Immediate versus modified release hydrocortisone in mitotane treated patients with adrenocortical cancer

Abstract

Objective

Mitotane induces hepatic CYP3A4 activity, resulting in accelerated cortisol inactivation, and also increases cortisol binding globulin (CBG). Therefore, higher hydrocortisone doses are required in patients with adrenocortical cancer (ACC) on mitotane treatment. Modified release hydrocortisone has not been used in mitotane-treated ACC patients yet.

Aim

Case series to compare serum cortisol, calculated free serum cortisol and ACTH levels in ACC patients on mitotane treatment with immediate and modified release hydrocortisone.

Design

Pharmacokinetics of immediate and modified release hydrocortisone, each administered at a dose of 40-20-0mg, in 9 patients with ACC and adjuvant mitotane treatment. For comparison, ten patients with secondary adrenal insufficiency (SAI) on three different hydrocortisone regimens, and ten healthy males were included.

Methods

Serum cortisol and plasma ACTH were measured by chemiluminescent enzyme immunoassay, and CBG by RIA, followed by calculation of free cortisol.

Results

Calculated free serum cortisol levels after 40mg immediate release hydrocortisone in ACC patients (46±14nmol/l) were similar to those after 10mg immediate release hydrocortisone intake in men with SAI (64±16nmol/l) or to the physiological morning free cortisol levels in healthy subjects (31±5nmol/l), Compared to immediate release hydrocortisone, free cortisol levels after 40mg modified release hydrocortisone in ACC patients were significantly lower (12±3nmol/l; p=0.03) resulting in a generally lower AUC (98±21 vs 149±37 nmol*h/l; p=0.02).

Conclusions

40-20-0mg immediate release, but not modified release hydrocortisone, resulted in sufficient glucocorticoid coverage in patients with ACC receiving mitotane treatment. The use of equivalent doses of modified release hydrocortisone preparation should be avoided in patients on mitotane treatment.

This article is protected by copyright. All rights reserved.

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A case of severe movement disorder with GNAO1 mutation responsive to topiramate

Publication date: Available online 1 December 2016
Source:Brain and Development
Author(s): Saori Sakamoto, Yukifumi Monden, Ryoko Fukai, Noriko Miyake, Hiroshi Saito, Akihiko Miyauchi, Ayumi Matsumoto, Masako Nagashima, Hitoshi Osaka, Naomichi Matsumoto, Takanori Yamagata
We report the case of a 19-year-old female patient who had progressive chorea associated with a GNAO1 mutation. Chorea was refractory to multiple anticonvulsants, and the patient suffered from tiapride-induced neuroleptic malignant syndrome. After identification of a GNAO1 missense mutation at the age of 18years, topiramate treatment was initiated and the frequency of chorea decreased dramatically. The efficacy of topiramate may have been related to the inhibitory modulation of voltage-activated Ca²⁺ channels. Given the side effects and complications associated with neuroleptics and deep brain stimulation, respectively, topiramate is recommended for the first-line management of severe chorea associated with a GNAO1 mutation.



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Glucocorticoids curtail stimuli-induced CREB phosphorylation in TRH neurons through interaction of the glucocorticoid receptor with the catalytic subunit of protein kinase A

Abstract

Purpose

Corticosterone prevents cold-induced stimulation of thyrotropin-releasing hormone (Trh) expression in rats, and the stimulatory effect of dibutyryl cyclic-adenosine monophosphate (dB-cAMP) on Trh transcription in hypothalamic cultures. We searched for the mechanism of this interference.

Methods

Immunohistochemical analyses of phosphorylated cAMP-response element binding protein (pCREB) were performed in the paraventricular nucleus (PVN) of Wistar rats, and in cell cultures of 17-day old rat hypothalami, or neuroblastoma SH-SY5Y cells. Cultures were incubated 1h with dB-cAMP, dexamethasone and both drugs combined; their nuclear extracts were used for chromatin immunoprecipitation; cytosolic or nuclear extracts for coimmunoprecipitation analyses of catalytic subunit of protein kinase A (PKAc) and of glucocorticoid receptor (GR); their subcellular distribution was analyzed by immunocytochemistry.

Results

Cold exposure increased pCREB in TRH neurons of rats PVN, effect blunted by corticosterone previous injection. Dexamethasone interfered with forskolin increase in nuclear pCREB and its binding to Trh promoter; antibodies against histone deacetylase-3 precipitated chromatin from nuclear extracts of hypothalamic cells treated with tri-iodothyronine but not with dB-cAMP + dexamethasone, discarding chromatin compaction as responsible mechanism. Co-immunoprecipitation analyses of cytosolic or nuclear extracts showed protein:protein interactions between activated GR and PKAc. Immunocytochemical analyses of hypothalamic or SH-SY5Y cells revealed diminished nuclear translocation of PKAc and GR in cells incubated with forskolin + dexamethasone, compared to either forskolin or dexamethasone alone.

Conclusions

Glucocorticoids and cAMP exert mutual inhibition of Trh transcription through interaction of activated glucocorticoid receptor with protein kinase A catalytic subunit, reducing their nuclear translocation, limiting cAMP-response element binding protein phosphorylation and its binding to Trh promoter.

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Joint Attention and Brain Functional Connectivity in Infants and Toddlers

Initiating joint attention (IJA), the behavioral instigation of coordinated focus of 2 people on an object, emerges over the first 2 years of life and supports social-communicative functioning related to the healthy development of aspects of language, empathy, and theory of mind. Deficits in IJA provide strong early indicators for autism spectrum disorder, and therapies targeting joint attention have shown tremendous promise. However, the brain systems underlying IJA in early childhood are poorly understood, due in part to significant methodological challenges in imaging localized brain function that supports social behaviors during the first 2 years of life. Herein, we show that the functional organization of the brain is intimately related to the emergence of IJA using functional connectivity magnetic resonance imaging and dimensional behavioral assessments in a large semilongitudinal cohort of infants and toddlers. In particular, though functional connections spanning the brain are involved in IJA, the strongest brain-behavior associations cluster within connections between a small subset of functional brain networks; namely between the visual network and dorsal attention network and between the visual network and posterior cingulate aspects of the default mode network. These observations mark the earliest known description of how functional brain systems underlie a burgeoning fundamental social behavior, may help improve the design of targeted therapies for neurodevelopmental disorders, and, more generally, elucidate physiological mechanisms essential to healthy social behavior development.

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Seeing Wisely: Imaging Recommendations for Suspected Childhood Stroke

Publication date: Available online 7 January 2017
Source:Pediatric Neurology
Author(s): E. Steve Roach




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Post-Anoxic Reticular Reflex Myoclonus in a Child & Proposed Classification of Post-Anoxic Myoclonus

Publication date: Available online 7 January 2017
Source:Pediatric Neurology
Author(s): Min Tsui Ong, Ptolemaios Georgios Sarrigiannis, Peter Stuart Baxter
ObjectiveTo describe a childhood case of post-anoxic myoclonus of the reticular reflex type and discuss the classification of post-anoxic myoclonus.ResultsA 9 year old boy with severe hypoxic-ischemic encephalopathy due to submersion developed early epileptic spasms followed by stimulus sensitive multifocal generalised myoclonus and later dystonia. Video EMG (electromyography) polygraphy performed before treatment showed the discharges associated with the myoclonus lasted less than 50ms. Cortical myoclonus was excluded by jerk-locked averaging (JLA) using arm muscles, which showed no cortical correlates. The recruitment order on EMG polygraphy was consistent with a brainstem generator for the myoclonus, characteristic of reticular reflex myoclonus. Both myoclonus and dystonia responded to Clonazepam. He has remained in a persistent vegetative state.ConclusionReticular reflex myoclonus can be demonstrated by detailed neurophysiological assessment in children as in adults, and has a similar poor prognosis. Post-anoxic myoclonus can have several differing mechanisms and should not be considered synonymous with Lance-Adams myoclonus.



