Cardiac Review and Evaluation Committee criteria for the diagnosis of cardiac dysfunction. Adapted from Seidman, et al. (2002). Cardiac dysfunction in the trastuzumab clinical trials experience. Journal of Clinical Oncology, Vol. 20, pp. 1215 – 1221
\r\n\t
",isbn:"978-1-83968-571-2",printIsbn:"978-1-83968-570-5",pdfIsbn:"978-1-83968-599-6",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,hash:"dd81bc60e806fddc63d1ae22da1c779a",bookSignature:"Dr. Sebahattin Demirkan and Dr. Irem Demirkan",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10818.jpg",keywords:"Decision Making, Blockchain, Accounting, Earnings Management, Strategic Alliances, Innovation, Performance, Corporate Governance, Accounting Quality, Digital Assets, Internationalization, MNCs",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"January 28th 2021",dateEndSecondStepPublish:"February 25th 2021",dateEndThirdStepPublish:"April 26th 2021",dateEndFourthStepPublish:"July 15th 2021",dateEndFifthStepPublish:"September 13th 2021",remainingDaysToSecondStep:"6 hours",secondStepPassed:!1,currentStepOfPublishingProcess:2,editedByType:null,kuFlag:!1,biosketch:"Academician in the area of accounting who believes in the impact of interdisciplinary research. Dr. Sebahattin Demirkan's research interests are in the areas of financial accounting, capital markets, auditing, corporate governance, strategic alliances, taxation, CSR, and data analytics.",coeditorOneBiosketch:"Researcher of strategic management, corporate entrepreneurship, and international business; specific interests include innovation, the ambidexterity framework, inter-organizational relationships, and networks. Experienced in teaching graduate and undergraduate courses in strategy, entrepreneurship, and international business and management areas.",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"336397",title:"Dr.",name:"Sebahattin",middleName:null,surname:"Demirkan",slug:"sebahattin-demirkan",fullName:"Sebahattin Demirkan",profilePictureURL:"https://mts.intechopen.com/storage/users/336397/images/system/336397.jpg",biography:"Dr. Sebahattin Demirkan is a Professor of Accounting. He earned his Ph.D. in Accounting/Management Science at Jindal School of Management of the University of Texas at Dallas where he got his MS in Accounting, MSA Supply Chain, and MBA degrees. He got his BA in Economics and Management at the Faculty of Economics and Administrative Sciences at Bogazici University, Istanbul. He worked at Koc Holding, a private venture capital firm, and the University of California, Berkeley during and after his education at Bogazici University. His research interests are in the areas of financial accounting, capital markets, auditing, corporate governance, strategic alliances, taxation, CSR, and data analytics. Dr. Sebahattin Demirkan has published articles in Contemporary Accounting Research, JAPP, JAAF, TEM, Journal of Management, and other top academic journals. He teaches several different classes in both undergraduate and graduate levels in Accounting and Analytics programs. He is a treasurer and vice president of the TASSA, board member of the BURCIN and member of the American Accounting Association.",institutionString:"Manhattan College",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Manhattan College",institutionURL:null,country:{name:"United States of America"}}}],coeditorOne:{id:"342242",title:"Dr.",name:"Irem",middleName:null,surname:"Demirkan",slug:"irem-demirkan",fullName:"Irem Demirkan",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000033HrA8QAK/Profile_Picture_1606729803873",biography:"Dr. Irem Demirkan earned her Ph.D. in International Management Studies and M.S. in Administrative Studies at Jindal School of Management at the University of Texas at Dallas, USA. She got her BA in Economics at the Faculty of Economics and Administrative Sciences at Bogazici University, Istanbul, Turkey. She worked in the finance and textile industries before joining to academia. Dr. Demirkan has published research in the areas of strategic management and corporate entrepreneurship in journals such as the Journal of Management, Journal of Business Research, Management Science, European Journal of Innovation and Management, IEEE Transactions on Engineering Management, among others. Dr. Demirkan currently teaches strategic management, entrepreneurship, and international business at Loyola University Maryland in Baltimore, MD.",institutionString:"Loyola University Maryland",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Loyola University Maryland",institutionURL:null,country:{name:"United States of America"}}},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"7",title:"Business, Management and Economics",slug:"business-management-and-economics"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"301331",firstName:"Mia",lastName:"Vulovic",middleName:null,title:"Mrs.",imageUrl:"https://mts.intechopen.com/storage/users/301331/images/8498_n.jpg",email:"mia.v@intechopen.com",biography:"As an Author Service Manager, my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3621",title:"Silver Nanoparticles",subtitle:null,isOpenForSubmission:!1,hash:null,slug:"silver-nanoparticles",bookSignature:"David Pozo Perez",coverURL:"https://cdn.intechopen.com/books/images_new/3621.jpg",editedByType:"Edited by",editors:[{id:"6667",title:"Dr.",name:"David",surname:"Pozo",slug:"david-pozo",fullName:"David Pozo"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"32613",title:"Trastuzumab and Cardiotoxicity",doi:"10.5772/34093",slug:"trastuzumab-and-cardiotoxicity",body:'\n\t\tIn the last two decades relevant improvements have been achieved in cancer therapy with a significant increase in overall survival. However these achievements have also been accompanied by a rise in the occurrence of side effects involving several organs, in particular the cardiovascular system. Indeed, the incidence of cardiotoxicity is continuously growing which can vanish the effectiveness of cancer therapy.
\n\t\t\tBreast cancer is the second most common form of cancer in women and the leading cause of death caused by malignancy. Over the past 25 years, breast cancer incidence has risen globally, with the highest rates in industrialized countries. However, the survival rate of cancer patients has greatly increased because of early detection through screening, as well as improvement in pharmacologic treatment. Women are, therefore, now living sufficiently long for delayed consequences of treatment to become increasingly evident.
\n\t\t\tApproximately 20-25% of breast cancer overexpresses the human epidermal growth factor receptor II (HER-2). Amplification of HER-2 gene confers aggressive behavioral traits on breast cancer cells, including incresead growth and proliferation, enhanced invasiveness and metastatic capability. (Slamon, 1987)
\n\t\t\tHER-2 is a transmembrane tyrosine kinase receptor and a member of the epidermal growth factor receptor (EGFR) family,and regulate many important cell-type specific functions, particularly cell growth, proliferation and survival. (Slamon, 1987, Chien, 2006)
\n\t\t\tThe use of trastuzumab (a humanized monoclonal antibody against HER-2 receptor) has changed the natural history of patients with HER-2 positive breast cancer. In the metastatic setting, the combination of trastuzumab plus chemotherapy has significantly improved survival, response rate, time to progression, and quality of life when compared with standard chemotherapy (Slamon 1987, 2001, Vogel, 2002). In the adjuvant setting, the use of trastuzumab decreased the risk of recurrence and death (Buzdar, 2005). Given these impressive results, trastuzumab has become the standard of care for treatment of patients with HER-2 positive breast cancer.
\n\t\t\tAlthough trastuzumab is devoid of the classical toxicities related with cancer treatment, one of major concerns noted is the occurrence of symptomatic and asymptomatic cardiac dysfunction. In fact, this treatment showed to be associated with an increased incidence of heart failure that ranged from 4.1% in the adjuvant setting to 27% in patients with metastatic disease who received concurrent anthracycline therapy (Perez E., 2004). Early identification of patients at risk for cardiotoxicity is a major challenge for both cardiologists and oncologists, for the definition of more tailored antineoplastic therapeutic interventions. The use of cardiac biomarkers such as BNP, N-terminal pro-BNP, and troponin I, has been suggested as a method for early detection of cardiotoxicity. Also, newer measurements of LV function such as strain, strain rate and speckle tracking may be sensitive tools to detect myocardial dysfunction before changes in EF are evident, possibly identifying at-risk patients at an earlier stage.
\n\t\tBased in substantial improvement achieved with trastuzumab in the trials performed, US Food and Drug Administration approved in 1998 this agent for the treatment of metastatic breast cancer. Indeed, in phase 2 trial was found an objective response in 12% of patients. (Baselga et al., 1996) These benefits were further confirmed in larger phase 2 and phase 3 trials (Cobleigh et al., 1999, Slamon et al., 2001). The phase 3 trial was design to compare a conventional chemotherapy regime with and without additional trastuzumab treatment. The data demonstrated that trastuzumab association to chemotherapy produced substantial response rate, improvement in time to disease progression, as well as reduction in 1-year mortality. (Slamon et al., 2001)
\n\t\t\t\tSince 2006 the use of trastuzumab has been extended to treat HER-2 positive early breast cancer patients. Five major randomized trials (Herceptin Adjuvant trial - HERA, National Surgical Adjuvant Breast and Bowel Project - NSABP B-31, North Central Cancer Treatment Group - NCCTG N9831, Breast Cancer International Research Group – BCIRG 006 and Finland Herceptin trial - FinHer) have proven the benefit of adjuvant trastuzumab in early breast cancer patients. More than 11 000 patients were enrolled and treatment with trastuzumab led to about 50% improvement in disease-free survival and 33% improvement in overall survival. (Romond et al., 2005, Piccart-Gebhart et al., 2005, Tan-Chiu et al., 2005, Slamon et al., 2005, Joensuu et al., 2006).
\n\t\t\t\tThus, concurrent treatment with trastuzumab is actually the standard of care for patients with early HER-2 positive breast cancer.
\n\t\t\tA precise definition of cardiotoxicity is still lacking. The Cardiac Review and Evaluation Committee supervising trastuzumab trials created a practical and easily applicable definition, which considered chemotherapy-induced cardiotoxicity as one or more of the following: 1) cardiomyopathy characterized by a decrease in LVEF, either global or more severe in the septum, 2) heart failure (HF) symptoms, 3) signs associated with HF, such as S3 gallop, tachycardia, edema, 4) decline in initial LVEF of at least 5% to less than 55% with accompanying signs or symptoms of HF, or asymptomatic decrease in LVEF in the range of equal to or greater than 10% to less than 55% (Seidman, 2002). (Table 1)
\n\t\t\t\t1.Cardiomyopathy characterized by a decrease in LVEF or changes of contraction most apparent in the interventricular septum 2.Heart failure symptoms 3.Signs associated with heart failure 4.Decline in initial LVEF of at least 5% to less than 55% with signs and symptoms of heart failure or asymptomatic decrease in LVEF of at least 10% to less than 55% | \n\t\t\t\t\t\t
Cardiac Review and Evaluation Committee criteria for the diagnosis of cardiac dysfunction. Adapted from Seidman, et al. (2002). Cardiac dysfunction in the trastuzumab clinical trials experience. Journal of Clinical Oncology, Vol. 20, pp. 1215 – 1221
Cardiotoxicity can develop in a subacute, acute, or chronic manner:
\n\t\t\t\tAcute or subacute cardiotoxicity develop during the treatment period up to 2 weeks after therapy. It is characterized by electrocardiographic abnormalities such as QT-intervals changes, ventricular repolarization abnormalities, supraventricular and ventricular arrhythmias or by acute heart failure, pericarditis, myocarditis or acute coronary syndromes.
Chronic cardiotoxicity is the most frequent and feared form. It can be divided in 2 groups according to the timing of symptoms onset: early, when occur in the first year after treatment and late when manifests more than 1 year after chemotherapy. The most common feature of chronic cardiotoxicity is asymptomatic systolic left ventricular dysfunction that can further lead to congestive HF. The incidence of this type of cardiotoxicity depends on several factors such as, total administered dose of chemotherapy, time of follow-up, age, history of previous cardiac disease, previous mediastinal radiation, as well as on the criteria used for cardiotoxicity assessment, ranging in different studies from 5% to 65% of patients. (Dolci, 2008, Pai, 2000).
The classic example of cardiotoxicity from anticancer treatment is anthracycline-related cardiomyopathy that remains the most common cardiotoxic chemotherapy agent. However many other agents can cause cardiotoxicity, namely the monoclonal antibody trastuzumab.
\n\t\t\t\tThe development of chemotherapy-induced cardiomyopathy has significant implications. It has not only a negative impact on the cardiac outcome of cancer patients, but also limits their therapeutic options.
\n\t\t\tCardiotoxicity was an unexpected finding in the phase 3 trials, as early clinical trials provided little or no indication of trastuzumab-induced cardiomyopathy. Although heart failure was seen in some patients enrolled in phase 2 trials, the rate of occurrence was low and patients were at increased risk due to previous anthracycline treatment. Subsequent reports of trastuzumab-related cardiotoxicity in the phase 3 combination chemotherapy trials prompted a retrospective analysis of seven phase 2 and 3 trastuzumab trials by an independent Cardiac Review and Evaluation Committee (CREC). (Seidman, Hudis, & Pierri, 2002) An accurate assessment of cardiotoxicity in these trials has proved difficult because their design was different in what concerns the number of patients, definition of cardiotoxicity, analysis of end points and duration of follow-up. CREC used a new set of criteria to define cardiotoxicity (Table 1) and events were also classified by the New York Heart Association (NYHA) functional classification system. Data from 1219 patients enrolled in those 7 trials were retrospectively analyzed and cardiotoxicity was detected in 112 patients (9.2%). The incidence of trastuzumab-induced cardiomyopathy ranged from 1% to 27% in different arms of trials and was higher when trastuzumab and anthracyclines were used concurrently (Seidman, Hudis, & Pierri, 2002)(Table 2)
\n\t\t\t\tRetrospective analysis conducted by the Cardiac Review and Evaluation Committee of seven studies to detect trastuzumab-related cardiotoxicity. Adapted from Keefe DL (2002). Trastuzumab-associated cardiotoxicity. Cancer, Vol. 95, pp. 1592-1600AC=anthracycline plus cyclophosphamide, CD=cardiac dysfunction, NYHA=New York Heart
Concerns about cardiotoxicity, together with the remarkable tumor response to this therapy, served as an impetus for several large trials collectively known as the trastuzumab adjuvant trials, which incorporate appropriate cardiac monitoring (Buzdar,2005, Perez, 2004, Cobleigh, 1999, Slamon 2001, Romond, 2005). The study protocol in these trials determined baseline assessment of LVEF using echocardiogram or myocardial scintigraphy and the exclusion of patients with impaired cardiac function, high doses of cumulative anthracycline exposure, and previous history of heart disease. Data from these trials are summarized in Table 3.
