International consensus guidelines on Clinical Target Volume delineation in rectal cancer

Publication date: Available online 12 August 2016
Source:Radiotherapy and Oncology
Author(s): Vincenzo Valentini, Maria Antonietta Gambacorta, Brunella Barbaro, Giuditta Chiloiro, Claudio Coco, Prajnan Das, Francesco Fanfani, Ines Joye, Lisa Kachnic, Philippe Maingon, Corrie Marijnen, Samuel Ngan, Karin Haustermans
IntroductionThe delineation of Clinical Target Volume (CTV) is a critical step in radiotherapy. Several guidelines suggest different subvolumes and anatomical boundaries in rectal cancer (RC), potentially leading to a misunderstanding in the CTV definition. International consensus guidelines (CG) are needed to improve uniformity in RC CTV delineation.Material and methodsThe 7 radiation oncologist experts defined a roadmap to produce RC CG. Step 1: revision of the published guidelines. Step 2: selection of RC cases with different clinical stages. Step 3: delineation of cases using Falcon following previously published guidelines. Step 4: meeting in person to discuss the initial delineation outcome, followed by a CTV proposal based on revised and if needed, adapted anatomical boundaries. Step 5: peer review of the agreed consensus. Step 6: peer review meeting to validate the final outcome. Step 7: completion of RC delineation atlases.ResultsA new ontology of structure sets was defined and the related table of anatomical boundaries was generated. The major modifications were about the lateral lymph nodes and the ischio-rectal fossa delineation. Seven RC cases were made available online as consultation atlases.ConclusionThe definition of international CG for RC delineation endorsed by international experts might support a future homogeneous comparison between clinical trial outcomes.



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A prospective study of DWI, DCE-MRI and FDG PET imaging for target delineation in brachytherapy for cervical cancer

Publication date: Available online 12 August 2016
Source:Radiotherapy and Oncology
Author(s): Kathy Han, Jennifer Croke, Warren Foltz, Ur Metser, Jason Xie, Tina Shek, Brandon Driscoll, Cynthia Ménard, Doug Vines, Catherine Coolens, Anna Simeonov, Akbar Beiki-Ardakani, Eric Leung, Wilfred Levin, Anthony Fyles, Michael F. Milosevic
Background and purposeWe examined the utility of dynamic contrast-enhanced MRI (DCE-MRI), diffusion-weighted MRI (DWI), and FDG-PET imaging for brachytherapy target delineation in patients with locally advanced cervical cancer.Materials and methodsTwenty-two patients had DWI, DCE-MRI, and FDG-PET/CT scans after brachytherapy applicator insertion, in addition to standard T2-weighted (T2w) 3T MRI. Gross tumor volume (GTVB) and high-risk clinical target volume (HRCTV) were contoured first on T2w images, and then modified if indicated upon review of DWI/DCE-MRI/FDG-PET images by two observers. The primary endpoint was utility, determined by the number of patients whose volumes were modified, and interobserver variability.ResultsEleven patients' T2w-GTVB were modified based on DWI/DCE-MRI/FDG-PET by observer 1, due to clearer demarcation (7) and residual disease not well visualized on T2w MRI (4). GTVB was modified in 17 patients by observer 2 (11 and 6, respectively). Incorporation of functional imaging improved the conformity index (CI) for GTVB from 0.54 (T2w alone) to 0.65 (P=0.003). HRCTV was modified in 3 and 8 patients by observers 1 and 2, respectively, with a trend toward higher CI using functional imaging (0.71 to 0.76, P=0.06).ConclusionsDWI/DCE-MRI/FDG-PET imaging as a supplement to T2w MRI decreased interobserver variability in GTVB delineation.



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The accuracy of extracted target motion trajectories in four-dimensional cone-beam computed tomography for lung cancer patients

Publication date: Available online 12 August 2016
Source:Radiotherapy and Oncology
Author(s): Hiraku Iramina, Mitsuhiro Nakamura, Yusuke Iizuka, Takamasa Mitsuyoshi, Yukinori Matsuo, Takashi Mizowaki, Masahiro Hiraoka, Ikuo Kanno
PurposeTo quantify the accuracy of extracted target motion trajectories in dual-source four-dimensional cone-beam computed tomography (4D-CBCT) by comparison with the actual three-dimensional (3D) target motion acquired simultaneously during 4D-CBCT scan.Materials and methods4D-CBCT scans were performed for 19 different sinusoidal-like patterns and 13 lung cancer patients with implanted markers. Internal (In) or external (Ex) surrogates with amplitude (Amp)- or phase (Ph)-based sorting were used for the reconstructions. The targets were a pseudo-tumor and implanted marker for the phantom and clinical studies, respectively. The accuracy was evaluated by determining the maximum error (MaxEi) between the 3D target position extracted from 4D-CBCT and the actual 3D target position detected by fluoroscopy in each ith phase (0⩽i⩽7).ResultsMedian peak-to-peak target displacements in the superior–inferior (SI) direction were 20.6 and 20.6mm in the phantom and clinical studies, respectively. In the phantom and clinical studies, the maximum of median MaxEis in the SI direction was 4.6 and 9.2mm in the In_Ph reconstruction. In the clinical study, the maximum of median MaxEis was observed during the end-inhalation phase among all reconstruction approaches.ConclusionsThis study showed the magnitude of underestimation toward the inferior direction of target motion in clinical 4D-CBCT.



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Impact of organ shape variations on margin concepts for cervix cancer ART

Publication date: Available online 12 August 2016
Source:Radiotherapy and Oncology
Author(s): Yvette Seppenwoolde, Markus Stock, Martin Buschmann, Dietmar Georg, Kwei-Yuang Bauer-Novotny, Richard Pötter, Petra Georg
Background and purposeTarget and organ movement motivate adaptive radiotherapy for cervix cancer patients. We investigated the dosimetric impact of margin concepts with different levels of complexity on both organ at risk (OAR) sparing and PTV coverage.Material and methodsWeekly CT and daily CBCT scans were delineated for 10 patients. The dosimetric impact of organ shape variations were evaluated for four (isotropic) margin concepts: two static PTVs (PTV6mm and PTV15mm), a PTV based on ITV of the planning CT and CBCTs of the first treatment week (PTVART ITV) and an adaptive PTV based on a library approach (PTVART Library).ResultsUsing static concepts, OAR doses increased with large margins, while smaller margins compromised target coverage. ART PTVs resulted in comparable target coverage and better sparing of bladder (V40Gy: 15% and 7% less), rectum (V40Gy: 18 and 6cc less) and bowel (V40Gy: 106 and 15cc less) compared to PTV15mm. Target coverage evaluation showed that for elective fields a static 5mm margin sufficed.ConclusionPTVART Library achieved the best dosimetric results. However when weighing clinical benefit against workload, ITV margins based on repetitive movement evaluation during the first week also provide improvements over static margin concepts.



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Analyse de livres

Publication date: Available online 11 August 2016
Source:Revue de Stomatologie, de Chirurgie Maxillo-faciale et de Chirurgie Orale
Author(s): E. Euvrard




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Arthroscopie de l’articulation temporo-mandibulaire. Mise au point