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X-linked cobalamin disorder (HCF1) mimicking nonketotic hyperglycinemia with increased both CSF glycine and methylmalonic acid

Publication date: Available online 7 January 2017
Source:Pediatric Neurology
Author(s): Emmanuel Scalais, Elise Osterheld, Christiane Weitzel, Linda De Meirleir, Frederic Mataigne, Geert Martens, Tamim H. Shaikh, Curtis R. Coughlin, Hung-Chun Yu, Michael Swanson, Marisa W. Friederich, Gunter Scharer, Daniel Helbling, Jamie Wendt-Andrae, Johan Van Hove
BackgroundAutosomal recessive or X-linked inborn errors of intracellular cobalamin metabolism can lead to methylmalonic aciduria and homocystinuria. In neonates, both increased cerebrospinal fluid (CSF) glycine and CSF/plasma glycine ratio is a biochemical feature of non-ketotic hyperglycinemia.Patient DescriptionWe describe a boy presenting in the neonatal period with hypotonia, tonic, clonic and later myoclonic seizures, subsequently evolving into refractory epilepsy and severe neurocognitive impairment. Increased CSF glycine and CSF/plasma glycine ratio were indicative of nonketotic hyperglycinemia. Early magnetic resonance imaging showed restricted diffusion and decreased apparent diffusion coefficient (ADC) values in posterior limb of internal capsules and later in entire internal capsules and posterior white matter. Sequencing did not show a mutation in AMT, GLDC or GCSH. Biochemical analysis identified persistently elevated CSF levels of glycine and methylmalonic acid (MMA) and increased urinary MMA and plasma homocysteine levels, which improved on higher parenteral hydroxocobalamin dose. Exome sequencing identified a known pathogenic sequence variant in X-linked Cobalamin (HCFC1), c. 344C>T, p. Ala115Val. Additionally, a hemizygous mutation was found in the ATRX (c. 2728A>G, p. Lys910Glu). Retrospective review of two other patients with X-linked cobalamin also identified elevated CSF glycine levels.ConclusionThis boy had cobalamin X-linked (HCFC1 deficiency) with increased CSF glycine and MMA and increased CSF/plasma glycine ratio suggesting a brain hyperglycinemia. Putative binding sites for HCFC1 and its binding partner THAP11 were identified near genes of the glycine cleavage enzyme, providing a potential mechanistic link between HCFC1 mutations and elevated glycine.



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A Wrinkle in the Time of Mitochondrial Medicine

Publication date: Available online 7 January 2017
Source:Pediatric Neurology
Author(s): Jaime-Dawn E. Twanow




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Catch my drift? Making sense of genomic intra-tumour heterogeneity

Publication date: Available online 7 January 2017
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Andrea Sottoriva, Chris P Barnes, Trevor A Graham
The cancer genome is shaped by three components of the evolutionary process: mutation, selection and drift. While many studies have focused on the first two of these evolutionary components, the role of drift in cancer evolution has received little attention. Drift occurs when all individuals in the population have the same likelihood of producing surviving offspring, and so by definition a drifting population is one that is evolving neutrally. Here we focus on how neutral evolution is manifested in the cancer genome. We discuss how neutral passenger mutations provide a magnifying glass that reveals the evolutionary dynamics underpinning cancer development, and outline how statistical inference can be used to quantify these dynamics from sequencing data. We argue that only after we understand the impact of neutral drift on the genome can we begin to make full sense of clonal selection.This article is part of a Special Issue entitled: Evolutionary principles - heterogeneity in cancer?, edited by Dr. Robert A. Gatenby.



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Dissecting thyroid hormone transport and metabolism in dendritic cells

We reported thyroid hormone (TH) receptor expression in murine dendritic cells (DCs) and 3,5,3'-triiodothyronine (T₃)-dependent stimulation of DC maturation and ability to develop a Th1-type adaptive response. Moreover, an increased DC capacity to promote antigen-specific cytotoxic T-cell activity, exploited in a DC-based antitumor vaccination protocol, was revealed. However, putative effects of the main circulating TH, l-thyroxine (T₄) and the mechanisms of TH transport and metabolism at DC level, crucial events for TH action at target cell level, were not known. Herein, we show that T₄ did not reproduce those registered T₃-dependent effects, finding that may reflect a homoeostatic control to prevent unspecific systemic activation of DCs. Besides, DCs express MCT10 and LAT2 TH transporters, and these cells mainly transport T₃ with a favored involvement of MCT10 as its inhibition almost prevented T₃ saturable uptake mechanism and reduced T₃-induced IL-12 production. In turn, DCs express iodothyronine deiodonases type 2 and 3 (D2, D3) and exhibit both enzymatic activities with a prevalence towards TH inactivation. Moreover, T₃ increased MCT10 and LAT2 expression and T₃ efflux from DCs but not T₃ uptake, whereas it induced a robust induction of D3 with a parallel slight reduction in D2. These findings disclose pivotal events involved in the mechanism of action of THs on DCs, providing valuable tools for manipulating the immunogenic potential of these cells. Furthermore, they broaden the knowledge of the TH mechanism of action at the immune system network.

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Indispensable role of the voltage-gated calcium channels in the procognitive effects of angiotensin IV

Publication date: Available online 6 January 2017
Source:Brain Research Bulletin
Author(s): Jan Józef Braszko
BACKGROUNDVoltage-gated calcium channels (VGCCs) play a major role in brain functioning, including that of cognition-related structures such as cerebral cortex and hippocampus. Cellular mechanisms underlying learning and memory enhancing effect of the neuropeptide angiotensin IV (Ang IV) have been linked to VGCCs but only in respect of its long-term potentiation (LTP)-inducing effect.OBJECTIVETo assess behaviorally effects of L- and T-type VGCCs blocking drugs in low, behaviorally inactive, doses on Ang IV facilitation of recall of aversively (foot-shock) and appetitively (curiosity for novelty) motivated behaviors.METHODSAbout 240 male Wistar rats were used. All animals received oral (p.o.) dose of nimodipine (12mg/kg) or mibefradil (1mg/kg) dissolved in saline or saline alone followed by an intracerebroventricular (i.c.v.) injection of 1nmol of Ang IV dissolved in 2μl of normal saline or saline alone 15min later. Groups of about 10 rats, separate for each experiment, were tested for recall of aversively (inhibitory avoidance, IA) and appetitively (object recognition, OR) reinforced behaviors. To verify lack of unspecific motor and emotional effects of our treatments separate groups of rats were tested in open field (OF) and elevated 'plus' maze (EPM), respectively.RESULTSBoth, nimodipine and mibefradil prevented recall facilitating effects of subsequently injected Ang IV. The peptide as well as both VGCCs blocking drugs had no (OF), or only negligible (EPM) effects on motor performance and emotionality of rats.CONCLUSIONThe data support a notion about key role of the functional VGCCs in neuronal procognitive effects of Ang IV.

Graphical abstract

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Streptozotocin causes neurotoxic effect in cultured cerebellar granule neurons

Publication date: Available online 6 January 2017
Source:Brain Research Bulletin
Author(s): Elisaveta E. Genrikhs, Elena V. Stelmashook, Sergey A. Golyshev, Olga P. Aleksandrova, Nickolay K. Isaev
Streptozotocin (STZ) is a glucosamine-nitrosourea compound used for experimental simulation of sporadic Alzheimer's disease at intracerebroventricular administration in vivo. The studies of STZ influence on neurons of central nervous system performed on the primary cultures are practically absent. We have shown the application of STZ (1–5mM) in primary culture for 48h induced strong dose-dependent death in cultured cerebellar granule neurons. This toxic effect was decreased by pyruvate, insulin partially. Using the indicator Fluo-4 AM for measurements of intracellular calcium ions and tetramethylrhodamine ethyl ester (TMRE) for detection of changes of mitochondrial membrane potential in live cells we have shown that 5 h-exposure to STZ induced intensive increase of Fluo-4 and decrease TMRE fluorescence in neurons. STZ exposure caused considerable ultrastructural alterations in granule neurons: chromatin clumping, swelling of the endoplasmic reticulum and mitochondria, and disruption of the mitochondrial cristae. Probably, STZ significantly impaired glucose metabolism and mitochondrial function that, in turn, resulted in mitochondrial membrane potential damage, excessive calcium overload and neuronal death.



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Astrocytes and presynaptic plasticity in the striatum: Evidence and unanswered questions

Publication date: Available online 6 January 2017
Source:Brain Research Bulletin
Author(s): Anton Dvorzhak, Igor Melnick, Rosemarie Grantyn
One of the main functions of astrocytes is to ensure glutamate homeostasis by glutamate uptake and glutamine synthesis. However, during the past ten years it has become clear that astrocytes may also induce changes in synaptic glutamate release when respective pathways must cope with the consequences of brain damage or other alterations in their functional requirements. The loss of glutamatergic synapses in Parkinson's and Huntington's disease is likely to associate with a continuous redistribution of presynaptic activity within the pool of surviving synapses, and astrocytes may have a role in the maintenance of independent control at individual glutamate release sites. The rodent striatum should be a good model structure to analyse astrocyte-synapse interactions underlying disease-related plasticity, because it does not itself contain any glutamatergic neurons. Here we examine recent results that may shed light on the mechanisms underlying pathway-specific alterations in the corticostriatal or thalamostriatal synaptic transmission with a possible involvement of astrocytic release or uptake of glutamate. The conclusions emphasize the need of exploring the highly compartmentalised and presumably heterogeneous synapse astrocyte-interactions at a single synapse level.



