Παρασκευή, 21 Απριλίου 2017

Protein corona: a new approach for nanomedicine design

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Case Studies in the Environment

Case Studies in the Environment, published by University of California Press, last updated on 2017-04-21, available at http://cse.ucpress.edu

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Qui Parle

Qui Parle, published by Duke University Press, last updated on 2017-04-21, available at http://ift.tt/2p1Jodx

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SIRT better tolerated than sorafenib, but doesn't increase overall survival in HCC

Results of the SARAH trial presented today demonstrate that SIRT resulted in median overall survival (OS) of 8.0 months compared to 9.9 months with sorafenib (p=0.179), in patients with locally advanced and inoperable hepatocellular carcinoma (HCC). The...

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Rifampicin as a novel tyrosinase inhibitor: Inhibitory activity and mechanism

Publication date: September 2017
Source:International Journal of Biological Macromolecules, Volume 102
Author(s): Wei-Ming Chai, Mei-Zhen Lin, Fang-Jun Song, Ying-Xia Wang, Kai-Li Xu, Jin-Xin Huang, Jian-Ping Fu, Yi-Yuan Peng
In this study, the inhibitory effect and mechanism of rifampicin on the activity of tyrosinase were investigated for developing a novel tyrosinase inhibitor. It was found to have a significant inhibition on the activity of tyrosinase (IC50=90±0.6μM). From the kinetics analysis, it was proved to be a reversible and noncompetitive type inhibitor of the enzyme with the KI value of 94±3.5μM. The results obtained from intrinsic fluorescence quenching indicated that rifampicin could interact with tyrosinase. In particular, the drastic decrease of fluorescence intensity was due to the formation of a rifampicin-enzyme complex in a static procedure which was mainly driven by hydrophobic forces and hydrogen bonding. Moreover, the ANS-binding fluorescence analysis suggested that rifampicin binding to tyrosinase changed the polarity of the hydrophobic regions. Molecular docking analysis further revealed that the hydrogen bonds were generated between rifampicin and amino residues Leu7, Ser52, and Glu107 in the B chain of the enzyme. And the hydrophobic forces produced through the interaction of rifampicin with B chain residues Pro9, Pro14, and Trp106. This work identified a novel tyrosinase inhibitor and potentially contributed to the usage of rifampicin as a potential hyperpigmentation drug.

Graphical abstract


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Twente spine model: A complete and coherent dataset for musculo-skeletal modeling of the thoracic and cervical regions of the human spine

Publication date: Available online 20 April 2017
Source:Journal of Biomechanics
Author(s): Riza Bayoglu, Leo Geeraedts, Karlijn H.J. Groenen, Nico Verdonschot, Bart Koopman, Jasper Homminga
Musculo-skeletal modeling could play a key role in advancing our understanding of the healthy and pathological spine, but the credibility of such models are strictly dependent on the accuracy of the anatomical data incorporated. In this study, we present a complete and coherent musculo-skeletal dataset for the thoracic and cervical regions of the human spine, obtained through detailed dissection of an embalmed male cadaver. We divided the muscles into a number of muscle-tendon elements, digitized their attachments at the bones, and measured morphological muscle parameters. In total, 225 muscle elements were measured over 39 muscles. For every muscle element, we provide the coordinates of its attachments, fiber length, tendon length, sarcomere length, optimal fiber length, pennation angle, mass, and physiological cross-sectional area together with the skeletal geometry of the cadaver. Results were consistent with similar anatomical studies. Furthermore, we report new data for several muscles such as rotatores, multifidus, levatores costarum, spinalis, semispinalis, subcostales, transversus thoracis, and intercostales muscles. This dataset complements our previous study where we presented a consistent dataset for the lumbar region of the spine (Bayoglu et al., 2017). Therefore, when used together, these datasets enable a complete and coherent dataset for the entire spine. The complete dataset will be used to develop a musculo-skeletal model for the entire human spine to study clinical and ergonomic applications.

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Die „mean disease alleviation“


Die Bewertung von Therapieverfahren bei der obstruktiven Schlafapnoe (OSA) bezieht sich bisher vornehmlich auf die Reduktion der respiratorischen Ereignisse. Darüber hinaus ist jedoch die Akzeptanz und Compliance gegenüber einer Therapie nicht weniger bedeutsam. Aktuelle Studien haben mehrfach die Bedeutung einer ausreichenden Nutzungszeit insbesondere für die langfristigen klinischen Endpunkte herausgestellt. Wie die Compliance beurteilt bzw. quantifiziert werden soll, ist nicht einheitlich geklärt, sie unterscheidet sich zwischen den Therapieverfahren jedoch erheblich, was sich auch auf das klinische Therapieergebnis auswirkt. Zur Frage, wie die Unterschiede in der Beurteilung des Therapieeffektes und im Vergleich zwischen Therapieverfahren berücksichtigt werden sollen, wurden in der Literatur verschiedene Vorschläge unterbreitet. Aktuell erscheint das Konzept der „mean disease alleviation" (MDA) von besonderem Interesse. Die MDA lässt sich am ehesten mit „mittlere Reduktion der Krankheitslast" übersetzen. Sie beruht auf der Effektivität (der Reduktion der respiratorischen Ereignisse) und der Compliance in Prozent und ergibt einen mittleren prozentualen Wert zur Reduktion der Krankheitslast. Der Vorteil dieses Konzepts liegt in der anschaulichen Darstellung und direkten Vergleichbarkeit der Effektivität verschiedener Verfahren. Die Limitation liegt in der Definition der Compliance, da die Werte für die MDA nur dann direkt vergleichbar sind, wenn identische Definitionen für die Compliance zugrunde gelegt werden. Mit der MDA steht jedoch ein neues und anschauliches Werkzeug zur Beurteilung und zum Vergleich von Therapieverfahren zur Verfügung, das zukünftig stärker berücksichtigt werden sollte.


IJMS, Vol. 18, Pages 889: Pathogenic or Therapeutic Extracellular Vesicles in Rheumatic Diseases: Role of Mesenchymal Stem Cell-Derived Vesicles

Extracellular vesicles (EVs) are important mediators of cell-to-cell communication pathways via the transport of proteins, mRNA, miRNA and lipids. There are three main types of EVs, exosomes, microparticles and apoptotic bodies, which are classified according to their size and biogenesis. EVs are secreted by all cell types and their function reproduces that of the parental cell. They are involved in many biological processes that regulate tissue homeostasis and physiopathology of diseases. In rheumatic diseases, namely osteoarthritis (OA) and rheumatoid arthritis (RA), EVs have been isolated from synovial fluid and shown to play pathogenic roles contributing to progression of both diseases. By contrast, EVs may have therapeutic effect via the delivery of molecules that may stop disease evolution. In particular, EVs derived from mesenchymal stem cells (MSCs) reproduce the main functions of the parental cells and therefore represent the ideal type of EVs for modulating the course of either disease. The aim of this review is to discuss the role of EVs in OA and RA focusing on their potential pathogenic effect and possible therapeutic options. Special attention is given to MSCs and MSC-derived EVs for modulating OA and RA progression with the perspective of developing innovative therapeutic strategies.

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Alternative process for quantifying Na+ and K+ electrolytes in plasma with high paraprotein concentration using an automated analyzer

Publication date: Available online 22 April 2017
Source:Clinical Biochemistry
Author(s): V. Platzer, B. Hebraud, E. Caussé

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Writer's cramp

Dystonia, writer's cramp: A dystonia that affects the muscles of the hand and sometimes the forearm and only occurs during handwriting. Similar focal dystonias have also been called typist's cramp, pianist's cramp, musician's cramp, and golfer's cramp.

MedTerms (TM) is the Medical Dictionary of MedicineNet.com.
We Bring Doctors' Knowledge To You

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Pembrolizumab-induced Stevens–Johnson syndrome in non-melanoma patients

Pembrolizumab is an anti-PD1 monoclonal antibody initially used in metastatic melanoma which has also been found to be active in other cancer types. Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but potentially fatal complications of anti-PD-1 therapy. To our knowledge, there have been 2 cases of nivolumab-induced TEN [1,2] and 1 case of SJS after radiotherapy with anti-PD-1 therapy [3] in patients with metastatic melanoma reported in literature. We present 2 cases of pembrolizumab-induced SJS, which we believe is the first case report in non-melanoma patients.

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Cobalt chloride induces RhoA/ROCK activation and remodeling effect in H9c2 cardiomyoblasts: Involvement of PI3K/Akt and MAPK pathways

Publication date: Available online 21 April 2017
Source:Cellular Signalling
Author(s): Cheng-I Cheng, Yueh-Hong Lee, Po-Han Chen, Yu-Chun Lin, Ming-Huei Chou, Ying-Hsien Kao
Chronic heart failure is a serious complication of myocardial infarction, one of the major causes of death worldwide that often leads to adverse cardiac hypertrophy and poor prognosis. Hypoxia-induced cardiac tissue remodeling is considered an important underlying etiology. This study aimed to delineate the signaling profile of RhoA/ROCK, PI3K/Akt, and MAPK and their involvement in regulation of remodeling events in cultured H9c2 cardiomyoblast cells. In addition to its growth-suppressive effect, the hypoxia-mimetic chemical, cobalt chloride (CoCl2) significantly induced RhoA kinase activation as revealed by increased MBS phosphorylation and ROCK1/2 expression in H9c2 cells. CoCl2 treatment up-regulated type I collagen and MMP-9, but did not affect MMP-2, implicating its role in tissue remodeling. Kinetic signal profiling study showed that CoCl2 also elicited Smad2 hyperphosphorylation and its nuclear translocation in the absence of TGF-β1. In addition, CoCl2 activated Akt-, ERK1/2-, JNK-, and p38 MAPK-mediated signaling pathways. Kinase inhibition experiments demonstrated that hydroxyfasudil, a RhoA kinase inhibitor, significantly blocked the CoCl2- and lysophosphatidic acid-evoked Smad2 phosphorylation and overexpression of type I collagen and MMP-9, and that PI3K and ERK interplayed with RhoA and its downstream Smad2 signaling cascade. In conclusion, this study demonstrated that RhoA/ROCK, PI3K/Akt, and MAPK pathways are mechanistically involved in the CoCl2-stimulated tissue remodeling in H9c2 cardiomyoblast cells. Targeting signaling mediators might be used to mitigate hypoxia-related Smad2 phosphorylation and cardiac remodeling events in ischemic cardiomyopathy.

