Clinical manifestations of conceptuses resulting from the infection of pregnant women by viral disease.
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:{caption:"Highly Cited",originalUrl:"/media/original/117"}},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"945",leadTitle:null,fullTitle:"Global Perspectives on Bronchoscopy",title:"Global Perspectives on Bronchoscopy",subtitle:null,reviewType:"peer-reviewed",abstract:"Bronchoscopy has become an essential part of modern medicine . 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It is time to abandon unethical or impossible to introduce into clinical pathways and look again at rudiments and face limitations. This book takes the reader from stem cell biology through clinical applications, ethics, law, and future possibilities. It is a solid base for every scientist interested in the topic of stem cells. Growing recognition of the limitations of stem cell therapies on the one hand and the rapidly increasing number of unethical therapies available in many countries force the quick establishment of the status quo of knowledge in a form accessible to all interested. This book is the answer to the multi-level and complex aspect of using stem cells in humans. It reveals real possibilities of introducing the latest research in the field of stem cell research. Material summarizes the ups and downs of this complex topic and shows the current trends in global markets and universities.
",isbn:"978-1-83768-033-7",printIsbn:"978-1-83768-032-0",pdfIsbn:"978-1-83768-034-4",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"13092df328080c762dd9157be18ca38c",bookSignature:"Ph.D. Diana Kitala",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11673.jpg",keywords:"Organoids, Organotypic Cultures, Pluripotent Stem Cells, Graft-Versus-Tumor, GvHD, Immunomodulation, Cell Transplant, Regenerative Medicine, Nanotechnology, Cell Environment, Law, Ethics",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 11th 2022",dateEndSecondStepPublish:"June 8th 2022",dateEndThirdStepPublish:"August 7th 2022",dateEndFourthStepPublish:"October 26th 2022",dateEndFifthStepPublish:"December 25th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"14 days",secondStepPassed:!1,areRegistrationsClosed:!1,currentStepOfPublishingProcess:2,editedByType:null,kuFlag:!1,biosketch:"A researcher involved in stem cell research from basic studies to clinical application (from GLP, through GMP to GCP). She worked for 10 years as GMP Head of Quality Assurance, at Dr. Stanisław Sakiel Burns Treatment Center, and as a University Lecturer. Assistant Professor Kitala is currently involved in writing national programs for medical research and evaluation of clinical research at the Medical Research Agency.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"203598",title:"Ph.D.",name:"Diana",middleName:null,surname:"Kitala",slug:"diana-kitala",fullName:"Diana Kitala",profilePictureURL:"https://mts.intechopen.com/storage/users/203598/images/system/203598.png",biography:"Assistant Professor Diana Paula Kitala graduated with degrees in Biotechnology and Biomedical Engineering, and while writing her doctoral thesis she completed postgraduate studies in the fields of clinical research, biostatistics, laboratory diagnostics, LEAN methodology, and Six Sigma management. 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More than a half of all new diagnosed patients with non-small cell lung cancer (NSCLC) presents in stage IV disease with a median overall survival (OS) of 10–12 months. Stage IV NSCLC is generally considered incurable disease with a 5-year survival ranged from 0 to 10% [2]. However, the sub segment of patients in stage IV was recognized years ago with different clinical presentation and prolonged survival that overcomes expected for metastatic disease [3]. Oligometastatic disease was first described in 1995 as a state of limited systemic metastatic burden in which treatment of oligometastases with radical local therapies could be curative in selected patients [3, 4]. For decades, no high-level evidence has been introduced for management of these patients subset. Moreover, no uniform definition and staging requirements for usage the term oligometastatic NSCLC have been accepted until recently. Clinical data indicate that the number of patients with oligometastatic disease that undergo ablative local treatment is increasing at a great rate [5]. With the extension of imaging diagnostic methods like 2-deoxy-2-[fluorine-18]fluoro-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) and magnetic resonance imaging (MRI), oligometastatic NSCLC patients who benefit most from radical treatment could be selected precisely [6]. On the other hand, development in technical improvement of modern local treatment approaches and advances in new systemic treatment options for NSCLC patients offer new hope for improvement of outcomes in oligometastatic NSCLC. In this chapter, we present most relevant scientific evidence regarding oligometastatic NSCLC and discuss future perspectives in treatment of these patients in the era of molecular targeted treatment and immunotherapy.
\nEven the oligometastatic disease was first described in 1995, no uniform and clear definition has been accepted for years [3]. Most past clinical trial protocols have used an upper limit of metastases between one and eight as inclusion criteria; however, 90% of included patients actually had one metastasis [5, 7].
\nThe concept of oligometastatic NSCLC include different clinical scenarios of limited number of metastatic lesions that are feasible to local ablative treatment. Regarding the time of presentation, in synchronous oligometastatic disease metastatic lesions are detected at the time of diagnosis of the primary tumor. In metachronous oligometastatic disease new metastatic lesions not present at the time of the primary diagnosis develop [8, 9]. Other related terms are currently used, like oligorecurrence, in which limited number of metastatic lesions develop in otherwise controlled primary tumor site followed radical treatment. Oligoprogression describes metastatic disease with controlled primary tumor and most metastases due to systemic therapy followed by progression of one or few metastatic lesions. Oligoressistance follows systemic therapy of patients with widespread metastases who have a near complete response but limited number of persistent lesions remains. First attempt to unify the oligometastatic state was inclusion oligometastatic disease in the 8th edition of the Tumor, Node, Metastasis (TNM) published by the International Association for the Study of Lung Cancer (IASLC). In the assessment for M descriptor, 225 (22%) of the 1025 metastatic patients were reported with a single metastasis in a single organ that had significantly better prognosis than those with multiple metastases in one or several organs [10]. Accordingly, single metastatic lesion in a single distant organ was assigned to the new M1b category [2, 10].