Publication date: Available online 11 August 2016
Source:Revue de Stomatologie, de Chirurgie Maxillo-faciale et de Chirurgie Orale
Author(s): J.M. Foletti, F. Cheynet, N. Graillon, L. Guyot, C. Chossegros
IntroductionLes syndromes algiques et dysfonctionnels de l'appareil manducateur (SADAM) associent douleurs, trismus et bruits articulaires. Les échecs du traitement médical peuvent conduire à l'arthroscopie. Le but de ce travail a été d'évaluer l'intérêt actuel de l'arthroscopie dans le traitement des SADAM.Matériel et méthodesL'utilisation des mots clés « tmj » et « arthroscopy » a permis de colliger 1668 articles dans Sciencedirect. Nous avons sélectionné 17 articles parus entre septembre 2012 et mai 2016. Six questions ont été posées : (1) quel traitement proposer à un patient présentant un SADAM articulaire ? (2) Quel traitement proposer à un patient présentant un SADAM articulaire réfractaire aux traitements conservateurs ? (3) Le stade selon Wilkes change-t-il l'indication opératoire ? (4) Que proposer à un patient qui a échoué à l'arthroscopie ? (5) La position du disque peut-elle être améliorée par la chirurgie de l'ATM ? (6) Faut-il chercher à améliorer la position du disque ?Résultats et discussion(1) En première intention, il faut toujours débuter par les traitements conservateurs. (2) En cas d'échec d'un traitement conservateur, un geste interventionnel peut être proposé en débutant par le moins agressif possible. (3) Quel que soit le stade de Wilkes, il faut débuter par le traitement le moins invasif possible. (4) En cas d'échec de l'arthroscopie, une arthrotomie peut se discuter. (5) La position du disque en IRM peut être améliorée à long terme mais elle est complexe à obtenir (1 seule publication). (6) Il n'est pas prouvé que le repositionnement discal soit nécessaire.IntroductionTemporomandibular joint (TMJ) dysfunction associates pain, limited mouth opening and joint noise. Failures of conservative treatments may lead to arthroscopy. The aim of our study was to evaluate the current interest of arthroscopy in the treatment of TMJ dysfunction.Material and methodsUsing the keywords "TMJ" and "Arthroscopy", 1668 articles were found in the Sciencedirect database. We selected 17 papers published between September 2012 and May 2016. Six questions were asked: (1) what treatment should be given to patients suffering from TMJ dysfunction? (2) What treatment should be performed for TMJ disorders when conservative treatments failed? (3) Does Wilkes staging change the surgical indication? (4) What has to be done in case of arthroscopy failure? (5) Can disc position be improved after surgery? (6) Should the disc position be improved?Results and discussion(1) Conservative treatment should always be considered in first intention (2) In case of conservative treatment failures, surgery can be proposed, beginning with the less invasive one (3) Whatever the Wilkes stage, treatment should begin by the less invasive one (4) In case of arthroscopy failure, TMJ arthrotomy can be indicated (5) Disc position may be improved in the long term but it is complex to obtain (only one paper) (6) there is no evidence that disk has to be repositioned.



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Les articulations temporomandibulaires et les pathologies rhumatismales inflammatoires

Publication date: Available online 11 August 2016
Source:Revue de Stomatologie, de Chirurgie Maxillo-faciale et de Chirurgie Orale
Author(s): H. Marotte
Différentes pathologies rhumatismales inflammatoires peuvent avoir une répercussion au niveau des articulations temporomandibulaires (ATM), dont la polyarthrite rhumatoïde et les spondyloarthrites. Le but de notre travail était d'évaluer la prévalence actuelle de ces atteintes articulaires inflammatoires de l'ATM, d'indiquer les nouvelles prises en charge et de décrire la collaboration entre le rhumatologue et le chirurgien maxillofacial dans ces pathologies.Some inflammatory rheumatic diseases can involve the temporomandibular joint, such as rheumatoid arthritis and spondylarthritis. The aim of our work was to evaluate the current prevalence of these inflammatory TMJ diseases, to indicate the new therapeutics and to describe the collaboration between rheumatologist and maxillofacial surgeon in these pathologies.



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CD8 down-regulation on cytotoxic T lymphocytes of patients with endometrioid endometrial carcinomas

Publication date: October 2016
Source:Human Pathology, Volume 56
Author(s): Mónica Pascual-García, Cristina Bértolo, Juan C. Nieto, Neus Serrat, Íñigo Espinosa, Emanuela D'Angelo, Raquel Muñoz, Ramón Rovira, Silvia Vidal, Jaime Prat
Carcinogenesis is a multistep process in which cancer cells and tumor stroma cells play important roles. T lymphocytes are immune constituents of tumor stroma and play a crucial function in anti–tumor response. By immunohistochemistry and flow cytometry, we studied T cytotoxic (CTLs) and T helper lymphocyte distribution and percentage in the tumor microenvironment and peripheral blood from 35 patients with endometrioid endometrial carcinomas (EEC). We also studied 23 healthy donors' blood samples as a control group. Tumor and non-tumoral endometrium samples were obtained. Immunohistochemistry revealed a high number of CTLs and T helper lymphocytes in the tumor stroma of myoinvasive EECs. T lymphocytes were mostly located in the invasive front. By flow cytometry, the percentages of CTLs and T helper lymphocytes were significantly higher in the tumor compared with the non-neoplastic endometrium (P = .0492 and P = .002). The mean fluorescence intensity of CD8 staining was lower in the tumor compared to the non-neoplastic endometrium (P = .001). There was also reduction of the mean fluorescence intensity of CD8 staining on peripheral blood from patients with grade 3 EECs compare to the peripheral blood from healthy donors (P = .0093). No alterations in the expression of granzymes A and B were found in the CTLs from the EEC cases. Finally, in a proteome profiler cytokine array we found that the growth differentiation factor 15 (GDF15) increased in blood in parallel to the tumor grade. EECs are capable of down-regulating CD8 expression of CTLs. Most likely, this effect is mediated by a soluble molecule present in plasma and is not a result of anergy or exhaustion state.



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The new “ethics” regulations and the “law of unintended consequences”

Publication date: October 2016
Source:Human Pathology, Volume 56
Author(s): W. Clark Lambert




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Mercy Patient's Powerful Video of Recovery Inspires Others

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Elbow Ultrasound

Abstract

Purpose of the Review

With high resolution real-time and dynamic imaging capabilities, ultrasound is an excellent imaging modality for the evaluation of the elbow. With the foundational understanding of elbow anatomy and pathology, ultrasound of the elbow can positively impact clinical care with both diagnostic examination and image-guided injections and treatments.

Recent Findings

Although there is a learning curve and image quality is operator dependent, knowledge of proper patient positioning, ultrasound technique, and tips for eliminating common pitfalls will significantly make an impact on performing and interpreting elbow ultrasound.

Summary

Elbow ultrasound is an excellent modality for the diagnosis of elbow joint pathology and image-guided injections and treatments. By understanding the anatomy and learning scanning techniques, ultrasound of the elbow can provide integral clinical value.

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CT and MR Update of Pericardial Diseases: A Systematic Review

Abstract

Purpose of review

Pericardial pathology represent a spectrum of entities that should be properly recognized and treated when necessary. To reach an accurate diagnosis, clinicians have at their disposal an ample armamentarium that includes invasive and non-invasive methods, including echocardiography, computed tomography (CT) and magnetic resonance (MR).

Recent findings

CT and MR can be performed as complementary methods when echocardiographic results are inconclusive. These modalities can give not only detailed information on cardiac and pericardial anatomy but also can evaluate physiologic changes. To the extent that in some instances, MR or CT could be the preferred method of choice, i.e., constrictive pericarditis.

Summary

Many disease processes can affect the pericardium. CT and MR, although not representing the initial method of choice which is usually echocardiography, they do play a crucial complementary role when those first line studies are equivocal. Familiarity with the imaging appearance of pericardial disease particularly tamponade and constrictive pericarditis will help treat these patients in a more expeditious fashion.

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The Supraclavicular Flap in Head and Neck Reconstruction

Abstract

Purpose of Review

The supraclavicular artery island flap has recently become increasingly used for the reconstruction of complex soft-tissue defects after head and neck oncologic ablative procedures. In an aging population with multiple comorbidities, with surgery often being performed in the salvage setting, many patients who are not good candidates for free tissue transfer are in still need of advanced reconstructive options. The goal of this article is to review the evolution of this flap and to highlight the recent technical modifications and outcomes data regarding the use of the supraclavicular flap in head and neck reconstruction.

Recent Findings

The supraclavicular artery island flap provides a versatile fasciocutaneous flap with minimal donor site morbidity that affords the reconstructive surgeon a thinness, pliability, color, and texture unmatched by other regional pedicled flaps. It is cost-effective and has been shown to have similar functional outcomes to free tissue transfer for a variety of ablative defects, including those of the lateral skull base and parotid, larynx, oral cavity, and oropharynx.

Summary

The supraclavicular artery island flap has a number of proven advantages in the reconstruction of complex soft-tissue defects after head and neck oncologic ablative procedures. In an era in which salvage surgery is increasingly being performed in an aging patient population with rising comorbidities, the supraclavicular artery island flap provides a reliable, efficient alternative to free tissue transfer reconstruction that can ultimately result in decreased healthcare costs and lower patient morbidity.