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Adenosine A2A receptor modulates neuroimmune function through Th17/retinoid-related orphan receptor gamma t (RORγt) signaling in a BTBR T+ Itpr3tf/J mouse model of autism

Publication date: Available online 21 April 2017
Source:Cellular Signalling
Author(s): Mushtaq A. Ansari, Ahmed Nadeem, Sabry M. Attia, Saleh A. Bakheet, Raish Mohammad, Sheikh F. Ahmad
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by abnormal social interactions, repetitive behaviors that impair social communication, and circumscribed interests. BTBR T+tf/J (BTBR) inbred mice are generally used as a model for ASD, as they show repetitive behaviors and social deficits that resemble signs of ADS in humans. Adenosine A2A receptors (A2ARs) are considered as potential targets in the treatment of immune, inflammatory, and neurodegenerative diseases. In this study, we investigated the potential effects of the A2A adenosine receptor (A2AR) antagonist SCH 5826 (SCH) and agonist CGS 21680 (CGS) on behavior (self-grooming), hot plate test results, and expression levels of IL-17A+, RORγt+, Foxp3+, and IL-10+ in CD4+ T spleen cells in BTBR and C57BL/6 (B6) mice. We also assessed IL-17A, RORγt, Stat3, pStat3, Foxp3, and IL-10 mRNA and protein expression levels in the brain tissue. The CGS-treated mice showed a significantly altered self-grooming score and a reduced response to the hot plate test. The results further revealed that the SCH efficiently increased the IL-17A+ and RORγt+ expression levels and decreased the Foxp3+ and IL-10+ expression levels in CD4+ cells. However, the treatment with CGS significantly reversed these effects. In addition, CGS significantly decreased the IL-17A, RORγt, Stat3, and pStat3 levels and increased the Foxp3 and IL-10 mRNA and protein expression levels as compared with the BTBR control and SCH treatments. Our results clearly indicate that the CGS A2AR agonist may represent a unique target for future therapeutic strategies for neuroimmune dysfunction.

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Monogenic diabetes syndromes: Locus-specific databases for Alström, Wolfram and Thiamine-responsive megaloblastic anaemia


We developed a variant database for diabetes syndrome genes, using the Leiden Open Variation Database platform, containing observed phenotypes matched to the genetic variations. We populated it with 628 published disease associated variants (December 2016) for: WFS1 (n = 309), CISD2 (n = 3), ALMS1 (n = 268), and SLC19A2 (n = 48) for Wolfram type 1, Wolfram type 2, Alström and Thiamine-responsive megaloblastic anaemia syndromes respectively; and included 23 previously unpublished novel germline variants in WFS1 and 17 variants in ALMS1. We then investigated genotype phenotype relations for the WFS1 gene. The presence of bi-allelic loss of function variants predicted Wolfram syndrome defined by insulin dependent diabetes and optic atrophy, with a sensitivity of 79% (95% CI 75–83%) and specificity of 92% (83–97%). The presence of minor loss of function variants in WFS1 predicted isolated diabetes, isolated deafness or isolated congenital cataracts without development of the full syndrome (sensitivity 100% (93–100%), specificity 78% (73–82%). The ability to provide a prognostic prediction based on genotype will lead to improvements in patient care and counseling. The development of the database as a repository for monogenic diabetes gene variants will allow prognostic predictions for other diabetes syndromes as Next Generation Sequencing expands the repertoire of genotypes and phenotypes. The database is publicly available online at http://ift.tt/2oe8R64.

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Varied pathological and therapeutic response effects associated with CHCHD2 mutant and risk variants


Mutations and polymorphic risk variant of coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) have been associated with late-onset Parkinson disease. In vivo pathological evidence of CHCHD2 mutations is currently lacking. Utilizing transgenic Drosophila model, we examined the relative pathophysiologic effect of the pathogenic (c.182C>T, p.Thr61Ile and c.434G>A, p.Arg145Gln) and the risk (c.5C>T, p.Pro2Leu) CHCHD2 variants. All the transgenic models exhibited locomotor dysfunction which could be exacerbated by rotenone exposure, dopaminergic neuron degeneration, reduction in lifespan, mitochondrial dysfunction, oxidative stress and impairment in synaptic transmission. However, both mutants showed more severe early motor dysfunction, dopaminergic neuronal loss and higher hydrogen peroxide production compared to risk variant. p.Thr61Ile (co-segregated in three independent PD families) displayed the most severe phenotype followed by p.Arg145Gln (present only in index patient). We treated the transgenic flies with Ebselen, a mitochondrial hydrogen peroxide scavenger compound and Ebselen appears to be more effective in ameliorating motor function in the mutant than the risk variant models. We provide the first in vivo evidence of the pathological effects associated with CHCHD2 mutations. There was a difference in the pathological and drug response effects between the pathogenic and the risk variants. Ebselen may be a useful neuroprotective drug for carriers of CHCHD2 mutations.

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Psoriasis, Depression, and Inflammatory Overlap: A Review


Psoriasis has an enormous impact on patients’ lives and is frequently associated with depression. Depression in psoriasis may be attributed, at least in part, to elevated proinflammatory cytokines rather than the psychosocial impact of psoriasis itself. Biologics that target inflammatory cytokines treat the clinical manifestations of psoriasis, but may also play a role in reducing associated depression. Multiple biologics have decreased symptoms of depression during clinical trials in psoriasis; however, these studies used a variety of depression screening tools, which limits comparison. Furthermore, it is difficult to distinguish whether improved depression is the result of the direct anti-inflammatory effect of the biologic, or the indirect effect of improved psoriasis leading to better psychological status. Future studies evaluating depression in patients with psoriasis could benefit from a standardized depression screening tool to mitigate discrepancies and facilitate comparison across treatment types. Here, we highlight the inflammatory overlap between psoriasis and depression by examining the pathophysiology of depression, and reviewing psoriasis clinical studies that assessed depression as an outcome measure.

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Rationale for New Checkpoint Inhibitor Combinations in Melanoma Therapy


The use of monoclonal antibodies that block immunologic checkpoints, which mediate adaptive immune resistance, has revolutionized the treatment of metastatic melanoma patients. Specifically, targeting single immune suppressive molecules such as cytotoxic T lymphocyte-associated protein 4 (CTLA-4), or programmed cell death protein 1 (PD-1) expressed on T cells or its primary ligand, programmed cell death ligand 1 (PD-L1), resulted in pronounced clinical benefit for a subset of melanoma patients. Although single-agent immune checkpoint inhibitor therapy has demonstrated promising clinical activity in metastatic melanoma patients, there is still a significant proportion of patients who show primary resistance to these therapies. Increased clinical efficacy was reported in phase II and III randomized studies by co-targeting CTLA-4 and PD-1 in the treatment of advanced melanoma, indicating the existence of multiple non-redundant immunosuppressive pathways in the tumor microenvironment. Nevertheless, only 50% of patients responded to combined anti-CTLA-4 and anti-PD-1 treatment. Additionally, the combination regimen was associated with severe toxicity in >50–60% of patients. In this review we summarize the rationale for new checkpoint inhibitor combinations in melanoma therapy and discuss how biologic-driven stratification enables the design of optimal combination therapies tailored to target different tumor microenvironments.

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The molluscum contagiosum virus death effector domain containing protein MC160 RxDL motifs are not required for its known viral immune evasion functions


The molluscum contagiosum virus (MCV) uses a variety of immune evasion strategies to antagonize host immune responses. Two MCV proteins, MC159 and MC160, contain tandem death effector domains (DEDs). They are reported to inhibit innate immune signaling events such as NF-κB and IRF3 activation, and apoptosis. The RxDL motif of MC159 is required for inhibition of both apoptosis and NF-κB activation. However, the role of the conserved RxDL motif in the MC160 DEDs remained unknown. To answer this question, we performed alanine mutations to neutralize the arginine and aspartate residues present in the MC160 RxDL in both DED1 and DED2. These mutations were further modeled against the structure of the MC159 protein. Surprisingly, the RxDL motif was not required for MC160′s ability to inhibit MAVS-induced IFNβ activation. Further, unlike previous results with the MC159 protein, mutations within the RxDL motif of MC160 had no effect on the ability of MC160 to dampen TNF-α-induced NF-κB activation. Molecular modeling predictions revealed no overall changes to the structure in the MC160 protein when the amino acids of both RxDL motifs were mutated to alanine (DED1 = R67A D69A; DED2 = R160A D162A). Taken together, our results demonstrate that the RxDL motifs present in the MC160 DEDs are not required for known functions of the viral protein.

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A live gI/gE-deleted pseudorabies virus (PRV) protects weaned piglets against lethal variant PRV challenge


Emerging pseudorabies virus (PRV) variant has led to frequent outbreaks of PRV infection among Bartha-K61-vaccinated swine population in Chinese swine farms and caused high mortality in pigs of all age since late 2011. Here, we generated a gE/gI-deleted PRV (rPRVXJ-delgI/gE-EGFP) based on PRV variant strain (PRV-XJ) through homologous DNA recombination. Compared to parental strain, rPRVXJ-delgI/gE-EGFP showed similar growth kinetics in vitro. Its safety and immunogenicity were evaluated in weaned piglets. Our results showed that piglets immunized with rPRVXJ-delgI/gE-EGFP did not exhibit any clinical symptoms, and a high level of gB-specific antibody was detected. After lethal challenge with variant PRV (PRV-FJ strain), all vaccinated piglets survived without showing any clinical symptoms except slight fever within 7 days post-challenge. In unvaccinated piglets, typical clinical symptoms of pseudorabies were observed, and the piglets were all died at 5 days post-challenge. These results indicated that a live rPRVXJ-delgI/gE-EGFP vaccine could be a maker vaccine candidate to control the currently epidemic pseudorabies in China.

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Metal–DNA Interactions Improve signal in High-Resolution Melting of DNA for Species Differentiation of Plasmodium Parasite


The success of high-resolution melting (HRM) analysis for distinguishing similar DNAs with minor base mismatch differences is limited. Here, metal-mediated structural change in DNA has been exploited to amplify HRM signals leading to differentiation of target DNAs in an orthologous gene corresponding to four Plasmodium species. Conserved 26-mer ssDNAs from ldh gene of the four Plasmodium species were employed as targets. A capture probe (CP) that is fully complementary to the Plasmodium falciparum target (FT) and has two base mismatches each, with the targets of Plasmodium vivax (VT), Plasmodium malariae, (MT), and Plasmodium ovale (OT), was considered. The DNA duplexes were treated with metal ions for structural perturbation and analyzed by HRM. Distinct resolution of melting fluorescence signal in otherwise identical HRM profiles for each of the DNA duplexes was achieved by using Ca+2 or Mg+2 ions, where, Ca+2 conferred higher resolution. The increase in resolution for CP-FT versus CP-OT, CP-FT versus CP-VT, CP-FT versus CP-MT, CP-VT versus CP-OT, and CP-MT versus CP-OT with Ca–DNA as compared to control was 67.3-, 20.4-, 22.0-, 10.9-, and 8.3-fold, respectively. The signal resolution was the highest at pH 8. The method could detect 0.25 pmol/µl of the target DNA. Structural analysis showed that Ca+2 and Mg+2 ions perturbed the structure of DNA. This perturbation helped to improve HRM signal resolution among DNA targets corresponding to the orthologous gene of four Plasmodium species. This novel approach has potential application not only for Plasmodium species-specific diagnosis but also for differentiation of DNAs with minor sequence variation.