\nRecently, a pan-European multidisciplinary consensus statement on the definition and staging of synchronous oligometastatic NSCLC was formulated [11]. As it was concluded, the definition is relevant when a radical treatment is technically feasible with acceptable toxicity, with all sites being amenable to local treatment modality that may result in long-term disease control. A maximum of 5 metastases and 3 organs is proposed for definition of oligometastatic NSCLC. The presence of diffuse serosal metastases (meningeal, pericardial, pleural, and mesenteric) or bone marrow involvement excludes cases from the definition, as these cannot be treated with radical intent. For pulmonary metastases, the eight TNM classification should be followed. Metastasis in the same lobe (T3) or in the same lung (T4) should not be counted as a metastatic site, but it can influence the possibility of treatment with radical intent. Mediastinal lymph nodes must be considered as regional disease, but their involvements are of importance in the decision of feasibility for radical treatment of locoregional disease. The recommendations for staging include 18F-FDG PET/CT and brain imaging, preferably magnetic resonance imaging (MRI), that are mandatory. Besides mediastinal lymph node staging with 18F-FDG PET/CT, pathological confirmation is required if this influences the treatment decision. In addition, pathological confirmation at least of one metastasis is required unless the risk outweighs the benefit.
\nOligometastatic disease used to be reported sporadically [12]; however, with the improvement in diagnostic imaging, mainly 18F-FDG PET/CT and MRI, oligometastases appear relatively frequent. While available data on incidence of oligometastatic NSCLC at diagnosis remains limited, even when published mostly in retrospective reports, the diversity of inclusion criteria about the maximum number of metastatic lesions accepted for study, makes it more difficult to compare. However, it has been estimated that aproximatelly 20–50% patients with metastatic NSCLC at diagnosis present with oligometastatic disease [10, 13, 14]. As mentioned before, in the IASLC TNM classification of lung cancer, 22% of all metastatic patients had a single metastatic lesion [10]. The most frequent site of a single lesion was bone, followed by brain, adrenals and liver. In an analysis of 725 NSCLC patients with metastatic disease at diagnosis, 186 (26%) were recognized with oligometastatic disease defined as ≤5 lesions [13]. Of those, 51% of the patients had a single metastatic lesion and in 81% of patients, metastases were limited to one organ site. As in previous analysis, the most common site of a single lesion appearance was brain, bone and adrenal glands. In the group of oligorecurrent NSCLC patients after treatment of the primary site, 50–60% were reported to present with only one to three metastatic sites [4, 15]. The majority of patients who have been treated with surgery, at recurrence presented with metastases in the brain, contralateral lung or adrenal gland. The pattern of oligoprogression in advanced or metastatic NSCLC patients after first-line chemotherapy has been barely reported. In a study of Rusthoven et al., local progression only, was the predominant pattern of failure in 64% of patients after systemic therapy, mostly platinum-based chemotherapy, suggesting that consolidation local therapy after first-line systemic treatment could potentially alter the patterns of failure and prolong time to progression in a substantial proportion of those patients [14]. With the introduction of new systemic treatment possibilities that prolong survival, like tyrosine kinase inhibitors (TKI) in patients with epidermal growth factor receptor (EGFR) mutation/anaplastic lymphoma kinase (ALK) rearrangement, oligoprogression has been reported more often. Molecular targeted therapy with TKI enable higher response rates and better progression-free survival (PFS), however, progression inevitably develops in most cases after 1 to 2 years of molecular targeted treatment due to acquired resistance [16]. Data from literature reveals that the proportion of patients progressing with an oligoprogressive pattern of disease ranges from 15 to 47% during EGFR TKI treatment [17, 18, 19]. Few series also suggest that as many as 25% of patient treated with TKI progress with single metastases and 50% with four or less lesions [17, 20]. For those patients with oligoprogressive or oligoresistance disease, local ablative therapy and continuation of molecular targeted therapy could result in more than 6 months of additional clinical benefits [20].
\nOligometastatic disease is highly divers in prognosis, ranged from rapid progression with demise during treatment to long-term survivals. It is assumed that about 25% of oligometastatic patients will have prolonged disease-free interval [7, 12, 21]. Therefore, the identification of oligometastatic patients that will benefit most from aggressive local treatment is of the crucial importance.
