick fluid until the onset of white-out in endoscopic images. Reflex latency was significantly shorter when injection occurred at the upper region of the esophagus than at the lower region, for both thin and thickened fluids (p<0.01). At the upper region of the esophagus, the latency was significantly shorter after injection with thin fluid than with thickened fluid (p<0.05). Injection with air did not induce the swallowing reflex at all sites. These findings suggest that while the swallowing reflex is evoked by varying types of stimulation via fluid injection of the esophagus in human, sensitivity is greatest in the upper region of the esophagus compared with the lower region, and can vary depending on the injecting material.

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Prevalence of skin disease in a population based sample of adults out of five European countries

Abstract

Background

There is a lack of prevalence data on skin diseases in the general adult population, most studies were carried out in small, national or consecutive clinical samples.

Objectives

To determine the prevalence of common skin disease in the general European population and to additionally assess differences in the characteristics of treatment between countries.

Methods

A random sample consisting out of 12,377 subjects aged 18 to 74 years was drawn from the general population of five European countries (Germany, Italy, The Netherlands, Portugal and Sweden). This was a cross-sectional study and all participants were interviewed with a standardized questionnaire assessing the occurrence of 10 common skin diseases during lifetime, past year and past month. If a skin disease was reported we additionally assessed who performed diagnosis and treatment and if drugs were prescribed.

Results

The most common skin disease was warts (41.3%) followed by acne (19.2%) and contact dermatitis (15.0%). In general females were more often affected by skin diseases compared to males, only in skin cancer the prevalence in males was slightly higher. The prevalence of skin diseases in northern countries (Germany, Netherlands & Sweden) was in general higher than in the southern countries (Italy & Spain). In the Netherlands the treatment of skin diseases was less often performed by a dermatologist compared to the other countries.

Conclusion

The prevalence estimates reported in this study are derived from a representative sample of the general population. Data assessment was performed comprehensively across countries, thus country specific prevalence estimates are comparable.

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Scleroderma skin ulcers definition, classification and treatment strategies our experience and review of the literature

Publication date: Available online 2 December 2017
Source:Autoimmunity Reviews
Author(s): Dilia Giuggioli, Andreina Manfredi, Federica Lumetti, Michele Colaci, Clodoveo Ferri
BackgroundSkin ulcers (SU) are one of the most frequent manifestations of systemic sclerosis (SSc). SSc-SU are very painful, often persistent and recurrent; they may lead to marked impairment of patient's activities and quality of life. Despite their severe impact on the whole SSc patient's management, the proposed definition, classification criteria, and therapeutic strategies of SSc-SU are still controversial.ObjectiveThe present study aimed to elaborate a comprehensive proposal of definition, classification, and therapeutic strategy of SSc-SU on the basis of our long-term single center experience along with a careful revision of the world literature on the same topic.MethodsA series of 282 SSc patients (254 females and 28 males; 84% with limited and 16% diffuse cutaneous SSc; mean age of 51.5±13.9SD at SSc onset; mean follow-up 5.8±4.6SDyears) enrolled during the last decade at our Rheumatology Unit were retrospectively evaluated with specific attention to SSc-SU. The SSc-SU were classified in 5 subtypes according to prominent pathogenetic mechanism(s) and localization, namely 1. digital ulcers (DU) of the hands or feet, 2. SU on bony prominence, 3. SU on calcinosis, 4. SU of lower limbs, and 5. DU presenting with gangrene. This latter is a very harmful evolution of both DU of the hands and feet needing a differential diagnosis with critical limb ischemia.ResultsDuring the follow up period, one or more episodes of SSc-SU were recorded in over half patients (156/282, 55%); skin lesions were often recurrent and difficult-to-heal because of local complications, mainly infections (67.3%), in some cases associated to osteomyelitis (19.2%), gangrene (16%), and/or amputation (11.5%). SSc-SU were significantly associated with lower patients' mean age at the disease onset (p=0.024), male gender (p=0.03), diffuse cutaneous subset (p=0.015), calcinosis (p=0.002), telangiectasia (p=0.008), melanodermia (p<0.001), abnormal PAPs (p=0.036), and/or altered inflammation reactant (CRP, p=0.001).Therapeutic strategy of SSc-SU included both systemic and local pharmacological treatments with particular attention to complicating infections and chronic/procedural pain, as well as a number of non-pharmacological measures. Integrated local treatments were often decisive for the SSc-SU healing; they were mainly based on the wound bed preparation principles that are summarized in the acronym TIME (necrotic Tissue, Infection/Inflammation, Moisture balance, and Epithelization).The updated review of the literature focusing on this challenging issue was analyzed in comparison with our experience.ConclusionsThe recent advancement of knowledge and management strategies of SSc-SU achieved during the last years lead to the clear-cut improvement of patients' quality of life and reduced long-term disability.



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Clinical and immunological aspects of anti-peptidylarginine deiminase type 4 (anti-PAD4) autoantibodies in rheumatoid arthritis

Publication date: Available online 2 December 2017
Source:Autoimmunity Reviews
Author(s): Zyanya Reyes-Castillo, José Francisco Muñoz-Valle, Mara A. Llamas-Covarrubias
Rheumatoid arthritis (RA) is the most common rheumatic autoimmune disease worldwide, which causes progressive joint damage and can lead to functional disability. Despite prominent advances in RA diagnosis and treatment during the last 20years, there is still a need for novel biomarkers that aid in diagnosis and prognosis of this heterogeneous disease. Citrullination is a key post-translational modification implicated on anti-citrullinated protein/peptide antibodies (ACPA) production in RA, catalyzed by human peptidylarginine deiminases (PADs). Among these enzymes, PAD4 has been recognized as an important player in RA pathogenesis and the enzyme itself is a target of autoantibodies (anti-PAD4) in a subgroup of RA patients. Accumulating evidence suggests that anti-PAD4 autoantibodies may be useful as a severity biomarker in RA and recent studies have also shed light on the functional significance of these autoantibodies. This review summarizes the evidence on anti-PAD4 autoantibodies in RA, and addresses its usefulness for disease diagnosis and prognosis. Novel immunological aspects of anti-PAD4 antibodies and their relevance to RA pathogenesis are also discussed.