Graphical Abstract

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Human perinatal immunity in physiological conditions and during infection


The intrauterine environment was long considered sterile. However, several infectious threats are already present during fetal life. This review focuses on the postnatal immunological consequences of prenatal exposure to microorganisms and related inflammatory stimuli. Both the innate and adaptive immune systems of the fetus and neonate are immature, which makes them highly susceptible to infections. There is good evidence that prenatal infections are a primary cause of preterm births. Additionally, the association between antenatal inflammation and adverse neonatal outcomes has been well established. The lung, gastrointestinal tract, and skin are exposed to amniotic fluid during pregnancy and are probable targets of infection and subsequent inflammation during pregnancy. We found a large number of studies focusing on prenatal infection and the host response. Intrauterine infection and fetal immune responses are well studied, and we describe clinical data on cellular, cytokine, and humoral responses to different microbial challenges. The link to postnatal immunological effects including immune paralysis and/or excessive immune activation, however, turned out to be much more complicated. We found studies relating prenatal infectious or inflammatory hits to well-known neonatal diseases such as respiratory distress syndrome, bronchopulmonary dysplasia, and necrotizing enterocolitis. Despite these data, a direct link between prenatal hits and postnatal immunological outcome could not be undisputedly established. We did however identify several unresolved topics and propose questions for further research.


Cancer statistics in Kamrup urban district: Incidence and mortality in 2007–2011

Jagannath Dev Sharma, Amal Chandra Kataki, Debanjana Barman, Arpita Sharma, Manoj Kalita

Indian Journal of Cancer 2016 53(4):600-606

Purpose: The aim of this study was to report cancer statistics in Kamrup Urban District, including incidence and, mortality. Introduction: In the last five year PBCR-Guwahati witnessed a remarkable growth in cancer incidence cases. The number of new cases of all cancer was increased from 155.3 to 188.5 and 102.7 to 165.3 per 100,000 men and women respectively from the year 2007 to 2011 in KUD. The data from KUD also have shown that for some of the specific types of cancer are highest or some of the highest incidence in rates in the world; particularly cancers of upper aero-digestive tract consist of anatomical sites such as oral cavity, hypopharynx, larynx gallbladder, stomach, lung, prostate and oesophageal cancer. Materials and Methods: Age-standardized rates (ASR) (per 100,000 person-years) for incidence, mortality were calculated using the World Standard Population as proposed by Segi and modified by Doll et al. Descriptive statistics were presented by tables and figures. Results: A total of 6623 number of cases (male = 3809, female = 2814) were diagnosed with cancer in the last five years (2007-2011) period of time. The overall age standardized cancer incidence rate is almost 21% higher in men than in women. The pooled ASR for the five year period is 175.2 and 144.7 per 100,000 men and women. Conclusion: Overall cancer incidence and mortality rates have increased since 2007.

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Detailed study of survival of patients with renal cell carcinoma in India

GP Abraham, T Cherian, P Mahadevan, TS Avinash, D George, E Manuel

Indian Journal of Cancer 2016 53(4):572-574

PURPOSE: Renal cell carcinoma (RCC) accounts for approximately 90% of all renal malignancies. The rates of kidney cancers are high in developed countries and low in eastern countries and Africa. The objective was to conduct a survival study among Indian population following nephrectomy for RCC as there was a paucity of Indian studies in medical literature. MATERIALS AND METHODS: We conducted a follow-up study of eighty RCC patients who had nephrectomy between January 2003 and December 2010. These patients had pathological diagnosis after nephrectomy. The follow-up was done up to December 2015. The survival statistics were compiled according to Kaplan–Meier survival curves. RESULTS: The overall survival of eighty patients was 77%. The patients with tumor size ≤7 cm and the patients with tumor size >7 cm showed significant statistical difference at 5-year survival (P < 0.0001). The patients with low nuclear grade (1 and 2) and the patients with high nuclear grade (3 and 4) showed significant statistical difference at 5-year survival (P < 0.0001). The patients with tumor node metastasis stage below T3 and the patients with clinical stage above or equal to T3 showed significant statistical difference at 5-year survival (P = 0.003). CONCLUSION: This study has demonstrated the importance of factors such as tumor size, nuclear grade, and stage in the assessment of prognosis of RCC patients. More studies in India with more patients are needed to demonstrate the importance of these prognostic factors.

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Tumors and tumor-like conditions of the nasal cavity, paranasal sinuses, and nasopharynx: A study of 206 cases

RN Satarkar, S Srikanth

Indian Journal of Cancer 2016 53(4):478-482

INTRODUCTION: The nasal cavity, paranasal sinuses, and nasopharynx though in continuity form a complex system of upper respiratory tract; this region is endowed with a variety of elements such as epithelial, glandular, lymphoid, cartilage, and bone and is also exposed to a variety of infections, tumor-like and true neoplastic conditions. AIMS AND OBJECTIVES: To find out the frequency of various tumors and tumor-like conditions of the nasal cavity, paranasal sinuses, and nasopharynx. MATERIALS AND METHODS: The present study is an analysis of 206 tumors and tumor-like conditions of the nasal cavity, paranasal sinuses, and nasopharynx diagnosed during a period of 5 years. RESULTS: The patients' age ranged from 14 months to 85 years. Benign lesions were predominant in the second and third decades, with 30 cases (68.1%) occurring in that age group. Malignancies occurred predominantly in the sixth and seventh decades with 28 (60.9%) cases in this age group. Benign lesions in the nasopharynx comprised 75% cases and malignancies 25%. Eighty-three (71.5%) tumor-like conditions occurred in the nose and antrochoanal region. CONCLUSION: Angiofibroma was the most common benign tumor accounting for 25.55% of all neoplastic lesions. Squamous cell carcinoma was the most common malignancy at this site constituting 50% of all malignancies.

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A case series of salvage CCNU in high-grade glioma who have previously received temozolomide from a tertiary care institute in Mumbai

VM Patil, R Abhinav, R Tonse, S Epari, T Gupta, R Jalali

Indian Journal of Cancer 2016 53(4):558-561

INTRODUCTION: In our center, we routinely use CCNU (Lomustine) as salvage treatment in high-grade glioma patients who cannot afford bevacizumab. This exploratory analysis was done to report the efficacy and toxicity associated with this regimen. METHODS: Patients who were treated with salvage CCNU (postexposure to temozolomide) between January 2015 and August 2016 were included for this retrospective analysis. SPSS version 16 was used for this analysis. Time-to-event analysis was performed using the Kaplan–Meier method. Progression-free survival (PFS) and overall survival (OS) were estimated. The maximum grade of toxicity during salvage CCNU was noted in accordance with CTCAE version 4.02. RESULTS: In the stipulated period, 16 patients were selected for the analysis. The median age of patients was 43 years (range 15–63 years), and 12 (80.0%) patients were males. The Eastern Cooperative Oncology Group performance status was 0–1 in 11 patients (73.3%) and 2–4 in 4 patients (26.7%). The tumor histopathology at diagnosis was glioblastoma in ten patients (66.6%), anaplastic astrocytoma in four (26.7%) patients, and anaplastic oligodendroglioma in one patient (6.7%). Grade 3–4 myelosuppression was seen in five patients (33.3%). The median PFS and OS were 192 days (95% confidence interval [CI]: 156.0–227.5 days) and 282 days (95% CI: 190.9–373.1 days), respectively. CONCLUSION: CCNU is associated with modest treatment outcomes in recurrent/relapsed high-grade gliomas. The high rate of myelosuppression is a concern. Urgent efforts are required to improve upon these results.

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Palliative hypofractionated radiation therapy in a patient of locally advanced nasopharyngeal cancer with cardiac implantable electronic device (CIED): Management of a challenging case

SA Varughese, SJ Bharti, A Biswas, S Verma

Indian Journal of Cancer 2016 53(4):482-482

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Opium consumption: A potential risk factor for lung cancer and pulmonary tuberculosis

A Safari, M Reazai, A Tangestaninejad, AR Mafi, SAJ Mousavi

Indian Journal of Cancer 2016 53(4):587-589

OBJECTIVE: Lung cancer is the most common malignancy, as well as the leading cause of cancer-related mortality worldwide. Several studies have shown the causative effect of cigarettes smoking in lung cancer, however, the effect of opium consumption has not yet been well studied. This study has been designed to evaluate the risk of developing lung cancer and pulmonary tuberculosis in pure opium addicts. MATERIALS AND METHODS: We designed an analytic case–control study with 490 participants. People were divided into three groups: Group A were pure opium addicts, Group B consisted of nonsmoker patients who visited the chest medicine clinic due to complaints such as asthma, respiratory tract infections, and other signs and symptoms unrelated to smoking. Group C were chosen from nonsmoker individuals who visited the Emergency Department due to nonrespiratory problems. RESULTS: Statistical analysis showed that the three groups were similar with respect to mean age and gender. In Group A, one patient was diagnosed as having bronchoalveolar carcinoma. No other case of lung cancer was found in all three groups. Furthermore, four patients in Group A (5.3%; 95% confidence interval, 1.3–10.3) were found to have pulmonary tuberculosis, as this was significantly higher as compared with groups B and C (P = 0.009 and P< 0.001, respectively). CONCLUSION: Although, owing to limited number of cases, a robust conclusion cannot be made, this study can be considered as a base for a well-designed, larger study to further clarify the potential effect of opium abuse in developing lung cancer.