\nAs already mentioned, results from IASLC 8th TNM classification validation study revealed significantly longer OS in patients with a single extrathoracic metastasis than in those with multiple metastases [10]. In the individual patients data meta-analysis of Ashworth et al. 757 oligometastatic NSCLC patients were included from 1985 to 2012 and managed with ablative treatments to all sites of disease, however, half of the patients had only a single metastasis [7]. Surgery was the most commonly used treatment for the primary tumor (83.9%) and metastases (62.3%). Factors predictive for OS were synchronous versus metachronous metastases (P < .001), N-stage (P = .002), and adenocarcinoma histology (P = .036). In recursive partitioning analysis, three risk groups were identified: low-risk, metachronous metastases (5-year OS, 47.8%); intermediate risk, synchronous metastases and N0 disease (5-year OS, 36.2%); and high risk, synchronous metastases and N1/N2 disease (5-year OS, 13.8%). In the analysis of Parikh et al., 186 patients with five or fewer distant metastatic lesions at diagnosis were included, of whom 52% patients had a single metastatic lesion [13]. On multivariable analysis, Eastern Cooperate Oncology Group (ECOG PS) performance status, nodal status N2–3, squamous pathology, and metastases to multiple organs were associated with a greater hazard of death (all P < .01). However, the number of metastatic lesions and radiologic size of the primary tumor were not associated with OS. Definitive local therapy to the primary tumor was associated with prolonged survival. Data from twenty-four studies that included altogether 1935 patients with oligometastatic NSCLC were analyzed in a meta-analysis by Li et al. [22]. Among patients with oligometastatic disease, defined as 5 or fewer lesions, they identified several factors associated with improved survival, including aggressive treatment to the primary lung tumor, female gender, lower nodal stage, adenocarcinoma histology and thoracic stage. Other retrospective publications reported importance of aggressive local treatment [23, 24]; moreover, the major predictors of OS were the extent of intra-thoracic disease including nodal status and possibilities for resection or radical radiotherapy [25, 26, 27]. In the trial by Gomez et al. besides treatment type (local treatment versus no local treatment) presence of driver mutations were associated with improved PFS [28, 29]. Aside of the number of metastases, mediastinal node involvement, time until onset of metastases, histology, PS, T stage, treatment of the primary and metastatic lesions, diagnosis-specific graded prognostic assessment (DS-GPA classification, and Lung-molGPA) is well known for patients with brain metastasis.
\nAdditionally, a specific genetic or epigenetic alterations (“initiation,” “progression,” and “virulence” genes) have been described so far that together with failures in immunosurveillance impact patients‘clinical outcomes. The oligometastatic tumors are believed to have more indolent biology [3]. Initial investigations of the mechanisms running occurrence of oligometastases identified a central role of microRNAs (miRNAs). Lussier and colleagues evaluated miRNA profiles in an analysis of patients with five metastases manageable for RT. They found that overexpression of the miR-200 family was correlated with polymetastatic progression [30]. Moreover, they observed a specific microRNA expression that identified the patients most likely to remain oligometastatic after metastases directed treatment and therefore associated with a better prognosis.
\nSince oligometastatic NSCLC is considered as intermediate state between localized lung cancer and widespread metastatic disease, the therapeutic approaches used for treatment of these patients besides standard systemic therapy include aggressive local therapy.
\nSeveral early case and retrospective reports showed that a subset of NSCLC patients with mostly solitary metastasis that were radically treated to all known metastatic sites, could achieve long-term survival [31, 32, 33]. Following years, more retrospective reports of oligometastatic patients treated with radical intent were published that demonstrating better-than-expected prolonged survival with median OS between 13.5 to 26 months and 5-year survival between 10 to 36% [13, 23, 24, 25, 34, 35, 36, 37]. In an individual patient data meta-analysis on 757 oligometastatic NSCLC treated between 1985 and 2012 with surgical metastasectomy, stereotactic radiotherapy/radiosurgery, or radical external-beam radiotherapy for metastases and with curative treatment of the primary lung cancer, median OS was 26 months, 1-year OS 70.2%, and 5-year OS 29.4% [7].
\nWhile the last decade use of effective local treatment with minimally invasive surgery or advanced radiation technics for oligometastatic lesions in NSCLC patients has risen, the evidence from prospective studies has been lacking. The first prospective single-arm phase II trial of oligometastatic NSCLC patient with up to five metastases at primary diagnosis amendable for radical local treatment was published in 2012 [27]. Forty patients were enrolled with brain, bone and adrenal gland metastases. Of all included, 87% had a single metastatic lesion and 95% of all received chemotherapy as part of their primary treatment. Median OS was 13.5 months and two- and three- year survival rates were 23.3% and 17.5%, respectively. In 2016, Gomez et al. published the results of a prospective multicentre randomized phase 2 trial that enrolled 74 oligometastatic NSCLC patients with the maximum of 3 metastatic lesion [28]. All patients received standard first-line systemic therapy including platinum-based chemotherapy or TKI in patients with EGFR mutations or ALK rearrangements. Patients were randomly assigned to either local consolidative therapy consisting of resection or (chemo) radiotherapy or to maintenance treatment alone. The study was terminated early after randomization of 49 patients as part of the annual analyses due to substantial efficacy improvement in the local consolidative group compared with the maintenance group. At a median follow-up time of 12.39 months, the median PFS in the consolidative group was significantly longer with 11.9 months versus 3.9 months in the maintenance group. Importantly, time to appearance of a new lesion was longer in the consolidative group arm (11.9 months vs. 5.7 months) suggesting that local consolidative treatment may have altered the natural course of the disease, either by limiting the potential for subsequent dissemination or by altering systemic anticancer immune response. In 2018, the updated survival data at a median follow-up of 38.8 month, confirmed the PFS benefit in consolidative group with 14.2 months compared to 4.4 months in the maintenance group and median OS of 41.2 months in the consolidative arm versus 17.0 months in the maintenance arm [29].