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Pitfalls in the detection of citrullination and carbamylation

Publication date: Available online 2 December 2017
Source:Autoimmunity Reviews
Author(s): M.K. Verheul, P.A. van Veelen, M.A.M. van Delft, A. de Ru, G.M.C. Janssen, T. Rispens, R.E.M. Toes, L.A. Trouw
Carbamylation and citrullination are both post-translational modifications against which (auto)antibodies can be detected in sera of rheumatoid arthritis (RA) patients. Carbamylation is the chemical modification of a lysine into a homocitrulline, whereas citrullination is an enzymatic conversion of an arginine into a citrulline. It is difficult to distinguish between the two resulting amino acids due to similarities in structure. However, differentiation between citrulline and homocitrulline is important to understand the antigens that induce antibody production and to determine which modified antigens are present in target tissues.We have observed in literature that conclusions are frequently drawn regarding the citrullination or carbamylation of proteins based on reagents that are not able to distinguish between these two modifications. Therefore, we have analyzed a wide spectrum of methods and describe here which method we consider most optimal to distinguish between citrulline and homocitrulline.We have produced several carbamylated and citrullinated proteins and investigated the specificity of (commercial) antibodies by both ELISA and western blot. Furthermore, detection methods based on chemical modifications, such as the anti-modified citrulline-"Senshu" method and also mass spectrometry were investigated for their capacity to distinguish between carbamylation and citrullination.We observed that some antibodies are able to distinguish between carbamylation and citrullination, but an overlap in reactivity is often present in the commercially available anti-citrulline antibodies. Finally, we conclude that the use of mass spectrometry is currently essential to differentiate between citrullinated and carbamylated proteins present in complex biological samples.



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Imaging modalities for the diagnosis and disease activity assessment of Takayasu's arteritis: A systematic review and meta-analysis

Publication date: Available online 5 December 2017
Source:Autoimmunity Reviews
Author(s): Lillian Barra, Tahir Kanji, Jacqueline Malette, Christian Pagnoux
BackgroundEarly diagnosis of Takayasu's Arteritis (TAK) and detection of disease activity may reduce the risk of vascular complications. The objective of this study was to determine the effectiveness of imaging modalities for the management of TAK.MethodsMEDLINE and EMBASE were searched for studies of patients undergoing various imaging modalities for TAK diagnosis or to assess disease activity. We excluded case reports, reviews and case series with <10 patients. The methodologic quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2). Random effects meta-analyses with inverse-variance weighting were performed.ResultsFrom the 1126 citations screened, 57 studies met our inclusion criteria. Many of the studies were of small sample size (average N=27), cross-sectional design and low methodological quality. Ultrasound (US) had a lower pooled sensitivity (SN) of 81% (95% CI: 69–89%) than Magnetic Resonance Angiography (MRA) with SN=92% (95% CI: 88–95%) for TAK diagnosis (by clinical criteria and/or X-Ray angiography). Both had high specificities (SP) of >90% for TAK diagnosis. Fewer studies investigated computed tomography angiography (CTA), but SN and SP for TAK diagnosis was high (>90%). The utility of vessel wall thickening and enhancement by MRA and CTA to predict disease activity varied across studies. The pooled SN and SP of ¹⁸F-fluorodeoxyglucose-Positron Emission Tomography (FDG-PET) for disease activity was 81% (95% CI: 69–89%) and 74% (95% CI: 55–86%), respectively.ConclusionUS, CTA and/or MRA are effective for the diagnosis of TAK. The utility of these imaging modalities for assessing disease activity remains unclear.



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Combined therapies to treat complex diseases: The role of the gut microbiota in multiple sclerosis

Publication date: Available online 28 November 2017
Source:Autoimmunity Reviews
Author(s): Laura Calvo-Barreiro, Herena Eixarch, Xavier Montalban, Carmen Espejo
The commensal microbiota has emerged as an environmental risk factor for multiple sclerosis (MS). Studies in experimental autoimmune encephalomyelitis (EAE) models have shown that the commensal microbiota is an essential player in triggering autoimmune demyelination. Likewise, the commensal microbiota modulates the host immune system, alters the integrity and function of biological barriers and has a direct effect on several types of central nervous system (CNS)-resident cells. Moreover, a characteristic gut dysbiosis has been recognized as a consistent feature during the clinical course of MS, and the MS-related microbiota is gradually being elucidated. This review highlights animal studies in which commensal microbiota modulation was tested in EAE, as well as the mechanisms of action and influence of the commensal microbiota not only in the local milieu but also in the innate and adaptive immune system and the CNS. Regarding human research, this review focuses on studies that show how the commensal microbiota might act as a pathogenic environmental risk factor by directing immune responses towards characteristic pathogenic profiles of MS. We speculate how specific microbiome signatures could be obtained and used as potential pathogenic events and biomarkers for the clinical course of MS. Finally, we review recently published and ongoing clinical trials in MS patients regarding the immunomodulatory properties exerted by some microorganisms. Because MS is a complex disease with a large variety of associated environmental risk factors, we suggest that current treatments combined with strategies that modulate the commensal microbiota would constitute a broader immunotherapeutic approach and improve the clinical outcome for MS patients.



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A concise review of significantly modified serological biomarkers in giant cell arteritis, as detected by different methods

Publication date: Available online 28 November 2017
Source:Autoimmunity Reviews
Author(s): B. Burja, T. Kuret, S. Sodin-Semrl, K. Lakota, Ž. Rotar, R. Ješe, K. Mrak-Poljšak, P. Žigon, G.G. Thallinger, J. Feichtinger, S. Čučnik, M. Tomšič, S. Praprotnik, A. Hočevar
Giant cell arteritis (GCA) is a primary systemic vasculitis present in subjects older than 50years with involvement of large- and medium-sized arteries. Early diagnosis for GCA is essential to prevent serious complications, such as permanent vision loss and/or cerebrovascular events. Elevated inflammatory cytokines, with acute phase and other proteins dominate large- and medium-sized arteries leading to stenosis or occlusion of arterial lumen. To date, there are no reliable serological markers for monitoring GCA. The review aims to provide concise overview of published GCA studies in order to: a) identify significantly changed serological biomarkers in GCA and compare the influences of techniques for marker evaluation and b) investigate most promising markers in GCA using analyte frequency and meta-analysis.