\n\t\t\t\tSummary of trastuzumab-induced cardiotoxicity from adjuvant trials. Adapted form Popat & Smith. (2008). Therapy insight: anthracyclines and trastuzumab – the optimal management of cardiotoxic side effects. Nature Clinical Practice, Vol. 5, pp. 324-335
In the combined analysis of NCCTG N9831 and NSABP B-31 trials (administration of trastuzumab concurrent with adjuvant taxanes after anthracycline chemotherapy), was found that trastuzumab was withdrawal before 52 weeks in 31.4% of patients treated. In 14.2% of them was due to asymptomatic LVEF decline and in 4.7% due to HF symptoms (Romond et al., 2005). The 3-year cumulative incidence of NYHA class III or IV HF or death from cardiac causes reported in N9831 trial was 2.9% in the trastuzumab group, compared to 0% in the control group. In B-31 trial this endpoint was detected in 4.1% in those treated with trastuzumab and 0.8% in the control group. Twenty-seven patients from the total of 31 women who developed trastuzumab-induced cardiomyopathy, were followed for at least 6 months and only 1 patient had persistent symptoms of heart failure. (Slamon, 2001) These results were subsequently analysed by an independent group of reviewers that constituted the Adjuvant Cardiac Review and Evaluation Committee (ACREC) (Seidman, 2002). This independent review confirmed earlier risk estimates by showing that the concurrent use of trastuzumab and anthracycline based chemotherapy, increased the rate of congestive heart failure (CHF) nearly four-fold, from 0.45% to 2.0%, at a median follow-up of 1.9 and 2.0 years, respectively.
\n\t\t\t\tIn HERA trial (Perez, 2004) was reported a smaller number of cardiac events compared with B-31 and N9831 studies. This trial is a three-group, randomized trial that compared 1 year or 2 years of trastuzumab with observation in women with HER-2 positive early breast cancer. The overall rate of trastuzumab withdrawal due to safety issues was 6.8%, with 4% stopping the treatment due to cardiac issues. The rate of symptomatic CHF was 2% in the trastuzumab group and 0.2% in the control group, with NYHA class III or IV CHF occurring in 0.6% of patients receiving trastuzumab and 0% of the control group. An asymptomatic or mildly symptomatic decline in LVEF was seen in 7.4% of women on trastuzumab and 2.3% of controls (Perez, 2004, Seidman, 2002). The overall risk of severe CHF reported in HERA was lower than that in B-31 (0.6% versus 4%) as was the proportion of patients who discontinued trastuzumab due to cardiac issues. The explanation for these differences is not clearly established, but we can speculate that it may be due to the longer interval between stopping anthracyclines and initiating trastuzumab or to the inclusion criteria that determined a LVEF≥55% in HERA trial compared to 50% for N9831/B-31 trials.
\n\t\t\t\tAn aspect of interest in the BCIRG trial is that one arm of this study did not include concomitant or sequential therapy with anthracyclines. This fact permitted the assessment of the true effect of trastuzumab on the heart without having to adjust for previous anthracycline lesion, that otherwise interfere with interpretation of cardiotoxicity. The incidence of NYHA class III or class IV CHF was 5.1-fold greater in the anthracycline group than in the nonanthracycline arm (1.96% versus 0.38%) and the number of patients with LVEF decline of more than 10% from baseline was 19% and 9%, respectively.
\n\t\t\tCardiotoxicity came to the forefront of concerns over chemotherapy in the early 1970s, when was detected a cumulative dose-related cardiac dysfunction was detected related with anthracycline treatment.
\n\t\t\t\tThis agent produces a cardiac dysfunction identified as type I, characterized by ultrastructural abnormalities, morphological cellular (vacuoles, myofibrillar disarray and dropout, necrosis) and heart (dilated cardiomyopathy) changes and subsequent clinical evident dysfunction. (Billingham, 1978, Lefrak, 1973, Billingham, 1978) It is dose-related and virtually irreversible. Described methods to minimize type I cardiotoxicity include prolonged infusional administration schedules (Legha, 1982) and use of the free-radical scavenger dexrazoxane (Swain, 2004). Additionally, liposomal delivery, are being studied liposomal delivery systems (Ewer, 2002 ) and less-toxic analogs and less toxic analogs are being study.
\n\t\t\t\tIn contrast, type II cardiac dysfunction associated with trastuzumab therapy does not seem to cause any ultrastructural change, while a myocardial dysfunction under cardiac stress is present. (Ewer, 2005) Other specific features are: it seems not to be dose-related, it increases when trastuzumab is given concurrently with anthracyclines, it seems to be reversible, and normal cardiac function may be restored with medical management of heart failure (Seidman, 2002, Valero, 2004, Perez, 2004, Ewer, 2008). Table 4 compares type I and type II chemotherapy-related cardiac dysfunction.
\n\t\t\t\tChemotherapy-related cardiac dysfunction. Reprinted from Ewer & Lippman (2005).Type II chemotherapy-related cardiac dysfunction: time to recognize a new entity. Journal of Clinical Oncology, Vol. 23, pp. 2900-2902
The mechanisms of type I and type II cardiac dysfunction are complex and distinct. Type I cardiotoxicity is due, predominantly to iron-based oxygen free-radical that induce oxidative stress on cardiac cells. These free radicals produce peroxidation of myocyte membranes and subsequent influx of intracellular calcium, accelerated degradation of key sarcomeric protein and disruption of new sarcomere protein synthesis. (Valero, 2004, Ewer, 2002)
\n\t\t\t\tThe molecular basis of type II chemotherapy related cardiac dysfunction is beginning to be elucidated (Speyer, 2002, Crone, 2002, Ozcelik, 2002, Sawyer, 2002, Negro, 2004). The mechanism of trastuzumab induced cardiotoxicity involves, at least in part, the ErbB2 pathway. This agent binds to the extracellular domain of the HER-2 protein and thus blocks ErbB2 signalling required for the growth, repair, and survival of cardiac cells. (Negro, 2004) ErbB2 signalling is highly complex, involving multiple ligand classes, cell systems, and pathway interactions. Of those actions, activation of the transcription factor nuclear-B (NF-B) seems to play an important rule. Indeed the NF-B pathway is also involved in cardiac cells under stress, such as in myocardial infarction and hypertension and it seems to be essential in restoring the reperfusion after ischemia and also in reducing apoptosis. (Feldman, 2007).
\n\t\t\t\tEvidence supports a critical role for neuregulin 1 (NRG1) signalling through HER-2/HER-4 heterodimerization in cardiomyocyte survival pathways and maintenance of function. (Sawyer, 2002) NRG1 is produced by cardiac endothelial cells, binds HER-4 on cardiomyocytes and leads to heterodimerization with HER-2, with consequent activation of diverse intracellular signalling pathways, such as the PI3-kinase/AKT and MAP kinase pathways. Mouse models have given important contributes to these discovers. Mice with HER428 and NRG131 knockouts are both embryonically lethal.
\n\t\t\t\tMoreover, the essential role of HER-2 in maintenance of cardiac contractile function and structure and the possible protective effect provided by HER-2 was shown in a mouse model with a cardiac-restricted conditional HER-2 deletion mutant. Indeed, these mice stayed alive, but developed a dilated cardiomyopathy. (Negro, 2004, Crone, 2002, Ozcelik, 2002) This model provided support to the hypothesis that cardiac lesion related to trastuzumab is the result of direct targeting and inhibition of the HER-2 receptor, rather than immune-mediated or non-cardiac effects. Additionally, these mice were also sensitized to develop an anthracycline-induced cardiac dysfunction reflecting that seen clinically.
\n\t\t\t\tInhibition of the previous described pathways after an insult such as anthracycline treatment could thus interfere with the heart’s repair mechanisms. Indeed, de Kort et al. (2007) showed that myocardial HER-2 is upregulated in humans shortly after anthracycline exposure, providing support for the vulnerable-window hypothesis. (Fig 1.)
\n\t\t\t\tA) Simplified flow diagram of myocyte injury after anthracycline administration. Cell death is preceded by a period of vulnerability during which cell repair may take place. (B) The addition of trastuzumab inhibits cell repair compounding the loss of cardiac myocytes. HER2= human epidermal growth factor receptor 2. Reprinted from Ewer, M. (2010). Troponin I Provides Insight Into Cardiotoxicity and the Anthracycline-Trastuzumab Interaction. Journal of Clinical Oncology, Vol. 28, No. 25, pp 3901-3909
Although inhibition of HER-2 signalling seems to be a central mechanism of trastuzumab-related cardiomyopathy, the pathophysiologic mechanism is likely more complex. Indeed early clinical results with lapatinib, an oral tyrosine kinase inhibitor, show minimal cardiotoxicity. (Geyer, 2006) Actually the explanation for this paradox is not sufficiently clear and remains an area of intense investigation. It is suggested that the difference between the two drugs may be explained by trastuzumab effect on adenosine triphosphate (ATP) depletion. Cardiac cells need an important quantity of ATP molecules and thus an agent that interferes with mitochondrial activity has the potential of alter normal myocyte function by decreasing the energy source. (Menendez, 2007) The binding between erbB2 and a specific antibody can unbalance BCL-XL/BCL-XS, leading to depolarization of the mitochondrial membrane potential, with reduction of ATP and subsequent alteration of contractility (Force, 2007).
\n\t\t\tThe most established risk factors for the development of trastuzumab-induced cardiotoxicity are age > 50 years and concurrent or prior exposure to anthracycline chemotherapy (Perez, 2004, Pinder, 2007). Based on data of the NSABP B-31 trial (Tan-Chiu, et al., 2005), baseline LVEF < 55% and post-chemotherapy LVEF < 55% were also considered as significant risk factors. Current or previous treatment with antihypertensive medication and a body mass index (BMI) >25 have been shown to increase the risk of cardiotoxicity in some trials, but the results are not uniform or consistent. Prior radiotherapy to a left-sided breast cancer, race or history of smoking were not associated to a increased risk of cardiac toxicity during trastuzumab treatment.
\n\t\t\t\tOne important aspect is that clinical trials are limited to women under 65 years old and with a good performance status (Hutchins, 1999). Thus, trastuzumab safety data only apply to a relatively young and healthy group of patients. As the incidence of cancer increases greatly with age and more than 70% of all newly diagnosed cancers are in patients >65 years, information about efficacy and safety of chemotherapy is needed in this population. This was the impetus of a recent study by C. Serrano et al (Serrano, 2011) that intended to assess the cardiac safety profile and potential cardiac risk factors associated with trastuzumab in breast cancer patients >70 years. The records of forty-five women between the ages of 70 and 92 were evaluated and was found a significantly increased incidence of cardiac events among patients with a history of cardiac disease (heart failure, arrhythmias, myocardial ischemia, or valvular heart disease) and diabetes. The overall incidence of cardiac events was 26.7%, and in 8.9% of them it was clinically evident. Thirty-three percent of women with known history of heart disease developed either asymptomatic or symptomatic cardiotoxicity compared to 9.1% with no previous cardiac disease (p=0.01). Additionally, 33.3% of diabetic women developed cardiac dysfunction compared to only 6.1% without diabetes. However, it is important to be cautious when interpreting these data given the small sample size and the very limited power to detect small differences in multivariate analysis.
\n\t\t\t\tIn patients being simultaneous treated with anthracyclines and trastuzumab the probability of develop cardiotoxicity increases after a cumulative dose of doxorubicin superior to 300 mg/m2 (Perez, 2004). The sequence in which chemotherapy agents are administered seem to influence the development of cardiac dysfunction. When anthracyclines and trastuzumab were administered simultaneously, the incidence of NYHA class III or IV HF was 16%. (Slamon, 2001). The interval between administration of anthracycline and trastuzumab was about 3 weeks in the NSABP B-31 and BCIRG 006 trials, and it was showed an incidence of class III or IV CHF of 4.1% and 1.9%, respectively (Romond 2005). This interval was larger in HERA trial, being approximately 3 months, and was found an incidence of cardiac dysfunction of 0.6%, similar to that obtained in the nonanthracycline arm of the BCIRG 006 trial (0.4%). (Piccart-Gebhart, 2005, Tan-Chiu, 2005, Joensuu, 2006) Thus, it seems that the greater the interval between treatment with these two drugs, the less cardiotoxicity is found. (Ewer, 2009) (Fig. 2)
\n\t\t\tIncidence of heart failure in the different trials in what concern timing post anthracycline treatment. Reprinted from Nat. Rev Cardiovasc Med ©2010 Nature Publishing
Current data on trastuzumab-induced cardiomyopathy suggest that either symptomatic or asymptomatic LVEF decline has potential to recover by stopping the agent and introducing medical therapy for HF.