\nIn a phase II randomized clinical trial conducted by Iyengar et al., a total of 29 patients with oligometastatic NSCLC were included [38]. Inclusion criteria allowed up to six sites of extra cranial lesions (including primary) and exclude patients receiving first-line molecular targeted therapy with EGFR/ALK TKI. Fourteen patients were assign to the stereotactic body radiation therapy
A third completed randomized phase II trial, SABR (stereotactic ablative radiotherapy)-COMET international trial included patients with a controlled primary malignancy of different solid cancers and 1–5 metastatic lesions manageable for SABR treated between 2012 and 2016 [39]. Ninety-nine patients, of those 18% NSCLC patients, were randomly assigned in a 1:2 ratio between standard-of-care treatments and standard-of-care treatments plus SABR. Median OS was 28 months in the control group versus 41 months in the SABR group. Adverse events of grade 2 or worse were significantly higher in SABR group (29% vs. 9%) with three deaths after SABR. Recently, results of extended follow-up were published [40]. With the median follow-up of 51 months, median OS was 28 months in the control arm versus 50 months in the SABR group. Five-year OS rates were 17.7% versus 42.3%, respectively. There were no new grade 2–5 adverse events.
\nAll three randomized studies have contributed increasingly in the evidence that radical local treatment approach added to standard therapy may yield prolonged survival in selected oligometastatic NSCLC. However, last decade most studies have still been retrospective in nature and biased with respect to definition of oligometastatic disease. Systematic review by Schanne et al. included 54 studies that were published between 1987 and 2018 with altogether 1994 patients with oligometastatic NSCLC [5]. Even with a wide range of oligometastatic definitions, 90% of patients were treated for a single metastasis. 60% of patients were diagnosed with adenocarcinoma and 55% of the metastases were located in the brain, 17% in the lung, 11% in the adrenal gland and 17% in other organs. Systemic therapy was used in 68% of patients in a variety of settings, mostly adjuvant/maintenance or neoadjuvant but also combined with RT. Molecular targeted therapy was used in 5% of cases; however, immunotherapy was not used treatment modality in any of analyzed studies. Surgical resection was the most common local treatment modality used in 76% of patients for primary tumor and in 65% of patients for distant metastases. RT was used as neoadjuvant/adjuvant or definitive treatment of primary tumor in 9% and 22%, respectively. Adjuvant RT after surgical resection for metastatic lesions was used in 27% of patients, mostly after resection of brain metastases. Radiation as primary treatment modality was more common for treatment of metastases than for primary tumors (69% vs. 35%). Median OS in the analyzed studies was 19.6 months (6.2–52.9 months) with an observed plateau and possible long-term survival of 20%. Importantly, this analysis also gives us insight in time trends of management oligometastatic NSCLC patients for the last three decades. Relating to time analysis, in the studies published after 2011 radiotherapy has almost surpassed surgical approaches. Local treatment changed in favor to wider use of radiotherapy for primary tumors from 23 to 41%. Moreover, wider adoption of SBRT instead of conventionally fractionated RT with an increase from 0 to 23% for primary tumors and from 15 to 60% for distant metastases was reported. Additionally, the number of patients receiving no systemic therapies was reduced from 45% before 2011 to 24% afterwards. Notably, a trend for improved median OS over time was observed: patients from reports published after 2011 revealed better OS compared to the earlier period: 28.1 months versus 17.2 months, respectively. Comparing the effect of different type of local treatment, when only studies after 2011 were included, no significant effect on median OS was detected neither for primary tumor nor for metastases.
\nDespite the lack of evidence for optimal treatment of patients with oligometastatic NSCLC, the concept of delivering local radical treatment in patients with oligometastatic NSCLC was incorporated in NSCLC guidelines. The European Society for Medical Oncology (ESMO) Clinical Practice Guidelines due to the limited available evidence propose preferred inclusion in clinical trials [41, 42]. The National Comprehensive Cancer Network (NCCN) guidelines state that patients with NSCLC with limited metastases can receive local radical treatment [43].