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A self tuning regulator design for nonlinear time varying systems based on evolving linear models

Abstract

Fostered by the current notion in the field of intelligent control systems which demands majority of controllers to be self-tuning, adaptive to parameters and structure changes, and above all, intelligent in the face of new circumstances, in this paper, for a general class of Single-Input Single-Output (SISO) nonlinear time-varying systems, a novel Self Tuning Regulator (STR) design based on an introduced Evolving Linear Model (ELM) is proposed. Under definite assumptions and specific constraints, even if there exists no priori knowledge about the system dynamics except its order and relative degree, a suggested online linearization technique based on Recursive Least Squares (RLS) method is applied in order to identify the plant and to derive an Adaptive Linear Regression (ALR) model for the system. An ALR could be treated as ELM when the number of independent regressors which construct the model varies over time. It is demonstrated that under certain constraints, SISO nonlinear systems could be represented by ELMs. Afterwards, an indirect STR strategy is explained and applied on the online identified ELM of the nonlinear system. Multifarious simulations were performed and results clearly demonstrated the privilege and effectiveness of the proposed approaches.

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Immune Modulation and Prevention of Autoimmune Disease by Repeated Sequences from Parasites Linked to Self Antigens

Abstract

Parasite proteins containing repeats are essential invasion ligands, important for their ability to evade the host immune system and to induce immunosuppression. Here, the intrinsic suppressive potential of repetitive structures within parasite proteins was exploited to induce immunomodulation in order to establish self-tolerance in an animal model of autoimmune neurological disease. We tested the tolerogenic potential of fusion proteins containing repeat sequences of parasites linked to self-antigens. The fusion constructs consist of a recombinant protein containing repeat sequences derived from the S-antigen protein (SAg) of Plasmodium falciparum linked to a CD4 T cell epitope of myelin. They were tested for their efficacy to control the development of experimental autoimmune encephalomyelitis (EAE), In addition, we used the DO11.10 transgenic mouse model to study the immune mechanisms involved in tolerance induced by SAg fusion proteins. We found that repeated sequences of P. falciparum SAg protein linked to self-epitopes markedly protected mice from EAE. These fusion constructs were powerful tolerizing agents not only in a preventive setting but also in the treatment of ongoing disease. The tolerogenic effect was shown to be antigen-specific and strongly dependent on the physical linkage of the T cell epitope to the parasite structure and on the action of anti-inflammatory cytokines like IL-10 and TGF-β. Other mechanisms include down-regulation of TNF-α accompanied by increased numbers of FoxP3⁺ cells. This study describes the use of repetitive structures from parasites linked to defined T cell epitopes as an effective method to induce antigen-specific tolerance with potential applicability for the treatment and prevention of autoimmune diseases.

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The effects of Chuanxiong on the pharmacokinetics of warfarin in rats after biliary drainage

Publication date: 4 December 2016
Source:Journal of Ethnopharmacology, Volume 193
Author(s): Haigang Li, Chunhu Zhang, Rong Fan, Hua Sun, Haitang Xie, Jiekun Luo, Yang Wang, Huiying Lv, Tao Tang
Ethnopharmacological relevanceChuanxiong Rhizoma (rhizomes of Ligusticum chuanxiong Hort), known as Chuanxiong in Chinese, has been used for treating cardiovascular diseases for centuries. Chuanxiong is a classical activating blood circulation herb in the treatment of thromboembolism heart diseases. Warfarin often combines with herbal prescriptions containing Chuanxiong in China.Aim of the studyThe herb-drug interaction involving enterohepatic circulation process remains unclear. This study aimed to elucidate the effects of Chuanxiong Rhizoma on the pharmacokinetics of warfarin in rats after biliary drainage.Materials and methodsThirty-two rats were randomly divided into four groups: WN (healthy rats after the gastric-administration of 0.5mg/kg warfarin sodium), WO (a rat model of biliary drainage after the gastric-administration of 0.5mg/kg warfarin sodium), WCN (healthy rats after the gastric-administration of 0.5mg/kg warfarin sodium and 10g/kg Chuanxiong decoction), and WCO (a rat model of biliary drainage after the gastric-administration of 0.5mg/kg warfarin sodium and 10g/kg Chuanxiong decoction). The levels of warfarin and internal standard were quantified by LC-MS/MS. Comparisons between groups were performed according to the main pharmacokinetic parameters calculated by the DAS 2.1.1 software.ResultsThe established LC-MS/MS method was specific, precise and rapid. The pharmacokinetic parameters showed a significant difference between the WN and WO groups. There were significant differences in the area under the curve (AUC0−t), peak concentration (Cmax), total plasma clearance (CLz/F) and mean residence time (MRT0–t) between the WCO and WCN groups; the AUC0–t of warfarin in the WCN group was 2.42 times than that of the WN group (p<0.01); the WCO group displayed a decreased to 61.6% in the Cmax compared the WO group (p<0.01).ConclusionBiliary drainage significantly influenced the disposition of warfarin, and Chuanxiong significantly affected the warfarin disposition in rat plasma.

Graphical abstract

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Antiplasmodial activities of a Thai traditional antipyretic formulation, Bencha-Loga-Wichian: A comparative study between the roots and their substitutes, the stems

Publication date: 4 December 2016
Source:Journal of Ethnopharmacology, Volume 193
Author(s): Thanutchaporn Nutmakul, Kovit Pattanapanyasat, Noppamas Soonthornchareonnon, Kazuro Shiomi, Mihoko Mori, Sompop Prathanturarug
Ethnopharmacological relevanceBencha-Loga-Wichian (BLW) is a polyherbal antipyretic formulation that is comprised of Capparis micracantha, Clerodendrum indicum, Ficus racemosa, Harrisonia perforata, and Tiliacora triandra. A traditional medical textbook has documented the use of this formulation for the treatment of many types of fever, including malaria-like fever. Traditionally, BLW is composed of the root parts of those plants. However, in current practice, the stem parts are frequently substituted. Thus, this study aimed to evaluate the antiplasmodial activities of BLW and compare the efficacy between the stem and root parts.Materials and methodsBLW formulations produced from either the stem or root parts of the various constituent plants as well as the stems or roots of the individual plants were separately extracted and tested against the chloroquine-sensitive (Pf3D7) and -resistant (PfW2) strains Plasmodium falciparum using flow cytometry. The cytotoxicity against peripheral blood mononuclear cells was evaluated using the WST-8 assay to determine the selectivity index (SI). The active compounds of BLW were isolated using antiplasmodial-guided isolation and quantified using Ultra-Performance Liquid Chromatography (UPLC).ResultsThe stem and root parts of BLW and the individual plants exhibited antiplasmodial activities at the same levels with good SI values in the range of 3.55–19.74. The extracts of BLW exhibited promising antiplasmodial activity against both Pf3D7 (IC50<5µg/mL) and PfW2 (IC50=6–10µg/mL). Among the five component plants, T. triandra was the most active and exhibited an IC50<5µg/mL against both strains of parasites with SI values >10. We isolated tiliacorinine and yanangcorinine as the major active compounds (IC50<2µg/mL). However, these two compounds demonstrated cytotoxic effects (SI<1). The UPLC analysis identified these compounds in both the stem and root parts of BLW in the range of 0.57–7.66%, which correlated with the antiplasmodial activity. The concentrations of these compounds in BLW, at comparable efficacy, were much less than those at the IC50s for the single compounds alone. It suggested that synergistic interactions increased the antiplasmodial effects as well as alleviated the toxicity of the active compounds in BLW.ConclusionThis study described a promising antiplasmodial activity of BLW that had good selectivity and a toxicity-alleviating effect. The results provided scientific support for the use of this formulation for the treatment of malaria. In addition, the stem and root parts of the plants in BLW exhibited equivalent activities, which indicates the potential for the substitution of the stem parts in the formulation. Thus, we recommend additional study of the stem parts of these plants for further development on the basis of the availability and sustainability.