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Macrophage activation status determines the internalization of mesoporous silica particles of different sizes: Exploring the role of different pattern recognition receptors

Publication date: March 2017
Source:Biomaterials, Volume 121
Author(s): Audrey Gallud, Olesja Bondarenko, Neus Feliu, Natalia Kupferschmidt, Rambabu Atluri, Alfonso Garcia-Bennett, Bengt Fadeel
Mesoporous silica-based particles are promising candidates for biomedical applications. Here, we address the importance of macrophage activation status for internalization of AMS6 (approx. 200 nm in diameter) versus AMS8 (approx. 2 μm) mesoporous silica particles and the role of different phagocytosis receptors for particle uptake. To this end, FITC-conjugated silica particles were used. AMS8 were found to be non-cytotoxic both for M-CSF-stimulated (anti-inflammatory) and GM-CSF-stimulated (pro-inflammatory) macrophages, whereas AMS6 exhibited cytotoxicity towards M-CSF-stimulated, but not GM-CSF-stimulated macrophages; this toxicity was, however, mitigated in the presence of serum. AMS8 triggered the secretion of pro-inflammatory cytokines in M-CSF-activated cells. Class A scavenger receptor (SR-A) expression was noted in both M-CSF and GM-CSF-stimulated macrophages, although the expression was higher in the former case, and gene silencing of SR-A resulted in a decreased uptake of AMS6 in the absence of serum. GM-CSF-stimulated macrophages expressed higher levels of the mannose receptor CD206 compared to M-CSF-stimulated cells, and uptake of AMS6, but not AMS8, was reduced following the downregulation of CD206 in GM-CSF-stimulated cells; particle uptake was also suppressed by mannan, a competitive ligand. These studies demonstrate that macrophage activation status is an important determinant of particle uptake and provide evidence for a role of different macrophage receptors for cell uptake of silica particles.



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Plant viral nanoparticles-based HER2 vaccine: Immune response influenced by differential transport, localization and cellular interactions of particulate carriers

Publication date: March 2017
Source:Biomaterials, Volume 121
Author(s): Sourabh Shukla, Jay T. Myers, Sarah E. Woods, Xingjian Gong, Anna E. Czapar, Ulrich Commandeur, Alex Y. Huang, Alan D. Levine, Nicole F. Steinmetz
Cancer vaccines are designed to elicit an endogenous adaptive immune response that can successfully recognize and eliminate residual or recurring tumors. Such approaches can potentially overcome shortcomings of passive immunotherapies by generating long-lived therapeutic effects and immune memory while limiting systemic toxicities. A critical determinant of vaccine efficacy is efficient transport and delivery of tumor-associated antigens to professional antigen presenting cells (APCs). Plant viral nanoparticles (VNPs) with natural tropism for APCs and a high payload carrying capacity may be particularly effective vaccine carriers. The applicability of VNP platform technologies is governed by stringent structure-function relationships. We compare two distinct VNP platforms: icosahedral cowpea mosaic virus (CPMV) and filamentous potato virus X (PVX). Specifically, we evaluate in vivo capabilities of engineered VNPs delivering human epidermal growth factor receptor 2 (HER2) epitopes for therapy and prophylaxis of HER2⁺ malignancies. Our results corroborate the structure-function relationship where icosahedral CPMV particles showed significantly enhanced lymph node transport and retention, and greater uptake by/activation of APCs compared to filamentous PVX particles. These enhanced immune cell interactions and transport properties resulted in elevated HER2-specific antibody titers raised by CPMV- vs. PVX-based peptide vaccine. The 'synthetic virology' field is rapidly expanding with numerous platforms undergoing development and preclinical testing; our studies highlight the need for systematic studies to define rules guiding the design and rational choice of platform, in the context of peptide-vaccine display technologies.

Graphical abstract

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Calcium phosphate-phosphorylated adenosine hybrid microspheres for anti-osteosarcoma drug delivery and osteogenic differentiation

Publication date: March 2017
Source:Biomaterials, Volume 121
Author(s): Zi-Fei Zhou, Tuan-Wei Sun, Feng Chen, Dong-Qing Zuo, Hong-Sheng Wang, Ying-Qi Hua, Zheng-Dong Cai, Jun Tan
Biocompatibility, biodegradability and bioactivity are significantly important in practical applications of various biomaterials for bone tissue engineering. Herein, we develop a functional inorganic-organic hybrid system of calcium phosphate-phosphorylated adenosine (CPPA). Both calcium phosphate and phosphorylated adenosine molecules in CPPA are fundamental components in mammalians and play important roles in biological metabolism. In this work, we report our three leading research qualities: (1) CPPA hybrid microspheres with hollow and porous structure are synthesized by a facile one-step microwave-assisted solvothermal method; (2) CPPA hybrid microspheres show high doxorubicin loading capacity and pH-responsive drug release properties, and demonstrate positive therapeutic effects on six osteosarcoma cell lines in vitro and a mouse model of 143B osteosarcoma subcutaneous tumor in vivo; (3) CPPA hybrid microspheres are favorable to promote osteogenic differentiation of human bone mesenchymal stem cells (hBMSCs) by activating the AMPK pathway, with satisfactory evidences from cellular alkaline phosphatase staining, alizarin red staining, real time PCR and western analysis. The as-prepared CPPA hybrid microspheres are promising in anti-osteosarcoma and bone regeneration, which simultaneously display excellent properties on drug delivery and osteogenic differentiation of hBMSCs.



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Sequentially-crosslinked bioactive hydrogels as nano-patterned substrates with customizable stiffness and degradation for corneal tissue engineering applications

Publication date: March 2017
Source:Biomaterials, Volume 120
Author(s): Muhammad Rizwan, Gary S.L. Peh, Heng-Pei Ang, Nyein Chan Lwin, Khadijah Adnan, Jodhbir S. Mehta, Wui Siew Tan, Evelyn K.F. Yim
Naturally-bioactive hydrogels like gelatin provide favorable properties for tissue-engineering but lack sufficient mechanical strength for use as implantable tissue engineering substrates. Complex fabrication or multi-component additives can improve material strength, but often compromises other properties. Studies have shown gelatin methacrylate (GelMA) as a bioactive hydrogel with diverse tissue growth applications. We hypothesize that, with suitable material modifications, GelMA could be employed for growth and implantation of tissue-engineered human corneal endothelial cell (HCEC) monolayer. Tissue-engineered HCEC monolayer could potentially be used to treat corneal blindness due to corneal endothelium dysfunction. Here, we exploited a sequential hybrid (physical followed by UV) crosslinking to create an improved material, named as GelMA+, with over 8-fold increase in mechanical strength as compared to regular GelMA. The presence of physical associations increased the subsequent UV-crosslinking efficiency resulting in robust materials able to withstand standard endothelium insertion surgical device loading. Favorable biodegradation kinetics were also measured in vitro and in vivo. We achieved hydrogels patterning with nano-scale resolution by use of oxygen impermeable stamps that overcome the limitations of PDMS based molding processes. Primary HCEC monolayers grown on GelMA+ carrier patterned with pillars of optimal dimension demonstrated improved zona-occludin-1 expression, higher cell density and cell size homogeneity, which are indications of functionally-superior transplantable monolayers. The hybrid crosslinking and fabrication approach offers potential utility for development of implantable tissue-engineered cell-carrier constructs with enhanced bio-functional properties.



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Nanoparticles for radiooncology: Mission, vision, challenges

Publication date: March 2017
Source:Biomaterials, Volume 120
Author(s): Leoni A. Kunz-Schughart, Anna Dubrovska, Claudia Peitzsch, Alexander Ewe, Achim Aigner, Samuel Schellenburg, Michael H. Muders, Silke Hampel, Giuseppe Cirillo, Francesca Iemma, Rainer Tietze, Christoph Alexiou, Holger Stephan, Kristof Zarschler, Orazio Vittorio, Maria Kavallaris, Wolfgang J. Parak, Lutz Mädler, Suman Pokhrel
Cancer is one of the leading non-communicable diseases with highest mortality rates worldwide. About half of all cancer patients receive radiation treatment in the course of their disease. However, treatment outcome and curative potential of radiotherapy is often impeded by genetically and/or environmentally driven mechanisms of tumor radioresistance and normal tissue radiotoxicity. While nanomedicine-based tools for imaging, dosimetry and treatment are potential keys to the improvement of therapeutic efficacy and reducing side effects, radiotherapy is an established technique to eradicate the tumor cells. In order to progress the introduction of nanoparticles in radiooncology, due to the highly interdisciplinary nature, expertise in chemistry, radiobiology and translational research is needed. In this report recent insights and promising policies to design nanotechnology-based therapeutics for tumor radiosensitization will be discussed. An attempt is made to cover the entire field from preclinical development to clinical studies. Hence, this report illustrates (1) the radio- and tumor-biological rationales for combining nanostructures with radiotherapy, (2) tumor-site targeting strategies and mechanisms of cellular uptake, (3) biological response hypotheses for new nanomaterials of interest, and (4) challenges to translate the research findings into clinical trials.