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Imaging aspects of interstitial lung disease in patients with rheumatoid arthritis: Literature review

Publication date: Available online 28 November 2017
Source:Autoimmunity Reviews
Author(s): Alexandra Balbir-Gurman, Ludmila Guralnik, Mordechai Yigla, Yolanda Braun-Moscovici, Emilia Hardak
ObjectiveInterstitial lung disease (ILD) is a frequent and severe complication of rheumatoid arthritis (RA), resulting in pulmonary fibrosis (PF) and respiratory failure.MethodsChest computed tomography (CT-c) or high resolution CT (HRCT) is the main modality for assessment of ILD. We performed a systematic literature review on CT-c/HRCT findings in patients with ILD-RA, using the MEDLINE database for the period from 1991 to 2015.ResultsFindings on CT-c/HRCT attributed to ILD-RA are variable (ground glass opacities, reticular and nodular pattern, as well as a combined pattern of emphysema and PF). Correlation of CT-c/HRCT findings with clinical data is inconsistent.ConclusionsILD-RA is part of a general autoimmune inflammation and should be integrated into the decision-making process for the treatment of RA. There is an unmet need to design an algorithm which will allow prediction of CT-c changes compatible with ILD-RA with a high probability. Hopefully, this will enable treating patients with ILD-RA early, with possible halting of the progression of ILD-RA toward PF.



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NK cells in autoimmune diseases: Linking innate and adaptive immune responses

Publication date: Available online 26 November 2017
Source:Autoimmunity Reviews
Author(s): Elena Gianchecchi, Domenico Vittorio Delfino, Alessandra Fierabracci
The pathogenesis of autoimmunity remains to be fully elucidated, although the contribution of genetic and environmental factors is generally recognized. Despite autoimmune conditions are principally due to T and B lymphocytes, NK cells also appear to play a role in the promotion and/or maintenance of altered adaptive immune responses or in peripheral tolerance mechanisms.Although NK cells are components of the innate immune system, they shows characteristics of the adaptive immune system, such as the expansion of pathogen-specific cells, the generation of long-lasting "memory" cells able to persist upon cognate antigen encounter, and the possibility to induce an increased secondary recall response to re-challenge.Human NK cells are generally identified as CD56⁺CD3⁻, conversely CD56⁺CD3⁺ cells represent a mixed population of NK-like T (NK T) cells and antigen-experienced T cells showing the up-regulation of several NK cell markers. CD56^dim constitute about 90% of NK cells in the peripheral blood, they are mature and involved in cytotoxicity responses; CD56^bright instead are more immature, mostly involved in cytokine production, having only a limited role in cytolytic responses, keen to leave the blood vessels as the principal population observed in lymph nodes. NK cells have been identified also in non-lymphoid tissues since, in pathologic conditions, they can quickly reach the target organs. A cross-talk between NK with dendritic cells and T cells is established throughout different receptor-ligand bindings.Several studies support the correlation between NK cell number and/or functional alterations, such as a defective cytotoxic activity and several autoimmune conditions. Among the different autoimmune pathologies and even within the same disease, NK cell function is significantly different either promoting or even protecting against the onset of the autoimmune condition.In this Review, we discuss recent literature supporting the role played by NK cells, as a bridge between innate and adaptive immunity, in the onset of autoimmune diseases.



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Belimumab in the treatment of systemic lupus erythematous: An evidence based review of its place in therapy

Publication date: Available online 24 November 2017
Source:Autoimmunity Reviews
Author(s): Frederico Marcondes, Morton Scheinberg
IntroductionSystemic lupus erythematous is an autoimmune disease with diverse clinical features and has its development associated with a complexity of genetic, hormonal and environmental factors and the development of autoantibodies. Identification of new treatments is currently an area of intense investigation. Belimumab is the first biologic approved for the treatment of the disease inhibiting the excessive B cell activity observed in these patients and consequently reduction of autoantibodies.AimTo review the current transition of the evidence available of its use in real life patients with persistent active disease while on conventional therapies.EvidenceThe results observed on the large series of patients (over 50 patients) followed for at least six months confirm the observations from phase 3 trials. In clinical practice close to two third of the patients remained on belimumab and one third discontinued mostly due to evaluation by the doctor or the patient or both of no detectable positive response. The presence of adverse events was considerably low and the subgroups with skin and joint manifestations appear to benefit the most. Daily steroid use is usually reduced to a significantly low when compared with the intake before introduction of the biologic Although not seen on trials in real life the addition of belimumab to the conventional therapy in lupus nephritis is being reported in several patients. Cost of the medication is still an issue that hampers its use. Further evidence of its use in certain specific groups is under investigation and its results should shed light on additional indications.Place in therapyConsidering what is currently published on the evidence here reviewed in the use of belimumab in clinical practice it is our understanding that belimumab it will be gradually incorporated in the armamentarium of treatment not necessarily on refractory patients. We believe that with the upcoming of the subcutaneous route in the near future should also help in widen the use of the belimumab to be considered in first line combination set ups.



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Clinical and microbiological characteristics of the infections in patients treated with rituximab for autoimmune and/or malignant hematological disorders

Publication date: Available online 24 November 2017
Source:Autoimmunity Reviews
Author(s): Jean-Jacques Tudesq, Guillaume Cartron, Sophie Rivière, David Morquin, Laura Iordache, Alfred Mahr, Valérie Pourcher, Kada Klouche, Diane Cerutti, Alain Le Quellec, Philippe Guilpain
IntroductionRituximab is commonly used for the treatment of hematological malignancies and autoimmune diseases. Despite a reputation for good tolerance, case-series and registries reported rituximab-related infections of variable severity including opportunistic infections. We aimed at describing the natural history of infectious events (IE) after treatment by rituximab providing clinical and microbiological features and outcome.Patients and methodsWe retrospectively analyzed the medical records of patients treated with rituximab in an internal medicine department of a tertiary hospital between 2007 and 2015, and identified all IE after this therapy. Events' severity was assessed using the Common Terminological Criteria of Adverse Events (version 4.3) definitions.ResultsAmong 101 patients treated with rituximab, we identified 228 IE in 74 (73.3%) of these patients (median follow-up 30.4months). Indication for rituximab was either autoimmune disease (AID) (52.5% of patients), or monoclonal hematological disease (MHD) (47.5%). Patients received an overall median number of 5 rituximab infusions [interquartile range: 4–8], representing a cumulative dose of 4340mg [2620–6160]. After last rituximab infusion, IE occurred after 3.1months [0.7–9.4]. Respectively, IE were severe in 28.1% of cases in patients treated for AID vs 58.0% in patients treated for MHD (p<0.001), due to opportunistic pathogens in 7.8% vs 11.0% (p=0.49) and fatal in 4.7% vs 13.0% (p=0.044). Factor associated with mortality were polymicrobial infection (p<0.001), monoclonal hematological disease (p=0.035), use of steroids over 10mg/d within the last two weeks (p=0.003), and rituximab cumulative dose (p<0.001). We identified a group of 10 patients (9.9%) showing life-threatening, polymicrobial, and opportunistic infections constituting a 'catastrophic infectious syndrome', which was lethal in 7 cases.ConclusionIE after treatment by rituximab can be extremely severe, especially in patients immunocompromised by several other drugs. Further studies should focus on the group with life-threatening polymicrobial infections.