Graphical abstract

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Identification of UQCRB as an oxymatrine recognizing protein using a T7 phage display screen

Publication date: 4 December 2016
Source:Journal of Ethnopharmacology, Volume 193
Author(s): Yan-hui Sun, Xiao-yuan Zhang, Wei-qun Xie, Guang-jian Liu, Xi-xin He, Ya-li Huang, Guang-xian Zhang, Jian Wang, Zao-yuan Kuang, Ren Zhang
Ethnopharmacological relevanceSophora flavescens Aiton (Radix Sophorae Flavescentis, Kushen) is used in traditional Chinese medicine to treat chronic hepatitis B (CHB), and has the ability to clear heat and dampness from the body. Oxymatrine is one of the major bioactive compounds extracted from Sophora flavescens Aiton and constitutes more than 90% of the oxymatrine injection commonly used for CHB treatment in clinics in China.Aim of the studyWe aim to analyze the protein binding target of oxymatrine in treating CHB by screening a T7 phage display cDNA library of human CHB and examine the biochemistry of protein-ligand binding between oxymatrine and its ligands.Materials and methodsA T7 phage cDNA library of human CHB was biopanned by affinity selection using oxymatrine as bait. The interaction of oxymatrine with its candidate binding protein was investigated by affinity assay, molecular docking, Isothermal Titration Calorimetry (ITC) and Surface Plasmon Resonance (SPR).ResultsA library of potential oxymatrine binding peptides was generated. Ubiquinol-cytochrome c reductase binding protein (UQCRB) was one of the candidate binding proteins of oxymatrine. UQCRB-displaying T7 phage binding numbers in the oxymatrine group were significantly higher than that in the control group, biotin group, and matrine group (p<0.05 or p<0.01). Three-dimensional structure modeling of the UQCRB with oxymatrine showed that their binding interfaces matched and oxymatrine inserted into a deeper pocket of UQCRB, which mainly involved amino acid residues Tyr21, Arg33, Tyr83, Glu84, Asp86, Pro88, and Glu91. The binding affinity constant (Kb) from SPR was 4.2mM. The Kb from ITC experiment was 3.9mM and stoichiometry was fixed as 1, which fit very well with the result of SPR. The binding of oxymatrine to UQCRB was driven by strong enthalpy forces such as hydrogen bonds and polar interactions as the heat released was about 157kcal/mol and ΔG was less than zero.ConclusionsIn this study, using the T7 phage display system, we have identified UQCRB as a direct binding protein of oxymatrine. Furthermore, the specificity and molecular interaction of oxymatrine with UQCRB were also determined. The binding of UQCRB to oxymatrine suggests that UQCRB is a potential target of oxymatrine in treating CHB. These results provide new understanding into the mechanism of oxymatrine and insights into the strategy on the treatment of CHB.

Graphical abstract

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The effects of Qi Teng Xiao Zhuo granules, traditional Chinese medicine, on the expression of genes in chronic glomerulonephritis rats

Publication date: 4 December 2016
Source:Journal of Ethnopharmacology, Volume 193
Author(s): Jia-Rong Gao, Xiu-Juan Qin, Hui Jiang, Ting Wang, Jun-Mei Song, Shuang-Zhi Xu
Background and aimChronic glomerulonephritis (CGN) is a primary glomerular disease that is related to immune-mediated inflammatory diseases. Qi Teng Xiao Zhuo granules have been proposed as a prescription of traditional Chinese medicine for treatment of CGN, but the comprehensive molecular mechanism underlying this therapeutic effect is not clear to date. The aim of this study was to evaluate and analyze the possible roles and molecular mechanisms of Qi Teng Xiao Zhuo granule-mediated treatment of CGN induced by adriamycin in rats.MethodsFor gene expression analysis, four samples of glomerular tissue from rats in the Qi Teng Xiao Zhuo granule group and four samples each from the adriamycin treated and control groups were hybridized with Agilent Rat 4×44K whole genome microarrays. KEGG and Gene Ontology (GO) analyses and LIMMA, String and Cytoscape software were used to analyze the functional microarray data and screen differentially expressed genes. Hub genes were identified using Pathway Studio software. Real-time PCR was performed to verify the selected genes.ResultsMicroarray gene expression analysis showed that Pnoc, Cacfd1, Fos, Igll1, Lcn2, and Syk were among the most downregulated genes in the Qi Teng Xiao Zhuo granule group compared with the adriamycin treated group, whereas Cyp2c7, Hsd3b6, Acsm5, and Ugt2b15 were significantly upregulated. Functional analysis demonstrated that metabolism of xenobiotics by cytochrome P450, the B cell receptor signaling pathway, and cytokine-cytokine receptor interaction pathways were significantly downregulated in the Qi Teng Xiao Zhuo granule group and that GO terms related to positive regulation of immune response, immune response-activating signal transduction, cell differentiation, cell cycle, proliferation, and adhesion were significantly affected. Fos and Syk were considered to be potential hub genes.ConclusionsIn the adriamycin-induced CGN rat model, comprehensive molecular mechanisms were involved with complex gene expression alterations containing many altered pathways and GO terms. However, how Qi Teng Xiao Zhuo granules regulate these events warrants further investigation.

Graphical abstract

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The total alkaloid fraction of bulbs of Fritillaria cirrhosa displays anti-inflammatory activity and attenuates acute lung injury

Publication date: 4 December 2016
Source:Journal of Ethnopharmacology, Volume 193
Author(s): Dongdong Wang, Jie Yang, Qingdan Du, Houcong Li, Shu Wang
Ethnopharmacological relevanceBulb of Fritillaria cirrhosa D.Don (BFC) has been wildly used in China for a long time for folk medicine since its significant therapeutic effects on respiratory diseases, such as cough, expectoration, pneumonia and bronchial inflammation, which are related to respiratory inflammatory response. However, there is a lack of investigation on the in vivo anti-inflammatory properties of BFC.Aim of the studyThe aim of this study was to evaluate the in vivo anti-inflammatory activity of the purified total alkaloid fraction of BFC (TAF) by using different animal models of inflammation to provide scientific evidence for its traditional use.Materials and methodsThe total alkaloid fraction from BFC was prepared by using H-103 resin column. Anti-inflammatory effect of TAF was evaluated by models of acetic acid-induced capillary permeability accentuation, carrageenan-induced rat paw edema, cotton pellet-induced granuloma formation and LPS-induced acute lung injury (ALI). The level of cytokines (TNF, IL-6, IL-4 and IL-10) was measured by ELISA. Histopathological analyses were performed by using hematoxylin and eosin staining.ResultsTAF can inhibit acetic acid-induced capillary permeability accentuation, carrageenan-induced paw edema, cotton pellet-induced granuloma formation, suppress inflammatory cells recruitment and cytokine production in the bronchoalveolar lavage fluid from LPS-induced ALI mice, and attenuate pathological changes in the lung tissues of ALI mice.ConclusionThis study provides scientific evidence for bulb of F. cirrhosa to treat respiratory inflammation.

Graphical abstract

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Chinese herbal medicines promote hippocampal neuroproliferation, reduce stress hormone levels, inhibit apoptosis, and improve behavior in chronically stressed mice

Publication date: 4 December 2016
Source:Journal of Ethnopharmacology, Volume 193
Author(s): Gao-Ge Sun, Jui-Hu Shih, Shih-Hwa Chiou, Chen-Jee Hong, Shao-Wei Lu, Li-Heng Pao
Ethnopharmacological relevanceAn efficacious antidepressant without unwanted side effects is need urgently at present. This study aimed to investigate whether treatment with four Chinese herbal medicines (CHMs), namely Radix Astragali, Saposhnikovia divaricate (SD), Eucommia ulmoides Oliv. bark (EU), and Corydalis yanhusuo W. T. Wang (C. yanhusuo), could reverse the effects of chronic mild stress (CMS) in a depression-like mouse model and the potential mechanism(s) of their action.Materials and methodsIn vitro study, the proliferation of NSCs was assessed using the MTS assay. In vivo study, chronic mild stress (CMS) was used in mice for 14 days to establish a depression-like mouse model. Plasma corticosterone levels were assessed by UPLC coupled to a triple-quadrupole mass spectrometer. The forced swim test (FST) was used to assess the effects of the four CHMs on depression. BrdU incorporation and TUNEL staining were used to assay hippocampal precursor cell proliferation rate and apoptosis.ResultsThe CHMs included Radix Astragali, EU, C. yanhusuo, and SD were shown to promote neuroproliferation in vitro. In vivo study, oral administration of these four CHMs for 14 days reversed the elevated plasma corticosterone levels, body weight loss, decrease in proliferation of hippocampal precursor cells; they also inhibited hippocampal cell apoptosis, and exhibited an antidepressant-like effect in a depression-like mouse model induced by CMS.ConclusionsOur study indicates that each of these CHMs has the potential to ameliorate depression. The possible mechanisms of action include modulation of the HPA axis, reduction in stress hormone levels, inhibition of apoptosis, and promotion of hippocampal neuronal plasticity and neurogenesis.