\n\t\t\t\tIn the CREC review (Seidman, 2002) of the 112 patients who developed cardiotoxicity, 79% responded to HF therapies. Further evidence of this phenomenon comes from MD Anderson series (Guarneri, 2006). In patients who developed symptomatic CHF, 79% recover after discontinuation of trastuzumab and with appropriate treatment. Of note, one patient recovered quickly with cardiac therapy during treatment with trastuzumab and one died of progressive CHF.
\n\t\t\t\tIn those patients with asymptomatic decline of LVEF, trastuzumab was stopped in 41%. Recovery of LVEF was observed in 89% of women, independently of HF treatment. For the remainder who continued trastuzumab, LVEF recovered in 75% of patients.
\n\t\t\t\t\n\t\t\t\t\tEwer et al (2005) published an observational study of 38 patients with trastuzumab-related cardiotoxicity. Thirty-one patients discontinued the agent and were treated with HF therapies. In all of them LVEF returned to baseline over a period of months (mean time: 1.5 months). In six women who stopped trastuzumab, but were not receiving HF treatment, 2 had persistent LV dysfunction during the 6 months follow-up. Trastuzumab was not withdrawal in one patient, despite evidence of cardiotoxicity, and after initiation of HF therapy was demonstrated a slight increase of LVEF. In a subgroup of patients (Ewer, 2002) treated with the maximum-tolerated doses of angiotensin converting enzyme inhibitors and beta-blockers, which had a full recovery of LVEF and had stable CHF, trastuzumab was reintroduced. The median duration of trastuzumab therapy was 8.4 months. In 88% of women (Ewer, 2005) LVEF remained stable and without recurrences of CHF, in the remainder, LVEF deteriorated and CHF reoccurred, necessitating permanent trastuzumab withdrawal. (Fig. 3) None of the patients died due to cardiac disease, and only one patient needed to be hospitalized because of CHF with volume overload.
\n\t\t\t\tChanges in left ventricular ejection fraction from baseline to re-treatment with trastuzumab (*) P<0.05 versus before trastuzumab therapy. (+) P<0.05 versus after trastuzumab therapy. Reprinted from Ewer et al. (2005) Reversibility of trastuzumab related cardiotoxicity: new insights based on clinical course and response to medical treatment. Journal of Clinical Oncology, Vol. 23, pp. 7820–7826
Similar results were obtained in trastuzumab adjuvant trials. In B-31 (Tan-Chiu et al. 2005) the majority of patients who developed cardiac dysfunction recovered completely (55.5%) or partially (30.6%), as in HERA trial (Piccart-Gebhart, 2005) were there was 81% of recovery.
\n\t\t\t\tAlthough current data is limited regarding the potential long-term effects of trastuzumab on cardiac function, actual evidence of trastuzumab-induced cardiotoxicity should be evaluated in the context of the improvements in disease-free survival, response rate and quality of life attributable to trastuzumab therapy. (Table 5) Thus efforts should be placed on close cardiac function monitoring and development of strategies to early diagnosis.
\n\t\t\tOutside the trials, the best cardiac monitoring strategy remains undefined. The British Society of Echocardiography (Fox, 2006) and more recently the European Society for Medical Oncology (Bovelli et al., 2010), issued a statement regarding the cardiac monitoring of patients proposed to receive trastuzumab. Clinical evaluation and assessment of cardiovascular risk factors and comorbidities should be performed to all women prior the initiation of this agent.
\n\t\t\t\tLong-term cardiac risk.benefit analysis of trastuzumab-based adjuvant chemotherapy. Reprinted from Patrick G. et al (2010). Trastuzumab-Related Cardiotoxicity Following Anthracycline-Based Adjuvant chemotherapy: How Worried Should We Be? Journal of Clinical Oncology, Vol 28, No. 21, pp 3407-3410
The statements specified that LV function must be assessed before treatment and at 3-month intervals during the administration of trastuzumab.
\n\t\t\t\tEchocardiography is the recommended method for evaluating LV function. (Bovelli et al., 2010) Among the imaging techniques, echocardiography has multiple advantages as it is easily accessible, with no radiation exposure and can assess LV systolic and diastolic dysfunction, heart valve disease, pericarditis and pericardial effusion.
\n\t\t\t\tLVEF is the most frequent parameter used for evaluation of cardiac function before initiating chemotherapy and a value less than 54% is considered a risk factor for subsequent development of HF. Extreme caution during consecutive assessment of LVEF is fundamental, in order to diminish the intra and interobserver variability. The use of 3-dimensional echocardiography or administration of contrast for left ventricle opacification can be useful strategies to achieve this proposal. However, LVEF is not a sensitive index to detect early systolic cardiac dysfunction. (Bovelli et al., 2010) Other echocardiographic techniques such as Doppler-derived parameters seem to show early changes in myocardial function in this setting. (Hare, 2009, Fallah-Rad, 2008).
\n\t\t\t\tMyocardial scintigraphy provides a very reliable measurement of LVEF, however does not allow evaluation of regional myocardial kinetic or diastolic function, which can be important aspects of cardiotoxicity. Additionally, it has the disadvantage of radiation exposure.
\n\t\t\t\tCardiac magnetic resonance imaging (MRI) is the gold standard for accurate assessment of LV volumes and LVEF, and also allows evaluation of myocardial perfusion and tissue characterization. The common feature of trastuzumab-induced cardiotoxicity is increase of LV volumes, decrease in LVEF and delayed enhancement within the mid-myocardium portion of LV (Fallah-Rad et al., 2008). MRI has already been validated for LV function monitoring in patients treated with trastuzumab, however, due to its high cost and limited availability, it can not be used as screening test.
\n\t\t\t\tIn this field, for an accurate monitoring oncologists and cardiologists should work as a team and prompt multidisciplinary approach to patient care, in order to detect damage caused by chemotherapy and achieve a positive resolution.
\n\t\t\tIdentification of patients who will develop heart failure as a result of trastuzumab treatment remains an ongoing challenge. Currently, clinical examination and consecutive LVEF measurements have been used to determine the cardiac toxicity of chemotherapy. However, it has important limitations, namely the fact that a decline of LVEF represents a relatively late stage of cardiac dysfunction. Earlier detection of subclinical cardiac damage could lead to identifying, intervening, and possibly preventing late adverse cardiac outcomes. In the setting of trastuzumab-induced cardiotoxicity, it could allow to identify patients at higher risk that could benefit from prophylactic therapy, and also identify those who may recover from cardiac dysfunction and thus, not discontinued indiscriminately trastuzumab therapy depriving most patients from drug’s effectiveness.
\n\t\t\t\tThere is an intense research in this area, especially in what concern the role of cardiac biomarkers and new echocardiographic techniques.
\n\t\t\t\tTwo dimensional evaluation of LVEF constitutes the most common way to assess cardiac function in chemotherapy-induced cardiomyopathy, but it has some limitations, namely low reproducibility and dependence of hemodynamic conditions.
\n\t\t\t\t\tMyocardial strain and strain rate (SR) are newer echocardiographic techniques for evaluation of LV function, offering sensitive measurement of myocardial deformation, and seem to be able to identify subclinical dysfunction in various settings, before impairment of LVEF becomes evident. (Geyer et al., 2010). These parameters can be assessed by tissue Doppler imaging (TDI) or more recently, by speckle tracking (ST).
\n\t\t\t\t\tTDI uses Doppler principles to quantify tissue-derived signals, enabling a quantitative analysis of systo-diastolic function in terms of global, regional, segmental and parietal function. Strain and SR assessed by TDI are pulsed Doppler measurements with spatial integration, obtained by determination of myocardial parietal displacement, taking into account the linear distance between the two points. (Ho & Solomon, 2006).
\n\t\t\t\t\tSpeckle tracking is a distinct method to evaluate global and regional LV function. It’s not Doppler based and thus, allow assessment of strain and SR independently of angle, a limitation of TDI. An important feature of this technique is the possibility of assessing longitudinal, radial and circumferential LV deformation in a single acquisition. Additionally, it is simple to perform, the processing can be done subsequently offline and has a reduced intra and interobserver variability (Geyer et al., 2010).
\n\t\t\t\t\tThese echocardiographic techniques have been evaluated in murine models of chemotherapy-related cardiotoxicity and more recently, in patients with anthracycline-induced cardiomyopathy. (Neilan et al, 2006, Jassal et al, 2009)
\n\t\t\t\t\tRecently some research has been done to elucidate the role of these imaging techniques in subclinical detection of trastuzumab-induced cardiotoxicity.
\n\t\t\t\t\t\n\t\t\t\t\t\tHare et al. (2009) studied 35 women treated with trastuzumab in the adjuvant and metastatic setting. LVEF measured either by 2D and 3D echocardiography, as well as myocardial E-velocity, did not demonstrate significant change in the patients evaluated. However, a reduction in longitudinal SR at 3 months after trastuzumab administration was detected in 18 patients. (Fig. 4) Three of them had a subsequent decrease in LVEF and another 2 patients showed a decline in LVEF within 20 months of follow-up. Data from this study suggest SR to be a parameter able to identify early impairment of cardiac function in trastuzumab-induced cardiomyopathy setting.
\n\t\t\t\t\tExample of preclinical reduction in myocardial deformation. Reductions in TDI SR and 2D speckle-tracking strain from initial echocardiogram (A) over 2 months during therapy with trastuzumab (B), with no concomitant reduction in 3D LVEF in a patient who ceased trastuzumab for symptoms consistent with myocardial dysfunction. GS, Global strain. Reprinted from Hare, J. et al (2009). Natasha Woodward, Thomas H. Marwick Use of myocardial deformation imaging to detect preclinical myocardial dysfunction before conventional measures in patients undergoing breast cancer treatment with trastuzumab. American Heart Journal, Vol. 158, No. 2, pp. 294-301
The study published by Fallah et al. (2011) showed similar results. Indeed it was found that an early reduction in TDI and strain values was subsequently followed by a significant decline of LVEF. Forty two patients were studied and 10 of them developed cardiac dysfunction, necessitating withdrawal of trastuzumab. There weren’t significant differences in baseline TDI and strain parameters between patients who developed cardiotoxicity and those who maintain normal LVEF measurements. However, at 3 months after initiation of therapy was found a significant decrease in lateral S’ value in patients who developed cardiac dysfunction, as well as a reduction in peak global longitudinal and radial strain. Although LVEF was normal at 3 months, TDI and strain measurements were reduced in all 10 patients who demonstrated an impairment of LVEF at 6 months follow up.
\n\t\t\t\t\tA possible explanation for the increased sensitivity of strain in early detection of chemotherapy-induce cardiotoxicity can be a preferential regional pattern of damage, such that normal myocardial segments compensate the impaired function of the other, leading to a preserved LVEF.
\n\t\t\t\t\tTDI and speckle tracking imaging are thus, very promissory tools for early detection of LV systolic dysfunction in trastuzumab treated patients.
\n\t\t\t\tTroponin I (TNI) has high sensibility and specificity to detect myocardial ischemia. Raised levels have been found after anthracycline administration and seem to predict subsequent cardiac morbidity and mortality. Indeed, Cardinale et al. 2004) showed that detectable TNI after high-dose chemotherapy is a predictor of LVEF impairment and higher rate of major cardiac events, especially in women who maintain elevation of TNI for more than a month (Fig.5).
\n\t\t\t\t\tIn addition, they reported a high negative predictive value for TNI (99%), which is important to identify low-risk patients who probably don’t need close monitoring after treatment.
\n\t\t\t\t\tCumulative cardiac events rate in 3 study groups. P<0.001 for TnI +/+ vs TnI-/- and TnI+/-, and for TnI +/- vs TnI-/-. Reprinted from Cardinale, D. et al. (2004). Prognostic Value of Troponin I in Cardiac Risk Stratification of Cancer Patients Undergoing High-Dose Chemotherapy. Circulation, Vol. 109, pp. 2749-2754
The role of TNI in the clinical setting of trastuzumab-induced cardiotoxicity was recently assessed by Cardinale et al. (2010). A substantial finding of the study was that TNI assessment permits to detect patients more likely to developed LVEF impairment and to identify those who are less prone to recover. Indeed, trastuzumab-induced cardiotoxicity was detected in 72% of those who had elevation of TNI and in 7% of patients with normal TNI. From those who developed cardiac dysfunction, 60% recovered. The patients, whom LVEF did not return to baseline values had previous elevation of TNI, and additionally was found that this subgroup had a higher rate of cardiac events along the follow up (Fig.6). Interestingly, in those women with normal TNI who developed trastuzumab-related cardiotoxicity, was observed a subsequent normalization of LVEF and a lower rate of major cardiac events. These data are consistent with the hypothesis that a normal TNI value can predict LVEF recovery.
\n\t\t\t\t\tAdditionally, the rate of major cardiac events, and thus increased morbidity, was higher in the patients who showed elevation of TNI.
\n\t\t\t\t\tCan be inferred that TNI permit to divide patients in two subgroups: those with good outcome, from those more prone to adverse events in whom close surveillance and prevention of further cardiotoxicity is needed.