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Radical chemo-irradiation using intensity-modulated radiotherapy for locally advanced head and neck cancer in elderly patients: Experience from a tertiary care center in South India

JR Chalissery, PC Sudheeran, KM Varghese, K Venkatesan

Indian Journal of Cancer 2016 53(4):483-486

OBJECTIVE: To assess the feasibility, tolerance and response of radical chemo irradiation using Intensity modulated Radiotherapy [IMRT] in elderly patients [age >65] with locally advanced head and neck cancer. MATERIAL AND METHODS: Patients aged 65 and above [range 65 to 84years] registered in oncology outpatient unit in our institution between December 2011 to 2014, with stage III and IV head and neck cancer were treated with radical dose of radiotherapy using IMRT and concurrent chemotherapy with cisplatin 40mg/sq.m weekly. Response evaluation and toxicity profile assessment was done 6 to 8 weeks after completion of treatment and 3 monthly thereafter with median follow up of 3 years. RESULTS: Total number of patients analysed were 47. 43(91.5%) patients tolerated 66-.70Gy of radiotherapy and 4 or more cycles of weekly chemotherapy with cisplatin. First follow up evaluation at 6 to 8 weeks showed 81% patients having complete loco regional response. Grade III skin reaction and mucositis was noticed in 24% and 47% respectively. No grade III neutropenia observed. Median follow up of 3 years showed a complete local control in 53% and overall survival of 60%. CONCLUSION: Radical chemo irradiation with IMRT in elderly patients is a feasible option. Long term local control and overall survival benefits needs to be followed up.

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Plasma cell leukemia: Single institution experience

K Govind Babu, Linu Abraham Jacob, Ankit Agarwal, KC Lakshmaiah, D Lokanatha, MC Suresh Babu, LK Rajeev, KN Lokesh, AH Rudresha

Indian Journal of Cancer 2016 53(4):619-620

BACKGROUND: The first case of plasma cell leukemia (PCL) was recognized by Gluzinski and Reichentein. It is the most aggressive among the monoclonal gammopathies. It is diagnosed by the presence of more than 20% plasma cells in the peripheral blood or an absolute plasma cell count of >2000/mm3. Because of the relatively low incidence, most data come from case reports and retrospective studies. No prospective series have been published, and only seven reports including more than twenty patients have been identified. We report a retrospective series of 18 patients identified as PCL. AIM: To study the clinical features and outcome of patients with PCL. MATERIALS AND METHODS: A retrospective study was conducted from the year 2006 to 2015 wherein all the patients diagnosed with PCL were identified. Complete clinical and treatment details and outcome were obtained from the records. RESULTS: There were total 18 cases of PCL (3.7% of cases with multiple myeloma) diagnosed between the year 2006 and 2015. 16 cases (84%) were primary PCL, and two cases were secondary PCL. Twelve patients were males and six were females. The median age was 56.5 years. All patients had aggressive clinical course and median overall survival even with immunomodulatory agents was only 3 months. CONCLUSION: PCL is a very aggressive disease, and no prospective trials have been conducted. Patients with PCL require induction with immunomodulators, proteasome inhibitors, and further trials are needed to evaluate the role of autologous stem cell transplant in this disease.

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Efficacy and toxicity of cetuximab with chemotherapy in recurrent and metastatic head and neck cancer: A prospective observational study

S Tiwari, V Goel, MC John, N Patnaik, DC Doval

Indian Journal of Cancer 2016 53(4):487-492

BACKGROUND: In squamous cell carcinoma of the head and neck (SCCHN), epidermal growth factor receptor is expressed at very high levels. Hence, we have done this study to assess the response and tolerability of cetuximab and platinum-based chemotherapy in recurrent and metastatic (R/M) head and neck squamous cell cancer (HNSCC) in view of paucity of data from the Indian subcontinent. MATERIALS AND METHODS: In this prospective study, patients of R/M SCCHN were randomly enrolled from September 2012 to April 2015. Chemotherapy (cisplatin/carboplatin/5-fluorouracil) and cetuximab-based treatment were administered up to 6 cycles or unacceptable toxicity. The response rates (RRs), progression-free survival (PFS), and overall survival (OS) were analyzed. RESULTS: In total, fifty patients were enrolled. The median age was 51.0 years. A total of 255 cycles of treatment were administered (median = 6 cycles/patient). Four patients (8.0%) experienced complete response and 21 (42.0%) experienced partial response. Twenty-one patients (42.0%) had stable disease and four patients (8.0%) experienced progressive disease. The disease control rate was 92.0%. Median PFS was 5.3 months (95% confidence interval [CI]: 4.52–6.14 months). Median OS was 9.933 months (95% CI: 8.58–11.28 months). There was statistically significant correlation between overall response and Eastern Cooperative Oncology Group performance status (P = 0.014), site of tumor (P = 0.027), and histological grade of tumor (P = 0.001). The main Grade 3/4 side effects seen were hematological in 44 (88%) and gastrointestinal in 28 (56%) patients. CONCLUSIONS: The RR of cetuximab plus chemotherapy of >45% and the promising PFS rates are strong arguments for clinically testing this combination and this treatment schedule further in R/M HNSCC.

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An institutional analysis of clinicopathological features of triple negative breast cancer

D Sharma, G Singh

Indian Journal of Cancer 2016 53(4):566-568

AIM: Most common breast cancer in India among female is breast cancer. This is heterogeneous disease, one of the subtypes, triple negative breast cancer (TNBC) defined as no expression of estrogen, progesterone receptor and neither expression nor amplification of human epidermal growth factor receptor 2/neu. TNBC is more frequent and aggressive in younger age group. The aim of this study was to evaluate clinicopathological features and outcome in TNBC versus non-TNBC group of patients. MATERIALS AND METHODS: Medical record of 373 patients diagnosed with invasive breast cancer from January 2011 to December 2014 was retrieved. The last follow-up was done in December 2015. Patients were evaluated and grouped on the basis of receptor status (TNBC vs. non-TNBC). Baseline categorical variables were analyzed using the Chi-square test or Fisher's exact test. Noncategorical variables were analyzed using t-test. RESULTS: Out of 373 cases, 149 (39.94%) were diagnosed as TNBC. Patients with TNBC had a significantly lower median age (45 vs. 48 years). Data analysis revealed significant difference in number of metastasis in TNBC as compared to non-TNBC group (45.6% vs. 25.6%, P = 0.001). In the present study, mean disease-free survival was 14.73 versus 17.03 months (P = 0.22, not significant) and mean overall survival was 24.71 versus 27.38 months (P = 05, significant) in TNBC versus non-TNBC group, respectively. CONCLUSION: TNBC represented 39.94% which is higher than the range normally reported in literature. TNBC is associated with younger age, high-grade tumors, and a higher rate of distant metastasis.

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Outcomes in nasopharyngeal carcinoma: Results from a nonendemic cohort

SG Laskar, L Gurram, T Gupta, A Budrukkar, V Murthy, JP Agarwal

Indian Journal of Cancer 2016 53(4):493-498

INTRODUCTION: The treatment of nasopharyngeal carcinoma (NPC) has come a long way from treatment with conventional radiotherapy (RT) alone for the use of concurrent chemoradiotherapy (CCRT) and sequential chemotherapy (CT). We report the outcomes of patients treated with combined modality at a tertiary cancer center in India over a period of 10 years. MATERIALS AND METHODS: A total of 206 patients with NPC between 1994 and 2004, who completed planned treatment, were retrospectively analyzed. Demographic features, disease, and treatment-related factors were analyzed for their impact on loco-regional control (LRC), disease-free survival (DFS), and overall survival (OS). RESULTS: Most patients had Stage III or IV (70.8%) disease. Twenty-six percent received RT alone, 37% received neoadjuvant chemotherapy (NACT) followed by RT alone, 29% received NACT + CCRT, and 8% received CCRT alone. Median RT dose was 64 Gy with 84% receiving RT doses of ≥60 Gy. At a median follow-up of 29 months, 112 (54.4%) patients were alive and disease free. Three-year DFS and OS were 64% and 82.3%, respectively. LRC at 3 years was 71.1%. Independent factors for significantly better LRC and DFS were younger age at presentation, RT dose of more than 64 Gy, and immediate response to RT. The use of CCRT in advanced nodal stages (N2–N3) resulted in significantly better LRC and DFS on multivariate analysis. CONCLUSIONS: Combined modality treatment in advanced stage NPC results in favorable outcomes. RT doses of more than 64 Gy should be considered in all patients, respecting normal tissue tolerances. The role of NACT remains debatable.

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Patterns of care and outcomes for second-line targeted therapy in metastatic renal cell carcinomas: A registry based analysis

S Zanwar, A Joshi, V Noronha, VM Patil, N Sable, P Popat, S Menon, R Kothari, P Bhargava, A Kapoor, K Prabhash

Indian Journal of Cancer 2016 53(4):579-582

AIM: Patterns of care for metastatic renal cell carcinomas (mRCC) have seen tremendous reform in the last decade. Here, we present our pattern of care in second-line targeted therapy for mRCC. METHODS: Patients with mRCC treated with second-line therapy were included from a prospective database. Demographics, risk stratification, and treatment details were noted. Event-free survival (EFS) and overall survival (OS) was calculated using Kaplan–Meier method. Log-rank test was used to identify factors affecting EFS and OS. Multivariate analysis was performed using cox regression. RESULTS: Nearly 21.7% (46/212) of patients received second-line targeted treatment. Heng score for risk stratification showed 21.7% of patients in low risk, 36.9% in intermediate, and 34.8% in high risk group. Everolimus followed by pazopanib were the most common second-line therapies used in 65.2% and 13% of patients, respectively. The estimated median EFS was 3.5 months (95% confidence interval [CI] 2.7–4.26 months) and estimated median OS from the start of second-line therapy was 6.2 months (95% CI 3.4–9.0 months) with a median follow-up of 4.3 months. On univariate log-rank analysis, EFS of more than 6 months with first-line therapy was associated with improvement in EFS with second-line therapy (9.5 vs. 2.0 months; hazard ratio (HR) 0.364; P = 0.002). There was no factor independently associated with EFS or OS on multivariate analysis. CONCLUSION: Patterns of care for second line targeted therapy tend to vary with setting. A longer EFS with first-line therapy predicts improved outcomes with second-line treatment.