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Engineering hepatitis B virus core particles for targeting HER2 receptors in vitro and in vivo

Publication date: March 2017
Source:Biomaterials, Volume 120
Author(s): Izzat Fahimuddin Bin Mohamed Suffian, Julie Tzu-Wen Wang, Naomi O. Hodgins, Rebecca Klippstein, Mitla Garcia-Maya, Paul Brown, Yuya Nishimura, Hamed Heidari, Sara Bals, Jane K. Sosabowski, Chiaki Ogino, Akihiko Kondo, Khuloud T. Al-Jamal
Hepatitis B Virus core (HBc) particles have been studied for their potential as drug delivery vehicles for cancer therapy. HBc particles are hollow nano-particles of 30–34 nm diameter and 7 nm thick envelopes, consisting of 180–240 units of 21 kDa core monomers. They have the capacity to assemble/dis-assemble in a controlled manner allowing encapsulation of various drugs and other biomolecules. Moreover, other functional motifs, i.e. receptors, receptor binding sequences, peptides and proteins can be expressed. This study focuses on the development of genetically modified HBc particles to specifically recognise and target human epidermal growth factor receptor-2 (HER2)-expressing cancer cells, in vitro and in vivo, for future cancer therapy. The non-specific binding capacity of wild type HBc particles was reduced by genetic deletion of the sequence encoding arginine-rich domains. A specific HER2-targeting was achieved by expressing the ZHER2 affibodies on the HBc particles surface. In vitro studies showed specific uptake of ZHER2-ΔHBc particles in HER2 expressing cancer cells. In vivo studies confirmed positive uptake of ZHER2-ΔHBc particles in HER2-expressing tumours, compared to non-targeted ΔHBc particles in intraperitoneal tumour-bearing mice models. The present results highlight the potential of these nanocarriers in targeting HER2-positive metastatic abdominal cancer following intra-peritoneal administration.



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Graphene quantum dots with nitrogen-doped content dependence for highly efficient dual-modality photodynamic antimicrobial therapy and bioimaging

Publication date: March 2017
Source:Biomaterials, Volume 120
Author(s): Wen-Shuo Kuo, Hua-Han Chen, Shih-Yao Chen, Chia-Yuan Chang, Pei-Chi Chen, Yung-I Hou, Yu-Ting Shao, Hui-Fang Kao, Chih-Li Lilian Hsu, Yi-Chun Chen, Shean-Jen Chen, Shang-Rung Wu, Jiu-Yao Wang
Reactive oxygen species is the main contributor to photodynamic therapy. The results of this study show that a nitrogen-doped graphene quantum dot, serving as a photosensitizer, was capable of generating a higher amount of reactive oxygen species than a nitrogen-free graphene quantum dot in photodynamic therapy when photoexcited for only 3 min of 670 nm laser exposure (0.1 W cm^-2), indicating highly improved antimicrobial effects. In addition, we found that higher nitrogen-bonding compositions of graphene quantum dots more efficiently performed photodynamic therapy actions than did the lower compositions that underwent identical treatments. Furthermore, the intrinsically emitted luminescence from nitrogen-doped graphene quantum dots and high photostability simultaneously enabled it to act as a promising contrast probe for tracking and localizing bacteria in biomedical imaging. Thus, the dual modality of nitrogen-doped graphene quantum dots presents possibilities for future clinical applications, and in particular multidrug resistant bacteria.



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MANAGEMENT OF ENDOCRINE DISEASE: The impact of subclinical hypothyroidism on anthropometric characteristics, lipid, glucose and hormonal profile of PCOS patients: a systematic review and meta-analysis

Objective

Subclinical hypothyroidism (SCH) is encountered in 10–25% of women with PCOS. To date, it remains unclear whether this coexistence influences the severity of metabolic and hormonal profile of these patients. The purpose of our systematic review is to investigate this potential relation.

Methods

We systematically searched Medline, Scopus, ClinicalTrials.gov, Cochrane Central Register of Controlled Trials (CENTRAL) and Google Scholar databases together with reference lists from included studies. All prospective and retrospective observational cohort studies that investigated the impact of subclinical hypothyroidism on hormonal and metabolic parameters of PCOS patients were included. The methodological quality of studies was assessed with the Ottawa–Newcastle criteria. Statistical meta-analysis was performed with the RevMan 5.3 software.

Results

Twelve studies were finally included in the present review, which enrolled 2341 PCOS patients. Among them, 577 had subclinical hypothyroidism, whereas the remaining 2077 were PCOS women with normal thyroid function. The presence of SCH significantly affected HDL (MD –3.92 mg/dL 95% CI: –6.56, –1.29) and triglycerides levels (26.91 mg/dL 95% CI: –3.79, 50.02). HOMA-IR was also affected (MD 0.82 95% CI: 0.15, 1.50). On the other hand, LDL, fasting glucose and 2-h OGTT were not influenced. Similarly, prolactin, FSH, LH, LH/FSH ratio and sex hormone-binding globulin remained unaffected.

Conclusion

Subclinical hypothyroidism does not influence the hormonal profile of women with PCOS. On the other hand, it results in mild metabolic abnormalities, which are not clinically important in a short-term setting.

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The predictive accuracy of sentinel nodes mapping in the setting of pulmonary metastasectomy

Abstract

This is the first study to evaluate the feasibility of mediastinal lymph node dissection (MLND) based on sentinel lymph node (SLN) status during pulmonary metastasectomy. A total of 22 patients (16 men, 6 women; age 63.3 ± 7.01 years) who were candidates for metastasectomy through segmentectomy or lobectomy with MLND owing to cancers metastatic to the lung were enrolled in this study. Radiotracer was administered at the peritumoral region before surgery or soon after initiating surgery. During the operation, the radioactivity of the lymph nodes (ex vivo) was counted with a handheld gamma probe after MLND. Lobectomy was performed in 17 patients, and segmentectomy, in 5 patients. The number of dissected lymph nodes per patient was 14.4 ± 8.69 (range, 5–36). In all patients, the SLN could be detected, and the number of SLNs identified was 2.0 ± 1.15 (range, 1–5) per patient. Lymph node metastasis was identified in 3 of the 22 patients (13.6%), and none of the 3 patients with N1 or N2 disease had false-negative SLNs. SLN identification might be an indicator of whether or not MLND should be performed during pulmonary metastasectomy. However, further large-volume and multi-institutional studies are needed.

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Does a Standalone Cancer Center Improve Head and Neck Microsurgical Outcomes?

J reconstr Microsurg
DOI: 10.1055/s-0036-1597757

Objectives To evaluate the role of hospital setting (standalone cancer center vs. large multidisciplinary hospital) on free tissue transfer (FTT) outcomes for head and neck reconstruction. Methods Medical records were reviewed of 180 consecutive patients undergoing FTT for head and neck reconstruction. Operations occurred at either a standalone academic cancer center (n = 101) or a large multidisciplinary academic medical center (n = 79) by the same surgeons. Patient outcomes, operative comparisons, and hospital costs were compared between the hospital settings. Results The cancer center group had higher mean age (65.2 vs. 60 years; p = 0.009) and a shorter mean operative time (12.3 vs. 13.2 hours; p = 0.034). Postoperatively, the cancer center group had a significantly shorter average ICU stay (3.45 vs. 4.41 days; p < 0.001). There were no significant differences in medical or surgical complications between the groups. Having surgery at the cancer center was the only significant independent predictor of a reduced ICU stay on multivariate analysis (Coef 0.73; p < 0.020). Subgroup analysis, including only patients with cancer of the aerodigestive tract, demonstrated further reduction in ICU stay for the cancer center group (3.85 vs. 5.1 days; p < 0.001). A cost analysis demonstrated that the reduction in ICU saved $223,816 for the cancer center group. Conclusion Standalone subspecialty cancer centers are safe and appropriate settings for FTT. We found both reduced operative time and ICU length of stay, both of which contributed to lower overall costs. These findings challenge the concept that FTT requires a large multidisciplinary hospital. Level of Evidence 4.
[...]