\n\t\t\t\t\tA) Kaplan-Meier curve of time to first cardiac event in patients developing trastuzumab-induced cardiotoxicity (TIC) and in patients who did not (No TIC). (B) Cumulative major adverse cardiac events in patients who recovered from cardiac dysfunction (Recovery) and in those who did not (No-recovery). Time zero refers to detection of cardiotoxicity and start of heart failure (HF) therapy. Reprinted from: Cardinale et al. (2010). Trastuzumab-Induced Cardiotoxicity: Clinical and Prognostic Implications of Troponin I Evaluation. Journal of Clinical Oncology, Vol. 28, No. 25, pp. 3910-3916
Other studies such as the one published by Sawaya et al. (2011) showed similar results. Indeed an elevated TNI at three months predicted cardiac dysfunction at six months, as these patients were nine times more prone to developed cardiotoxicity than those with normal TNI values.
\n\t\t\t\t\tB-type natriuretic peptide (BNP) is a marker of increased filling pressure of LV, as it is a hormone released by myocardial cells in volume overload setting. An important feature is that it can be detectable in a subclinical stage of HF and its value reflects HF severity. (Emdin et al., 2005)
\n\t\t\t\t\tThus it seemed reasonable to assume that BNP would be increased in patients with chemotherapy-induced cardiomyopathy. However, data currently available are heterogeneous. Some studies reported an elevation of BNP after treatment (Sandri et al., 2005, Pinchon et al., 2005), others obtained negative results (Sawaya et al., 2011). Therefore, the utility of BNP as a biomarker of cardiac damage induced by chemotherapy was not confirmed.
\n\t\t\t\t\tLarger, prospective trials are needed to elucidate BNP role in this setting.
\n\t\t\t\tGuidelines suggest HF standard therapy in patients with symptomatic or asymptomatic evidence of trastuzumab-induced cardiac dysfunction. However, as these patients have been excluded from almost all large randomized trials assessing the efficacy of HF treatment, there isn’t definite evidence whether the long-term benefits of HF therapy can be directly transferred to this setting (Bovelli, 2010, Eschenhagen, 2011).
\n\t\t\tNevertheless, data from adjuvant trials of trastuzumab and observational studies, such as the one conducted by Ewer et al (2005), support the use of HF therapy specially angiotensin converting enzyme inhibitors (ACEI) and beta-blockers.
\n\t\t\tSome other questions in this setting need to be addressed. Should we withdraw trastuzumab in patients who developed cardiotoxicity independently of the grade of LVEF impairment? Some authors proposed an evaluation scheme showed in Table 6, in which trastuzumab should be stopped in asymptomatic patients if LVEF declines more than 20 points from baseline or LVEF<30%, and in symptomatic patients if LVEF reduces more than 30 points from baseline. And should we discontinue the drug in all patients who developed cardiotoxicity or just in high-risk patients? Based on results of the study by Cardinale et al. (2010) we can speculate that patients with normal value of TNI and reduction in LVEF could be maintained in trastuzumab therapy while receiving HF therapy and close monitoring. However we don’t have yet a definite answer. Another important issue is, should we treat prophylactically high-risk patients? The data from Cardinale et al. (2006) suggest that early treatment with enalapril in patients with TNI positive after high-dose chemotherapy, prevent the development of cardiac dysfunction. (Fig. 7) Indeed, in those patients treated with ACEI, LVEF remained normal and compared with the untreated patients, a lower rate of adverse cardiac events was seen. (Table 6)
\n\t\t\tCardiac events in the study groups. Reprinted from Cardinale, D. et al. (2006). Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition. Circulation, Vol. 114, pp. 2474-2481
Patients showing increased TNI value during follow-up in the ACEI group (open bars) and control subjects (solid bars). P<0.001 (log-rank test). Mean ± SD TNI values at each considered step are given at the bottom. *P<0.05 vs ACEI group. Reprinted from Cardinale, D. et al. (2006). Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition. Circulation, Vol. 114, pp. 2474-2481
\n\t\t\t\tKalay et al. (2006) studied the impact of prophylactic carvedilol use in patients receiving anthracycline chemotherapy and showed that LVEF maintained stable in those treated with beta-blocker, contrary to what occurred in the untreated group.
\n\t\t\tProbably the MANTICORE - Multidisciplinary Approach to Novel Therapies In Cardiology Oncology Research - trial, will add some light to this issue. This is a randomized, placebo-controlled trial that aims to determine if standard HF therapies can prevent trastuzumab-induced cardiotoxicity. (Pituskin, 2011)
\n\t\t\tProposal for the evaluation and treatment of heart failure in patients undergoin treatment with trastuzuma. Adapted from Keefe DL. (2002). Trastuzumab-associated cardiotoxicity. Cancer, Vol. 95, pp. 1592-1600 ↓=decrease, B=beta-blockers, CF=cardiac failure, LVEF=left ventricular ejection fraction, NC=noncardiac pathology. trastuzumab
Some authors suggest other strategies to minimize cardiotoxicity (Sengupta, 2008), such as the adoption of non-anthracyclines regimes, to prefer larger intervals between the administration of anthracyclines and trastuzumab or to diminish the duration of trastuzumab adjuvant therapy. However, our conviction is that we should prompt effort in early diagnosis of cardiac dysfunction and appropriate treatment, in order to not deprive patients to a treatment with such substantial therapeutic benefits and propose the algorithm presented in Figure 8, for the management of patients receiving trastuzumab.
\n\t\tProposed algorithm for the management of patients receiving treatment with trastuzumab. Abbreviations: ACEI, angiotensin-converting enzyme inhibitor, ARB, angiotensin II receptor blocker, ECG, electrocardiography, HF, heart failure, LVEF, left ventricular ejection fraction (adapted from Martin M et al (2009),
Trastuzumab is the standard of care for treatment of patients with ERB2-positive breast cancer. When used in combination with chemotherapy, trastuzumab can improve overall survival in patients with ERB2-positive metastatic breast cancer and disease free survival and overall survival in patients with early ERB2-positive breast cancer. Because of the risk of cardiac dysfunction associated with trastuzumab therapy, cardiac function should be monitored closely (Carver, 2010).
\n\t\t\tCardiotoxicity has a strong impact on patients with cancer. This paradigm suggests that a multidisciplinar team of cardiologists and oncologists may provide a more comprehensive care to this complex patient population.
\n\t\t\tThe main strategy is early detection of high risk patients and prompt prophylatic treatment. New echocardiographic methods to detect subclinical myocardial changes, measurement of cardiospecific biomarkers may become useful routine methods for identifying patients more prone to developing cardiotoxicity and in whom a preventive pharmacologic approach together with a closer cardiac monitoring could reduce a major cause of mortality in women with breast cancer.
\n\t\tWater is the most important resource essential for sustenance of life on earth and drive the economic development of human society. Nearly 97% of the total water on earth is in oceans in the form of saline water and only the remaining 3% is fresh water. Out of this, nearly 70% of fresh water is in the form of ice present in the polar region and higher mountain ranges. Underground water constitutes 27% of fresh water and only <1% is in the form of surface water present in lakes and rivers. Rapid changes in human lifestyle coupled with urbanization and industrialization has created pressure on the limited fresh water resources. Further, the impending climate change has favoured salinization of both land and water across many parts of the world [1].
\nThe projection given by FAO indicated increase of food requirements as a result of burgeoning population by 20% in developed countries and 60% in developing countries. In other words food requirements are increasing quicker than crop production. Hence, there is urgent need to improve alternative agricultural strategies [2, 3]. Among the many reasons affecting agricultural productivity in the tropical region, salinity and associated factors, like waterlogging and/or drought exaggerated by climate change have contributed significantly. The increase in saline areas has been directly attributed to both water and soil salinity problems. In the coastal areas inundation of low-lying areas by sea water and sea water intrusion into the fresh water aquifers contribute to the coastal salinization.
\nSince the balance between water demand and water availability has reached critical levels in many regions of the world and increased demand for water and food production is likely in the future, a sustainable approach to water resource use and salinity management has become imperative [4]. A number of approaches have been developed to combat the salinity problems and increase the food grain production, based on specific types of site, regional and global problems. This chapter highlights concepts of water resources, its availability, human demand and use of fresh water, the effect of climate change and other factors on salinity and water resources in the future and also discusses the ways to manage this precious natural resource.
\nThe concept of water resources encompasses qualitative socio-economic and environmental dimensions besides its quantitative and physical aspects. The source of all forms of water either directly or indirectly is precipitation, often used interchangeable with total rainfall in literatures. However, with reference to water resources, precipitation is considered as gain, evapotranspiration is viewed as loss and human use including for agriculture is described as demand. When the resources are contaminated by human activities or turned into saline by natural means, the fresh water resources get reduced which intensify the water demand. At the same time part of the rainfall after reaching the ground get evapotranspired or moves to the fresh water resources (surface and ground water).
\nThere are several reports on global total fresh water resources which are estimated with reference to a particular year, and may vary with the progress of time as it is depend on several dynamic components. The total freshwater resources spread across the world are estimated to be in the order of 43,750 km3 year−1. At the continental level on an average America has the largest share of the world’s total freshwater resources with 45%, followed by Asia (28%), Europe (16%), and Africa (9%) [5]. Due to uneven distribution of population and water resources, continent wise estimation of water resource per inhabitant showed that America has highest amount with 24,000 m3 year−1 followed by Europe (9300 m3 year−1), Africa (5000 m3 year−1) and Asia (3400 m3 year−1) [6]. At the regional level, tropical humid region has fairly good IPWR per capita due to good amount of annual rainfall and water resources. However at the country level, countries located in the Arabian Gulf and Northern Africa (Morocco, Algeria, Bahrain, Jordan, Kuwait, Libyan Arab Jamahiriya, Maldives, Malta, Qatar, Saudi Arabia, United Arab Emirates and Yemen) are having very low total renewable water resources (TRWR) of 500 m3 per inhabitant. In terms of internal renewable resources (IRWR), the threshold of 1000 m3 per inhabitant is considered as water stress, which showed that countries located in North Africa and the Middle East are at the most critical stress level with values ranging from 0 to 1000 m3 year−1 per person.
\nWater is withdrawn from the available resources for various purposes which creates the demand. In other words, to understand the relation between supply and demand, the ratio between water withdrawal by agriculture, municipalities and industries over total renewable water resources is used. This also indicates the level of human pressure on water resources. Arid and semi-arid regions in Asia and Africa have maximum withdrawal of more than 90% of renewable water as given in Figure 1. In these areas surface flow is seasonal due to less rainfall. As a consequence this region exploits more ground water resources than other region.
\nPercentage of renewable water resources withdrawn.
Agriculture accounts for roughly 70% of total freshwater withdrawals globally and for over 90% in the majority of Least Developed Countries (LDCs) [7]. If remedial measures to improve the efficiency are not seriously implemented, by 2050 global agricultural water consumption is projected to increase by about 20%. Globally, some 38% of irrigated areas depend on groundwater [8] which has contributed to a 10-fold increase of groundwater abstraction for agricultural irrigation over the last 50 years. Conversely, almost half of the world’s population depends on groundwater for drinking consequently salinization or overexploitation will affect the freshwater availability for domestic purpose.
\nIn the context of global water resources, demand and salinity, it is imperative to define salinity as it various in intensity and the severity is different based on the intended purpose. Salinity is a measure of the content of salts in soil or water. Salts are highly soluble in surface and groundwater and can be transported with water movement. There are two kinds of salinity viz., primary and secondary salinity.
Primary salinity is produced by natural processes such as weathering of rocks or wind and rain depositing salt over thousands of years. Nevertheless, the distribution of salt deposits in the world natural region is uneven, and the impacts of salinity vary due to different topography and the age of the landscapes.
Secondary salinity occurs due to the accumulation of salt from the primary source. This may be due to extensive land clearing and unjust land use practices. This is mostly observed in the form of ‘dryland salinity’ or ‘irrigation-induced salinity.’ Dryland salinity occurs due to the replacement of deep-rooted native plants by shallow-rooted plants having less water requirement. In addition, farmers apply excess irrigation water once the irrigation water is made available to them. Consequently this leads to raising the water table and bringing salt to the surface where it can be left behind as the water evaporates. On the other hand, irrigation-induced salinity occurs when excess water applied to crops travels past the root zone to groundwater, raising the water table and salt to the surface. Salt may also be transported across surface and groundwater systems.
The term salinity used herein refers to the total dissolved concentration of inorganic ions (Na, Ca, Mg, K, HCO3, SO4 and Cl) in irrigation, drainage and ground waters. Individual concentrations of these cations and anions in a unit volume of water can be expressed either on a chemical equivalent basis (mmolc/l) or on a mass basis (mg/l). The total salt concentration in water is expressed either in terms of the sum of either the cations or anions (mmolc/l) or the sum of cations plus anions (mg/l). But for analytical convenience, salinity is measured as electrical conductivity (EC) expressed in units of (dS/m) [6]. As the solubility of salt vary at different temperature, EC values are always expressed at a standard temperature of 25°C to enable comparisons. This also helps to back convert EC into total salt concentration which is 1 dS/m = 10 mmolc/l = 700 mg/l. In spite of certain shortcomings, EC is a fair indicator of salinity as plants are mainly sensitive to total salt concentration rather than to the proportions of individual salt constituents. At the same time, for comparison purposes, ‘soil salinity’, is commonly expressed in terms of the electrical conductivity of an extract of a saturated paste (ECe; in dS/m) made using a sample of the soil. Normally due to the involvement of different modifying factors rigid water quality classifications are not advised but for the purpose of identifying the levels of water salinities water classification scheme is used.