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Clinical observation and retrospective study of the influential factors of liver metastasis in 306 cases of colon cancer

X Lin, M Lin, X Wei, Q Chen

Indian Journal of Cancer 2016 53(4):499-504

PURPOSES/OBJECTIVES: By observing and analyzing the clinical features of the colon cancer and the influence factors of liver metastasis, we try to find out independent risk factors with significant influence on colon cancer liver metastasis as well as to provide reference for clinical treatment. MATERIALS AND METHODS: A total of 306 cases of colon cancer patients' clinical data, including gender, age, primary focal size, primary focal intestinal segment, degree of differentiation, infiltration depth, level of serum carcinoembryonic antigen (CEA) before surgery, lymph node metastasis, liver basic diseases were collected and recorded. Single-factor Chi-square analysis and multifactor logistic regression analysis (SPSS 16.0 software) were used to retrospectively study the possible influence factors of colon liver metastases and to preliminary discuss the potential risk factors of liver metastasis in colon cancer patients. RESULTS: The Chi-square analysis showed that patients' primary focal segment, degree of differentiation, infiltration depth, level of serum CEA before surgery, and states of hepatitis B does 2 half-and-half had significant effect on the incidence of liver metastasis. However, in the further logistic regression analysis, it showed that only the infiltration depth and the states of hepatitis B does 2 half-and-half were the independent risk factors that influence the hepatic metastases. What was more, the both subgroups of positive hepatitis B with infection and vaccine showed significant statistical differences when comparing with hepatitis B all negative in the event of the probability of liver metastases (P = 0.011 and 0.004). CONCLUSIONS: The infiltration depth and the states of hepatitis B does 2 half-and-half were the independent risk factors on colon cancer patients' hepatic metastases. Those with the infiltration depth of T4 had a higher rate of hepatic metastases. Patients with does 2 half-and-half-positive hepatitis B (whether subgroup of hepatitis B virus infection or subgroup hepatitis B vaccine related) had a lower incidence rate of liver metastasis than those with hepatitis B all negative.

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Monotherapy versus combination therapy against carbapenem-resistant Gram-negative bacteria: A retrospective observational study

A Ghafur, V Devarajan, T Raja, J Easow, MA Raja, S Sreenivas, B Ramakrishnan, SG Raman, D Devaprasad, B Venkatachalam, R Nimmagadda

Indian Journal of Cancer 2016 53(4):592-594

BACKGROUND: Colistin-based combination therapy (CCT) is extensively used to treat infections due to carbapenem-resistant Gram-negative bacteria (CRGNB). There are no data available from India on the usefulness of combination therapy, especially in the oncology setup. The aim of this study was to analyze the clinical effectiveness of CCT over monotherapy in patients with CRGNB. MATERIALS AND METHODS: We conducted a retrospective, observational study of patients with CRGNB bloodstream infections in our oncology and bone marrow transplant center. RESULTS: Over a 3-year study period (2011–2014), we could identify 91 patients satisfying study criteria. There was no statistically significant difference in the 28-day mortality between monotherapy and combination therapy arms (mono n = 26, mortality 10 (38.5%); combination n = 65, mortality 28 (40%); P = 0.886). Neutropenic patients with Enterobacteriaceae bloodstream infections performed better with combination therapy (mono n = 7, mortality 6 (85.7%); combination therapy n = 22, mortality 8 (36.4%); P = 0.035). There was no significant difference in the 28-day mortality between the two treatment arms in other subgroups. CONCLUSION: Our study did not find CCT superior to colistin monotherapy in patients with CRGNB blood stream infections; except in the subgroup of neutropenic patients with Enterobacteriaceae bloodstream infections, where combination therapy performed better.

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Human epidermal growth factor receptor 2 expression in gastric carcinoma and its association with histopathological parameters in Indian population

P Gupta, S Rao, S Bhalla

Indian Journal of Cancer 2016 53(4):505-511

Introduction: Gastric carcinoma is a leading cause of death worldwide with a five year survival of 10-15% even after curative resection. Trastuzumab has emerged as a potential targeted therapy in treatment of Her 2 positive gastric cancer. Her2 positivity ranges from 7-34% in studies across the world. There is a paucity of Indian studies hence a need for determination of Her2 expression in Indian population for better patient management. This study was carried out to determine the frequency of Her 2 expression in gastric carcinoma by immunohistochemistry (IHC) technique and to evaluate its association with histopathological parameters. Material and Methods: A total of 110 cases of gastric adenocarcinoma diagnosed on histopathological examination from July 2013 to June 2015 were included. Of these, 40 cases were resection specimens and 70 were biopsies. Histological typing of gastric carcinoma was done on the basis of Lauren classification. IHC for Her2 was done in all 110 cases. Her 2 expression was correlated with various histopathological parameters. Results: Positive Her 2 expression (IHC 3+) was seen in 24.5% cases of gastric carcinoma. Patients in older age group(> 60 years) showed higher Her 2 positivity rate as compared to middle age (40-60 years) and younger population (<40 years). Higher percentage of Her 2 positivity was noted in male patients as compared to female patients. Her 2 positivity was seen more commonly in intestinal type of tumor as compared to diffuse and mixed types. Her 2 positivity was seen more in well differentiated carcinoma and higher stage tumors (pT3 and pT4). However, out of all, a statistically significant association of Her2 expression was found only with (intestinal) type of tumors (p= 0.005) and no significant association was seen with age, gender, site of tumor, tumor stage, lymph node status, lymphovascular, perineural and perinodal invasion or survival. Conclusion: Inspired by promising results of Trastuzumab therapy in Her 2 positive gastric carcinoma worldwide, it is recommended to routinely test all cases of gastric carcinoma for Her 2 expression and to use the targeted therapy with curative intentions in Indian population.

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A review of squamous cell carcinoma arising in mature cystic teratoma of the ovary

N Abhilasha, UD Bafna, VR Pallavi, PS Rathod, S Krishnappa

Indian Journal of Cancer 2016 53(4):612-614

INTRODUCTION: Germ cell tumors account for 20-25% of ovarian neoplasms. Mature cystic teratoma (MCT) is the most common ovarian germ cell tumor. Malignancy in MCT is seen in 1-2% of the cases. Squamous cell carcinoma (SCC) accounts for 80% of the cases and carries a poor prognosis. AIM: To study the clinicopathological factors, management protocols and its outcome. MATERIALS AND METHODS: Case records reviewed from August 2006 to August 2011 at our institute identified 10 women with SCC in ovarian MCT. Staging was done according to FIGO 2009 guidelines. Primary surgery followed by adjuvant treatment with platinum based chemotherapy was given. RESULTS: Median age was 53.5 years. Six out of 10 patients were postmenopausal and aged above 50 years. Abdominal pain and abdominal mass were the most common presenting symptoms. According to FIGO: Two in stage 1, five in stage 2, two in stage 3 and one in stage 4. Among six optimally cytoreduced patients, five (83%) had no evidence of disease with a median follow up of 10 months. Whereas all four (100%) suboptimally cytoreduced patients had progressive disease within 3 to 4 months of primary surgery despite chemotherapy. CONCLUSION: Squamous cell carcinoma in MCT of ovary is a rarity. It carries a poor prognosis, especially in advanced stages and suboptimally cytoreduced patients. Platinum with or without taxane based chemotherapy may be useful as adjuvant treatment. However, further studies and standardization of treatment protocols are required for any recommendations.

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Incidence and pattern of childhood cancers in India: Findings from population-based cancer registries

Abu Bashar

Indian Journal of Cancer 2016 53(4):511-512

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Current status of systemic therapy for recurrent and/or metastatic squamous cell carcinoma of the head and neck

LA Jacob, T Chaudhuri, KC Lakshmaiah, KG Babu, L Dasappa, MCS Babu, AH Rudresha, KN Lokesh, LK Rajeev

Indian Journal of Cancer 2016 53(4):471-477

Head and neck squamous cell carcinoma (HNSCC) is now the seventh most common cancer worldwide. The median overall survival for patients with recurrent and/or metastatic (R/M) HNSCC remains <1 year despite modern systemic chemotherapy and targeted agents. Palliative systemic therapy for patients with R/M HNSCC typically includes a platinum-based doublet, with an understanding that the increase in efficacy compared with single agents is primarily related to improved response rate, and not survival. Till date, the only systemic therapy regimen to demonstrate survival superiority over platinum-5-fluorouracil (5-FU) doublet is platinum, FU, and cetuximab. Epidermal growth factor receptor inhibitors, including monoclonal antibodies and tyrosine kinase inhibitors, have achieved only a modest success in R/M HNSCC. Immunotherapy represents an attractive treatment option for R/M HNSCC, with encouraging preliminary data from studies involving immune checkpoint inhibitors (e.g., pembrolizumab, nivolumab) and toll-like receptor agonists (e.g., motolimod). Given the poor prognosis of R/M HNSCC, enrollment of patients into clinical trials to investigate novel systemic agents, is necessary for further improvement of oncologic outcomes in this patient population.

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Microsatellite instability in stage II colorectal cancer: An Indian perspective

AP Dubey, S Vishwanath, P Nikhil, A Rathore, A Pathak

Indian Journal of Cancer 2016 53(4):513-517

INTRODUCTION: Around 80% of colorectal carcinoma are associated with chromosomal instability (CIN) while rest of 20 % are euploid, possessing defect in mis match repair system (MMR) quintessential for surveillance and correction of errors in introduced into microsatellites. MATERIALS AND METHODS: We analyse all stage II CRC for MSI who presented at MDTC at Army hospital (research and refrral) new delhi during last 2 years (Jan 14 to Dec 2015). RESULTS: We found that 22.2% patients out of 45 patients with stageII CRC being MSI-. high. We also noticed all suchcases were associated with loss of expression of PMS2 & MLH1, that was in contrast other studies where loss of MLH1 and MSH@, MSH6 were seen more commonly. CONCLUSION: MSI occurs in a significant proportion of colorectal cancers in young (<50 years old) patients. Young age at colorectal cancer diagnosis, proximal tumor location, family history of colorectal cancer were independent predictors of MSI status in our patients. In a proportion of these young patients with MSI tumors, loss of expression of proteins by 2 MMR genes PMS2 and hMLH1 has been identified.

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Pediatric brain tumors: An analysis of 5 years of data from a tertiary cancer care center, India

R Madhavan, BP Kannabiran, AM Nithya, J Kani, P Balasubramaniam, S Shanmugakumar

Indian Journal of Cancer 2016 53(4):562-565

BACKGROUND: Pediatric brain tumors are the most common solid tumors in children and a leading cause of mortality and morbidity in children worldwide. Even though there are enough data about the epidemiology of pediatric brain tumors in western population, there are only a few reports from developing countries like India. AIMS: To study the epidemiological patterns of brain tumors in children, to study the patterns of care, and to assess the treatment response. MATERIALS AND METHODS: A retrospective epidemiological approach is used. The records of children <18 years registered in our department from August 2006 to July 2011 diagnosed as primary brain tumors are selected. Data regarding age, sex, site of the tumor, clinical features, histology, treatment plan, and treatment response are collected. The World Health Organization classification of neoplasms was adopted. RESULTS: Of 250 cases, females (57%) slightly outnumbered males. The present study revealed that astrocytoma (52%) is the most common brain tumor in childhood. Surgery was the main modality of treatment. Chemotherapy was given to 16% of patients. Even though radiation therapy was offered to 74% of patients, only 42% completed radiotherapy. There was subjective clinical improvement in 68% of patient population after treatment. CONCLUSIONS: This is the second study from Tamil Nadu that deals with epidemiology of brain tumors. Multimodality management including surgery, chemotherapy, and radiation therapy remains the cornerstone in the management of pediatric brain tumors.