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Childhood- versus adult-onset ANCA-associated vasculitides: A nested, matched case–control study from the French Vasculitis Study Group Registry

Publication date: Available online 24 November 2017
Source:Autoimmunity Reviews
Author(s): Michele Iudici, Christian Pagnoux, Pierre Quartier, Matthias Büchler, Ramiro Cevallos, Pascal Cohen, Claire de Moreuil, Philippe Guilpain, Alain Le Quellec, Jacques Serratrice, Benjamin Terrier, Loïc Guillevin, Luc Mouthon, Xavier Puéchal
ObjectiveTo investigate differences between childhood-onset ANCA-associated vasculitides (cAAVs) and matched adult-onset controls (aAAVs).MethodscAAV clinical pictures at onset and outcomes were compared to a randomly selected sample of aAAV patients from the French Vasculitis Study Group Registry. Cases and controls were matched for AAV (granulomatosis with polyangiitis [GPA], microscopic polyangiitis [MPA] or eosinophilic granulomatosis with polyangiitis [EGPA]), sex and year of enrollment. Medications, disease activity and damage were prospectively recorded. Kaplan–Meier curves and the log-rank test were used to analyze case-vs.-control differences for predefined outcomes.ResultsComparing 35 cAAVs (25 GPA, 4 MPA, 6 EGPA) to 151 aAAVs (106 GPA, 17 MPA, 28 EGPA), their respective median follow-up durations were 71 and 64months (P=0.49), and, at baseline, children had less frequent myalgias (P=0.005) and peripheral neuropathy (P<0.001) but were more frequently febrile (P<0.05). Rates of renal involvement were comparable (13 [37%] cAAVs vs. 73 [48%] aAAVs; P=0.31). Initial GPA-associated ischemic abdominal pain and nasal cartilage damage were more common in cAAVs than aAAVs (P<0.05). During follow-up, the cAAV relapse rate was higher (24.5 vs. 18.7 flares per 100 patient-years; P<0.05) and, at last visit, cases had accumulated more damage, mostly ear, nose & throat sequelae (P=0.001), associated with longer maintenance therapy (P=0.03), than aAAV controls. Four (11.4%) cAAV and 13 (8.6%) aAAV patients died (P=0.53).ConclusioncAAVs are severe diseases, characterized by a higher relapse rate, more accrued damage and longer maintenance therapy than for aAAVs.



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Modulation of the Tumor Microenvironment by Epstein-Barr virus Latent Membrane Protein-1 in Nasopharyngeal Carcinoma

Abstract

Latent membrane protein 1 (LMP1) is a primary oncogene encoded by the Epstein-Barr virus, and various portions of LMP1 are detected in nasopharyngeal carcinoma (NPC) tumor cells. LMP1 has been extensively studied since the discovery of its transforming property in 1985. LMP1 promotes cancer cell growth during NPC development and facilitates the interaction of cancer cells with surrounding stromal cells for invasion, angiogenesis, and immune modulation. LMP1 is detected in 100% of pre-invasive NPC tumors and in approximately 50% of advanced NPC tumors. Moreover, a small population of LMP1-expressing cells in advanced NPC tumor tissue is proposed to orchestrate NPC tumor tissue maintenance and development through cancer stem cells and progenitor cells. Recent studies suggest that LMP1 activity shifts according to tumor development stage, but still has a pivotal role during all stages of NPC development.

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Ovarian cancer risk, ALDH2 polymorphism and alcohol drinking: Asian data from the Ovarian Cancer Association Consortium

Summary

The ALDH2 polymorphism rs671 (Glu504Lys) causes ALDH2 inactivation and adverse acetaldehyde exposure among Asians, but little is known of the association between alcohol consumption and rs671 and ovarian cancer (OvCa) in Asians. We conducted a pooled analysis of Asian ancestry participants in the Ovarian Cancer Association Consortium. We included seven case-control studies and one cohort study comprising 460 invasive OvCa cases, 37 borderline mucinous OvCa and 1,274 controls of Asian descent with information on recent alcohol consumption. The pooled odds ratios (OR) with 95% confidence intervals (CI) for OvCa risk associated with alcohol consumption, rs671 and their interaction were estimated using logistic regression models adjusted for potential confounders. No significant association was observed for daily alcohol intake with invasive OvCa (OR comparing any consumption to none =0.83; 95% CI=0.58-1.18) or with individual histotypes. A significant decreased risk was seen for carriers of one or both Lys alleles of rs671 for invasive mucinous OvCa (OR=0.44; 95% CI=0.20-0.97) and for invasive and borderline mucinous tumors combined (OR=0.48; 95% CI=0.26-0.89). No significant interaction was observed between alcohol consumption and rs671 genotypes. In conclusion, self-reported alcohol consumption at the quantities estimated was not associated with OvCa risk among Asians. Because the rs671 Lys allele causes ALDH2 inactivation leading to increased acetaldehyde exposure, the observed inverse genetic association with mucinous ovarian cancer is inferred to mean that alcohol intake may be a risk factor for this histotype. This association will require replication in a larger sample.