\nThe management of oligometastatic NSCLC has changed significantly over the past decades. While surgery, radiotherapy, stereotactic radiotherapy and systemic therapy are the cornerstones of current treatment strategies, treatment modalities have varied over time with respect to the advantages of local treatment techniques as introduction of new systemic treatment possibilities. According to the literature, surgery has been mostly used in oligometastatic NSCLC patients for resection of brain, contralateral lung and adrenal gland metastases [5, 23, 35, 44] Considering the significant morbidity associated with surgical resection of multiple sites of metastatic disease, SBRT has become an alternative treatment approach for achieving local ablation. The highest level of evidence for incorporation of local treatment in oligometastatic NSCLC patients based on small randomize phase II clinical trials, which regularly reported higher PFS and OS with the use of SBRT compared with no SBRT [28, 29, 38, 39, 40]. However, the efficacy of SBRT in potentially curable patients with the stage I NSCLC is already confirmed [45]. The broader adoption of SBRT in clinical practice reflects its non-invasive nature, ability to simultaneous treatment of multiple sites in a short time, feasibility of concurrent local and systemic treatment, utility to treatment in the outpatient setting and relatively low toxicity profile [46, 47]. Moreover, SBRT to the progressing lesions may delay the need to start or change systemic therapy that might reflect in prolonged PFS, OS and quality of life for the patients [48, 49, 50]. In a systematic review by Tsao et al., reported median OS ranged from 13.5 to 55 months and PFS from 4.4 to 14.7 months. [50] SBRT has currently become a treatment option for tumors in almost any body site, with many publications documenting its efficacy for lung, liver, adrenal, and bone/spine metastases, achieving high as much as 70–90% of local control [51].
\nSystemic therapy is the backbone treatment for metastatic NSCLC patients; though it is not well defined in management for oligometastatic NSCLC [41, 42, 43]. Despite potentially successful local treatment, the majority of oligometastatic NSCLC patients will develop distant progression due to undetectable micrometastases at the time of diagnosis. Therefore, all recent prospective trials combined local treatment with addition of systemic therapy standardly used at the time of the study. However, the therapeutic sequence of systemic therapy might be important for oligometastatic disease, as usually only the patients who do not progress with induction systemic treatment were capable for aggressive local treatment. We are currently not able to reliably predict the course of oligometastatic disease at the time of diagnosis, therefore upfront local therapy colud represent an overtreatment due to rapid progression to multimetastatic disease. Although studies with oligometastatic NSCLC have included patients treated with systemic therapy, mostly chemotherapy and minority molecular targeted therapies, current clinical practice and guidelines for treatment of metastatic NSCLC include molecular targeted agents, immunotherapy or combination of immunotherapy and chemotherapy in first-line setting [52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64]. The introduction of new agents as molecular targeted and immunotherapy has resulted in the improved survival in patients with metastatic and locally advanced NSCLC. As a result, the first line systemic therapies used in most retrospective and prospective studies of oligometastatic NSCLC do not reflect those currently used. With onset of new systemic therapies in the management of NSCLC patients, great interest has risen in exploring the safety and efficacy of combined SBRT with new agents to improve the therapeutic outcomes in metastatic NSCLC as well as in oligometastatic disease.
\nPatients with actionable tumor mutations have high response rates and long PFS times when treated with molecular targeted therapy [54, 55, 56, 57, 58, 59, 60, 61, 62]. However, progression inevitably occurs due to either insufficient CNS passage of the drug in some cases of CNS progression, or to acquired resistance with biological change in the tumor cells. The concept of oligoprogression supports the idea of disease progression due to the development of TKI-resistant clones with subsequent distant progression [65]. Different scenarios of progression in patients with actionable tumor mutations including oligoressistance, oligoreccurence or oligoprogression requiring consideration for local treatment. In the analysis of Guo et al. the majority of progressive disease on osimertinib was reported within residual lesions in initially involved sites, thus consolidative SBRT may prolong time to progression in a selected subgroup of patients [66]. In a retrospective study of Xu et al., 145 patients with oligometastatic EGFR-mutant NSCLC diagnosed from 2010 to 2016 were enrolled [67]. According to consolidative local treatment with surgery or radiotherapy, patients were grouped in three category, 51 in the all-local therapy group (consolidative to all residual disease, including primary tumor, lymph nodes, and metastatic sites), 55 in the part-local therapy group (consolidative to either primary tumor or oligometastatic sites), and 39 in the non-local therapy group (not receive any local therapy). Radiotherapy included standard-fractionation radiotherapy (60 Gy in 2-Gy fractions), aggressive palliation radiotherapy (45 Gy in 3-Gy fractions, a biologically equivalent dose of approximately 60 Gy) or stereotactic radiosurgery (SRS), with curative intent when possible. The median PFS in all-local, part-local, and non-local groups were 20.6, 15.6, and 13.9 months, respectively (p < 0.001). The median OS in all-local, part-local, and non-local groups were 40.9, 34.1, and 30.8 months, respectively (p < 0.001). The difference was significant between the all-local group and part-local or non-local group. The median OS was significantly better with consolidative local therapy for primary tumor (40.5 versus 31.5 months, p < 0.001), brain metastases (38.2 versus 29.2 months, p < 0.002), and adrenal metastases (37.1 versus 29.2 months, p < 0.032). Radiation toxicity was acceptable, included grade ≥ 3 pneumonitis (7.7%) and esophagitis (16.9%). No grade 5 toxicity was reported. A retrospective multi-institutional analysis by Magnuson et al. explored the optimal management of patients with EGFR-mutant NSCLC who developed brain metastases and have not received EGFR TKI [68]. A total of 351 patients from six institutions were included. Patients were treated with SRS followed by EGFR-TKI, WBRT followed by EGFR-TKI, or EGFR-TKI followed by SRS or WBRT at intracranial progression. The median OS for the SRS, WBRT, and EGFR-TKI cohorts was 46, 30 and 25 months, respectively (P < .001). On multivariable analysis, SRS versus EGFR-TKI, WBRT versus EGFR-TKI, age, performance status, EGFR exon 19 mutation, and absence of extracranial metastases were associated with improved OS. SRS followed by EGFR-TKI resulted in the longest OS and allowed patients to avoid the potential neurocognitive sequelae of WBRT.