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Folate-dependent methylation of septins governs ciliogenesis during neural tube closure [Research]

Periconception maternal folic acid (vitamin B9) supplementation can reduce the prevalence of neural tube defects (NTDs), although just how folates benefit the developing embryo and promote closing of the neural tube and other morphologic processes during development remains unknown. Folate contributes to a 1-carbon metabolism, which is essential for purine biosynthesis and methionine recycling and affects methylation of DNA, histones, and nonhistone proteins. Herein, we used animal models and cultured mammalian cells to demonstrate that disruption of the methylation pathway mediated by folate compromises normal neural tube closure (NTC) and ciliogenesis. We demonstrate that the embryos with NTD failed to adequately methylate septin2, a key regulator of cilia structure and function. We report that methylation of septin2 affected its GTP binding activity and formation of the septin2-6-7 complex. We propose that folic acid promotes normal NTC in some embryos by regulating the methylation of septin2, which is critical for normal cilia formation during early embryonic development.—Toriyama, M., Toriyama, M., Wallingford, J. B., Finnell, R. H. Folate-dependent methylation of septins governs ciliogenesis during neural tube closure.

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Clinical predictors of remission and persistence of adult-onset asthma

Adult-onset asthma remission occurs in 16% of the patients within 5 years after diagnosis. Nasal polyposis and moderate to severe bronchial hyperresponsiveness at the time of asthma diagnosis reduces the chance of remission to <1%.

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The Lon protease-like domain in the bacterial RecA paralog RadA is required for DNA binding and repair [Protein Structure and Folding]

Homologous recombination (HR) plays an essential role in the maintenance of genome integrity. RecA/Rad51 paralogs have been recognized as an important factor of HR. Among them, only one bacterial RecA/Rad51 paralog - RadA - is involved in HR as an accessory factor of RecA recombinase. RadA has a unique Lon protease-like domain (LonC) at its C-terminus, in addition to a RecA-like ATPase domain. Unlike Lon protease, RadA's LonC domain does not show protease activity but is still essential for RadA-mediated DNA repair. Reconciling these two facts has been difficult because RadA's tertiary structure and molecular function are unknown. Here, we describe the hexameric ring structure of RadA's LonC domain, as determined by X-ray crystallography. The structure revealed the two positively charged regions unique to the LonC domain of RadA are located at the intersubunit cleft and the central hole of a hexameric ring. Surprisingly, a functional domain analysis demonstrated the LonC domain of RadA binds DNA, with site-directed mutagenesis showing that the two positively charged regions are critical for this DNA-binding activity. Interestingly, only the intersubunit cleft was required for the DNA-dependent stimulation of ATPase activity of RadA, and at least the central hole was essential for DNA repair function. Our data provide the structural and functional features of the LonC domain and their function in RadA-mediated DNA repair.

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Two glycosaminoglycan-binding domains of the mouse cytomegalovirus-encoded chemokine MCK-2 are critical for oligomerization of the full-length protein [Immunology]

Chemokines are essential for antimicrobial host defenses and tissue repair. Herpesviruses and poxviruses also encode chemokines, copied from their hosts and repurposed for multiple functions, including immune evasion. The CC chemokine MCK-2 encoded by mouse cytomegalovirus (MCMV) has an atypical structure consisting of a classic chemokine domain N-terminal to a second unique domain, resulting from the splicing of MCMV ORFs m131 and m129. MCK-2 is essential for full MCMV infectivity in macrophages and for persistent infection in the salivary gland. However, information about its mechanism of action and specific biochemical roles for the two domains has been lacking. Here, using genetic, chemical and enzymatic analyses of multiple mouse cell lines as well as primary mouse fibroblasts from salivary gland and lung, we demonstrate that MCK-2 binds glycosaminoglycans (GAGs) with affinities in the following order: heparin > heparan sulfate > chondroitin sulfate=dermatan sulfate. Both MCK-2 domains bound these GAGs independently, and computational analysis together with site-directed mutagenesis identified five basic residues distributed across the N-terminus and the 30s and 50s loops of the chemokine domain that are important GAG-binding determinants. Both domains were required for GAG-dependent oligomerization of full-length MCK-2. Thus, MCK-2 is an atypical viral chemokine consisting of a CC chemokine domain and a unique non-chemokine domain, both of which bind GAGs and are critical for GAG-dependent oligomerization of the full-length protein.

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Sequential Adaptive Changes in a c-Myc-Driven Model of Hepatocellular Carcinoma [Metabolism]

Hepatocellular carcinoma (HCC) is a common cancer that frequently over-expresses the c-Myc (Myc) oncoprotein. Using a mouse model of Myc-induced HCC, we studied the metabolic, biochemical and molecular changes accompanying HCC progression, regression and recurrence. These involved altered rates of pyruvate and fatty acid β-oxidation and the likely re-directing of glutamine into biosynthetic rather than energy-generating pathways. Initial tumors also showed reduced mitochondrial mass and differential contributions of electron transport chain Complexes I and II to respiration. The uncoupling of Complex II's electron transport function from its succinate dehydrogenase activity also suggested a mechanism by which Myc generates reactive oxygen species. RNA-Seq studies revealed an orderly progression of transcriptional changes involving pathways pertinent to DNA damage repair, cell cycle progression, insulin-like growth factor signaling, innate immunity and further metabolic re-programming. Only a subset of functions deregulated in initial tumors were similarly deregulated in recurrent tumors thereby indicating that the latter can "normalize" some behaviors to suit their needs. An interactive and freely available software tool was developed to allow continued analyses of these and other transcriptional profiles. Collectively, these studies define the metabolic, biochemical and molecular events accompanying HCC evolution, regression and recurrence in the absence of any potentially confounding therapies.

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Regulation of neurite morphogenesis by interaction between R7 regulator of G protein signaling complexes and G protein subunit G{alpha}13 [Cell Biology]

The R7 regulator of G protein signaling family (R7-RGS) critically regulates nervous system development and function. Mice lacking all R7-RGS subtypes exhibit diverse neurological phenotypes, and humans bearing mutations in the retinal R7-RGS isoform RGS9-1 have vision deficits. Although each R7-RGS subtype forms heterotrimeric complexes with Gβ5 and R7-RGS binding protein (R7BP) that regulate G protein-coupled receptor signaling by accelerating deactivation of Gi/o α-subunits, several neurological phenotypes of R7-RGS knockout mice are not readily explained by dysregulated Gi/o signaling. Accordingly, we used tandem affinity purification and LC-MS/MS to search for novel proteins that interact with R7-RGS heterotrimers in the mouse brain. Among several proteins detected we focused on Gα13 because it had not been linked to R7-RGS complexes before. Split-luciferase complementation assays indicated that Gα13 in its active or inactive state interacts with R7-RGS heterotrimers containing any R7-RGS isoform. LARG, PDZ-RhoGEF and p115RhoGEF augmented interaction between activated Gα13 and R7-RGS heterotrimers, indicating that these effector RhoGEFs can engage Gα13/R7-RGS complexes. Because Gα13/R7-RGS interaction required R7BP, we analyzed phenotypes of neuronal cell lines expressing RGS7 and Gβ5 with or without R7BP. We found that neurite retraction evoked by Gα12/13-dependent lysophosphatidic acid receptors was augmented in R7BP-expressing cells. R7BP expression blunted neurite formation evoked by serum starvation by signaling mechanisms involving Gα12/13 but not Gαi/o. These findings provide the first evidence that R7-RGS heterotrimers interact with Gα13 to augment signaling pathways that regulate neurite morphogenesis. This mechanism expands the diversity of functions whereby R7-RGS complexes regulate critical aspects of nervous system development and function.

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An Amphipathic {alpha}-Helix Directs Palmitoylation of the Large Intracellular Loop of the Sodium/Calcium Exchanger [Cell Biology]

The electrogenic sodium/calcium exchanger (NCX) mediates bidirectional calcium transport controlled by the transmembrane sodium gradient. NCX inactivation occurs in the absence of phosphatidylinositol 4,5-bisphosphate (PIP2), and is facilitated by palmitoylation of a single cysteine at position 739 within NCX's large intracellular loop. The aim of this investigation was to identify the structural determinants of NCX1 palmitoylation. Full-length NCX1 (FL-NCX1) and a YFP fusion protein of the NCX1 large intracellular loop (YFP-NCX1) were expressed in HEK cells. Single amino acid changes around C739 in FL-NCX1 and deletions on the N-terminal side of C739 in YFP-NCX1 did not affect NCX1 palmitoylation, with the exception of the rare human polymorphism S738F, which enhanced FL-NCX1 palmitoylation, and D741A, which modestly reduced it. In contrast, deletion of a 21-amino-acid segment enriched in aromatic amino acids on the C-terminal side of C739 abolished YFP-NCX1 palmitoylation. We hypothesized that this segment forms an amphipathic α-helix whose properties facilitate C739 palmitoylation. Introduction of negatively charged amino acids to the hydrophobic face or of helix-breaking prolines impaired palmitoylation of both YFP-NCX1 and FL-NCX1. Alanine mutations on the hydrophilic face of the helix significantly reduced FL-NCX1 palmitoylation. Of note, when the helix-containing segment was introduced adjacent to cysteines that are not normally palmitoylated, they became palmitoylation sites. In conclusion, we have identified an amphipathic α-helix in the NCX1 large intracellular loop that controls NCX1 palmitoylation. NCX1 palmitoylation is governed by a distal secondary structure element rather than by local primary sequence.