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Supraclavicular Flap Reconstruction of Cutaneous Defects Has Lower Complication Rate than Mucosal Defects

J reconstr Microsurg
DOI: 10.1055/s-0036-1597718

Background The objective of this study was to determine whether there was a difference in complication rate between cutaneous and mucosal defects reconstructed with the supraclavicular artery flap. Methods Retrospective review of postoperative complications in 63 patients from 2008 to 2015 with cutaneous and mucosal head and neck defects following oncologic ablation reconstructed with the supraclavicular flap, with a minimum follow-up duration of 6 months. Of the 63 patients, 38 patients had cutaneous defects, whereas 25 had mucosal defects. Patients were followed up postoperatively to determine the presence of wound infection, partial flap necrosis, complete flap necrosis, and fistula formation. Complications in both defect groups as well as a statistical comparison of total complications were analyzed. Results Patients with cutaneous defects reconstructed with the supraclavicular flap had significantly lower postoperative complications than those with mucosal defects (p = 0.002). Flap necrosis, both partial and complete, was also lower in this same group (p = 0.0052). Conclusion The supraclavicular artery flap may be a more suitable option for patients with cutaneous defects, given the reliability and lower propensity for postoperative complications Level of Evidence The level of evidence is 4.
[...]

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

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Breast Reconstruction in Elderly Patients: Risk Factors, Clinical Outcomes, and Aesthetic Results

J reconstr Microsurg
DOI: 10.1055/s-0036-1597822

Background Correlation among age, clinical, and aesthetic outcomes in implant-based and autologous breast reconstructions was investigated. Methods Between 2004 and 2014, a retrospective study was performed on patients who underwent reconstruction following mastectomy. Patients were divided in group A (< 50 years), group B (≥ 50–59 years), group C (≥ 60–69 years), and group D (≥ 70 years). Demographics, comorbidities, American Society of Anesthesiologists (ASA) class, and length of stay were assessed using chi-square and Kruskal–Wallis H analysis considering p ≤ 0.05 as significant. Pre- and postoperative photographs were taken to grade aesthetic results by patients and blinded plastic surgery team. Results A total of 993 patients underwent 1,251 breast reconstructions, of which 356 (28.5%) were implant-based, 402 (32.1%) pedicled-flap, 445 (35.6%) free-flap, and 48 (3.8%) fat-graft reconstructions. There were 316 (25.2%) complications, of which 124 (34.8%) in implant-based, 74 (18.4%) in pedicled-flap, 111 (24.9%) in free-flap, and 2 (4.2%) in fat-graft reconstructions. Mean length of stay was 5.4 days without significant difference between age groups (p = 0.357). The incidence of overall complications was not significantly related to age, ASA class, smoking history, and previous radiotherapy. Body mass index was a significant predictor (p = 0.001), but odds ratio (OR: 1.2) demonstrated only a minimal increase in risk. Implant-based reconstruction was associated with a higher risk for complications compared with the other ones (OR: 2.5, p = 0.001). Patient and surgeon aesthetic surveys demonstrated an overall positive opinion in all age groups for each reconstructive option. Conclusion Advanced age should not be considered a risk factor for breast reconstruction, while implant-based technique was associated with a higher risk for complications compared with autologous that may provide older women with greater benefits.
[...]

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

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Innovation in chemotherapy administration process

A Aziz

Indian Journal of Cancer 2016 53(2):331-332

Introduction: This project was started after patient's complaints of increased cost burden on patients with increase stay of patient in hospital for chemotherapy administration for 3–4 days, how to decrease this hospital stay and financial burden and how can we improve services to decrease hospital stay and expedite the process of chemotherapy administration. Methods: A total of 100 patients' confidential files reviewed from February 12, 2013 to May 15, 2013, patients, who were admitted for chemotherapy administration only in inpatient area and all services timings, were reviewed and documented on sheet named as delays chemotherapy sheet, nine processes timings checked against their benchmarks. Results: All services process timings analyzed and compared with their benchmarks, results of all services timings are nearly close to benchmark except lab test results of patients who were admitted without labs test for chemotherapy administration delays seen in collecting blood sample and sending this sample to the laboratory, significant delay is seen in chemotherapy order entry by physician if patient is admitted after 4 p.m. for chemotherapy administration. Delays also identified in administration of chemotherapy. Conclusion: After identifying the reasons of delays in chemotherapy administration, improvement and innovation in chemotherapy administration process done which not only decrease hospital stay, but also decrease the cost of chemotherapy administration.

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Primary gastrointestinal lymphomas in children: An experience of 12 years from a tertiary care center of North India

SK Qadri, A Shah, NH Hamdani, KM Baba

Indian Journal of Cancer 2016 53(2):300-303

Background and Aim: Lymphomas are among the dominant solid tumors in children and primary gastrointestinal lymphomas (PGILs), although rare, are the most common extranodal lymphomas and the most common malignancies affecting the gastrointestinal tract in children. This study was undertaken to analyze childhood PGIL with reference to clinical presentation, anatomic distribution, histopathologic, and immunohistochemical (IHC) characteristics. Materials and Methods: In this 12 year combined retrospective and prospective descriptive study, all the cases of PGIL in children were selected according to Dawson's criteria. Results: A total of 11 cases were found which included 9 boys and 2 girls (male:female - 4.5:1) ranging in age from 1 to 14 years (mean 6.6 years). Abdominal pain (81.8%) and intestinal obstruction (63.6%) were the most common presenting features. Grossly, most of the lesions were ulcero-infiltrative (72.7%) and involved the terminal part of the ileum (36.4%) and ileocecal region (27.3%) most commonly. Histopathologically and IHC, all the cases were high-grade lymphomas of diffuse large B-cell type except for one case of mucosa-associated lymphoid tissue lymphoma. No case of Burkitt's lymphoma was found. Conclusion: PGILs are an important cause of morbidity and mortality in children worldwide with considerable variation in their clinicopathological features and treatment modalities. Only some studies are available in literature for comparison. Further studies are required to define the genetic and molecular basis of the different histopathological pattern found in our setting.

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Microsomal epoxide hydrolase gene polymorphisms and susceptibility to prostate cancer: A systematic review

DSL Srivastava

Indian Journal of Cancer 2016 53(2):213-215

Microsomal epoxide hydrolase (mEH) is a crucial biotransformation enzyme that has capability to metabolize a large number of structurally divergent, highly reactive epoxides, and numerous environmentally exposed carcinogens. It catalyzes the conversion of xenobiotic epoxide compounds into more polar diol metabolites and may play important part of the enzymatic defense against adverse effects of foreign compounds. Most commonly, two functional polymorphisms affecting mEH enzyme activity have been identified: One in exon 3 and other in exon 4 of the mEH gene, which results in His113Tyr and Arg139His amino acid substitutions, respectively. Recent reports have shown that polymorphisms in mEH gene loci may an important risk factor for susceptibility of prostate cancers (PCs), worldwide, but inconsistent finding were also be illustrated. To the best of our knowledge, globally, there is no any systematic review has been published related to mEH gene polymorphisms and PC risk. Thus, in the current review, we have discussed the association between mEH gene polymorphisms, gene–environmental interaction, and PC risk.

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An audit of cytoreductive surgeries in ovarian cancer from a rural based cancer center

SB Dessai, VM Patil, S Chakraborty, S Babu, A Bhattacharjee, S Nayanar, S Vikram, S Balasubramanian

Indian Journal of Cancer 2016 53(2):284-287

Background and Objective: Ovarian cancers are frequently seen at an advanced stage in our center. This audit was planned to see the morbidity and efficacy of different types of cytoreductive surgeries (radical vs. ultra-radical) done in such patients. Methods: This was a retrospective analysis of all ovarian cancer patients who underwent cytoreductive surgery at our center from January 2009 to August 2013. The case records of these patients were reviewed and the demographic, disease-related and treatment-related data were extracted. Results: Fifty-fivepatients were identified. Ten (18.2%) patients underwent primary cytoreduction while 45 patients had (81.8%) interval cytoreduction. The resections achieved were optimal in 50 patients (90.9%) and suboptimal in five patients (9.1%). The postoperative median blood loss was 400 (350–600) mL. The median time interval for surgery was 4.0 h (3–5 h). The type of resection achieved (optimal vs. suboptimal) was the only factor affecting the progression free survival (PFS) (Hazard ratio = 0.08 95% confidence interval 0.02–0.3). There was no significant difference in postoperative morbidity in patients undergoing the ultra-radical surgery as compared to those who underwent radical surgery. Conclusion: Optimal cytoreduction may improve PFS in advanced ovarian cancer patients and needs to be done even if it mandates an ultra-radical surgery.