\nIn a retrospective analysis of Elamin et al. 129 patients with EGFR-mutant NSCLC who were treated with first-line TKI and 12 that were treated with TKI followed by local consolidation therapy were included [69]. Among the 12 patients treated with TKI plus local consolidative treatment, 8 patients had oligometastatic disease (defined as 3 metastases), and 4 patients had >3 metastases. Local consolidative treatment regimens were hypofractionated radiotherapy or SBRT for 11 patients and surgery for 1 patient. TKI followed by local consolidative treatment resulted in a significantly longer PFS (36 months) compared with TKI alone (14 months). Recently, Wang et al. presented an interim result of a randomized phase III, open-label clinical trial of first-line tyrosine kinase inhibitor with or without upfront local RT in patients with EGFR oligometastatic NSCLC [70]. From January 2016 to January 2019, 133 participants were enrolled, including 65 in the TKI arm who received standard of care TKI alone and 68 in the SBRT arm who received SBRT and TKI. At a median follow-up of 19.6 months, the median PFS for TKI alone was 12.5 months, and for TKI and SBRT was 20.20 months, respectively (P < .001). The median OS in the TKI alone arm was 17.40 months, and for TKI and SBRT arm was 25.50 months, respectively (P < .001).
\nConcerning the safety profile for combining EGFR or ALK TKI inhibitors and high dose RT, treatment was well tolerated and none of the available studies reported a significant increase in side effects [66, 67, 68, 69]. To conclude, SBRT in combination with molecular targeted agents in actionable mutations NSCLC patients seem rationale for improving long-lasting disease control in synchronous oligometastatic oncogene addicted NSCLC patients; however no prospective data are available to confirm this.
\nImmunotherapy with immune checkpoint inhibitors has revolutionized the management of stage IV NSCLC. In recent years, the blockade of programmed cell death 1 (PD-1) / programmed cell death ligand 1 (PD-L1) axis which served as a mechanism for tumor evasion of host tumor antigen-specific T-cell immunity, has demonstrated evident benefit in PFS and OS in metastatic and locally advanced NSCLC [61, 62, 63, 64, 71, 72]. The indications for PD-1/PD-L1 blockade with immune checkpoint inhibitors (ICI) currently include most metastatic NSCLC patients without actionable tumor mutations, either as a single agent or combined with cytotoxic chemotherapy. The anti-PD-1/PD-L1 drugs approved at the moment for NSCLC are pembrolizumab, nivolumab, atezolizumab and durvalumab. Despite this paradigm shift, most patients present some kind of resistance to ICI, therefore arise the interest of researchers to combine multiple therapies. According to growing preclinical data describing mechanistic synergy between radiotherapy and immunotherapy, the most promising investigated combination is ICI with RT [73, 74]. Rational for combining radiotherapy and immunotherapy arises from the significant immune-stimulatory effects they both possess increasing the natural antitumor immune response through synergistic potentiation of an immunomodulatory effect [75, 76]. Increasing evidence indicates that cancer cells killed by radiation release tumor-associated antigens and immunoregulatory cytokines that serve as a kind of in situ vaccine against cancer [77, 78]. Cytokines also activate systemic tumor-specific immune response to eliminate tumor cells even outside the radiation field, so called abscopal effect [79]. This radiation-induced immune-mediated systemic antitumor phenomenon has high therapeutic potential, but is rare and relating to preclinical data more probable induced by high ablative doses, combined with checkpoint inhibitors [80, 81]. SBRT, through released neo-antigens and consequent maturation and proliferation of naive T-cells, and immunotherapy through activation and amplification of naive T-cells, may reciprocally potentiate each other amplification of T-cells-mediated tumoricidal effects [82, 83, 84]. Due to the lack of evidence, most “immunogenic” time sequencing of radio-immunotherapy and radiation dose-fractionation is not determined. Some data indicate that concurrent treatment or close sequencing of immunotherapy following radiotherapy may be the most effective [82]. However, according to data the radiation dose for the optimal antitumor immune response should be sub-tumoricidal. Several preclinical studies suggested that 8 to 10 Gy per fraction in 1–3 fractions represent optimal immunogenic dose [82, 83, 84].