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Dual Regulation of Stat1 and Stat3 by the Tumor Suppressor Protein PML Contributes to IFN{alpha}-Mediated Inhibition of Angiogenesis [Cell Biology]

IFNs are effective in inhibiting angiogenesis in preclinical models and in treating several angio-proliferative disorders. However, the detailed mechanisms of IFNα-mediated anti-angiogenesis are not completely understood. Stat1/2/3 and PML are IFNα downstream effectors and are pivotal regulators of angiogenesis. Here, we investigated PML′s role in the regulation of Stat1/2/3 activity. In Pml knockout (KO) mice, ablation of Pml largely reduces IFNα angiostatic ability in Matrixgel plug assays. This suggested an essential role for PML in IFNα′s anti-angiogenic function. We also demonstrated that PML shared a large cohort of regulatory genes with Stat1 and Stat3, indicating an important role of PML in regulating Stat1 and Stat3 activity. Using molecular tools and primary ECs, we demonstrated that PML positively regulates Stat1 and Stat2 isgylation, a ubiquitination-like protein modification. Accordingly, manipulation of the isgylation system by knocking down USP18 altered IFNα-PML axis-mediated inhibition of EC migration and network formation. Furthermore, PML promotes turnover of nuclear Stat3 and knockdown of PML mitigates the effect of LLL12, a selective Stat3 inhibitor, on IFNα-mediated anti-angiogenic activity. Taken together, we elucidated an unappreciated mechanism in which PML, an IFNα-inducible effector, possess potent angiostatic activity, doing so in part, by forming a positive feedforward loop with Stat1/2 and a negative feedback loop with Stat3. The interplay between PML, Stat1/Stat2 and Stat3 contributes to IFNα-mediated inhibition of angiogenesis and disruption of this network results in aberrant IFNα signaling and altered angiostatic activity.

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Applying SDN for Data Extraction and Mining: An Enhanced Architecture


Software defined network (SDN) is a very popular notion and has drawn much attention from academia. In this study, we propose an enhanced SDN architecture for data extraction and mining. We also design the interactions between each layer during the process of data extraction services. The proposed SDN architecture achieves high performance on providing extraction and mining when the amount of data is large.


Quercetin Remodels the Tumor Microenvironment To Improve the Permeation, Retention, and Antitumor Effects of Nanoparticles

TOC Graphic

ACS Nano
DOI: 10.1021/acsnano.7b01522

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Predicting fluid responsiveness in whom? A simulated example of patient spectrum influencing the receiver operating characteristics curve


The influence of patient spectrum on the sensitivities and specificities of diagnostic methods has been termed spectrum bias or spectrum effect. Receiver operating characteristics curves are often used to assess the ability of diagnostic methods to predict fluid responsiveness. As a receiver operating characteristics curve is a presentation of sensitivity and specificity, the purpose of the present manuscript was to explore if patient spectrum could affect areas under receiver operating characteristics curves and their gray zones. Relationships between stroke volume variation and change in stroke volume in two different patient populations using simulated data. Simulated patient populations with stroke volume variation values between 5 and 15 or 3 and 25% had median (2.5th–97.5th percentiles) areas under receiver operating characteristics curves of 0.79 (0.65–0.90) and 0.93 (0.85–0.99), respectively. The gray zones indicating range of diagnostic uncertainty were also affected. The patient spectrum can affect common statistics from receiver operating characteristics curves, indicating the need for considering patient spectrum when evaluating the abilities of different methods to predict fluid responsiveness.


David Byrne's Joan of Arc: Into the Fire

David Byrne’s musical at The Public Theater is an achievement rich in sensory stimulation and delightful deception.

-- Read more on ScientificAmerican.com
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Wrong in Public: the Paris Streets Edition

Rue Sophie Germain is not the only Paris street named for a mathématicienne

-- Read more on ScientificAmerican.com
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Posterior cranial fossa tumours in children at National Cancer Institute, Sudan: a single institution experience



Posterior cranial fossa tumours (PCF) comprise 54–70% of childhood brain tumours. The clinical profile and outcomes of these tumours differ in area of the world. The aim of this study is to describe clinical characteristics, treatment and outcome of posterior cranial fossa tumours in Sudan.

Material and methods

A retrospective study of children diagnosed with posterior cranial fossa tumours and treated between January 1998 and December 2015 at National Cancer Institute, Sudan.


A total of 31 paediatric patients with a posterior cranial fossa brain tumour were identified over the study period. The mean age was 7.9 years (standard deviation (SD) = 3.37). Females were slightly more affected (51%) than males (49%), and the majority of patients were from rural areas (71%). Brainstem tumours were the most frequent tumour type (48%) followed by medulloblastoma (36%). The mean pre-diagnostic symptomatic interval was 3.6 months (SD = 3.95). Overall survival rate of our total study population at 1, 2 and 5 years was 23, 19 and 13%, respectively.


Overall, this study draws attention to the situation of paediatric brain tumours in Sudan. Late presentation, misdiagnosis and limited diagnostic and treatment resources are challenges that may contribute to poor outcome in these patients.


Concurrent paediatric medulloblastoma and Chiari I malformation with syringomyelia


The problem with myelomeningoceles, hydrocephalus, and progressive neurological deficits—what do we know?


Effect of a 16-week Bikram yoga program on heart rate variability and associated cardiovascular disease risk factors in stressed and sedentary adults: A randomized controlled trial

Chronic activation of the stress-response can contribute to cardiovascular disease risk, particularly in sedentary individuals. This study investigated the effect of a Bikram yoga intervention on the high freq...

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Prevention of advanced glycation end-products formation in diabetic rats through beta-cell modulation by Aegle marmelos

Although the anti-diabetic activity of Aegle marmelos (AM) is known, however, its anti-glycation activity is not reported yet. In this study, we have investigated its anti-glycation activity under in vitro and in...

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Delayed Presentation of Acute Cholecystitis: Comparative Outcomes of Same-Admission Versus Delayed Laparoscopic Cholecystectomy



Studies have shown that same-admission laparoscopic cholecystectomy (SALC) is superior to delayed laparoscopic cholecystectomy (DLC) for acute cholecystitis (AC). However, no studies have compared both modalities in patients with delayed presentation. The aim of the study was to compare outcomes between SALC and DLC in AC patients with more than 7-day symptom duration.


A retrospective analysis of 83 AC patients who underwent LC after presenting with >7 days of symptoms from June 2010 to June 2015 was performed. Patients were divided into L-SALC and L-DLC, defined as LC performed within the same admission and between 4 and 24 weeks after discharge, respectively. Peri-operative outcomes were evaluated.


In L-SALC patients, the intra-operative severity was higher (p < 0.001) and median operative time was longer (L-SALC, 107 min (46–220) vs L-DLC, 95 mins (25–186)) (p = 0.048). Conversion rates were also higher in L-SALC than that in L-DLC (L-SALC, 21.4% vs L-DLC, 4.9%) (p = 0.048). While post-operative morbidity was similar, L-SALC was associated with a longer post-operative length of stay as compared to L-DLC (L-SALC, 2 (1–17) vs L-DLC, 1 (1–6)) (p < 0.001).


DLC provides lower conversion rates and shorter length of stay in AC patients presenting beyond 7 days of symptoms. This group of patients should be offered DLC.


Early Experience with Laparoscopic Frey Procedure for Chronic Pancreatitis: a Case Series and Review of Literature


The Frey procedure has been demonstrated to be an effective surgical technique to treat patients with painful large duct chronic pancreatitis. More commonly reported as an open procedure, we report our experience with a minimally invasive approach to the Frey procedure. Four consecutive patients underwent a laparoscopic Frey procedure at our institution from January 2012 to July 2015. We herein report our technique and describe short- and medium-term outcomes. The median age was 40 years old. The median duration of pancreatic pain prior to surgery was 12 years. Median operative time and intraoperative blood loss was 130 min (100–160 min) and 60 mL (50–100 mL), respectively. The median length of stay was 7 days (3–40 days) and median follow-up was 26 months (12–30 months). There was one major postoperative complication requiring reoperation. Within 6 months, in all four patients, frequency of pain and analgesic requirement reduced significantly. Two patients appeared to have resolution of pancreatic exocrine insufficiency. The Frey procedure is possible laparoscopically with acceptable short- and medium-term outcomes in well-selected patients.


Distal Pancreatectomy with Celiac Axis Resection Combined with Reconstruction of the Left Gastric Artery


Distal pancreatectomy with celiac axis resection is one of the most aggressive approaches for the treatment of locally advanced pancreatic cancer with common hepatic artery and/or celiac axis invasion. However, ischemic complications such as ischemic gastropathy and liver failure are problematic. To avoid these complications, we developed left gastric artery-reconstructing distal pancreatectomy with celiac axis resection. We used the middle colic artery for reconstruction. We performed this procedure in 10 patients, using the middle colic artery in three different ways: left branch reconstruction, right branch reconstruction, and reverse reconstruction. On postoperative images, 90% of the reconstructed left gastric arteries were patent. No complications associated with arterial reconstruction occurred. No patients developed ischemic gastropathy or liver failure. The R0 resection rate was 70%. Nine patients underwent adjuvant chemotherapy and seven patients were able to start it within 90 days. Distal pancreatectomy with celiac axis resection combined with reconstruction of the left gastric artery using the middle colic artery is a feasible option and would enhance the safety for carefully selected patients. Multicenter validation is needed to clarify the benefits of this new procedure.


Early Detection of Hepatocellular Carcinoma in Patients with Hepatocirrhosis by Soluble B7-H3


Increasing evidence has demonstrated an association between increased soluble B7-H3 (sB7-H3) levels and unfavorable progression in patients with malignant tumors. In the present study, we detected sB7-H3 levels in serum to investigate the value of sB7-H3 as a tool for differential diagnosis of cirrhotic patients with or without early-stage hepatocellular carcinoma (ESHCC). We also assessed the diagnostic value of sB7-H3regarding the prediction of overall survival (OS) of cirrhotic patients with ESHCC. sB7-H3 expression was measured in 91 healthy volunteers, 149 cirrhotic patients with ESHCC, and 87 cirrhotic patients by ELISA, and correlations between DCP1a level and clinical characteristics were analyzed. SB7-H3 concentrations were significantly higher in patients with ESHCC than in cirrhotic patients (P < 0.001). Using 48.34 ng/mL as a cutoff value, the sensitivity and specificity of sB7-H3 in differentiating between cirrhotic patients and cirrhotic patients with ESHCC were 76.5 and 93.1%, respectively. Moreover, high serum sB7-H3 in cirrhotic patients with ESHCC correlated with tumor size, tumor stage, vascular invasion, and tumor differentiation. The area under the curve (AUC) value for sB7-H3 (0.898) was significantly higher than those for AFP (0.789), CA199 (0.627), and CA125 (0.545) for differentiating between cirrhotic patients with ESHCC and sex- and age-matched cirrhotic patients without ESHCC. Our data indicate that serum sB7-H3 serves as a valuable biomarker for cirrhotic patients with ESHCC and that high levels of sB7-H3 correlate with poor clinical outcomes.