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Expression of Raf kinase inhibitor protein in human hepatoma tissues by two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight methods

DA Tsao, YF Shiau, CS Tseng, HR Chang

Indian Journal of Cancer 2016 53(2):216-219

Purpose: Hepatocellular carcinoma (HCC) is the most common malignant liver tumor. To reduce the mortality and improve the effectiveness of therapy, it is important to search for changes in tumor-specific biomarkers whose function may involve in disease progression and which may be useful as potential therapeutic targets. Materials and Mehtods: In this study, we use two-dimensional polyacrylamide gel electrophoresis (2-DE) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry to observe proteome alterations of 12 tissue pairs isolated from HCC patients: Normal and tumorous tissue. Comparing the tissue types with each other, 40 protein spots corresponding to fifteen differentially expressed between normal and cancer part of HCC patients. Results: Raf kinase inhibitor protein (RKIP), an inhibitor of Raf-mediated activation of mitogen-activated protein kinase/extracellular signal-regulated kinase, may play an important role in cancer metastasis and cell proliferation and migration of human hepatoma cells. RKIP may be considered as a marker for HCC, because its expression level changes considerably in HCC compared with normal tissue. In addition, we used the methods of Western blotting and real time-polymerase chain reaction to analysis the protein expression and gene expression of RKIP. The result showed RKIP protein and gene expression in tumor part liver tissues of HCC patient is lower than peritumorous non-neoplastic liver tissue of the corresponding HCC samples. Conclusion: These results strongly suggest that RKIP may be considered to be a marker for HCC and RKIP are down-regulated in liver cancer cell.

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Epidemiology of male seminomatous and nonseminomatous germ cell tumors and response to first-line chemotherapy from a tertiary cancer center in India

A Joshi, S Zanwar, N Shetty, V Patil, V Noronha, G Bakshi, G Prakash, S Menon, K Prabhash

Indian Journal of Cancer 2016 53(2):313-316

Introduction: Unlike the developed countries, there is a lack of good epidemiologic data for testicular germ cell tumors (GCTs) in India with majority presenting in advanced stage. This study aims to elaborate on the epidemiology of testicular GCTs and response to standard first-line chemotherapy (CT). Methods: GCTs treated at our center from January 2013 to June 2014 were retrospectively analyzed. Patients underwent orchidectomy either outside or at our hospital. Based on stage and risk group, standard CT (bleomycin, etoposide, and cisplatin/etoposide and cisplatin/carboplatin AUC7) and radiotherapy were given as appropriate. Response was calculated based on the Response Evaluation Criteria in Solid Tumors. Statistical analysis was performed using SPSS 18 software. Results: Fifty nonseminomatous germ cell tumor (NSGCT) and 36 of SGCT cases were studied. 30%, 46%, and 64% of NSGCT and 11%, 28%, and 22% of SGCT had N2, N3, and M1 diseases, respectively. The mean nodal size was 7 cm (1.5–19) in NSGCT and 5.5 cm (1.3–11) in SGCT. As per the International Germ Cell Cancer Collaborative Group classification, in patients with metastatic disease, 9% of NSGCT were good, 53% were intermediate, and 38% were poor risk whereas 75% of SGCT were good and 25% were intermediate risk. Following CT among NSGCT, 5% and 71% had radiologic complete response (CR) and partial response (PR), respectively. Among SGCT, 46% and 38% had radiologic CR and PR, respectively. 22%, 53%, and 13% of NSGCT and 12%, 24%, and 20% of SGCT developed febrile neutropenia, Grade 3 or 4 hematological and nonhematological toxicities, respectively, after standard chemotherapy. Conclusions: GCTs in India present with high nodal and high-risk diseases wherein the standard first-line CT may not be adequate as curative therapy; however, significant chemotoxicity is also a hindrance.

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Clinical and pathologic response following taxane based neoadjuvant chemotherapy in locally advanced breast cancer patients in a tertiary care centre in India

M Siva Sanker, SC Sistla, S Ali Manwar, S Vivekanandam

Indian Journal of Cancer 2016 53(2):220-225

Background: Neoadjuvant chemotherapy has become the standard recommendation in the management of patients with locally advanced breast cancer. At present anthracycline based regimen such as CAF (cyclophosphamide, adriamycin and 5-FU) is widely used in clinical practice. The introduction of taxanes has revolutionized this field because of superior results. Aims and Objectives: This study is designed to compare the efficacy of paclitaxel plus doxorubicin regimen and CAF (cyclophosphamide, doxorubicin and 5-fluorouracil) regimen as neoadjuvant treatment of locally advanced breast cancer and to compare their toxicity profiles and also to correlate the hormonal receptor status in predicting response to the NACT. Materials and Methods: In this prospective study, 101 patients with newly diagnosed locally advanced breast cancer were randomized to receive either CAF or Paclitaxel/adriamycin as NACT for three cycles. The response was assessed objectively using CT scans and applying RECIST criteria. The patients were monitored for hematologic, cardiac and other minor toxicities. Results: There was a significantly increased complete and objective response seen in the AP group when compared to CAF group (24% and 58% in the AP group versus 7.8% and 39.2% in the CAF group, P value 0.0313 for complete response). The pCR rate was also significantly higher in the AP group compared to CAF group. (20.93% versus 4.34%, P value 0.0237). There was no significant difference between the groups with respect to cardiotoxicity and hematotoxicity. Patients with ER negative tumors have responded well to neoadjuvant chemotherapy better than ER positive patients. (Objective response 62.8% vs. 40%, P - 0.0473). Conclusions: Based on these results, taxane based regimen such as Paclitaxel/adriamycin can be recommended as a first line neoadjuvant regimen in patients with locally advanced breast cancer.

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Importance of nutrition in pediatric oncology

R Bhoite

Indian Journal of Cancer 2016 53(2):211-212



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In silico analysis to predict lack of carcinogenicity of Zika virus

B Joob, V Wiwanitkit

Indian Journal of Cancer 2016 53(2):225-225



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Ovarian tumors in children: 10-year experience from a tertiary care center in South India

B Rajeswari, M Nair, A Ninan, K Parukuttyamma

Indian Journal of Cancer 2016 53(2):292-295

Background: Ovarian tumors are uncommon in childhood and constitute around 1% of childhood malignancies. Two thirds of pediatric ovarian tumors are germ cell tumors. Epithelial ovarian tumors and stromal tumors are less frequent. We share our experience in childhood ovarian cancers, analyzing a series of cases with respect to the clinical profile, treatment and survival. Methods: All newly diagnosed ovarian tumors in children up to 14 years of age, registered in our Pediatric Oncology Division between January 2000 and December 2009 were retrospectively reviewed. Observations: There were 47 patients with newly diagnosed ovarian tumors. The mean age at presentation was 10.0 ± 3.4 years. The most common symptoms at presentation were acute abdominal pain (48.9%) and abdominal mass (40.4%). Precocious puberty was uncommon (6.3%). Histology was germ cell tumors in 44 cases and nongerm cell tumors in three cases. The benign teratomas (mature and immature grade 1 and 2; n=9) underwent complete surgical resection alone; none had recurrence on follow up. Of the remaining 35 GCTs, 31 patients were given chemotherapy and 4 refused treatment.26 out of the 31 patients completed chemotherapy with BEP (bleomycin, etoposide, cisplatin) regimen with acceptable toxicities. 5 children i.e.; (19.2%) developed recurrence. At a median follow up of 80 months, 10 year disease free survival was 80.8 ± 7.7% and 10 year overall survival was 92.7 ± 4.9%. Conclusion: Germ cell tumors are the most common ovarian malignancy in children. With surgery and chemotherapy using BEP, good outcome can be expected in these patients.

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Knowledge, attitude and practice about breast cancer and breast self-examination among women seeking out-patient care in a teaching hospital in central India

Rao Siddharth, D Gupta, R Narang, P Singh

Indian Journal of Cancer 2016 53(2):226-229

Background: Breast cancer (BC) continues to be a major cause of morbidity and mortality throughout the world. Early detection of BC and early treatment increases the chance of survival. According to Breast Health Global Initiative guidelines for low and middle income countries, diagnosing BCs early by promoting breast self-awareness; clinical breast examination (CBE) and resource adapted mammographic screening will reduce BC mortality. There is a paucity of data on the knowledge and awareness of BC and self-breast examination in India. We designed this hospital based cross sectional descriptive study to evaluate the current status of knowledge, awareness and practices related to BC and breast self-examination in the female rural population attending a teaching hospital. Materials and Methods: We did a random sampling to identify and enroll 360 women and their female relatives. We excluded a participant from the study if she had already undergone a screening mammography or had had a BC. The data was collected by a self-administered questionnaire in vernacular language. Results: Our study population included 360 women with a mean age of 45.81 (±10.9) years. Only 5 (1.38%) females had a family history of BC. A whopping 81% of women did not have any knowledge about BC. All the women thought that CBE by doctors was the only way for screening BC. Conclusions: We concluded that with the results of this study, it is imperative to increase awareness about BC and its detection methods in the community through health education campaigns. We should have major policy changes to increase future screening programs and health education programs which would have an overall positive impact on reducing the disease burden.