\nClinical interest for the combination of ICI and RT in NSCLC started to arise after the results of the KEYNOTE-001 study that enrolled progressive locally advanced or metastatic NSCLC [85]. A secondary analysis of the phase I trial revealed that of 97 included patients, 43% had been treated with RT prior to the administration of pembrolizumab. Those patients had significantly longer PFS (4.4 vs. 2.1 months) and OS (11.6 vs. 5.3 months) comparing patients with no RT. A single-arm phase 2 study of Bauml et al. included 45 patients with oligometastatic NSCLC with up to 4 metastatic sites [86]. Pembrolizumab was administered 4 to 12 weeks after prior comprehensive locally ablative therapy consisting of radiotherapy, chemoradiotherapy, surgery, or radiofrequency ablation, but most received ablative radiotherapy. Median PFS was 19.1 months, significantly greater than the historical median of 6.6 months (P = .005). OS at 12 months was 90.9% and at 24 months 77.5%. Even not conducted in oligometastatic NSCLC patients, the results of a multicetre, randomized phase 2 study (PEMBRO-RT) are interested. 92 patients were enrolled with advanced NSCLC after at least one regiment of chemotherapy with at least two metastases but upper limit was not specified [87]. Altogether, 76 patients were randomized to the pembrolizumab alone (control, 40 patients) or pembrolizumab after radiotherapy (3 fraction of 8 Gy) that was applied to a single metastatic site (experimental, 36 patients) to increase the likelihood of abscopal effect. The overall response rate at 12 weeks was 18% in the control arm vs. 36% in the experimental arm (P = .07). Median PFS was 1.9 months vs. 6.6 months (P = .19), and median OS was 7.6 months vs. 15.9 months (P = .16). Although a doubling of overall response rate was observed, the results did not meet the study’s prespecified end point criteria for meaningful clinical benefit. Interestingly, subgroup analyses showed the largest benefit of radiotherapy in patients with PD-L1 – negative tumors. In a retrospective study of Samstein et al. 758 patients treated with ICI and RT were analyzed [88]. Median OS was 9 months in the entire cohort. Subanalysis regarding sequencing ICI and RT revealed increased OS in patients who received ICI and RT simultaneously. Median OS was 20 months for patients who started with ICI for at least 1 month before RT and continued throughout RT compared with 11 months for those that started ICI less than 30 days prior to RT and continued ICI throughout RT. In the cohort of patients who received concurrent therapy, hypofractionated radiotherapy (dose >4.00 Gy per fraction) and ICI greater than 30 days before RT was associated with improved OS.
\nProspective data for management of patients with oligometastatic NSCLC in the era of immunooncology is scarce. Most of the available data on combining ICI and SBRT has been retrospective experiences on patients with metastatic NSCLC; however the benefit of combined treatment has been persistently demonstrated [89, 90, 91]. Importantly, the available data suggest that toxicity profile from the combination treatment has not increased in comparison to immunotherapy alone in the metastatic setting. A recent systematic review from prospective studies revealed grade ≥ 3 median toxicity rates of 14.5% with anti-PD-1/L1 plus SABR and 26% with anti-CTLA-4 plus SABR [92]. Concerning toxicity, no increased rates of immune-related adverse events using SBRT in the different organs or tissue types have been reported. However, reports from the studies that combined dual ICI therapy with SBRT in different cancers in prospective trials detected more toxicity.
\nIn the future management of oligometastatic NSCLC patients, more questions should be answered. In the era of immunooncology, local treatment still presents the backbone of management with adding ICI to improve outcome of oligometastatic NSCLC patients. However, future prospective studies should give us answers to what sequence of local treatment and ICI is the most optimal combination, which radiation technique and fractionation would offer the best results, which patients should be selected for radical-intent treatment regarding biomarkers. A great number of trials combining ICI and RT are ongoing. Regarding oligometastatic NSCLC, one is of particular interest, a randomized trial of consolidative immunotherapy with vs. without thoracic radiotherapy and/or SBRT after first-line systemic therapy for metastatic NSCLC comparing PFS as primary objective (NCT03867175).
\nAn important growing subsegment of NSCLC patients is a group with oligoprogressive disease. With more effective systemic therapies that offer high response rates and long PFS times in patients with metastatic NSCLC, the oligoprogressive disease has become more and more common clinical scenario. Oligoprogressive disease, presented in oncogene driven NSCLC mostly occur due to the isolated emergence of well-described resistance mutations [65]. According to the literature, the occurrence of oligoprogression during TKI treatment seems to be quite frequent, reported in the range of 32–49% [17, 19, 20]. However, the optimal therapeutic approach in these patients is still unclear. Three main treatment options include changing systemic therapy, continuing the same systemic therapy beyond progression or using local therapy for eradicate the resistant clones while continuing the same systemic therapy [41]. The evidence supporting local treatment is limited to small retrospective reports. Weckhard et al. reported that 49% of ALK or EGFR positive metastatic NSCLC patients are treated with TKI presented with intracranial or extracranial oligoprogression suitable for local treatment [20]. Of 25 patients, 24 were treated with RT and one underwent surgery; however, 19 of 25 locally treated patients progressed again with PFS of 6.2 months. Yu et al. reported on 184 patients with EGFR mutation, of these 42 progressed with intracranial and 18 with extracranial oligometastases. These 18 were treated with local therapy, including surgery, radiofrequency ablation or RT with the median TTP of 10 months. Gan et al. reported on 33 ALK+NSCLC patients treated with crizotinib that had extracranial oligoprogression. Of these, 14 were suitable for local treatment with SBRT. Median overall time on crizotinib among those treated with SBRT versus those who progressed but were not suitable for SBRT was 28 and 10.1 months, respectively. Patients remaining on crizotinib for >12 months vs. ≤12 months had a 2 year OS of 72% vs. 12%, respectively (p < 0.0001) [93]. Xu et al. reported on 206 EGFR-mutant NSCLC patients included in the analysis of the survival benefit of adding local ablative therapy after oligoprogression during first-line TKI. With the median follow-up time of 42 months, the median PFS1, median PFS2 and median OS were 10.7 months, 18.3 months and 37.4 months, respectively. Survival rates of 1 year, 2 years and 3 years were 94.1%, 78.9%, and 54.7%, respectively. Altogether, the data suggest that local ablative treatment of progressive lesions in actionable mutations NSCLC patients can prolong treatment with first-line TKI without reported unacceptable excess toxicity. Moreover, despite the paucity and the heterogeneity of clinical data the use of local therapy in oligoprogressive oncogene driven NSCLC is already considered as standard clinical practice [94].