Editorial for clinical investigations: toward the vision and spirit of CARS with innovative clinical investigations


Design, development and clinical validation of computer-aided surgical simulation system for streamlined orthognathic surgical planning



There are many proven problems associated with traditional surgical planning methods for orthognathic surgery. To address these problems, we developed a computer-aided surgical simulation (CASS) system, the AnatomicAligner, to plan orthognathic surgery following our streamlined clinical protocol.


The system includes six modules: image segmentation and three-dimensional (3D) reconstruction, registration and reorientation of models to neutral head posture, 3D cephalometric analysis, virtual osteotomy, surgical simulation, and surgical splint generation. The accuracy of the system was validated in a stepwise fashion: first to evaluate the accuracy of AnatomicAligner using 30 sets of patient data, then to evaluate the fitting of splints generated by AnatomicAligner using 10 sets of patient data. The industrial gold standard system, Mimics, was used as the reference.


When comparing the results of segmentation, virtual osteotomy and transformation achieved with AnatomicAligner to the ones achieved with Mimics, the absolute deviation between the two systems was clinically insignificant. The average surface deviation between the two models after 3D model reconstruction in AnatomicAligner and Mimics was 0.3 mm with a standard deviation (SD) of 0.03 mm. All the average surface deviations between the two models after virtual osteotomy and transformations were smaller than 0.01 mm with a SD of 0.01 mm. In addition, the fitting of splints generated by AnatomicAligner was at least as good as the ones generated by Mimics.


We successfully developed a CASS system, the AnatomicAligner, for planning orthognathic surgery following the streamlined planning protocol. The system has been proven accurate. AnatomicAligner will soon be available freely to the boarder clinical and research communities.


Darting Primates: Steps Toward Procedural and Reporting Standards


Darting, a common method of capturing wild primates, poses risks to the individuals that must be appropriately minimized. A recent article in the International Journal of Primatology by Cunningham et al. (International Journal of Primatology, 36(5), 894–915, 2015) presented a literature review of the reporting of darting procedures in primatology and anonymously surveyed primatologists on darting methods and their effects, to report general trends in the field. We quantitatively reexamined 29 articles described by the authors as having information on fatalities and/or injuries. We think that the various body masses of primates (1 kg–150 kg), along with their locations and habitat types, and the degree of experience of the darting team, should be considered when estimating mortality and injury rates, and thus preclude the computation of an average mortality value across taxa. Nevertheless, we computed an average (mean) for comparison with the previous analyses. Our mean estimated mortality rate was 2.5% and the mean estimated injury risk was 1.5% (N = 21 articles). Thus, our estimated mortality rate is smaller than the combined mortality and injury rate of 5% reported by Cunningham et al. (International Journal of Primatology, 36(5), 894–915, 2015) and smaller than the mortality rates of medium-sized terrestrial mammals they used for comparison. Our study strongly suggests the critical need for more data to be analyzed in a standardized fashion.


Humeral Lengthening with the PRECICE Magnetic Lengthening Nail



Different types of external fixators have been used for humeral lengthening with successful outcomes reported in literature. Motorized intramedullary (IM) lengthening nails have been developed as an alternative to external fixators for long bone lengthening in the lower extremity.


This case series reports on using the new technology of IM lengthening nails for humeral lengthening. We assessed the radiological healing and functional outcomes after using the PRECICE IM nail for humeral lengthening.


This multicenter retrospective study included a total of six humeri in five patients (mean age was 20 years) that underwent lengthening with the magnetic IM PRECICE nail in two centers in the USA. The etiology was humeral growth arrest post-bone cyst (two segments), post-septic growth arrest (two segments), and multiple hereditary exostosis (bilateral segments in one patient). The outcomes measured were the length achieved, distraction index (DI; the length achieved in mm divided by the duration of lengthening in days), consolidation index (CI; number of days from surgery until consolidation divided by the length of the regenerate in cm), complications encountered, and functional outcomes (shoulder and elbow range of motion, the upper extremity functional index (UEFI), and QuickDASH functional scores).


The mean follow-up period was 1.8 years (0.9 to 2.4 years). All segments achieved the goal of lengthening; the mean was 5.1 cm (4.5 to 5.8 cm). Mean DI was 0.7 mm/day (0.5 to 0.8). Mean CI was 36 days/cm (25 to 45 days/cm). No complications were observed. At the last follow-up, all patients maintained their preoperative range of motion (ROM) except one patient had reduced shoulder ROM. QuickDASH score and upper extremity functional index showed postoperative improvement compared to the preoperative scores.


IM lengthening nails can provide successful and safe humeral lengthening. Specifically, the PRECICE nail has accurate control over the lengthening process.


Note on the coefficient of variations of neuronal spike trains


It is known that many neurons in the brain show spike trains with a coefficient of variation (CV) of the interspike times of approximately 1, thus resembling the properties of Poisson spike trains. Computational studies have been able to reproduce this phenomenon. However, the underlying models were too complex to be examined analytically. In this paper, we offer a simple model that shows the same effect but is accessible to an analytic treatment. The model is a random walk model with a reflecting barrier; we give explicit formulas for the CV in the regime of excess inhibition. We also analyze the effect of probabilistic synapses in our model and show that it resembles previous findings that were obtained by simulation.


Effectiveness of the capsaicin 8% patch in the management of peripheral neuropathic pain in European clinical practice: the ASCEND study



In randomised studies, the capsaicin 8% patch has demonstrated effective pain relief in patients with peripheral neuropathic pain (PNP) arising from different aetiologies.


ASCEND was an open-label, non-interventional study of patients with non-diabetes-related PNP who received capsaicin 8% patch treatment, according to usual clinical practice, and were followed for ≤52 weeks. Co-primary endpoints were percentage change in the mean numeric pain rating scale (NPRS) 'average daily pain' score from baseline to the average of Weeks 2 and 8 following first treatment; and median time from first to second treatment. The primary analysis was intended to assess analgesic equivalence between post-herpetic neuralgia (PHN) and other PNP aetiologies. Health-related quality of life (HRQoL, using EQ-5D), Patient Global Impression of Change (PGIC) and tolerability were also assessed.


Following first application, patients experienced a 26.6% (95% CI: 23.6, 29.62; n = 412) reduction in mean NPRS score from baseline to Weeks 2 and 8. Equivalence was demonstrated between PHN and the neuropathic back pain, post-operative and post-traumatic neuropathic pain and 'other' PNP aetiology subgroups. The median time from first to second treatment was 191 days (95% CI: 147, 235; n = 181). Forty-four percent of all patients were responders (≥30% reduction in NPRS score from baseline to Weeks 2 and 8) following first treatment, and 86.9% (n = 159/183) remained so at Week 12. A sustained pain response was observed until Week 52, with a 37.0% (95% CI: 31.3, 42.7; n = 176) reduction in mean NPRS score from baseline. Patients with the shortest duration of pain (0–0.72 years) experienced the highest pain response from baseline to Weeks 2 and 8. Mean EQ-5D index score improved by 0.199 utils (responders: 0.292 utils) from baseline to Week 2 and was maintained until Week 52. Most patients reported improvements in PGIC at Week 2 and at all follow-up assessments regardless of number of treatments received. Adverse events were primarily mild or moderate reversible application site reactions.


In European clinical practice, the capsaicin 8% patch provided effective and sustained pain relief, substantially improved HRQoL, improved overall health status and was generally well tolerated in a heterogeneous PNP population.

Trial registration

NCT01737294 Date of registration - October 22, 2012.


Bioresorbable vascular scaffolds in coronary chronic total occlusions revascularization: safety assessment related to struts coverage and apposition in 6-month OCT follow-up


Beneficial properties of bioresorbable vascular scaffolds (BVS) regarding to vasomotility restoration and no caging of the vessel make them attractive devices in chronic total occlusions (CTO) revascularization. However, more evidence is needed attending to their use in this specific setting. We aim to determine feasibility and safety of BVS use in CTO revascularization attending to struts coverage and apposition, as well as re-stenosis and stent thrombosis (ST) rates. 29 BVS were deployed in 9 CTO lesions revascularization (mean J-CTO score ≥3) with an acute procedural success rate of 100%. Clinical and angiographic follow-up was performed 6 months later, including intracoronary analyses from optical coherence tomography (OCT) images. 44,723 struts were analyzed within the total 636 mm of scaffolded vessel. Mean length scaffolded per lesion was 70.66 ± 31.01 mm with a mean number of 3.22 BVS. 2051 struts (4.59%) were identified as uncovered, being most of them (98.4%) neither malapposed nor disrupted. Mean thickness of struts' coverage was 0.13 ± 0.05 mm. Incomplete strut apposition (ISA) percentage was 0% as no malapposed struts were detected and 134 struts were identified as disrupted, which represents a 0.29% from the total. Mean vessel, scaffold, and lumen diameters were 3.87 ± 0.51, 2.97 ± 0.49, and 2.68 ± 0.50 mm, respectively. Neither in-stent re-stenosis nor ST was detected. During follow-up, none of our patients died, suffered from stroke or needed target lesion revascularization. Clinical and angiographic 6-month follow-up (including OCT analyses) of BVS in CTO revascularization suggests their effectiveness and safety, even in very complex chronic occluded lesions. Nevertheless, more evidence is needed


A critical appraisal of the quality of adult dual-energy X-ray absorptiometry guidelines in osteoporosis using the AGREE II tool: An EuroAIM initiative



Dual energy X-ray absorptiometry (DXA) is the most widely used technique to measure bone mineral density (BMD). Appropriate and accurate use of DXA is of great importance, and several guidelines have been developed in the last years. Our aim was to evaluate the quality of published guidelines on DXA for adults.


Between June and July 2016 we conducted an online search for DXA guidelines, which were evaluated by four independent readers blinded to each other using the AGREE II instrument. A fifth independent reviewer calculated scores per each domain and agreement between reviewers' scores.


Four out of 59 guidelines met inclusion criteria and were included. They were published between 2005 and 2014. Three out of four guidelines reached a high level of quality, having at least five domain scores higher than 60%. Domain 1 (Scope and Purpose) achieved the highest result (total score = 86.8 ± 3.7%). Domain 6 (Editorial Independence) had the lowest score (total score = 54.7 ± 12.5%). Interobserver agreement ranged from fair (0.230) to good (0.702).


Overall, the quality of DXA guidelines is satisfactory when evaluated using the AGREE II instrument. The Editorial Independence domain was the most critical, thus deserving more attention when developing future guidelines.

Main messages

Three of four guidelines on DXA had a high quality level (>60%).

Scope/purpose had the highest score (86.8 ± 3.7%).

Editorial Independence had the lowest score (54.7 ± 12.5%).

Interobserver agreement ranged from fair (0.230) to good (0.702).


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