\nIn terms of total salt concentration, which is the major water quality factor generally limiting the use of waters for crop production and other purposes, water classes are defined (Table 1). As per this scheme, only very hardy and tolerant crops can be successfully grown with waters having salinity of 10 dS/m in EC or more. Many drainage waters, including shallow ground waters underlying irrigated lands, fall in the range of 2–10 dS/m in EC. Such waters have good potential for selected crop production with suitable salinity management practices. Reuse of second-generation drainage waters for irrigation in selected locations is sometimes possible particularly for purposes of reducing drainage volume in preparation for ultimate disposal or treatment. Such waters will generally have ECs in the range 10–25 dS/m. Very highly saline waters (25–45 dS/m in EC) and brine (>45 dS/m in EC) are beyond the scope of these guidelines and their uses for crop production are therefore not discussed herein. In summary water having EC more than 10 are not recommended for irrigation and water with EC value <10 are used with suitable salinity management methods.
\nWater class | \nElectrical conductivity (dS/m) | \nSalt concentration (mg/l) | \nType of water | \n
---|---|---|---|
Non-saline | \n<0.7 | \n<500 | \nDrinking and irrigation water | \n
Slightly saline | \n0.7–2 | \n500–1500 | \nIrrigation water | \n
Moderately saline | \n2–10 | \n1500–7000 | \nPrimary drainage water and groundwater | \n
Highly saline | \n10–25 | \n7000–15,000 | \nSecondary drainage water and groundwater | \n
Very highly saline | \n25–45 | \n1 5000–35,000 | \nVery saline groundwater | \n
Brine | \n>45 | \n>45,000 | \nSeawater | \n
Classification of saline waters.
The availability of fresh water for farming is an essential condition for achieving satisfactory and profitable yields, both in terms of unit yields and quality. In coastal regions due to excessive withdrawal of ground water, high evapotranspiration, rise of saline ground water and sea water intrusion pose major challenge. The most common reasons for the increase in salt-affected lands are the mismanagement of irrigated areas. Increase in groundwater pumping results in the intrusion of seawater into the fresh water aquifers. In certain region/islands due to the exhaustion of fresh water aquifers the overlying saline water layers mix with fresh water, resulting in the increase of salinity in the groundwater. In the dry region, high rates of irrigation water application and inadequate or absence of drainage systems has resulted in the movement and deposition of salt on the surface of the soil profile favoured by high evapotranspiration rates. As a result nearly 5–10% of the existing fresh water resources are getting salinized. The critical values of renewable fresh water resources and economic water scarcity and salinization indicate the necessity for regional water use policy and appropriate water management strategies at various levels.
\nAs discussed above the salinity level, both soil and water, has been increasing in many of the regions particularly in the tropics and arid regions though the processes of occurrence of salt affected soils are different. Salinity can be found in different altitudes, from territories below sea level, e.g. the district of the Dead Sea, to mountains rising over 5000 m as the Tibetan Plateau of the Rocky Mountains [9]. Older estimates [10] suggest that 10% of the total arable land is affected by salinity and sodicity, extending over more than 100 countries occupying different proportions of their territory. The description of the types of salt-affected soils, causes of formation and hypothetical salinization cycle has been reported by many researchers [11].
\nDue to the non-availability of updated information or lack of compilation of regional level assessments the current extent of salt-affected soils are unknown. Based on the FAO/UNESCO Soil Map of the World, Massoud [12] made an estimate of 880 M ha of salt-affected soils of which 36% are in developing countries. These are the potential areas where land can be leased for food production or alternate energy sources using suitable technologies which are currently available. However, Balba [13] gave a global estimate of only 600 M ha as salt-affected soils which included 340 M ha in Asia, 140 M ha in Australia, 60 M ha in South America 30 M ha in Africa, 26 M ha in North America and 1 M ha in Europe. The recent estimate quoted 954.8 M ha of salt-affected soils which is much higher than the previous estimates [14].
\nSimilar to that of soils, the availability of freshwater is a major limiting factor for sustainable agriculture and other developmental activities. In certain regions of the world the water crisis is so severe than the availability of land. Unlike soils, there are several assessments and projection for future water requirements and availability. Global assessment of water availability and projections found decrease in water availability in the developing regions with increasing population pressure [15, 16]. The assessment grouped the water scarcity into physical water scarcity, approaching physical water scarcity and economic water scarcity to understand the water shortage which includes all purpose of water (Figure 2). Physical water scarcity means water resource development is approaching or has exceeded sustainable limits. Here water availability is related to water demand which implies that dry areas are not necessarily water scarce. This physical scarcity analysis showed that more than 75% of river flows are withdrawn for agriculture, industry and domestic purposes. In approaching physical water scarcity nearly 60% of river flows are withdrawn and these basins may experience physical water scarcity in the future. The situation may get worsen with more withdrawal to produce more food. Whereas in economic water scarcity even though water in nature is available locally to meet human demands factors such as human, institutional and financial capital limits access to water. The tropical developing region mostly faces the challenges of water scarcity. Economic water scarcity is the major limits for production in sub-Saharan Africa while physical water scarcity limits the production in South Asia.
\nAreas of physical and economical water scarcity at the basin level in 2007 [16].
In contrast to the crisis, some countries have developed technologies to utilize the saline water. For example, in Israel, farmers carryout crop production with unconventional water resources irrigation and desalination plants have been installed to get fresh water from saline water. In some tropical regions of Asia technologies have been developed to address this issue and we can find agriculture practices based on alternative plant species, most of them are halophytes, which are able to tolerate high temperatures and/or low water availability [17]. Similar attempts are being made in some of the South Asian countries to meet the challenges but in many cases these are at experimental stage.
\nLarge scale withdrawal of ground water (over exploitation), especially from the artesian aquifers can sometimes result in local land subsidence due to compression of the aquifers. Land subsidence poses serious problems to buildings, other structures and affects the equilibrium of freshwater-sea water interface region. Sometimes this causes inundation of low lying areas, resulting in sea water ingress. The subsidence depends on the nature of sub surface formations, their extent, magnitude and duration of the artesian pressure decline.
\nThis is one of the most serious emerging problems in the coastal regions. When groundwater is pumped out of coastal aquifers which is in hydraulic connection with the sea due to gradients salt water from the sea may flow towards the well (Figure 3). There is a dynamic equilibrium in the seawater-fresh water interface which gets disturbed due to over exploitation of ground water or reduced freshwater recharge. This result in movement of salt water into freshwater aquifers under the influence of groundwater development or by over exploitation which is known as seawater intrusion. Sometime there is a propensity to point out the occurrence of any saline water along the coastal zone to sea water intrusion. But there may be many reasons for the occurrence of salinity. In order to avoid mistaken diagnoses of seawater intrusion as evidenced by temporary increases of total dissolved salts, chloride-bicarbonate ratio as a criterion to evaluate the intrusion.
\nFresh water-salt water interface.
This phenomenon occurs due to the local rise of the interface between fresh and saline water. This happens when an aquifer having underlying layer of saline water is pumped by a well penetrating only the upper freshwater portion of the aquifer. This rise in interface layer below the well due to excess removal of water is called upcoming of saline water. Generally the interface lies near horizontal at the start of pumping which rises to progressively higher levels with continued pumping of water until eventually it reaches the well. At that point it necessitates closing of the well because of the degrading influence of the saline water. When pumping is stopped, the denser saline water tends to settle downward and to return to its former position. In such areas, the rainwater tend to float over saline water as a thin lens and in such conditions the saline water rises by 40 units for every unit of the fresh water withdrawn. Because of this very fragile ground water system of small islands the fresh water needs to be skimmed to prevent upcoming.
\nThis kind of salinity is a common water quality problem observed in the coastal aquifers. In these aquifers, the salinity is caused because of leaching of salts in the aquifer material. In certain areas the formation water gets freshened regularly due to the leaching effect. This happens mostly for the water soluble salts only.
\nThe observed and projected increase in mean sea level due to global warming poses a serious threat to the coastal aquifers particularly located in the small islands. The projected SLR will drive the fresh water-seawater interface more towards inland along coastal aquifers and consequently submerge the lowlying areas with saline sea water. This will result in direct salinization of shallow coastal aquifers. Water resources of the small islands located in the tropical region (Indian Ocean and Polynesian islands) will be significantly affected by the rise in sea level and with the change in rainfall pattern the negative effect will be even greater.
\nWater has become a scarce natural commodity due to its declining availability and increase in demand for various purposes. This has created huge pressure on the available fresh water resources around the globe. Several reports state that the magnitude of stress on water resources is expected to increase as a consequence of climate change, population growth, economic development and land-use change including urbanization [18]. In consequence several studies were carried out focusing on the assessment of global water demand and its availability. In reality water demand has reached critical levels in several parts of the world, particularly in countries with very limited water availability. Many researchers have concluded that besides climate change, misuse of water, over exploitation and limited infrastructures for water supply are the major reasons for water scarcity.
\nGlobally water consumption for all sectors amounts to 9% of total freshwater resources in the world with agriculture being the largest user, in turn accounting for approximately 70% of total water withdrawals which is equivalent to 2700 km3 year−1 [19]. Agricultural sector receives up to two-thirds of the total water withdrawals and accounts for almost 90% of the total water consumption in the world [5]. As more than 80% of global agricultural land is rainfed water demand is met mostly from the green water resource [16]. In Asia, Africa, Central and South America, the values for specific water withdrawal range from 50 to 100% which experiences great diversity in climatic conditions. Irrigation water withdrawals range between 96 km3 in Sub-Saharan Africa and 708 km3 in East Asia; the highest values for specific water withdrawal are observed in South Asia, with 913 km3 [20].
\nAnalysis of factors affecting water supply and demand indicated that the water demand will be influenced by population growth, industrial development and food production besides climate change. At the same time the water supply will be decided by land use change, ecological and economic restriction, pollution besides climate change (Figure 4). The balance between these two will decide the fresh water availability [21]. The future global water situation and development until 2025 was analysed with different scenarios. Under the business as usual scenario the present contrast in water situation between industrialized and developing countries is likely to continue in the future. Withdrawal of water from the available resources in most of the industrialized countries is projected to decline or will remain at the present level due to technological and efficient water management. Consequently the pressure on available freshwater resources will decline. In contrast withdrawal will continue to grow in developing countries due to urbanization and industrialization. Further, the push for development will also be expected to increase the salinity level. This will increase the pressure on the available freshwater resources by increasing severe water stress area from 36.4 to 38.6 million km2. The increase will be significant in Southern Africa, Western Africa and South Asia which will be a limiting factor in the future for industrial and agricultural growth due to competition for water [15]. On an average globally 40% water deficit will be experienced by 2030 under a business-as-usual scenario.
\nDriving forces of future water supply and demand (modified from Hornbogen and Schultz [21]).
In spite of efforts by various stakeholders and global level organizations, lots of gap still persists in our understanding of the global water resources and the emerging salinity problems. Meanwhile there are several disputes in utilizing and sharing this precious resource. Human activities have rendered water unusable at several places due to pollution, salinity and over exploitation. There should be proper regulations and monitoring which involve measures like precaution/prevention; control/restriction and remedial/restoration measures. Efforts should be made to study sea-level rise and sea water intrusion. In summary, the available information suggests that water security and the salinity will remain a challenge for many tropical countries today and in the future until suitable remedial measures are implemented and relevant technologies are developed.
\n"I work with IntechOpen for a number of reasons: their professionalism, their mission in support of Open Access publishing, and the quality of their peer-reviewed publications, but also because they believe in equality. Throughout the world, we are seeing progress in attracting, retaining, and promoting women in STEMM. IntechOpen are certainly supporting this work globally by empowering all scientists and ensuring that women are encouraged and enabled to publish and take leading roles within the scientific community." Dr. Catrin Rutland, University of Nottingham, UK
",metaTitle:"Advantages of Publishing with IntechOpen",metaDescription:"We have more than a decade of experience in Open Access publishing. \n\n ",metaKeywords:null,canonicalURL:null,contentRaw:'[{"type":"htmlEditorComponent","content":"We have more than a decade of experience in Open Access publishing. The advantages of publishing with IntechOpen include:
\\n\\nOur platform – IntechOpen is the world’s leading publisher of OA books, built by scientists, for scientists.
\\n\\nOur reputation – Everything we publish goes through a two-stage peer review process. We’re proud to count Nobel laureates among our esteemed authors. We meet European Commission standards for funding, and the research we’ve published has been funded by the Bill and Melinda Gates Foundation and the Wellcome Trust, among others. IntechOpen is a member of all relevant trade associations (including the STM Association and the Association of Learned and Professional Society Publishers) and has a selection of books indexed in Web of Science's Book Citation Index.
\\n\\nOur expertise – We’ve published more than 4,500 books by more than 118,000 authors and editors.
\\n\\nOur reach – Our books have more than 130 million downloads and more than 146,150 Web of Science citations. We increase citations via indexing in all the major databases, including the Book Citation Index at Web of Science and Google Scholar.
\\n\\nOur services – The support we offer our authors and editors is second to none. Each book in our program receives the following:
\\n\\nOur end-to-end publishing service frees our authors and editors to focus on what matters: research. We empower them to shape their fields and connect with the global scientific community.
\\n\\n"In developing countries until now, advancement in science has been very limited, because insufficient economic resources are dedicated to science and education. These limitations are more marked when the scientists are women. In order to develop science in the poorest countries and decrease the gender gap that exists in scientific fields, Open Access networks like IntechOpen are essential. Free access to scientific research could contribute to ameliorating difficult life conditions and breaking down barriers." Marquidia Pacheco, National Institute for Nuclear Research (ININ), Mexico
\\n\\nInterested? Contact Ana Pantar (book.idea@intechopen.com) for more information.