Graphical abstract

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The next generation of novel therapies for the management of relapsed multiple myeloma

Future Oncology Ahead of Print.


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Are virus-induced cancers more sensitive to checkpoint inhibitors?

Future Oncology Ahead of Print.


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miRNA-24-3p promotes cell proliferation and regulates chemosensitivity in head and neck squamous cell carcinoma by targeting CHD5

Future Oncology Ahead of Print.


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Can we improve referrals for fertility preservation? Evolution of practices after the creation of a fertility network

Future Oncology Ahead of Print.


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A dynamic study of the anterior cruciate ligament of the knee using an open MRI

Abstract

Recent anatomical and radiological studies of the anterior cruciate ligament (ACL) suggest the ACL length and orientation change during knee flexion, and an open MRI sequencing during knee flexion enables a dynamic ACL analysis. This study's goal is to describe a normal ACL using a 1T open MRI and, in particular, variations in length and insertion angles at different degrees of flexion. Twenty-one volunteers with clinically healthy knees received a dynamic MRI with their knees in hyperextension, neutral position, and flexed at 45° and 90° angles. For each position, two radiologists measured the ACL lengths and angles of the proximal insertion between the ACL's anterior edge and the roof of the inter-condylar notch. Additionally, we measured the ACL's and the tibial plateau's distal angle insertion between their anterior edges and then compared these with the nonparametric Wilcoxon test. The ACL had a significant extension between the 90° flexion and all other positions (hyperextension: 31.75 ± 2.5 mm, neutral position: 32.5 ± 2.6 mm, 45°: 35.6 ± 1.6 mm, 90°: 35.6 ± 1.6 mm). There was also a significant increase of the angle insertion between the proximal 90° flexion and all other positions, as well as between hyperextension and bending to 45° (hyperextension: 2.45° ± 3.7°, neutral: 13.4° ± 9.7°, 45°: 33 25 ± 9.3, 90: 51.85° ± 9.3°). Additionally, there is a significant increase in the distal angle insertion for all positions (hyperextension: 133.2° ± 5.4°, neutral position: 134.95° ± 4.4°, 45°: 138.35° ± 5.9°, 90°: 149.15° ± 8.6°). Our study is the first to exhibit that a dynamic MRI has a significant ACL extension in vivo during bending. This concept opens the way for further studies to improve the diagnosis of traumatic ACL injuries using a dynamic MRI.

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Juvenile Idiopathic Arthritis: Diagnosis and Treatment

Abstract

Juvenile idiopathic arthritis is a broad term that describes a clinically heterogeneous group of arthritides of unknown cause, which begin before 16 years of age. This term encompasses several disease categories, each of which has distinct presentation, clinical manifestations, and, presumably, genetic background and etiopathogenesis. Although none of the available drugs has curative potential, prognosis has greatly improved as a result of substantial progresses in disease management. The most important new development has been the introduction of the biologic medications, which constitute a valuable treatment option for patients who are resistant to conventional antirheumatic agents. Further insights into the disease pathogenesis and treatment will be provided by the continuous advances in understanding of the mechanisms related to the immune response and inflammatory process, and by the development of new drugs that are capable of selectively inhibiting single molecules or pathways.

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A Simple Flow Cytometric Method to Measure Glucose Uptake and Glucose Transporter Expression for Monocyte Subpopulations in Whole Blood

Monocytes are integral components of the human innate immune system that rely on glycolytic metabolism when activated. We describe a flow cytometry protocol to measure glucose transporter expression and glucose uptake by total monocytes and monocyte subpopulations in fresh whole blood.

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A nomogram for predicting the need for sciatic nerve block after total knee arthroplasty

Abstract

Purpose

Sciatic nerve block (SNB) is commonly performed in combination with femoral nerve block (FNB) for postoperative analgesia following total knee arthroplasty (TKA). Despite the fact that 10–20 % of TKA patients require SNB for postoperative posterior knee pain, there are no existing studies that suggest a model to predict the need for SNB. The aim of our study was to develop a prediction tool to measure the likelihood of patients undergoing TKA surgery requiring a postoperative SNB.

Methods

With institutional review board approval, we obtained data from the electronic medical record of patients who underwent TKA at the Cleveland Clinic. A multivariable logistic regression was used to estimate the probability of requiring a postoperative SNB. Clinicians selected potential predictors to create a model, and the potential nonlinear association between continuous predictors and SNB was assessed using the restricted cubic spline model.

Results

In total 6279 TKA cases involving 2329 patients with complete datasets were used for building the prediction model, including 276 (12 %) patients who received a postoperative SNB and 2053 (88 %) patients who did not. The estimated C statistic of the prediction model was 0.64. The nomogram is used by first locating the patient position on each predictor variable scale, which has corresponding prognostic points. The cut-off of 11.6 % jointly maximizes the sensitivity and specificity.

Conclusion

This is the first study to be published on SNB prediction after TKA. Our nomogram may prove to be a useful tool for guiding physicians in terms of their decisions regarding SNB.

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Retrolaminar block: analgesic efficacy and safety evaluation

Abstract

Purpose

Retrolaminar block (RLB) is a thoracic truncal block that can produce analgesia for the thoracic and abdominal wall. However, the characteristics of RLB are not well known. The aim of this study was to determine analgesic efficacy by measuring postoperative consume of patient-controlled analgesia (PCA), additional nonsteroidal antiinflammatory drug (NSAID) rescue, and opioid rescue. Our secondary analysis included assessment of the chronological change in arterial levobupivacaine concentrations after the block.

Methods

This prospective, randomized, double-blinded study included 30 patients scheduled for modified radical mastectomy under general anesthesia. The patients were randomized to receive either a landmark-guided RLB or paravertebral block (PVB) catheter placement on T4. Continuous infusion with 4 ml/h of 0.25 % levobupivacaine was started for 72 h, after initial injection of 20 ml 0.375 % levobupivacaine before surgery. Postoperative pain was compared using the amount of block PCA (3 ml 0.25 % levobupivacaine with 30-min lockout), NSAID, and opioid rescue. Arterial blood was sampled for 120 min after the initial injection.

Results

The frequency of postoperative block PCA use was significantly high after RLB in 24 h [p = 0.01; 6 (3–12) vs. 2.5 (0.3–3) times, respectively]. There was no PCA use after 24 h in either group. There was no postoperative opioid rescue use throughout the study. After RLB and PVB, there was no significant difference in T _max (p = 0.14; 15 ± 8 vs. 15 ± 8 min, respectively) and C _max (p = 0.2; 0.9 ± 0.2 vs. 0.9 ± 0.3 µg/ml, respectively), and all the concentrations were below the threshold of local anesthetic systemic toxicity.

Conclusion

Continuous RLB was not inferior to PVB except for the first 24 h, and was satisfactory after mastectomy. RLB showed safe, low peak arterial levobupivacaine concentrations.

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The Surgical Robotics Lab at UTwente

The Surgical Robotics Lab (SRL) led by Sarthak Misra "is part of the Department of Biomechanical Engineering (Faculty of Engineering Technology) at the University of Twente, The Netherlands. SRL is directed by Prof. Sarthak Misra. We are also part of the Department of Biomedical Engineering at the University of Groningen and University Medical Center Groningen. SRL is affiliated with MIRA-Institute for Biomedical Technology and Technical Medicine and an active member within the Center for Medical Imaging.

SRL has a dynamic research agenda, and we consist of a multi-disciplinary team of engineers, clinicians, and industrial collaborators. We focus on developing innovative solutions for a broad range of clinically-relavent challenges.

The research of SRL focuses on developing novel techniques to reach challenging locations within the body.

We design a range of flexible minimally invasive surgical instruments and microrobotic systems, and robotically control them using various clinical imaging modalities such as ultrasound, computed tomography and magnetic resonance images. For further details on our activities please refer to our Research and Publications pages.