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MiR-155 promotes gastric cancer growth and invasion by negatively regulating Transforming Growth Factor Beta Receptor 2

Summary

Gastric cancer (GC) has a high morbidity and mortality among the common malignancies worldwide. It is essential to elucidate the molecular events of GC proliferation and invasion, which will provide new therapeutic targets for GC. The inactivation of TGFβR2 is correlates with cancer cells growth and metastasis, but the mechanisms underlying the down-regulation of TGFβR2 expression remain unknown. MicroRNAs (miRNAs) act as post-transcriptional regulators play a key role in the development of cancers. The bioinformatics analysis and luciferase reporter assay demonstrated that miR-155 directly bind the 3′-untranslated region (3′-UTR) of TGFβR2 mRNA. In this study, we found that the TGFβR2 protein levels, but not mRNA levels, were down-regulated in GC tissues, while the levels of miR-155 were significantly increased in GC tissues. We deduced miR-155 inversely correlated with TGFβR2 in GC cells. In vitro studies showed that over-expression of miR-155 in SGC7901 inhibited the expression of TGFβR2 and then promoted GC cell proliferation and migration, whereas miR-155 inhibitor showed opposite effects. In addition, the tumor suppressing function of TGFβR2 was verified by using siRNA (small interfering RNA) and TGFβR2 over-expressing plasmid respectively. The results illustrated the miR-155 promotes cell growth and migration by negatively regulating TGFβR2. Thus, miR-155-regulated TGFβR2 as a potential therapeutic target in GC.

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ADAM9 is over-expressed in human ovarian clear cell carcinomas and suppresses cisplatin-induced cell death

Abstract

ADAMs (a disintegrin and metalloproteinases) are involved in various biological events such as cell adhesion, migration and invasion, membrane protein shedding and proteolysis. However, there have been no systematic studies on the expression of ADAMs in human ovarian carcinomas. We therefore examined the mRNA expression of all the proteolytic ADAM species including ADAM8, 9, 10, 12, 15, 17, 19, 20, 21, 28, 30, 33 and ADAMDEC1 in human ovarian carcinomas, and found that prototype membrane-anchored ADAM9m, but not secreted isoform ADAM9s, is significantly over-expressed in the carcinomas than in the control non-neoplastic ovarian tissue. Among the histological sub-types of serous, endometrioid, mucinous and clear cell carcinomas, the ADAM9m expression was highest in the clear cell carcinomas. Immunohistochemistry demonstrated that all the clear cell carcinoma samples exhibit ADAM9m primarily on the carcinoma cell membrane. By immunoblotting, ADAM9m was detected mainly in an active form in the clear cell carcinoma tissues. When two clear cell carcinoma cell lines (RMG-I and TOV21G cells) with ADAM9m expression were treated with cisplatin, the viability was significantly reduced and apoptosis increased in ADAM9m knock-down cells compared with mock transfectants. In addition, treatment of the cells with neutralizing anti-ADAM9m antibody significantly decreased viability compared with non-immune IgG, whereas ADAM9m over-expression significantly increased viability compared with mock transfectants. Our data demonstrate, to the best of our knowledge, for the first time that ADAM9m is over-expressed in an activated form in human ovarian clear cell carcinomas, and suggest that ADAM9m plays a key role in the cisplatin-resistance.

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Whole exome sequencing to identify genetic markers for trastuzumab-induced cardiotoxicity

Abstract

Although trastuzumab-induced cardiotoxicity is an important determinant to limit the use of this drug, the molecular mechanism of risk for this toxicity is not well understood. To identify genetic variants determining the risk of trastuzumab-induced cardiotoxicity, we performed whole exome sequencing of germline DNA samples from 9 patients with trastuzumab-induced cardiotoxicity, and conducted a case–control association study of 2,258 genetic variants between 9 cases (with trastuzumab-induced cardiotoxicity) and general Japanese population controls registered in Human Genetic Variation Database (HGVD). The top variant which revealed the lowest P value in the screening study was rs139503277 in PHD Finger Protein 3 (P_min = 0.00012, odds ratio (OR) = 51.23). To further validate the result of screening study, we carried out a replication study of 10 variants showing P_min < 0.001 in the screening study using 234 independent patients treated with trastuzumab, including 10 cases and 224 controls (without trastuzumab-induced cardiotoxicity). In the replication study, we observed that three variants had effect in the same direction as in the screening study (rs78272919 in exon 2 of Keratin 15, rs5762940 in exon 2 of zinc and ring finger 3 and rs139944387 in exon 44 of Eyes shut homologs (EYS)). A combined result of the screening and the replication studies suggested an association of a locus on chromosome 6q12 with trastuzumab-induced cardiotoxicity (rs139944387 in EYS, combined-P_min = 0.00056, OR = 13.73). This finding provides new insights into personalized trastuzumab therapy for the patients with HER2 positive cancer.

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Oropharynx-directed ipsilateral irradiation for p16-positive squamous cell carcinoma involving the cervical lymph nodes of unknown primary origin

Abstract

Background

The purpose of this study was to present our findings on the use of limited-field, oropharynx-directed ipsilateral irradiation for p16-positive squamous cell carcinoma of unknown primary origin.

Methods

Between April 2011 and January 2016, 25 patients with a histological diagnosis of p16-positive squamous cell carcinoma were selectively irradiated to the ipsilateral oropharynx and cervical neck for tumors of unknown primary origin. The dose to the oropharynx ranged from 54-60 Gy (median 60 Gy) in 30-33 fractions. Concurrent cisplatin-based chemotherapy was administered to 8 patients (32%).

Results

The actuarial 2-year estimates of locoregional control, progression-free survival, and overall survival were 91%, 87%, and 92%, respectively. One patient failed in the contralateral neck. There was no grade 3 + toxicity in either the acute or late setting.

Conclusion

Oropharynx-directed, ipsilateral radiation results in disease control that compares favorably with historical controls treated by comprehensive mucosal and bilateral neck radiation.

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American Thyroid Association ultrasound system for the initial assessment of thyroid nodules: Use in stratifying the risk of malignancy of indeterminate lesions

Abstract

Background

The ultrasound risk stratification system of the American Thyroid Association (ATA) is frequently adopted in clinical practice. Here, we evaluated its performance in a series of nodules with indeterminate fine-needle aspiration cytology (FNAC) report.

Methods

Indeterminate thyroid nodules diagnosed at 2 medical centers were retrospectively screened, ultrasound images were reevaluated, and lesions were classified according to the ATA. Single ultrasound parameters were also analyzed.