\\n"}]'},components:[{type:"htmlEditorComponent",content:'We have more than a decade of experience in Open Access publishing. The advantages of publishing with IntechOpen include:
\n\nOur platform – IntechOpen is the world’s leading publisher of OA books, built by scientists, for scientists.
\n\nOur reputation – Everything we publish goes through a two-stage peer review process. We’re proud to count Nobel laureates among our esteemed authors. We meet European Commission standards for funding, and the research we’ve published has been funded by the Bill and Melinda Gates Foundation and the Wellcome Trust, among others. IntechOpen is a member of all relevant trade associations (including the STM Association and the Association of Learned and Professional Society Publishers) and has a selection of books indexed in Web of Science's Book Citation Index.
\n\nOur expertise – We’ve published more than 4,500 books by more than 118,000 authors and editors.
\n\nOur reach – Our books have more than 130 million downloads and more than 146,150 Web of Science citations. We increase citations via indexing in all the major databases, including the Book Citation Index at Web of Science and Google Scholar.
\n\nOur services – The support we offer our authors and editors is second to none. Each book in our program receives the following:
\n\nOur end-to-end publishing service frees our authors and editors to focus on what matters: research. We empower them to shape their fields and connect with the global scientific community.
\n\n"In developing countries until now, advancement in science has been very limited, because insufficient economic resources are dedicated to science and education. These limitations are more marked when the scientists are women. In order to develop science in the poorest countries and decrease the gender gap that exists in scientific fields, Open Access networks like IntechOpen are essential. Free access to scientific research could contribute to ameliorating difficult life conditions and breaking down barriers." Marquidia Pacheco, National Institute for Nuclear Research (ININ), Mexico
\n\nInterested? Contact Ana Pantar (book.idea@intechopen.com) for more information.
\n'}]},successStories:{items:[]},authorsAndEditors:{filterParams:{sort:"featured,name"},profiles:[{id:"58592",title:"Dr.",name:"Arun",middleName:null,surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/58592/images/1664_n.jpg",biography:"Arun K. Shanker is serving as a Principal Scientist (Plant Physiology) with the Indian Council of Agricultural Research (ICAR) at the Central Research Institute for Dryland Agriculture in Hyderabad, India. He is working with the ICAR as a full time researcher since 1993 and has since earned his Advanced degree in Crop Physiology while in service. He has been awarded the prestigious Member of the Royal Society of Chemistry (MRSC), by the Royal Society of Chemistry, London in 2015. Presently he is working on systems biology approach to study the mechanism of abiotic stress tolerance in crops. His main focus now is to unravel the mechanism of drought and heat stress response in plants to tackle climate change related threats in agriculture.",institutionString:null,institution:{name:"Indian Council of Agricultural Research",country:{name:"India"}}},{id:"4782",title:"Prof.",name:"Bishnu",middleName:"P",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/4782/images/system/4782.jpg",biography:"Bishnu P. Pal is Professor of Physics at Mahindra École\nCentrale Hyderabad India since July 1st 2014 after retirement\nas Professor of Physics from IIT Delhi; Ph.D.’1975 from IIT\nDelhi; Fellow of OSA and SPIE; Senior Member IEEE;\nHonorary Foreign Member Royal Norwegian Society for\nScience and Arts; Member OSA Board of Directors (2009-\n11); Distinguished Lecturer IEEE Photonics Society (2005-\n07).",institutionString:null,institution:{name:"Indian Institute of Technology Delhi",country:{name:"India"}}},{id:"69653",title:"Dr.",name:"Chusak",middleName:null,surname:"Limsakul",slug:"chusak-limsakul",fullName:"Chusak Limsakul",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Prince of Songkla University",country:{name:"Thailand"}}},{id:"75563",title:"Dr.",name:"Farzana Khan",middleName:null,surname:"Perveen",slug:"farzana-khan-perveen",fullName:"Farzana Khan Perveen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/75563/images/system/75563.png",biography:"Dr Farzana Khan Perveen (FLS; Gold-Medallist) obtained her BSc (Hons) and MSc (Zoology: Entomology) from the University of Karachi, MAS (Monbush-Scholar; Agriculture: Agronomy) and from the Nagoya University, Japan, and PhD (Research and Course-works from the Nagoya University; Toxicology) degree from the University of Karachi. She is Founder/Chairperson of the Department of Zoology (DOZ) and Ex-Controller of Examinations at Shaheed Benazir Bhutto University (SBBU) and Ex-Founder/ Ex-Chairperson of DOZ, Hazara University and Kohat University of Science & Technology. \nShe is the author of 150 high impact research papers, 135 abstracts, 4 authored books and 8 chapters. She is the editor of 5 books and she supervised BS(4), MSc(50), MPhil(40), and Ph.D. (1) students. She has organized and participated in numerous international and national conferences and received multiple awards and fellowships. She is a member of research societies, editorial boards of Journals, and World-Commission on Protected Areas, International Union for Conservation of Nature. Her fields of interest are Entomology, Toxicology, Forensic Entomology, and Zoology.",institutionString:"Shaheed Benazir Bhutto University",institution:{name:"Shaheed Benazir Bhutto University",country:{name:"Pakistan"}}},{id:"23804",title:"Dr.",name:"Hamzah",middleName:null,surname:"Arof",slug:"hamzah-arof",fullName:"Hamzah Arof",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/23804/images/5492_n.jpg",biography:"Hamzah Arof received his BSc from Michigan State University, and PhD from the University of Wales. Both degrees were in electrical engineering. His current research interests include signal processing and photonics. Currently he is affiliated with the Department of Electrical Engineering, University of Malaya, Malaysia.",institutionString:null,institution:{name:"University of Malaya",country:{name:"Malaysia"}}},{id:"41989",title:"Prof.",name:"He",middleName:null,surname:"Tian",slug:"he-tian",fullName:"He Tian",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"East China University of Science and Technology",country:{name:"China"}}},{id:"33351",title:null,name:"Hendra",middleName:null,surname:"Hermawan",slug:"hendra-hermawan",fullName:"Hendra Hermawan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/33351/images/168_n.jpg",biography:null,institutionString:null,institution:{name:"Institut Teknologi Bandung",country:{name:"Indonesia"}}},{id:"11981",title:"Prof.",name:"Hiroshi",middleName:null,surname:"Ishiguro",slug:"hiroshi-ishiguro",fullName:"Hiroshi Ishiguro",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Osaka University",country:{name:"Japan"}}},{id:"45747",title:"Dr.",name:"Hsin-I",middleName:null,surname:"Chang",slug:"hsin-i-chang",fullName:"Hsin-I Chang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/no_image.jpg",biography:null,institutionString:null,institution:{name:"National Chiayi University",country:{name:"Taiwan"}}},{id:"61581",title:"Dr.",name:"Joy Rizki Pangestu",middleName:null,surname:"Djuansjah",slug:"joy-rizki-pangestu-djuansjah",fullName:"Joy Rizki Pangestu Djuansjah",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/61581/images/237_n.jpg",biography:null,institutionString:null,institution:{name:"University of Technology Malaysia",country:{name:"Malaysia"}}},{id:"94249",title:"Prof.",name:"Junji",middleName:null,surname:"Kido",slug:"junji-kido",fullName:"Junji Kido",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Yamagata University",country:{name:"Japan"}}},{id:"12009",title:"Dr.",name:"Ki Young",middleName:null,surname:"Kim",slug:"ki-young-kim",fullName:"Ki Young Kim",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/12009/images/system/12009.jpg",biography:"Http://m80.knu.ac.kr/~doors",institutionString:null,institution:{name:"National Cheng Kung University",country:{name:"Taiwan"}}}],filtersByRegion:[{group:"region",caption:"North America",value:1,count:5763},{group:"region",caption:"Middle and South America",value:2,count:5227},{group:"region",caption:"Africa",value:3,count:1717},{group:"region",caption:"Asia",value:4,count:10365},{group:"region",caption:"Australia and Oceania",value:5,count:897},{group:"region",caption:"Europe",value:6,count:15784}],offset:12,limit:12,total:10365},chapterEmbeded:{data:{}},editorApplication:{success:null,errors:{}},ofsBooks:{filterParams:{topicId:"6"},books:[{type:"book",id:"8977",title:"Protein Kinase - New Opportunities, Challenges and Future Perspectives",subtitle:null,isOpenForSubmission:!0,hash:"6d200cc031706a565b554fdb1c478901",slug:null,bookSignature:"Dr. Rajesh Kumar Singh",coverURL:"https://cdn.intechopen.com/books/images_new/8977.jpg",editedByType:null,editors:[{id:"329385",title:"Dr.",name:"Rajesh",surname:"Singh",slug:"rajesh-singh",fullName:"Rajesh Singh"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9659",title:"Fibroblasts - Advances in Cancer, Autoimmunity and Inflammation",subtitle:null,isOpenForSubmission:!0,hash:"926fa6446f6befbd363fc74971a56de2",slug:null,bookSignature:"Ph.D. Mojca Frank Bertoncelj and Ms. Katja Lakota",coverURL:"https://cdn.intechopen.com/books/images_new/9659.jpg",editedByType:null,editors:[{id:"328755",title:"Ph.D.",name:"Mojca",surname:"Frank Bertoncelj",slug:"mojca-frank-bertoncelj",fullName:"Mojca Frank Bertoncelj"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10797",title:"Cell Culture",subtitle:null,isOpenForSubmission:!0,hash:"2c628f4757f9639a4450728d839a7842",slug:null,bookSignature:"Prof. Xianquan Zhan",coverURL:"https://cdn.intechopen.com/books/images_new/10797.jpg",editedByType:null,editors:[{id:"223233",title:"Prof.",name:"Xianquan",surname:"Zhan",slug:"xianquan-zhan",fullName:"Xianquan Zhan"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10800",title:"Ligase",subtitle:null,isOpenForSubmission:!0,hash:"1f10ff112edb1fec24379dac85ef3b5b",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10800.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10801",title:"Uric Acid",subtitle:null,isOpenForSubmission:!0,hash:"d947ab87019e69ab11aa597edbacc018",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10801.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10837",title:"Peroxisomes",subtitle:null,isOpenForSubmission:!0,hash:"0014b09d4b35bb4d7f52ca0b3641cda1",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10837.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10838",title:"Ion Channels",subtitle:null,isOpenForSubmission:!0,hash:"048017b227b3bdfd0d33a49bac63c915",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10838.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10840",title:"Benzimidazole",subtitle:null,isOpenForSubmission:!0,hash:"9fe810233f92a9c454c624aec634316f",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10840.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10841",title:"Hydrolases",subtitle:null,isOpenForSubmission:!0,hash:"64617cf21bf1e47170bb2bcf31b1fc37",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10841.