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Place of birth and risk of gallbladder cancer in India

SS Mhatre, RT Nagrani, A Budukh, S Chiplunkar, R Badwe, P Patil, M Laversanne, P Rajaraman, F Bray, R Dikshit

Indian Journal of Cancer 2016 53(2):304-308

Context: Within India, the incidence of gallbladder cancer (GBC) is characterized by marked geographical variation; however, the reasons for these differences are unclear. AIMS: To evaluate the role of place of birth, length of residence, and effect of migration from high- to low-risk region on GBC development. Settings and Design: Population-based cancer registries (PBCRs); case–control study. Subjects and Methods: Data of PBCRs were used to demonstrate geographical variation in GBC incidence rates. A case–control study data examined the role of birth place, residence length, and effect of migration in etiology of GBC. Statistical Analysis: Rate ratios for different PBCRs were estimated using Chennai Cancer Registry as the reference population. Odds ratios (ORs) for developing GBC in a high-risk region compared to a low-risk region and associated 95% confidence interval (CI) were estimated through unconditional logistic regression models using case–control study. Results: GBC shows marked variation in incidence with risk highest in Northeast regions and lowest in South India. OR of 4.82 (95% CI: 3.87–5.99) was observed for developing GBC for individuals born in a high-risk region compared to those born in a low-risk region after adjusting for confounders. A dose–response relationship with increased risk with increased length of residence in a high-risk region was observed (OR lifetime 5.58 [95% CI: 4.42–7.05]; Ptrend ≤ 0.001). The risk persisted even if study participant migrated from high- to low-risk region (OR = 1.36; 95% CI: 1.02–1.82). Conclusions: The present study signifies the importance of place of birth, length of stay, and effect of migration from high- to low-risk region in the development of GBC. The data indicate role of environmental and genetic factors in etiology of disease.

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Presenting features, treatment patterns and outcomes of patients with breast cancer in Pakistan: Experience at a university hospital

S Kumar, AJ Shaikh, YA Rashid, N Masood, ATV Mohammed, UZ Malik, G Haider, N Niamutullah, S Khan

Indian Journal of Cancer 2016 53(2):230-234

Background: Breast cancer is the most common cancer in Pakistani women. We report the presenting features, treatment patterns and survival of breast cancer from a University Hospital in Southern Pakistan and compare the data with international population based studies. Materials and Methods: Medical records of patients diagnosed to have breast cancer between January 1999 and November 2008 were reviewed retrospectively. Results: A total of 845 patients were identified. Median age of diagnosis was 48 years (range 18-92). Clinical stage was as follows: Stage I 9.9%; Stage II 48.5%; Stage III 26.2%; Stage IV 13.8%; data not available 1.5%. Approximately, half (51.6%) were estrogen receptor (ER) positive and 17.5% over-expressed Her2/neu. Nearly 23% patients received neo-adjuvant chemotherapy while 68.9% received adjuvant chemotherapy. Anthracycline based treatment was the most common treatment until 2003 while later on, patients also received taxanes and trastuzumab based therapy. Age, stage, tumor size, lymph node status, tumor grade, ER status, treatment with hormonal therapy and radiation were the major predictive factors for overall survival (OS). We report an impressive 5 year OS of 75%, stage specific survival was 100%, 88% and 58% for Stages I, II and III respectively. Conclusion: The majority of patients present at a younger age and with locally advanced disease. However, short term follow-up reveals that the outcomes are comparable with the published literature from developed countries. Long-term follow-up and inclusion of data from population-based registries are required for accurate comparison.

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Smokeless tobacco use and perceptions of risk among students in Mumbai municipal schools

ML Rose, D Chadha, TD Bhutia

Indian Journal of Cancer 2016 53(2):322-324

Introduction: Nearly 15% of youth in India use tobacco. However, few studies have explored the use, knowledge, and attitudes of smokeless tobacco use among youth. AIM: To determine the patterns of use as well as knowledge and perceptions of smokeless tobacco among youth in Mumbai attending municipal schools. Materials and Methods: A cross-sectional survey was performed among 1053 students in the 8th and 9th grades in 16 municipal schools in Mumbai to determine the knowledge and perceptions about smokeless tobacco products as well as the patterns of use. Results and Conclusions: Ever use of smokeless tobacco was reported by 47 (4.7%) students in the survey. Twenty-nine (2.9%) students reported ever using smoked tobacco. Students were more likely to identify cigarettes and bidis as tobacco products compared to smokeless tobacco products such as gutkha, mishri, and khaini. Betel nut products were used by 178 (17.9%) students. The high rate of smokeless tobacco and betel nut use coupled with low levels of knowledge about their contents and harms suggests that tobacco control programs targeting youth should ensure that these products are adequately explained and understood by students.

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Role of frozen section in the intra-operative margin assessment during breast conserving surgery

KR Anila, K Chandramohan, A Mathews, T Somanathan, K Jayasree

Indian Journal of Cancer 2016 53(2):235-238

Background: Breast conserving surgery (BCS) is increasingly done for early breast cancers in many countries since it has been demonstrated by randomized trials that survival rates after BCS followed by adjuvant therapy are equivalent to those obtained after mastectomy. Frozen section analyses (FSA) is a technique used for intra-operative assessment of margin status in BCS. The aim of this study was to assess the concordance of margin status assessment by FSA and permanent sections and to assess correlation with local recurrence. Materials and Methods: A total of 162 patients underwent BCS for in situ or invasive carcinoma with FSA of margins during the year 2008 at our center. The inclusion criteria in this study were patients with intact tumor at the time of surgery. After application of the inclusion criteria, 60 patients could be included in this study. Results: After frozen section, 20 patients had an initial negative margin. 40 subjects underwent additional excisions at the time of initial surgery because of close or positive margins. Of these 40 patients, in 32 patients a negative margin could be achieved with re-excisions. Pathological analyses of frozen section showed concordance to permanent sections in all cases. At a median follow-up of 40 months, there were no local recurrences. Conclusion: Intra-operative FSA allows resection of suspicious margins at the time of primary conservative surgery and results in low rates of local recurrence and second surgeries. There is good concordance between results of FSA and the final paraffin section in assessing margin status.

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A “Guided” technique for insertion of lumbar cerebrospinal fluid drains

SG Bakshi, NB Praveen, V Patil

Indian Journal of Cancer 2016 53(2):338-338



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Clinico-pathological factors affecting lymph node yield in Indian patients with locally advanced squamous cell carcinoma of mandibular Gingivo-Buccal sulcus

SS Muttagi, BR Patil, AS Godhi, DK Arora, SR Hallikerimath, AD Kale

Indian Journal of Cancer 2016 53(2):239-243

Aim: Lymph node yield (LNY) is a valid marker of prognosis in oral cancer. Precise estimation of LNY in Indian patients with T3/T4 gingivobuccal sulcus squamous cell carcinoma (GBS-SCC) has not been well documented. Hence, the primary objective of the study was to determine the LNY in patients with T3/T4 SCC of mandibular GBS, and the secondary objective was to study the association of LNY with clinicopathological factors such as tumor thickness, histological differentiation, number of positive nodes, and extracapsular spread (ECS). Materials and Methods: Study patients comprised biopsy proven T3/T4 SCC of mandibular GBS that underwent unilateral surgery (composite or bite composite resection with level I to level V-neck dissection and pectoralis major flap reconstruction) at our center between January 2012 and October 2014. Grossing of surgical specimens was done as per the guidelines established by the Royal College of Pathologists (December 2009). The data were analyzed using SPSS software (22nd version) and Chi-square test. Results: The surgical specimens of 106 patients yielded 2329 lymph nodes with the mean LNY of 21.97 ± 5.57. Higher mean LNY of over 21 was significantly associated with ECS, number of positive nodes, delay in surgery over 15 days, skin involvement by the tumor, and presence of oral potentially malignant disorders. Conclusion: With the single surgeon, pathologist and same surgical procedure, the mean LNY in Indian patients with T3/T4 SCC of mandibular GBS is 21.97 ± 5.57. Although clinicopathological factors affect the estimation of LNY, further studies are needed to validate the findings of this study.