Results

One hundred seventy-three indeterminate lesions were included with 24.8% of malignancy. The high suspicion class showed a cancer rate (75%) significantly (P < .001) higher than that recorded in the other categories (16.8%). Between ultrasound parameters, halo and microcalcifications were the most sensitive and specific ones. The most accurate receiver operating characteristic (ROC)-derived cutoff of nodule's diameter was >4.1 cm. At multivariate analysis, only the ATA class of high suspicion and size >4.1 cm were significantly associated with cancer (odds ratios [ORs] 19.4 and 5.4, respectively).

Conclusion

The ATA ultrasound system is reliable in the risk stratification of indeterminate thyroid lesions.

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Reduced deep regional cerebral venous oxygen saturation in hemodialysis patients using quantitative susceptibility mapping

Abstract

Cerebral venous oxygen saturation (SvO₂) is an important indicator of brain function. There was debate about lower cerebral oxygen metabolism in hemodialysis patients and there were no reports about the changes of deep regional cerebral SvO₂ in hemodialysis patients. In this study, we aim to explore the deep regional cerebral SvO₂ from straight sinus using quantitative susceptibility mapping (QSM) and the correlation with clinical risk factors and neuropsychiatric testing_. 52 hemodialysis patients and 54 age-and gender-matched healthy controls were enrolled. QSM reconstructed from original phase data of 3.0 T susceptibility-weighted imaging was used to measure the susceptibility of straight sinus. The susceptibility was used to calculate the deep regional cerebral SvO₂ and compare with healthy individuals. Correlation analysis was performed to investigate the correlation between deep regional cerebral SvO₂, clinical risk factors and neuropsychiatric testing. The deep regional cerebral SvO₂ of hemodialysis patients (72.5 ± 3.7%) was significantly lower than healthy controls (76.0 ± 2.1%) (P < 0.001). There was no significant difference in the measured volume of interests of straight sinus between hemodialysis patients (250.92 ± 46.65) and healthy controls (249.68 ± 49.68) (P = 0.859). There were no significant correlations between the measured susceptibility and volume of interests in hemodialysis patients (P = 0.204) and healthy controls (P = 0.562), respectively. Hematocrit (r = 0.480, P < 0.001, FDR corrected), hemoglobin (r = 0.440, P < 0.001, FDR corrected), red blood cell (r = 0.446, P = 0.003, FDR corrected), dialysis duration (r = 0.505, P = 0.002, FDR corrected) and parathyroid hormone (r = −0.451, P = 0.007, FDR corrected) were risk factors for decreased deep regional cerebral SvO₂ in patients. The Mini-Mental State Examination (MMSE) scores of hemodialysis patients were significantly lower than healthy controls (P < 0.001). However, the deep regional cerebral SvO₂ did not correlate with MMSE scores (P = 0.630). In summary, the decreased deep regional cerebral SvO₂ occurred in hemodialysis patients and dialysis duration, parathyroid hormone, hematocrit, hemoglobin and red blood cell may be clinical risk factors.

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No effect of prolonged pulsed high frequency ultrasound imaging of the basilar membrane on cochlear function or hair cell survival found in an initial study

Publication date: Available online 16 December 2017
Source:Hearing Research
Author(s): Thomas G. Landry, Manohar L. Bance, Robert B. Adamson, Jeremy A. Brown
Miniature high frequency ultrasound devices show promise as tools for clinical middle ear and basal cochlea imaging and vibrometry. However, before clinical use it is important to verify that the ultrasound exposure does not damage the cochlea. In this initial study, electrophysiological responses of the cochlea were measured for a range of stimulus frequencies in both ears of anesthetized chinchillas, before and after exposing the organ of Corti region of one ear to pulsed focused ultrasound for 30 min. Measurements were again taken after an 11 day survival period. Cochlear tissue was examined with a confocal microscope for signs of damage to the cochlear hair cells. No significant change in response thresholds due to exposure was found, and no signs of ultrasound-induced tissue damage were observed, although one animal (out of ten) did have a region of extensive tissue damage in the exposed cochlea. However, after further analysis this was concluded to be not likely a result of the ultrasound exposure.



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No effect of prolonged pulsed high frequency ultrasound imaging of the basilar membrane on cochlear function or hair cell survival found in an initial study

Publication date: Available online 16 December 2017
Source:Hearing Research
Author(s): Thomas G. Landry, Manohar L. Bance, Robert B. Adamson, Jeremy A. Brown
Miniature high frequency ultrasound devices show promise as tools for clinical middle ear and basal cochlea imaging and vibrometry. However, before clinical use it is important to verify that the ultrasound exposure does not damage the cochlea. In this initial study, electrophysiological responses of the cochlea were measured for a range of stimulus frequencies in both ears of anesthetized chinchillas, before and after exposing the organ of Corti region of one ear to pulsed focused ultrasound for 30 min. Measurements were again taken after an 11 day survival period. Cochlear tissue was examined with a confocal microscope for signs of damage to the cochlear hair cells. No significant change in response thresholds due to exposure was found, and no signs of ultrasound-induced tissue damage were observed, although one animal (out of ten) did have a region of extensive tissue damage in the exposed cochlea. However, after further analysis this was concluded to be not likely a result of the ultrasound exposure.



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Changing temporal trends in non-AIDS cancer mortality among people diagnosed with AIDS: San Francisco, California, 1996–2013

Publication date: February 2018
Source:Cancer Epidemiology, Volume 52
Author(s): Nancy A. Hessol, Danning Ma, Susan Scheer, Ling C. Hsu, Sandra K. Schwarcz
BackgroundAntiretroviral therapy (ART) has reduced AIDS-defining cancer (ADC) mortality, but its effect on non-AIDS-defining cancer (NADC) mortality is unclear. To help inform cancer prevention and screening, we evaluated trends in NADC mortality among people with AIDS (PWA) in the ART era.MethodsThis retrospective cohort study analyzed AIDS surveillance data, including causes of death from death certificates, for PWA in San Francisco who died in 1996–2013. Proportional mortality ratios (PMRs), and year, age, race, sex-adjusted standardized mortality ratios (SMRs) were calculated for 1996–1999, 2000–2005, and 2006–2013, corresponding to advances in ART.ResultsThe study included 5822 deceased PWA of whom 90% were male and 68% were aged 35–54 at time of death. Over time, the PMRs significantly decreased for ADCs (2.6%, 1.4%, 1.2%) and increased for NADCs (4.3%, 7.0%, 12.3%). For all years combined (1996–2013) and compared to the California population, significantly elevated SMRs were observed for these cancers: all NADCs combined (2.1), anal (58.4), Hodgkin lymphoma (10.5), liver (5.2), lung/larynx (3.0), rectal (5.2), and tongue (4.7). Over time, the SMRs for liver cancer (SMR 19.8, 11.2, 5.0) significantly decreased while the SMRs remained significantly elevated over population levels for anal (SMR 123, 48.2, 45.5), liver (SMR 19.8, 11.2, 5.0), and lung/larynx cancer (SMR 5.3, 4.7, 3.6).ConclusionA decline in ADC PMRs and increase in NADC PMRs represent a shift in the cancer burden, likely due to ART use. Moreover, given their elevated SMRs, anal, liver, and lung/larynx cancer remain targets for improved cancer prevention, screening, and treatment.