SRL is composed of an interdisciplinary team of engineers from diverse backgrounds (Mechanical, Electrical, Biomedical, Applied Physics, and Technical Medicine). We closely collaborate with our clinical partners at Univeristy Medical Center Groningen, Radboud University Nijmegen Medical Center, and Medisch Spectrum Twente.

SRL is equipped with rapid prototyping facilities such as 3D printer and laser cutter, and also access to the department workshop. Further, we also have 3D ultrasound (research) systems and several navigation instruments.

We are always looking for motivated students interested in Master's- or Bachelor's-level projects in the general area of surgical robotics.  Please peruse our Openings page, or look at the Research page if you would like to get involved in one of the projects.

SRL recevies generous support from the European Commission (Horizon 2020), European Research Council (ERC), Netherlands Organization for Scientific Research (NWO), Dutch Technology Foundation (STW), Netherlands Organization for Health Research and Development (ZonMw), Netherlands Enterprise Agency (RVO), and the Northern Netherlands Provinces Alliance (SNN)." 

Publications from 2016, Journal articles

• • T Araujo, M Abayazid, M J C M Rutten, and S Misra, "Segmentation and three-dimensional reconstruction of lesions using the Automated Breast Volume Scanner (ABVS)", International Journal of Medical Robotics and Computer Assisted Surgery, 2016. Accepted.
  • I S M Khalil, H Abass , M Shoukry , A Klingner , R M El-Nashar , M Serry and S Misra, "Robust and optimal control of magnetic microparticles inside fluidic channels with time-varying flow rates", International Journal of Advanced Robotic Systems, 2016. Accepted.
  • R J Roesthuis and S Misra, "Steering of multi-segment continuum manipulators using rigid-link modeling and FBG-based shape sensing", IEEE Transactions on Robotics, 32(2): 372 – 382, April 2016. 

    M Abayazid, P Moreira, N Shahriari, A Zompas, and S Misra, "Three-dimensional needle steering using Automated Breast Volume Scanner (ABVS)", Journal of Medical Robotics Research, 1(1), March 2016. In Press. 

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The use of inhaled corticosteroids in pediatric asthma: update

Despite the availability of several formulations of inhaled corticosteroids (ICS) and delivery devices for treatment of childhood asthma and despite the development of evidence-based guidelines, childhood asth...

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Metformin use and its effect on survival in diabetic patients with advanced non-small cell lung cancer

Abstract

Background

Previous population-based studies have demonstrated an association between metformin use and improved survival among diabetic patients with cancer. We sought to analyze the effects of diabetes and its treatment in terms of the survival of patients with lung cancer.

Methods

Overall, 1106 patients with non-small cell lung cancer (94.3 % with stage IV disease) were included. The outcomes were compared between the patients with (n = 186) and without diabetes (n = 920). The characteristics associated with antidiabetic treatment and proper glycemic control (defined as a mean plasma glucose <130 mg/dL) were examined at diagnosis. The overall survivals (OSs) of the different patient populations were analyzed using Kaplan-Meier curves, and a multivariate Cox proportional hazard model was used to determine the influences of the patient and tumor characteristics on survival.

Results

The OS for the entire population was 18.3 months (95 % CI 16.1-20.4). There was no difference in the OSs of the diabetic and non-diabetic patients (18.5 vs 16.4 months, p = 0.62). The diabetic patients taking metformin exhibited a superior OS than did those on other antidiabetic treatments (25.6 vs 13.2 months, p = 0.017). Those with proper glycemic control had a better OS than did those without proper glycemic control and the non-diabetics (40.5 vs 13.2 and 18.5 months, respectively, p < 0.001). Both the use of metformin (HR 0.53, p < 0.0001 and HR 0.57, p = 0.017, respectively) and proper glycemic control (HR 0.49, p < 0.0001 and HR 0.40, p = 0.002, respectively) were significant protective factors in all and only diabetic patients, respectively.

Conclusions

The diabetic patients with proper glycemic control exhibited a better OS than did those without proper glycemic control and even exhibited a better OS than did the patients without diabetes mellitus. Metformin use was independently associated with a better OS.

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Overexpression of KCNJ3 gene splice variants affects vital parameters of the malignant breast cancer cell line MCF-7 in an opposing manner

Abstract

Background

Overexpression the KCNJ3, a gene that encodes subunit 1 of G-protein activated inwardly rectifying K⁺ channel (GIRK1) in the primary tumor has been found to be associated with reduced survival times and increased lymph node metastasis in breast cancer patients.

Methods

In order to survey possible tumorigenic properties of GIRK1 overexpression, a range of malignant mammary epithelial cells, based on the MCF-7 cell line that permanently overexpress different splice variants of the KCNJ3 gene (GIRK1a, GIRK1c, GIRK1d and as a control, eYFP) were produced. Subsequently, selected cardinal neoplasia associated cellular parameters were assessed and compared.

Results

Adhesion to fibronectin coated surface as well as cell proliferation remained unaffected. Other vital parameters intimately linked to malignancy, i.e. wound healing, chemoinvasion, cellular velocities / motilities and angiogenesis were massively affected by GIRK1 overexpression. Overexpression of different GIRK1 splice variants exerted differential actions. While GIRK1a and GIRK1c overexpression reinforced the affected parameters towards malignancy, overexpression of GIRK1d resulted in the opposite. Single channel recording using the patch clamp technique revealed functional GIRK channels in the plasma membrane of MCF-7 cells albeit at very low frequency.

Discussion

We conclude that GIRK1d acts as a dominant negative constituent of functional GIRK complexes present in the plasma membrane of MCF-7 cells, while overexpression of GIRK1a and GIRK1c augmented their activity. The core component responsible for the cancerogenic action of GIRK1 is apparently presented by a segment comprising aminoacids 235–402, that is present exclusively in GIRK1a and GIRK1c, but not GIRK1d (positions according to GIRK1a primary structure).

Conclusions

The current study provides insight into the cellular and molecular consequences of KCNJ3 overexpression in breast cancer cells and the mechanism upon clinical outcome in patients suffering from breast cancer.

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Metabolic complete response with vinflunine as second-line therapy in a kidney-transplanted patient with advanced urothelial carcinoma: a case report

Abstract

Background

Patients undergone kidney transplantation present higher risk of Urothelial Carcinoma (UC) development and represent a subgroup of special interest. To date, vinflunine is the only drug approved in Europe for the treatment of advanced UC after failure of platinum-based chemotherapy. However, to our knowledge, no data on the concomitant administration of vinflunine and immunosuppressive agents are available.

Case presentation

The patient, a 45 years old Caucasian male, presented poorly differentiated UC of the bladder recurred after initial cystectomy with abdominal lymphadenopathies evidenced by FDG-PET/CT. Previously, at the age of 22, he had post-glomerulonephritis renal failure and underwent kidney transplantation from deceased donor. Since then, he has been in treatment with immunosuppressive therapy. At the time of UC recurrence, he was on treatment with cyclosporine. After progression to platinum-based chemotherapy, he received second-line therapy with vinflunine resulting in a complete metabolic response after two cycles. However, despite several dose reductions, the patient experienced severe hematologic toxicity. The pharmacological interaction between vinflunine and cyclosporine, both metabolized by CYP 3A4, may explain the excellent result and the concomitant severe toxicity.

Conclusions

Vinflunine is active on UC developed in kidney transplanted patients. However, special attention should be paid to concomitant administration with immunosuppressive agents that could result in increased toxicity.

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A germline mutation of CDKN2A and a novel RPLP1-C19MC fusion detected in a rare melanotic neuroectodermal tumor of infancy: a case report

Abstract

Background

Melanotic neuroectodermal tumor of infancy (MNTI) is exceptionally rare and occurs predominantly in the head and neck (92.8 % cases). The patient reported here is only the eighth case of MNTI presenting in an extremity, and the first reported in the fibula.