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Tolerance of weekly paclitaxel and carboplatin as neoadjuvant chemotherapy in advanced ovarian cancer patients who are unlikely to tolerate 3 weekly paclitaxel and carboplatin

SB Dessai, S Chakraborty, TVS Babu, S Nayanar, A Bhattacharjee, J Jones, S Balasubramanian, VM Patil

Indian Journal of Cancer 2016 53(2):280-283

Objective: There are little data regarding safety and effectiveness of neoadjuvant chemotherapy (NACT) in patients who are considered unfit for receiving 3 weekly paclitaxel and carboplatin. The aim of this study was to study the toxicity and response rates of weekly paclitaxel and carboplatin as NACT in such cohort of patients. Methods: Study population included advanced ovarian cancer patients who were unlikely to tolerate 3 weekly paclitaxel and carboplatin and hence received weekly paclitaxel (80 mg/m2) and carboplatin AUC-2 as NACT. The data regarding the baseline characteristics, chemotherapy tolerance, completion rates, toxicity (CTCAE version 4.02), and radiological response rates are presented. SPSS version 16 was used for analysis. Descriptive statistics is presented. Result: Eleven patients received this schedule. Nine patients completed nine cycles of NACT. Except one, all patients completed NACT with an average relative dose intensity of >0.8. There was no chemotherapy-related mortality. Grade 3–4 life-threatening complications were seen in two patients. The post NACT response rate was 100%. Conclusion: Weekly paclitaxel and carboplatin chemotherapy is safe and efficacious in patients who are unsuitable for 3 weekly paclitaxel and carboplatin chemotherapy schedules.

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Role of regional catheters for postoperative analgesia following reconstructive surgeries for breast cancer

SG Bakshi, S Pokhale, S Sharma

Indian Journal of Cancer 2016 53(2):243-243



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Clinical characteristics with patterns of relapse and survival analysis of ovarian clear cell carcinoma

S Kaur, RA Kerkar, A Maheshwari, TS Shylasree, S Gupta, K Deodhar

Indian Journal of Cancer 2016 53(2):288-291

Aims: To analyze clinical characteristics, patterns of relapse, and treatment outcomes of clearcell carcinoma of the ovary (CCO). Materials and Methods: Case files of 51 patients diagnosed with CCO between 2003 and 2010 were reviewed. Results: The median age at diagnosis was 48 years (27-64 years). Fifty percent presented with nonspecific gastrointestinal symptoms. The median serum Ca125 was 74 IU/ml (6-1567 U/ml). Optimal cytoreduction was achieved in 32 (62.7%) patients. Of the 51 patients in this series, 34 (66.6%) had Stage I disease; Stage Ia in 12 (23.6%), Stage Ib in 1(1.9%), and Stage Ic in 21 (41.1%). Thirteen (25.6%) presented with Stage III and 4 (7.8%) with Stage IV. No patient had Stage II disease. All patients received 4-6 cycles of platinum-based combination chemotherapy. There were 18 relapses (35.2%), with disease-free intervals <6 months in 9, 6-12 months in 4, and >12 months in 5, respectively. Of them 33.3% had a recurrent pelvic mass. The median survival after relapse was 14 months. There were 13 deaths, 11 due to disease progression, 1 due to chemo toxicity, and 1 unrelated to disease. At a median follow up of 28 months, disease-free survival (DFS) and overall survival (OS) of patients with Stage I-Stage II (early) disease was 64% and 80%, respectively. In patients with advanced disease, that is, Stages III and IV, DFS and OS were 35% and 38%, respectively. Conclusion: CCO generally presents at an early stage but has a high propensity for relapse. Patients with early-stage disease have a relatively good prognosis as compared with those with advanced-stage disease.

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Annals of Cardiac Anesthesia: Beacon journey toward excellence: 2015-2017

Poonam Malhotra Kapoor

Annals of Cardiac Anaesthesia 2017 20(1):1-3



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Demonstration of blood flow by color doppler in the femoral artery distal to arterial cannula during peripheral venoarterial-extracorporeal membrane oxygenation

KG Suresh Rao, T Muralikrishna, KR Balakrishnan

Annals of Cardiac Anaesthesia 2017 20(1):108-109



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Anesthesiology and the difficult airway - Where do we currently stand?

Martina Richtsfeld, Kumar G Belani

Annals of Cardiac Anaesthesia 2017 20(1):4-7



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Outcome of four pretreatment regimes on hemodynamics during electroconvulsive therapy: A double-blind randomized controlled crossover trial

Devangi Ashutosh Parikh, Sanchita Nitin Garg, Naina Parag Dalvi, Priyanka Pradip Surana, Deepa Sannakki, Bharati Anil Tendolkar

Annals of Cardiac Anaesthesia 2017 20(1):93-99



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Comparison of two doses of heparin on outcome in off-pump coronary artery bypass surgery patients: A prospective randomized control study

Murali Chakravarthy, Dattatreya Prabhakumar, Patil Thimmannagowda, Jayaprakash Krishnamoorthy, Antony George, Vivek Jawali

Annals of Cardiac Anaesthesia 2017 20(1):8-13



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Iatrogenic vocal cord paralysis after cardiac surgery: evocative note for surgeon and anesthesiologist

Monish S Raut, Sumir Dubey, Arun Maheshwari

Annals of Cardiac Anaesthesia 2017 20(1):117-118



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Extracorporeal membrane oxygenation in severe influenza infection with respiratory failure: A systematic review and meta-analysis

Shashvat Sukhal, Jaskaran Sethi, Malini Ganesh, Pedro A Villablanca, Anita K Malhotra, Harish Ramakrishna

Annals of Cardiac Anaesthesia 2017 20(1):14-21



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Goal-directed therapy improves the outcome of high-risk cardiac patients undergoing off-pump coronary artery bypass

Poonam Malhotra Kapoor, Rohan Magoon, Rajinder Singh Rawat, Yatin Mehta, Sameer Taneja, R Ravi, Milind P Hote

Annals of Cardiac Anaesthesia 2017 20(1):83-89



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Incidence and progression of cardiac surgery-associated acute kidney injury and its relationship with bypass and cross clamp time

Habib Md Reazaul Karim, Mohd Yunus, Manuj Kumar Saikia, Jyoti Prasad Kalita, Mrinal Mandal

Annals of Cardiac Anaesthesia 2017 20(1):22-27



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An unusual cause of postpartum heart failure

Ibrahim Khaddash, Amer Hawatmeh, Zaid Altheeb, Aiman Hamdan, Fayez Shamoon

Annals of Cardiac Anaesthesia 2017 20(1):102-103



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Selection of an appropriate left-sided double-lumen tube size for one-lung ventilation among Asians

Siti Salwani Ideris, Muhamad Rahimi Che Hassan, Mohd Ramzisham Abdul Rahman, Joanna Su Min Ooi

Annals of Cardiac Anaesthesia 2017 20(1):28-32



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Nucleic acid-based methods for early detection of sepsis

Sarvesh Pal Singh

Annals of Cardiac Anaesthesia 2017 20(1):112-113



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Remifentanil prevents increases of blood glucose and lactate levels during cardiopulmonary bypass in pediatric cardiac surgery

Tomohiro Chaki, Yuko Nawa, Keishi Tamashiro, Eri Mizuno, Naoyuki Hirata, Michiaki Yamakage

Annals of Cardiac Anaesthesia 2017 20(1):33-37



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Percutaneous tracheostomy

Yatin Mehta, Chitra Mehta

Annals of Cardiac Anaesthesia 2017 20(1):121-121



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Assessment of limited chest x-ray technique in postcardiac surgery management

Mehrdad Salehi, Kianoush Saberi, Mehrzad Rahmanian, Ali Reza Bakhshandeh, Shahnaz Sharifi

Annals of Cardiac Anaesthesia 2017 20(1):38-41



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Delirium after cardiac surgery: A pilot study from a single tertiary referral center

Ashok K Kumar, Aveek Jayant, VK Arya, Rohan Magoon, Ridhima Sharma

Annals of Cardiac Anaesthesia 2017 20(1):76-82



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Acute effect of treatment of mitral stenosis on left atrium function

Atooshe Rohani, Shahram Kargar, Afsoon Fazlinejad, Fereshte Ghaderi, Vida Vakili, Homa Falsoleiman, Ramin Khamene Bagheri

Annals of Cardiac Anaesthesia 2017 20(1):42-44



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Prayer sign as a marker of increased ventilatory hours, length of intensive care unit and hospital stay in patients undergoing coronary artery bypass grafting surgery

Tanveer Singh Kundra, Parminder Kaur, N Manjunatha

Annals of Cardiac Anaesthesia 2017 20(1):90-92



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Comparative effect of grape seed extract (Vitis vinifera) and ascorbic acid in oxidative stress induced by on-pump coronary artery bypass surgery

Naser Safaei, Hossein Babaei, Rasoul Azarfarin, Ahmad-Reza Jodati, Alireza Yaghoubi, Mohammad-Ali Sheikhalizadeh

Annals of Cardiac Anaesthesia 2017 20(1):45-51



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