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Cancers in France in 2015 attributable to high body mass index

Publication date: February 2018
Source:Cancer Epidemiology, Volume 52
Author(s): Melina Arnold, Marina Touillaud, Laure Dossus, Heinz Freisling, Freddie Bray, Irène Margaritis, Valérie Deschamps, Isabelle Soerjomataram
BackgroundOverweight, as defined by high body mass index (BMI), is an established risk factor for various morbidities including cancer. Globally, its prevalence has increased markedly over the past decades. The aim of this study was to estimate the proportion and number of cancers that were attributable to high BMI in France in 2015.MethodsPopulation attributable fractions (PAFs) and numbers of cancer cases attributable to high BMI (a population mean BMI above the optimum of 22kg/m²) were estimated by age and sex, for cancer sites with convincing or probable evidence of an established causal link. Assuming a 10-year lag-period, PAFs were calculated using mean BMI estimates from a cross-sectional French population survey, and relative risk estimates from published meta-analyses.ResultsAn estimated 18,639 cancer cases diagnosed in France in 2015 were attributable to high BMI, corresponding to 5.3% of all cancer cases (6.7% in women and 4.1% in men). This included 4507 cases of postmenopausal breast and 3380 cases of colon cancer. The highest estimated PAFs were for oesophageal adenocarcinoma and corpus uteri cancer (37% and 34%, respectively).ConclusionHigh BMI is associated with a substantial number of cancer cases in France, a country with a low but increasing prevalence of overweight and obesity when compared to other European countries. Assuming that the association between high BMI and cancer is causal, these results highlight the need to prioritise the prevention of this risk factor as part of cancer control planning in France and elsewhere in Europe.



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Incidence, prevalence, mortality, disability-adjusted life years and risk factors of cancer in Australia and comparison with OECD countries, 1990–2015: findings from the Global Burden of Disease Study 2015

Publication date: February 2018
Source:Cancer Epidemiology, Volume 52
Author(s): Yohannes Adama Melaku, Sarah L. Appleton, Tiffany K. Gill, Felix A. Ogbo, Elizabeth Buckley, Zumin Shi, Tim Driscoll, Robert Adams, Benjamin C. Cowie, Christina Fitzmaurice
BackgroundComparative evidence on the burden, trend, and risk factors of cancer is limited. Using data from the Global Burden of Disease (GBD) study, we aimed to assess cancer burden – incidence, prevalence, mortality, disability-adjusted life years (DALYs) – and attributable risk factors for Australia between 1990 and 2015, and to compare them with those of 34 members of the Organisation for Economic Co-operation and Development (OECD).MethodsThe general GBD cancer estimation methods were used with data input from vital registration systems and cancer registries. A comparative risk assessment approach was used to estimate the population-attributable fractions due to risk factors.ResultsIn 2015 there were 198,880 (95% uncertainty interval [UI]: 183,908–217,365) estimated incident cancer cases and 47,562 (95% UI: 46,061–49,004) cancer deaths in Australia. Twenty-nine percent (95% UI: 28.2–29.8) of total deaths and 17.0% (95% UI: 15.0–19.1) of DALYs were caused by cancer in Australia in 2015. Cancers of the trachea, bronchus and lung, colon and rectum, and prostate were the most common causes of cancer deaths. Thirty-six percent (95% UI: 33.1–37.9) of all cancer deaths were attributable to behavioral risks. The age-standardized cancer incidence rate (ASIR) increased between 1990 and 2015, while the age-standardized cancer death rate (ASDR) decreased over the same period. In 2015, compared to 34 other OECD countries Australia ranked first (highest) and 24^th based on ASIR and ASDR, respectively.ConclusionThe incidence of cancer has increased over 25 years, and behavioral risks are responsible for a large proportion of cancer deaths. Scaling up of prevention (using strategies targeting cancer risk factors), early detection, and treatment of cancer is required to effectively address this growing health challenge.



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Improvement of relative survival in elderly patients with acute myeloid leukaemia emerging from population-based cancer registries in Switzerland between 2001 and 2013

Publication date: February 2018
Source:Cancer Epidemiology, Volume 52
Author(s): Annatina Schnegg-Kaufmann, Anita Feller, Helen Baldomero, Alicia Rovo, Markus G. Manz, Michael Gregor, Anna Efthymiou, Mario Bargetzi, Urs Hess, Olivier Spertini, Yves Chalandon, Jakob R. Passweg, Georg Stussi, Volker Arndt, Nicolas Bonadies
Acute Myeloid Leukaemia (AML) is a rare and heterogeneous haematological malignancy with increasing incidence in the elderly. We performed a population-based, observational analysis of AML cases reported to the Cantonal Cancer Registries in Switzerland. Data was aggregated by the National Institute for Epidemiology and Cancer Registration and stratified for the two time periods 2001–2007 and 2008–2013. Overall, 2351 new AML cases were registered with a stable age-standardised incidence rate (3.0 [95 CI: 2.8-3.2] per 100,000 person-years). This indicates that our observed raise of annual AML cases (+10.9%) is mainly related to demographic ageing and not to an increase of age-specific risks. The fraction of non-classifiable AML cases decreased over time (54.6% to 41.8%) but remained high in elderly patients (65–74yrs: 44%; 75–84yrs: 54.2%, 85+yrs: 59.1%), suggesting less accurate diagnostics and reporting with increasing age. 5yrs relative survival (RS) correlated with AML risk class (favorable: 61.7%-68.4%; adverse risk: 11.4%-21.9%) and age (<65yrs: 42.6–43.3%; 75–84yrs: 2.0-3.0%), but improved only modestly overall (19.2% to 23.3%). Interestingly, we identified a significant improvement of RS in patients aged 65–74yrs (5yrs: 5.2% to 13.5%; p<0.001). As surrogate for changes in management, we found an increase of allogeneic haematopoietic stem cell transplantations (1.4 to 7%) and clinical trial activities (25 to 29%) for elderly AML patients during the observation period. Our analysis indicates that recent progress made in management of elderly AML patients results in an improvement of survival on a population-based level in Switzerland and that therapeutic nihilism is not justifiable.