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],filtersByTopic:[{group:"topic",caption:"Agricultural and Biological Sciences",value:5,count:13},{group:"topic",caption:"Biochemistry, Genetics and Molecular Biology",value:6,count:3},{group:"topic",caption:"Business, Management and Economics",value:7,count:1},{group:"topic",caption:"Chemistry",value:8,count:6},{group:"topic",caption:"Computer and Information Science",value:9,count:6},{group:"topic",caption:"Earth and Planetary Sciences",value:10,count:7},{group:"topic",caption:"Engineering",value:11,count:14},{group:"topic",caption:"Environmental Sciences",value:12,count:2},{group:"topic",caption:"Immunology and Microbiology",value:13,count:3},{group:"topic",caption:"Materials Science",value:14,count:4},{group:"topic",caption:"Mathematics",value:15,count:1},{group:"topic",caption:"Medicine",value:16,count:27},{group:"topic",caption:"Neuroscience",value:18,count:1},{group:"topic",caption:"Pharmacology, Toxicology and Pharmaceutical Science",value:19,count:2},{group:"topic",caption:"Physics",value:20,count:2},{group:"topic",caption:"Psychology",value:21,count:4},{group:"topic",caption:"Social Sciences",value:23,count:2},{group:"topic",caption:"Technology",value:24,count:1},{group:"topic",caption:"Veterinary Medicine and Science",value:25,count:1}],offset:12,limit:12,total:9},popularBooks:{featuredBooks:[{type:"book",id:"9385",title:"Renewable Energy",subtitle:"Technologies and Applications",isOpenForSubmission:!1,hash:"a6b446d19166f17f313008e6c056f3d8",slug:"renewable-energy-technologies-and-applications",bookSignature:"Tolga Taner, Archana Tiwari and Taha Selim Ustun",coverURL:"https://cdn.intechopen.com/books/images_new/9385.jpg",editors:[{id:"197240",title:"Associate Prof.",name:"Tolga",middleName:null,surname:"Taner",slug:"tolga-taner",fullName:"Tolga Taner"}],equalEditorOne:{id:"186791",title:"Dr.",name:"Archana",middleName:null,surname:"Tiwari",slug:"archana-tiwari",fullName:"Archana Tiwari",profilePictureURL:"https://mts.intechopen.com/storage/users/186791/images/system/186791.png",biography:"Dr. Archana Tiwari is Associate Professor at Amity University, India. Her research interests include renewable sources of energy from microalgae and further utilizing the residual biomass for the generation of value-added products, bioremediation through microalgae and microbial consortium, antioxidative enzymes and stress, and nutraceuticals from microalgae. She has been working on algal biotechnology for the last two decades. She has published her research in many international journals and has authored many books and chapters with renowned publishing houses. She has also delivered talks as an invited speaker at many national and international conferences. Dr. Tiwari is the recipient of several awards including Researcher of the Year and Distinguished Scientist.",institutionString:"Amity University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Amity University",institutionURL:null,country:{name:"India"}}},equalEditorTwo:{id:"197609",title:"Prof.",name:"Taha Selim",middleName:null,surname:"Ustun",slug:"taha-selim-ustun",fullName:"Taha Selim Ustun",profilePictureURL:"https://mts.intechopen.com/storage/users/197609/images/system/197609.jpeg",biography:"Dr. Taha Selim Ustun received a Ph.D. in Electrical Engineering from Victoria University, Melbourne, Australia. He is a researcher with the Fukushima Renewable Energy Institute, AIST (FREA), where he leads the Smart Grid Cybersecurity Laboratory. Prior to that, he was a faculty member with the School of Electrical and Computer Engineering, Carnegie Mellon University, Pittsburgh, PA, USA. His current research interests include power systems protection, communication in power networks, distributed generation, microgrids, electric vehicle integration, and cybersecurity in smart grids. He serves on the editorial boards of IEEE Access, IEEE Transactions on Industrial Informatics, Energies, Electronics, Electricity, World Electric Vehicle and Information journals. Dr. Ustun is a member of the IEEE 2004 and 2800, IEC Renewable Energy Management WG 8, and IEC TC 57 WG17. He has been invited to run specialist courses in Africa, India, and China. He has delivered talks for the Qatar Foundation, the World Energy Council, the Waterloo Global Science Initiative, and the European Union Energy Initiative (EUEI). His research has attracted funding from prestigious programs in Japan, Australia, the European Union, and North America.",institutionString:"Fukushima Renewable Energy Institute, AIST (FREA)",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"National Institute of Advanced Industrial Science and Technology",institutionURL:null,country:{name:"Japan"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8985",title:"Natural Resources Management and Biological Sciences",subtitle:null,isOpenForSubmission:!1,hash:"5c2e219a6c021a40b5a20c041dea88c4",slug:"natural-resources-management-and-biological-sciences",bookSignature:"Edward R. Rhodes and Humood Naser",coverURL:"https://cdn.intechopen.com/books/images_new/8985.jpg",editors:[{id:"280886",title:"Prof.",name:"Edward R",middleName:null,surname:"Rhodes",slug:"edward-r-rhodes",fullName:"Edward R Rhodes"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9027",title:"Human Blood Group Systems and Haemoglobinopathies",subtitle:null,isOpenForSubmission:!1,hash:"d00d8e40b11cfb2547d1122866531c7e",slug:"human-blood-group-systems-and-haemoglobinopathies",bookSignature:"Osaro Erhabor and Anjana Munshi",coverURL:"https://cdn.intechopen.com/books/images_new/9027.jpg",editors:[{id:"35140",title:null,name:"Osaro",middleName:null,surname:"Erhabor",slug:"osaro-erhabor",fullName:"Osaro Erhabor"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7841",title:"New Insights Into Metabolic Syndrome",subtitle:null,isOpenForSubmission:!1,hash:"ef5accfac9772b9e2c9eff884f085510",slug:"new-insights-into-metabolic-syndrome",bookSignature:"Akikazu Takada",coverURL:"https://cdn.intechopen.com/books/images_new/7841.jpg",editors:[{id:"248459",title:"Dr.",name:"Akikazu",middleName:null,surname:"Takada",slug:"akikazu-takada",fullName:"Akikazu Takada"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8620",title:"Mining Techniques",subtitle:"Past, Present and Future",isOpenForSubmission:!1,hash:"b65658f81d14e9e57e49377869d3a575",slug:"mining-techniques-past-present-and-future",bookSignature:"Abhay Soni",coverURL:"https://cdn.intechopen.com/books/images_new/8620.jpg",editors:[{id:"271093",title:"Dr.",name:"Abhay",middleName:null,surname:"Soni",slug:"abhay-soni",fullName:"Abhay Soni"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8558",title:"Aerodynamics",subtitle:null,isOpenForSubmission:!1,hash:"db7263fc198dfb539073ba0260a7f1aa",slug:"aerodynamics",bookSignature:"Mofid Gorji-Bandpy and Aly-Mousaad Aly",coverURL:"https://cdn.intechopen.com/books/images_new/8558.jpg",editors:[{id:"35542",title:"Prof.",name:"Mofid",middleName:null,surname:"Gorji-Bandpy",slug:"mofid-gorji-bandpy",fullName:"Mofid Gorji-Bandpy"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9668",title:"Chemistry and Biochemistry of Winemaking, Wine Stabilization and Aging",subtitle:null,isOpenForSubmission:!1,hash:"c5484276a314628acf21ec1bdc3a86b9",slug:"chemistry-and-biochemistry-of-winemaking-wine-stabilization-and-aging",bookSignature:"Fernanda Cosme, Fernando M. Nunes and Luís Filipe-Ribeiro",coverURL:"https://cdn.intechopen.com/books/images_new/9668.jpg",editors:[{id:"186819",title:"Prof.",name:"Fernanda",middleName:null,surname:"Cosme",slug:"fernanda-cosme",fullName:"Fernanda Cosme"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7847",title:"Medical Toxicology",subtitle:null,isOpenForSubmission:!1,hash:"db9b65bea093de17a0855a1b27046247",slug:"medical-toxicology",bookSignature:"Pınar Erkekoglu and Tomohisa Ogawa",coverURL:"https://cdn.intechopen.com/books/images_new/7847.jpg",editors:[{id:"109978",title:"Prof.",name:"Pınar",middleName:null,surname:"Erkekoglu",slug:"pinar-erkekoglu",fullName:"Pınar Erkekoglu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9660",title:"Inland Waters",subtitle:"Dynamics and Ecology",isOpenForSubmission:!1,hash:"975c26819ceb11a926793bc2adc62bd6",slug:"inland-waters-dynamics-and-ecology",bookSignature:"Adam Devlin, Jiayi Pan and Mohammad Manjur Shah",coverURL:"https://cdn.intechopen.com/books/images_new/9660.jpg",editors:[{id:"280757",title:"Dr.",name:"Adam",middleName:"Thomas",surname:"Devlin",slug:"adam-devlin",fullName:"Adam Devlin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9731",title:"Oxidoreductase",subtitle:null,isOpenForSubmission:!1,hash:"852e6f862c85fc3adecdbaf822e64e6e",slug:"oxidoreductase",bookSignature:"Mahmoud Ahmed Mansour",coverURL:"https://cdn.intechopen.com/books/images_new/9731.jpg",editors:[{id:"224662",title:"Prof.",name:"Mahmoud Ahmed",middleName:null,surname:"Mansour",slug:"mahmoud-ahmed-mansour",fullName:"Mahmoud Ahmed Mansour"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9864",title:"Hydrology",subtitle:null,isOpenForSubmission:!1,hash:"02925c63436d12e839008c793a253310",slug:"hydrology",bookSignature:"Theodore V. Hromadka II and Prasada Rao",coverURL:"https://cdn.intechopen.com/books/images_new/9864.jpg",editors:[{id:"181008",title:"Dr.",name:"Theodore V.",middleName:"V.",surname:"Hromadka II",slug:"theodore-v.-hromadka-ii",fullName:"Theodore V. Hromadka II"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9083",title:"Rodents",subtitle:null,isOpenForSubmission:!1,hash:"480148de5ecf236b3e0860fc3954b2d4",slug:"rodents",bookSignature:"Loth S. Mulungu",coverURL:"https://cdn.intechopen.com/books/images_new/9083.jpg",editors:[{id:"108433",title:"Dr.",name:"Loth S.",middleName:null,surname:"Mulungu",slug:"loth-s.-mulungu",fullName:"Loth S. Mulungu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],offset:12,limit:12,total:5220},hotBookTopics:{hotBooks:[],offset:0,limit:12,total:null},publish:{},publishingProposal:{success:null,errors:{}},books:{featuredBooks:[{type:"book",id:"9385",title:"Renewable Energy",subtitle:"Technologies and Applications",isOpenForSubmission:!1,hash:"a6b446d19166f17f313008e6c056f3d8",slug:"renewable-energy-technologies-and-applications",bookSignature:"Tolga Taner, Archana Tiwari and Taha Selim Ustun",coverURL:"https://cdn.intechopen.com/books/images_new/9385.jpg",editors:[{id:"197240",title:"Associate Prof.",name:"Tolga",middleName:null,surname:"Taner",slug:"tolga-taner",fullName:"Tolga Taner"}],equalEditorOne:{id:"186791",title:"Dr.",name:"Archana",middleName:null,surname:"Tiwari",slug:"archana-tiwari",fullName:"Archana Tiwari",profilePictureURL:"https://mts.intechopen.com/storage/users/186791/images/system/186791.jpg",biography:"Dr. Archana Tiwari is Associate Professor at Amity University, India. Her research interests include renewable sources of energy from microalgae and further utilizing the residual biomass for the generation of value-added products, bioremediation through microalgae and microbial consortium, antioxidative enzymes and stress, and nutraceuticals from microalgae. She has been working on algal biotechnology for the last two decades. She has published her research in many international journals and has authored many books and chapters with renowned publishing houses. She has also delivered talks as an invited speaker at many national and international conferences. Dr. Tiwari is the recipient of several awards including Researcher of the Year and Distinguished Scientist.",institutionString:"Amity University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Amity University",institutionURL:null,country:{name:"India"}}},equalEditorTwo:{id:"197609",title:"Prof.",name:"Taha Selim",middleName:null,surname:"Ustun",slug:"taha-selim-ustun",fullName:"Taha Selim Ustun",profilePictureURL:"https://mts.intechopen.com/storage/users/197609/images/system/197609.jpeg",biography:"Dr. Taha Selim Ustun received a Ph.D. in Electrical Engineering from Victoria University, Melbourne, Australia. He is a researcher with the Fukushima Renewable Energy Institute, AIST (FREA), where he leads the Smart Grid Cybersecurity Laboratory. Prior to that, he was a faculty member with the School of Electrical and Computer Engineering, Carnegie Mellon University, Pittsburgh, PA, USA. His current research interests include power systems protection, communication in power networks, distributed generation, microgrids, electric vehicle integration, and cybersecurity in smart grids. He serves on the editorial boards of IEEE Access, IEEE Transactions on Industrial Informatics, Energies, Electronics, Electricity, World Electric Vehicle and Information journals. Dr. Ustun is a member of the IEEE 2004 and 2800, IEC Renewable Energy Management WG 8, and IEC TC 57 WG17. He has been invited to run specialist courses in Africa, India, and China. He has delivered talks for the Qatar Foundation, the World Energy Council, the Waterloo Global Science Initiative, and the European Union Energy Initiative (EUEI). His research has attracted funding from prestigious programs in Japan, Australia, the European Union, and North America.",institutionString:"Fukushima Renewable Energy Institute, AIST (FREA)",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"National Institute of Advanced Industrial Science and Technology",institutionURL:null,country:{name:"Japan"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8985",title:"Natural Resources Management and Biological Sciences",subtitle:null,isOpenForSubmission:!1,hash:"5c2e219a6c021a40b5a20c041dea88c4",slug:"natural-resources-management-and-biological-sciences",bookSignature:"Edward R. Rhodes and Humood Naser",coverURL:"https://cdn.intechopen.com/books/images_new/8985.jpg",editors:[{id:"280886",title:"Prof.",name:"Edward R",middleName:null,surname:"Rhodes",slug:"edward-r-rhodes",fullName:"Edward R Rhodes"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9027",title:"Human Blood Group Systems and Haemoglobinopathies",subtitle:null,isOpenForSubmission:!1,hash:"d00d8e40b11cfb2547d1122866531c7e",slug:"human-blood-group-systems-and-haemoglobinopathies",bookSignature:"Osaro Erhabor and Anjana Munshi",coverURL:"https://cdn.intechopen.com/books/images_new/9027.jpg",editors:[{id:"35140",title:null,name:"Osaro",middleName:null,surname:"Erhabor",slug:"osaro-erhabor",fullName:"Osaro Erhabor"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7841",title:"New Insights Into Metabolic Syndrome",subtitle:null,isOpenForSubmission:!1,hash:"ef5accfac9772b9e2c9eff884f085510",slug:"new-insights-into-metabolic-syndrome",bookSignature:"Akikazu Takada",coverURL:"https://cdn.intechopen.com/books/images_new/7841.jpg",editors:[{id:"248459",title:"Dr.",name:"Akikazu",middleName:null,surname:"Takada",slug:"akikazu-takada",fullName:"Akikazu