Case presentation

A 2-month-old female presented with a mass arising in the fibula. Exhaustive genomic, transcriptomic, epigenetic and pathological characterization was performed on the excised primary tumor and a derived cell line. Whole-exome analysis of genomic DNA from both the tumor and blood indicated no somatic, non-synonymous coding mutations within the tumor, but a heterozygous, unique germline, loss of function mutation in CDKN2A (p16^INK4A, D74A). SNP-array CGH on DNA samples revealed the tumor to be euploid, with no detectable gene copy number variants. Multiple chromosomal translocations were identified by RNA-Seq, and fusion genes included RPLP1-C19MC, potentially deregulating the C19MC cluster, an imprinted locus containing microRNA genes reactivated by gene fusion in embryonal tumors with multilayered rosettes. Since the presumed cell of origin of MNTI is from the neural crest, we also compared gene expression with a dataset from human neural crest cells and identified 185 genes with significantly different expression. Consistent with the melanotic phenotype of the tumor, elevated expression of tyrosinase was observed. Other highly expressed genes encoded muscle proteins and modulators of the extracellular matrix. A derived MNTI cell line was sensitive to inhibitors of lysine demethylase, but not to compounds targeting other epigenetic regulators.

Conclusions

In the absence of somatic copy number variations or mutations, the fully transformed phenotype of the MNTI may have arisen in infancy because of the combined effects of a germline CDKN2A mutation, tumor promoting somatic fusion genes and epigenetic deregulation. Very little is known about the etiology of MNTI and this report advances knowledge of these rare tumors by providing the first comprehensive genomic, transcriptomic and epigenetic characterization of a case.

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A case report of a patient with metastatic ocular melanoma who experienced a response to treatment with the BRAF inhibitor vemurafenib

Abstract

Background

Conjunctival malignant melanoma (CMM) is a rare malignancy and in the advanced setting there is no effective treatment. In contrast, half of cutaneous melanomas have BRAF mutations and treatment with BRAF inhibitors is established for patients with disseminated disease. The most common form of ocular melanoma, uveal melanoma, lacks these mutations, however, their presence has been reported for CMM.

Case presentation

We used the BRAF inhibitor vemurafenib to treat a 53 year-old female suffering from a BRAF^V600E mutated metastatic CMM. The patient benefited from the treatment, a response was evident within a week and she experienced a progression free survival of four months.

Conclusions

To our knowledge, this is the first described case of response to vemurafenib treatment in a patient with ocular melanoma.

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Gd-EOB-DTPA-enhanced magnetic resonance imaging combined with T1 mapping predicts the degree of differentiation in hepatocellular carcinoma

Abstract

Background

Variable degrees of differentiation in hepatocellular carcinoma(HCC)under Edmondson-Steiner grading system has been proven to be an independent prognostic indicator for HCC. Up till now, there has been no effective radiological method that can reveal the degree of differentiation in HCC before surgery. This paper aims to evaluate the use of Gd-EOB-DTPA-Enhanced Magnetic Resonance Imaging combined with T1 mapping for the diagnosis of HCC and assessing its degree of differentiation.

Methods

Forty-four patients with 53 pathologically proven HCC had undergone Gd-EOB-DTPA enhanced MRI with T1 mapping before surgery. Out of the 53 lesions,13 were grade I, 27 were gradeII, and 13 were grade III. The T1 values of each lesion were measured before and at 20 min after Gd-EOB-DTPA administration (T1p and T1e). The absolute reduction in T1 value (T1d) and the percentage reduction (T1d %) were calculated. The one-way ANOVA and Pearson correlation were used for comparisons between the T1 mapping values.

Results

The T1d and T1d % of grade I, II and III of HCC was 660.5 ± 422.8ms、295.0 ± 99.6ms、276.2 ± 95.0ms and 54.0 ± 12.2 %、31.5 ± 6.9 %、27.7 ± 6.7 % respectively. The differences between grade Iand II, grade Iand III were statistically significant (p < 0.05), but there was no statically significant difference between grade II and III. The T1d % was the best marker for grading of HCC, with a Spearman correlation coefficient of −0.676.

Conclusions

T1 mapping before and after Gd-EOB-DTPA administration can predict degree of differentiation in HCC.

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Young patients and gastrointestinal (GI) tract malignancies - are we addressing the unmet needs?

Abstract

Background

Recent epidemiological studies indicate the rate of gastrointestinal (GI) malignancies among younger patients is increasing, mainly due to colorectal cancer. There is a paucity of data regarding the magnitude of treatment-related symptoms, psychosocial issues and potential unmet needs in this population. We aimed to characterize the needs of this population to evaluate whether unmet needs could be targeted by potential intervention.

Methods

Female and male patients diagnosed with cancer of the gastrointestinal tract <40y retrospectively completed a questionnaire to evaluate symptoms, daily function and unmet needs at pre-treatment, during and post-treatment. Comparisons were made by gender, disease stage and treatment modality. Multiple linear regression models evaluated effects of demographics, symptoms and needs on multiple domains of health-related-quality-of-life (using Short-Form Health Survey-12 and CARES).

Results

Fifty patients were enrolled (52 % female) to a pilot study. Median age at diagnosis was 35.5y (range, 21-40y). The symptoms that significantly increased from baseline to during and post-treatment were: diarrhea (37 %), sleeping disorder (32 %) and sexual dysfunction (40 %). Patients also reported significant deterioration in occupational activities and coping with children compared with baseline. Female patients reported significant unmet need for nutritional counseling and psychosocial support compared to male patients (p < 0.05). Patients treated with multimodality-treatment presented higher rates of unmet needs (p = 0.03).

Conclusions

Young patients with GI cancers represent a group with unique characteristics and needs compared with published evidence on other young-onset malignancies. The distinctive symptoms and areas of treatment-related functional impairments indicate there are unmet needs, especially in the area of psychosocial support and nutritional counseling.

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IAP antagonists Birinapant and AT-406 efficiently synergise with either TRAIL, BRAF, or BCL-2 inhibitors to sensitise BRAFV600E colorectal tumour cells to apoptosis

Abstract

Background

High expression levels of Inhibitors of Apoptosis Proteins (IAPs) have been correlated with poor cancer prognosis and block the cell death pathway by interfering with caspase activation. SMAC-mimetics are small-molecule inhibitors of IAPs that mimic the endogenous SMAC and promote the induction of cell death by neutralizing IAPs.

Methods

In this study, anti-tumour activity of new SMAC-mimetics Birinapant and AT-406 is evaluated against colorectal adenocarcinoma cells and IAP cross-talk with either oncogenic BRAF or BCL-2, or with the TRAIL are further exploited towards rational combined protocols.

Results

It is shown that pre-treatment of SMAC-mimetics followed by their combined treatment with BRAF inhibitors can decrease cell viability, migration and can very efficiently sensitize colorectal tumour cells to apoptosis. Moreover, co-treatment of TRAIL with SMAC-mimetics can efficiently sensitize resistant tumour cells to apoptosis synergistically, as shown by median effect analysis. Finally, Birinapant and AT-406 can synergise with BCL-2 inhibitor ABT-199 to reduce viability of adenocarcinoma cells with high BCL-2 expression.

Conclusions

Proposed synergistic rational anticancer combined protocols of IAP antagonists Birinapant and AT-406 in 2D and 3D cultures can be later further exploited in vivo, from precision tumour biology to precision medical oncology.

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Which is better for gastric cancer patients, perioperative or adjuvant chemotherapy: a meta-analysis

Abstract

Background

The preferred chemotherapy method for gastric cancer continues to be matter of debate. We performed a meta-analysis to comparing prognosis and safety between perioperative chemotherapy and adjuvant chemotherapy to identify the better chemotherapy option for gastric cancer.

Methods

We searched the PubMed, EMBASE, Cochrane Library, and Ovid databases for eligible studies until February 2016. The main endpoints were prognostic value (hazard ratio [HR] for overall survival [OS] and 1-, 2-, 3-, and 5-year survival rate), response rate of chemotherapy, radical resection rate, post-operative complication rate, and adverse effects of chemotherapy.

Results

Five randomized controlled trials and six clinical controlled trials involving 1,240 patients were eligible for analysis. Compared with the adjuvant chemotherapy group, the perioperative chemotherapy group had significantly better prognosis (HR, 0.74; 95 % CI, 0.61 to 0.89; P < 0.01). The difference between the two groups remained significant in the studies that used combination chemotherapy as the neoadjuvant chemotherapy regimen (HR, 0.59; 95 % CI, 0.46 to 0.76; P < 0.01) but were not significant in the studies that used fluoropyrimidine monotherapy (HR, 0.93; 95 % CI, 0.56 to 1.55; P = 0.84). Furthermore, the two groups showed no significant differences in the post-operative complication rates (relative risk, 0.98; 95 % CI, 0.63 to 1.51; P = 0.91) or adverse effects of chemotherapy (P > 0.05 for all adverse effects).