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Missing data and chance variation in public reporting of cancer stage at diagnosis: Cross-sectional analysis of population-based data in England

Publication date: February 2018
Source:Cancer Epidemiology, Volume 52
Author(s): Matthew E. Barclay, Georgios Lyratzopoulos, David C. Greenberg, Gary A. Abel
BackgroundThe percentage of cancer patients diagnosed at an early stage is reported publicly for geographically-defined populations corresponding to healthcare commissioning organisations in England, and linked to pay-for-performance targets. Given that stage is incompletely recorded, we investigated the extent to which this indicator reflects underlying organisational differences rather than differences in stage completeness and chance variation.MethodsWe used population-based data on patients diagnosed with one of ten cancer sites in 2013 (bladder, breast, colorectal, endometrial, lung, ovarian, prostate, renal, NHL, and melanoma). We assessed the degree of bias in CCG (Clinical Commissioning Group) indicators introduced by missing-is-late and complete-case specifications compared with an imputed 'gold standard'. We estimated the Spearman-Brown (organisation-level) reliability of the complete-case specification. We assessed probable misclassification rates against current pay-for-performance targets.ResultsUnder the missing-is-late approach, bias in estimated CCG percentage of tumours diagnosed at an early stage ranged from −2 to −30 percentage points, while bias under the complete-case approach ranged from −2 to +7 percentage points. Using an annual reporting period, indicators based on the least biased complete-case approach would have poor reliability, misclassifying 27/209 (13%) CCGs against a pay-for-performance target in current use; only half (53%) of CCGs apparently exceeding the target would be correctly classified in terms of their underlying performance.ConclusionsCurrent public reporting schemes for cancer stage at diagnosis in England should use a complete-case specification (i.e. the number of staged cases forming the denominator) and be based on three-year reporting periods. Early stage indicators for the studied geographies should not be used in pay-for-performance schemes.



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Nationwide analysis on the impact of socioeconomic land use factors and incidence of urothelial carcinoma

Publication date: February 2018
Source:Cancer Epidemiology, Volume 52
Author(s): Maximilian P. Brandt, Kilian M. Gust, Jens Mani, Stefan Vallo, Thomas Höfner, Hendrik Borgmann, Igor Tsaur, Christian Thomas, Axel Haferkamp, Eva Herrmann, Georg Bartsch
BackgroundIncidence rates for urothelial carcinoma (UC) have been reported to differ between countries within the European Union (EU). Besides occupational exposure to chemicals, other substances such as tobacco and nitrite in groundwater have been identified as risk factors for UC. We investigated if regional differences in UC incidence rates are associated with agricultural, industrial and residential land use.MethodsNewly diagnosed cases of UC between 2003 and 2010 were included. Information within 364 administrative districts of Germany from 2004 for land use factors were obtained and calculated as a proportion of the total area of the respective administrative district and as a smoothed proportion. Furthermore, information on smoking habits was included in our analysis. Kulldorff spatial clustering was used to detect different clusters. A negative binomial model was used to test the spatial association between UC incidence as a ratio of observed versus expected incidence rates, land use and smoking habits.ResultsWe identified 437,847,834 person years with 171,086 cases of UC. Cluster analysis revealed areas with higher incidence of UC than others (p=0.0002). Multivariate analysis including significant pairwise interactions showed that the environmental factors were independently associated with UC (p<0.001). The RR was 1.066 (95% CI 1.052–1.080), 1.066 (95% CI 1.042–1.089) and 1.067 (95% CI 1.045–1.093) for agricultural, industrial and residential areas, respectively, and 0.996 (95% CI 0.869–0.999) for the proportion of never smokers.ConclusionThis study displays regional differences in incidence of UC in Germany. Additionally, results suggest that socioeconomic factors based on agricultural, industrial and residential land use may be associated with UC incidence rates.



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Plasma magnesium is inversely associated with Epstein-Barr virus load in peripheral blood and Burkitt lymphoma in Uganda

Publication date: February 2018
Source:Cancer Epidemiology, Volume 52
Author(s): Ravell Juan, Isaac Otim, Hadijah Nabalende, Ismail D. Legason, Steven J. Reynolds, Martin D. Ogwang, Christopher M. Ndugwa, Vickie Marshall, Denise Whitby, James J. Goedert, Eric A. Engels, Kishor Bhatia, Michael J. Lenardo, Sam M. Mbulaiteye
BackgroundEpstein-Barr virus (EBV) causes endemic Burkitt lymphoma (eBL). EBV control was improved by magnesium (Mg²⁺) supplementation in XMEN, an X-linked genetic disease associated with Mg²⁺ deficiency, high circulating EBV levels (viral loads), and EBV-related lymphomas. We, therefore, investigated the relationship between Mg²⁺ levels and EBV levels and eBL in Uganda.MethodsPlasma Mg²⁺ was measured in 45 women with low or high circulating EBV levels, 40 pediatric eBL cases, and 79 healthy children. Mg²⁺ uptake by T-lymphocytes was evaluated in samples from healthy donors.ResultsPlasma Mg²⁺ deficiency (plasma level <1.8 mg/dl) was more likely in women with high- vs. low-EBV levels (76.0% vs. 35%; odds ratio [OR] 11.3, 95% CI 2.14–60.2), controlling for age, and in eBL cases than controls (42.0% vs. 13.9%; OR 3.61, 95% CI 1.32–9.88), controlling for sex, age group, and malaria status. Mg²⁺ uptake by T-lymphocytes was related to extracellular Mg²⁺ concentration.InterpretationPlasma Mg²⁺ deficiency is associated with high EBV levels and eBL.



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