Takada"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8558",title:"Aerodynamics",subtitle:null,isOpenForSubmission:!1,hash:"db7263fc198dfb539073ba0260a7f1aa",slug:"aerodynamics",bookSignature:"Mofid Gorji-Bandpy and Aly-Mousaad Aly",coverURL:"https://cdn.intechopen.com/books/images_new/8558.jpg",editors:[{id:"35542",title:"Prof.",name:"Mofid",middleName:null,surname:"Gorji-Bandpy",slug:"mofid-gorji-bandpy",fullName:"Mofid Gorji-Bandpy"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9668",title:"Chemistry and Biochemistry of Winemaking, Wine Stabilization and Aging",subtitle:null,isOpenForSubmission:!1,hash:"c5484276a314628acf21ec1bdc3a86b9",slug:"chemistry-and-biochemistry-of-winemaking-wine-stabilization-and-aging",bookSignature:"Fernanda Cosme, Fernando M. Nunes and Luís Filipe-Ribeiro",coverURL:"https://cdn.intechopen.com/books/images_new/9668.jpg",editors:[{id:"186819",title:"Prof.",name:"Fernanda",middleName:null,surname:"Cosme",slug:"fernanda-cosme",fullName:"Fernanda Cosme"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7847",title:"Medical Toxicology",subtitle:null,isOpenForSubmission:!1,hash:"db9b65bea093de17a0855a1b27046247",slug:"medical-toxicology",bookSignature:"Pınar Erkekoglu and Tomohisa Ogawa",coverURL:"https://cdn.intechopen.com/books/images_new/7847.jpg",editors:[{id:"109978",title:"Prof.",name:"Pınar",middleName:null,surname:"Erkekoglu",slug:"pinar-erkekoglu",fullName:"Pınar Erkekoglu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8620",title:"Mining Techniques",subtitle:"Past, Present and Future",isOpenForSubmission:!1,hash:"b65658f81d14e9e57e49377869d3a575",slug:"mining-techniques-past-present-and-future",bookSignature:"Abhay Soni",coverURL:"https://cdn.intechopen.com/books/images_new/8620.jpg",editors:[{id:"271093",title:"Dr.",name:"Abhay",middleName:null,surname:"Soni",slug:"abhay-soni",fullName:"Abhay Soni"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9660",title:"Inland Waters",subtitle:"Dynamics and Ecology",isOpenForSubmission:!1,hash:"975c26819ceb11a926793bc2adc62bd6",slug:"inland-waters-dynamics-and-ecology",bookSignature:"Adam Devlin, Jiayi Pan and Mohammad Manjur Shah",coverURL:"https://cdn.intechopen.com/books/images_new/9660.jpg",editors:[{id:"280757",title:"Dr.",name:"Adam",middleName:"Thomas",surname:"Devlin",slug:"adam-devlin",fullName:"Adam Devlin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9122",title:"Cosmetic Surgery",subtitle:null,isOpenForSubmission:!1,hash:"207026ca4a4125e17038e770d00ee152",slug:"cosmetic-surgery",bookSignature:"Yueh-Bih Tang",coverURL:"https://cdn.intechopen.com/books/images_new/9122.jpg",editors:[{id:"202122",title:"Prof.",name:"Yueh-Bih",middleName:null,surname:"Tang",slug:"yueh-bih-tang",fullName:"Yueh-Bih Tang"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],latestBooks:[{type:"book",id:"9550",title:"Entrepreneurship",subtitle:"Contemporary Issues",isOpenForSubmission:!1,hash:"9b4ac1ee5b743abf6f88495452b1e5e7",slug:"entrepreneurship-contemporary-issues",bookSignature:"Mladen Turuk",coverURL:"https://cdn.intechopen.com/books/images_new/9550.jpg",editedByType:"Edited by",editors:[{id:"319755",title:"Prof.",name:"Mladen",middleName:null,surname:"Turuk",slug:"mladen-turuk",fullName:"Mladen Turuk"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10065",title:"Wavelet Theory",subtitle:null,isOpenForSubmission:!1,hash:"d8868e332169597ba2182d9b004d60de",slug:"wavelet-theory",bookSignature:"Somayeh Mohammady",coverURL:"https://cdn.intechopen.com/books/images_new/10065.jpg",editedByType:"Edited by",editors:[{id:"109280",title:"Dr.",name:"Somayeh",middleName:null,surname:"Mohammady",slug:"somayeh-mohammady",fullName:"Somayeh Mohammady"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9313",title:"Clay Science and Technology",subtitle:null,isOpenForSubmission:!1,hash:"6fa7e70396ff10620e032bb6cfa6fb72",slug:"clay-science-and-technology",bookSignature:"Gustavo Morari Do Nascimento",coverURL:"https://cdn.intechopen.com/books/images_new/9313.jpg",editedByType:"Edited by",editors:[{id:"7153",title:"Prof.",name:"Gustavo",middleName:null,surname:"Morari Do Nascimento",slug:"gustavo-morari-do-nascimento",fullName:"Gustavo Morari Do Nascimento"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9888",title:"Nuclear Power Plants",subtitle:"The Processes from the Cradle to the Grave",isOpenForSubmission:!1,hash:"c2c8773e586f62155ab8221ebb72a849",slug:"nuclear-power-plants-the-processes-from-the-cradle-to-the-grave",bookSignature:"Nasser Awwad",coverURL:"https://cdn.intechopen.com/books/images_new/9888.jpg",editedByType:"Edited by",editors:[{id:"145209",title:"Prof.",name:"Nasser",middleName:"S",surname:"Awwad",slug:"nasser-awwad",fullName:"Nasser Awwad"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8098",title:"Resources of Water",subtitle:null,isOpenForSubmission:!1,hash:"d251652996624d932ef7b8ed62cf7cfc",slug:"resources-of-water",bookSignature:"Prathna Thanjavur Chandrasekaran, Muhammad Salik Javaid, Aftab Sadiq",coverURL:"https://cdn.intechopen.com/books/images_new/8098.jpg",editedByType:"Edited by",editors:[{id:"167917",title:"Dr.",name:"Prathna",middleName:null,surname:"Thanjavur Chandrasekaran",slug:"prathna-thanjavur-chandrasekaran",fullName:"Prathna Thanjavur Chandrasekaran"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9644",title:"Glaciers and the Polar Environment",subtitle:null,isOpenForSubmission:!1,hash:"e8cfdc161794e3753ced54e6ff30873b",slug:"glaciers-and-the-polar-environment",bookSignature:"Masaki Kanao, Danilo Godone and Niccolò Dematteis",coverURL:"https://cdn.intechopen.com/books/images_new/9644.jpg",editedByType:"Edited by",editors:[{id:"51959",title:"Dr.",name:"Masaki",middleName:null,surname:"Kanao",slug:"masaki-kanao",fullName:"Masaki Kanao"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10432",title:"Casting Processes and Modelling of Metallic Materials",subtitle:null,isOpenForSubmission:!1,hash:"2c5c9df938666bf5d1797727db203a6d",slug:"casting-processes-and-modelling-of-metallic-materials",bookSignature:"Zakaria Abdallah and Nada Aldoumani",coverURL:"https://cdn.intechopen.com/books/images_new/10432.jpg",editedByType:"Edited by",editors:[{id:"201670",title:"Dr.",name:"Zak",middleName:null,surname:"Abdallah",slug:"zak-abdallah",fullName:"Zak Abdallah"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9671",title:"Macrophages",subtitle:null,isOpenForSubmission:!1,hash:"03b00fdc5f24b71d1ecdfd75076bfde6",slug:"macrophages",bookSignature:"Hridayesh Prakash",coverURL:"https://cdn.intechopen.com/books/images_new/9671.jpg",editedByType:"Edited by",editors:[{id:"287184",title:"Dr.",name:"Hridayesh",middleName:null,surname:"Prakash",slug:"hridayesh-prakash",fullName:"Hridayesh Prakash"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8415",title:"Extremophilic Microbes and Metabolites",subtitle:"Diversity, Bioprospecting and Biotechnological Applications",isOpenForSubmission:!1,hash:"93e0321bc93b89ff73730157738f8f97",slug:"extremophilic-microbes-and-metabolites-diversity-bioprospecting-and-biotechnological-applications",bookSignature:"Afef Najjari, Ameur Cherif, Haïtham Sghaier and Hadda Imene Ouzari",coverURL:"https://cdn.intechopen.com/books/images_new/8415.jpg",editedByType:"Edited by",editors:[{id:"196823",title:"Dr.",name:"Afef",middleName:null,surname:"Najjari",slug:"afef-najjari",fullName:"Afef Najjari"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9731",title:"Oxidoreductase",subtitle:null,isOpenForSubmission:!1,hash:"852e6f862c85fc3adecdbaf822e64e6e",slug:"oxidoreductase",bookSignature:"Mahmoud Ahmed Mansour",coverURL:"https://cdn.intechopen.com/books/images_new/9731.jpg",editedByType:"Edited by",editors:[{id:"224662",title:"Prof.",name:"Mahmoud Ahmed",middleName:null,surname:"Mansour",slug:"mahmoud-ahmed-mansour",fullName:"Mahmoud Ahmed Mansour"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},subject:{topic:{id:"802",title:"Operations Management",slug:"industrial-engineering-and-management-operations-management",parent:{title:"Industrial Engineering and Management",slug:"industrial-engineering-and-management"},numberOfBooks:1,numberOfAuthorsAndEditors:1,numberOfWosCitations:2,numberOfCrossrefCitations:7,numberOfDimensionsCitations:10,videoUrl:null,fallbackUrl:null,description:null},booksByTopicFilter:{topicSlug:"industrial-engineering-and-management-operations-management",sort:"-publishedDate",limit:12,offset:0},booksByTopicCollection:[{type:"book",id:"3723",title:"Management and Services",subtitle:null,isOpenForSubmission:!1,hash:"fd3d170b6b6bfc78a9568d26c89ca435",slug:"management-and-services",bookSignature:"Mamun Habib",coverURL:"https://cdn.intechopen.com/books/images_new/3723.jpg",editedByType:"Edited by",editors:[{id:"12501",title:"Prof.",name:"Dr. Md. Mamun",middleName:null,surname:"Habib",slug:"dr.-md.-mamun-habib",fullName:"Dr. Md. Mamun Habib"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:1,mostCitedChapters:[{id:"11653",doi:"10.5772/9950",title:"An Empirical Research of ITESCM (Integrated Tertiary Educational Supply Chain Management) Model",slug:"an-empirical-research-of-itescm-integrated-tertiary-educational-supply-chain-management-model",totalDownloads:3047,totalCrossrefCites:7,totalDimensionsCites:9,book:{slug:"management-and-services",title:"Management and Services",fullTitle:"Management and Services"},signatures:"Mamun Habib",authors:null},{id:"11655",doi:"10.5772/9952",title:"Nonfunctional Requirements Validation Using Nash Equilibria",slug:"nonfunctional-requirements-validation-using-nash-equilibria",totalDownloads:2026,totalCrossrefCites:0,totalDimensionsCites:1,book:{slug:"management-and-services",title:"Management and Services",fullTitle:"Management and Services"},signatures:"Andreas Gregoriades and Vicky Papadopoulou",authors:null},{id:"11654",doi:"10.5772/9951",title:"Learning 2.0: Collaborative Technologies Reshaping Learning Pathways",slug:"learning-2-0-collaborative-technologies-reshaping-learning-pathways",totalDownloads:1493,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"management-and-services",title:"Management and Services",fullTitle:"Management and Services"},signatures:"Veronica Popovici and Ramona Nicoleta Bunda",authors:null}],mostDownloadedChaptersLast30Days:[{id:"11653",title:"An Empirical Research of ITESCM (Integrated Tertiary Educational Supply Chain Management) Model",slug:"an-empirical-research-of-itescm-integrated-tertiary-educational-supply-chain-management-model",totalDownloads:3046,totalCrossrefCites:7,totalDimensionsCites:9,book:{slug:"management-and-services",title:"Management and Services",fullTitle:"Management and Services"},signatures:"Mamun Habib",authors:null},{id:"11657",title:"Realization of Lowpass and Bandpass Leapfrog Filters Using OAs and CCCIIs",slug:"realization-of-lowpass-and-bandpass-leapfrog-filters-using-oas-and-ccciis",totalDownloads:3632,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"management-and-services",title:"Management and Services",fullTitle:"Management and Services"},signatures:"Yanhui Xi and Hui Peng",authors:null},{id:"11655",title:"Nonfunctional Requirements Validation Using Nash Equilibria",slug:"nonfunctional-requirements-validation-using-nash-equilibria",totalDownloads:2026,totalCrossrefCites:0,totalDimensionsCites:1,book:{slug:"management-and-services",title:"Management and Services",fullTitle:"Management and Services"},signatures:"Andreas Gregoriades and Vicky Papadopoulou",authors:null},{id:"11654",title:"Learning 2.0: Collaborative Technologies Reshaping Learning Pathways",slug:"learning-2-0-collaborative-technologies-reshaping-learning-pathways",totalDownloads:1493,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"management-and-services",title:"Management and Services",fullTitle:"Management and Services"},signatures:"Veronica Popovici and Ramona Nicoleta Bunda",authors:null},{id:"11656",title:"Constructing Geo-Information Sharing GRID Architecture",slug:"constructing-geo-information-sharing-grid-architecture",totalDownloads:1561,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"management-and-services",title:"Management and Services",fullTitle:"Management and Services"},signatures:"Qiang Liu and Boyan Cheng",authors:null}],onlineFirstChaptersFilter:{topicSlug:"industrial-engineering-and-management-operations-management",limit:3,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[{type:"book",id:"10176",title:"Microgrids and Local Energy Systems",subtitle:null,isOpenForSubmission:!0,hash:"c32b4a5351a88f263074b0d0ca813a9c",slug:null,bookSignature:"Prof. Nick Jenkins",coverURL:"https://cdn.intechopen.com/books/images_new/10176.jpg",editedByType:null,editors:[{id:"55219",title:"Prof.",name:"Nick",middleName:null,surname:"Jenkins",slug:"nick-jenkins",fullName:"Nick Jenkins"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],offset:8,limit:8,total:1},route:{name:"profile.detail",path:"/profiles/195555/prashantha-kumar-h-g",hash:"",query:{},params:{id:"195555",slug:"prashantha-kumar-h-g"},fullPath:"/profiles/195555/prashantha-kumar-h-g",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var t;(t=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(t)}()