Conclusion

Perioperative chemotherapy showed improved survival compared to adjuvant chemotherapy for gastric cancer. In addition, combination chemotherapy resulted in better survival compared to monotherapy in the neoadjuvant chemotherapy regimens.

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PNA clamping-assisted fluorescence melting curve analysis for detecting EGFR and KRAS mutations in the circulating tumor DNA of patients with advanced non-small cell lung cancer

Abstract

Background

Circulating cell-free DNA (cfDNA) is emerging as a surrogate sample type for mutation analyses. To improve the clinical utility of cfDNA, we developed a sensitive peptide nucleic acid (PNA)-based method for analyzing EGFR and KRAS mutations in the plasma cfDNA of patients with advanced non-small cell lung cancer (NSCLC).

Methods

Baseline tissue and plasma samples were collected from treatment-naïve advanced NSCLC patients participated in a randomized phase II study, which was registered with ClinicalTrials.gov at Feb. 2009 (NCT01003964). EGFR and KRAS mutations in the plasma cfDNA were analyzed retrospectively using a PNA clamping-assisted fluorescence melting curve analysis. The results were compared with those obtained from tissue analysis performed using the direct sequencing. Exploratory analyses were performed to determine survival predicted by the plasma and tissue mutation status.

Results

Mutation analyses in matched tissue and plasma samples were available for 194 patients for EGFR and 135 patients for KRAS. The mutation concordance rates were 82.0 % (95 % confidence interval [CI], 76.5–87.4) for EGFR and 85.9 % (95 % CI, 80.1–91.8) for KRAS. The plasma EGFR mutation test sensitivity and specificity were 66.7 % (95 % CI, 60.0–73.3) and 87.4 % (95 % CI, 82.7–92.1), respectively, and the plasma KRAS mutation test sensitivity and specificity were 50.0 % (95 % CI, 41.6–58.4) and 89.4 % (95 % CI, 84.2–94.6), respectively. The predictive value of the plasma EGFR and KRAS mutation status with respect to survival was comparable with that of the tissue mutation status.

Conclusions

These data suggest that plasma EGFR and KRAS mutations can be analyzed using PNA-based real-time PCR methods and used as an alternative to tumor genotyping for NSCLC patients when tumor tissue is not available.

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Prognostic relevance of molecular subtypes and master regulators in pancreatic ductal adenocarcinoma

Abstract

Background

Pancreatic cancer is poorly characterized at genetic and non-genetic levels. The current study evaluates in a large cohort of patients the prognostic relevance of molecular subtypes and key transcription factors in pancreatic ductal adenocarcinoma (PDAC).

Methods

We performed gene expression analysis of whole-tumor tissue obtained from 118 surgically resected PDAC and 13 histologically normal pancreatic tissue samples. Cox regression models were used to study the effect on survival of molecular subtypes and 16 clinicopathological prognostic factors. In order to better understand the biology of PDAC we used iRegulon to identify transcription factors (TFs) as master regulators of PDAC and its subtypes.

Results

We confirmed the PDAssign gene signature as classifier of PDAC in molecular subtypes with prognostic relevance. We found molecular subtypes, but not clinicopathological factors, as independent predictors of survival. Regulatory network analysis predicted that HNF1A/B are among thousand TFs the top enriched master regulators of the genes expressed in the normal pancreatic tissue compared to the PDAC regulatory network. On immunohistochemistry staining of PDAC samples, we observed low expression of HNF1B in well differentiated towards no expression in poorly differentiated PDAC samples. We predicted IRF/STAT, AP-1, and ETS-family members as key transcription factors in gene signatures downstream of mutated KRAS.

Conclusions

PDAC can be classified in molecular subtypes that independently predict survival. HNF1A/B seem to be good candidates as master regulators of pancreatic differentiation, which at the protein level loses its expression in malignant ductal cells of the pancreas, suggesting its putative role as tumor suppressor in pancreatic cancer.

Trial registration

The study was registered at ClinicalTrials.gov under the number NCT01116791 (May 3, 2010).

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Investigating the Role of the Stringent Response in Lipid Modifications during the Stationary Phase in E. coli by Direct Analysis with Time-of-Flight-Secondary Ion Mass Spectrometry

Analytical Chemistry

DOI: 10.1021/acs.analchem.6b01981

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TASER Electric Stun Gun Integrated with ECG Cardiac Monitoring

What if your friendly local police officer could tase you for being an idiot and detect a cardiac arrhythmia at the same time? This is now a possibility thanks to a prototype system from researchers at Wake Forest Baptist Medical Center that combines a TASER electric stun gun with ECG biomonitoring.

The cardiac monitor records the electric heart signals through the same electrodes that pierce the skin and deliver the electric shock. According to the researchers, this required little modification of the TASER, and in field tests conducted on a few very bold volunteers the researchers were able to confirm that the system works.

The study, published in journal Forensic and Legal Medicine, notes that so-called "conducted electrical weapons" have been shown to be pretty safe, but there's still considerable concern that some people's hearts react poorly to these thumping devices. Perhaps soon we'll see TASERs and other such weapons with integrated ECG monitoring being introduced, allowing a police officer to recognize a problem and take life saving action even if the perp really is an idiot.

Study in journal Forensic and Legal Medicine: A TASER conducted electrical weapon with cardiac biomonitoring capability: Proof of concept and initial human trial…

Via: Wake Forest Baptist Medical Center…

This post TASER Electric Stun Gun Integrated with ECG Cardiac Monitoring appeared first on Medgadget.

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Tumor screening in Beckwith–Wiedemann syndrome—To screen or not to screen?

Beckwith–Wiedemann syndrome (BWS) is the most common imprinting disorder and consequently, one of the most common cancer predisposition disorders. Over the past 20 years, our understanding of the genetics and epigenetics leading to BWS has evolved and genotype/phenotype correlations have become readily apparent. Clinical management of these patients is focused on omphaloceles, hypoglycemia, macroglossia, hemihypertrophy, and tumor screening. Until recently, the need for tumor screening has been thought to be largely uniform across all genetic and epigenetic causes of BWS. As tumor risk correlates with genetic and epigenetic causes of BWS, several groups have proposed alterations to tumor screening protocols based on the etiology of BWS. However, there are many challenges inherent in adapting screening protocols. Such protocols must accommodate not only the risk based on genetic and epigenetic causes but also the medical cost-benefit of screening, the psychological impact on families, and the social-legal implications of missing a treatable tumor. © 2016 Wiley Periodicals, Inc.

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In this issue

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Role of CFTR variants explored in developing cystic fibrosis symptoms

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Higher plasma orexin a levels in children with Prader–Willi syndrome compared with healthy unrelated sibling controls

Prader–Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder associated with maladaptive social behavior, hyperphagia and morbid obesity. Orexin A is a hypothalamic neuropeptide important as a homeostatic regulator of feeding behavior and in energy metabolism through actions in the lateral hypothalamus. Dysregulation of orexin signaling may contribute to behavioral problems and hyperphagia seen in PWS and we sought to assess orexin A levels in PWS relative to controls children. Morning fasting plasma orexin A levels were analyzed in 23 children (aged 5–11 years) with genetically confirmed PWS and 18 age and gender matched healthy unrelated siblings without PWS. Multiplex immune assays utilized the Milliplex Human Neuropeptide Magnetic panel and the Luminex platform. Natural log-transformed orexin A data were analyzed using general linear model adjusting for diagnosis, gender, age, total body fat, and body mass index (BMI). Plasma orexin A levels were significantly higher (P < 0.006) in children with PWS (average ±SD = 1,028 pg/ml ± 358) compared with unrelated siblings (average ±SD = 609 pg/ml ± 351; P < 0.001). Orexin A levels correlated with age in females and were significantly elevated in PWS even after these effects were controlled. These findings support the hypothesis that dysregulation of orexin signaling may contribute to behavioral problems and hyperphagia in PWS. Further studies are warranted to better understand the complex relationship between orexin A levels and the problematic behaviors consistently found in individuals with PWS. © 2016 Wiley Periodicals, Inc.

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HIPAA complaint alleges myriad genetics withheld variant data from patients

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