\nCurrently, a few prospective randomized clinical trials are ongoing researching the benefit of local ablative treatment in oligoprogressive NSCLC. A Canadian trial, the STOP-NSCLC (NCT02756793) is a randomized phase II trial with estimated enrolment of 54 patients with oligoprogressive NSCLC during TKI or maintenance chemotherapy that evaluate either SBRT with continuation of current systemic agents or standard of care that may include continuation of current systemic agent, observation or switch to next-line treatment. Primary end-point will be PFS, while secondary end-points will be OS, local control, toxicity, quality of life and patterns of further progression. Similarly, European HALT study (NCT03256981) is a phase II/III, randomized study with question whether the use of SBRT to ≤3 sites of oligoprogressive disease in mutation positive advanced NSCLC patients with continuation of TKI improves PFS compared to continuation of TKI alone. The study aims to recruit 110 patients with oligoprogressive mutation positive advanced NSCLC following initial response to TKI. Third ongoing randomized trial is PROMISE-004 (NCT03808662) study with heterogeneous cohort including breast and NSCLC patients and estimated enrolment of 160 patients with either no targetable mutations upfront or targetable mutations after progression on first-line TKI. The purpose of the study is to evaluate the role of SBRT when metastatic lesions have just begun to grow with PFS as primary end-point.
\nIn the context of immunotherapy in NSCLC patients, which includes the majority of lung cancer patients currently, tumor escape is not uncommon, but studies of oligoprogression are lacking. According to mechanism, oligoprogression might represent local immune tolerance due to stromal or tumor changes. Recently, in order to specify oligoprogression in NSCLC patients treated with immunotherapy, the results of a retrospective analysis of the failure pattern of 297 on ICI and 75 patients treated combined with chemotherapy and ICI were published [95]. Under ICI monotherapy in the first-line treatment, oligoprogression was more frequent (20% vs. 10%, p < .05), occurred later (median 11 vs. 5 months, p < .01) and affected fewer sites (mean 1.1 vs. 1.5, p < .05) compared to oligoprogression in patients treated with ICI monotherapy in later lines. Lymph nodes (42%, manly mediastinal) and the brain (39%) were mostly affected, followed by the lung (24%) and other organs. Compared to multifocal progression, oligoprogression occurred later (11 vs. 4 months, p < .001) and was associated with longer survival (26 vs. 13 months, p < .001) and higher tumor PD-L1 expression (p < .001). Chemoimmunotherapy showed a similar incidence of oligoprogression as ICI monotherapy (13% vs. 11% at 2 years). Local treatments were applied regularly for brain but only in 50% for extracranial lesions. However, oligoprogression in NSCLC patients is less common under ICI treatmnet than under TKI and its frequency descent with time. Few prospective trials evaluate the value of RT in oligoprogressive NSCLC treated with ICI, with one randomized phase II study designed to evaluate the effect of local consolidative RT to all sites of oligoprogressive disease in patients with metastatic NSCLC who have progressed through first-line systemic therapy containing an ICI (NCT04485026).
\nThe number of patients with oligometastatic NSCLC has increased significantly over the last decade as well as the use of the locally ablative therapy to treat these patients. The evidence supporting this approach includes three randomized phase II clinical trials and substantial retrospective data; however, the inclusion criteria in these trials were mostly incomparable. Oligometastatic NSCLC has recently been defined by a consensus of multidisciplinary group of European thoracic oncology experts and this was the first step to unify future researching regarding diagnostic procedures and inclusion criteria. Recently, the therapeutic landscape of metastatic NSCLC has dramatically changed with the introduction of new systemic agents as molecular targeted and immunotherapy resulting in the prolonged survival and changing the field of oligometastatic framework significantly. A new concept that emerged with more effective systemic therapy is oligoprogression, frequently presents in patients treated with TKI. Additionally, combining radiotherapy and immunotherapy represent an increasing filed of interest due to synergistic potentiation of an immunomodulatory effect as a way to overcome the resistance of immunotherapy that exist in a substantial part of metastatic NSCLC patients. Especially for oligometastatic NSCLC patients, this integration might be meaningful due to a low tumor burden that seems to be one of the most important predictive factors for the benefit of SBRT-immunotherapy combination. In the future, further studies are needed to assess different treatment variables in order to optimize management of oligometastatic NSCLC in the way that the intent of treatment might not be just prolonged survival but cure.
\nCoronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was declared a pandemic by the World Health Organization on March 11, 2020 [1]. The infection rate caused by the virus increased exponentially in 2020 until March 13, 2021, registering 119,165,535 confirmed cases and 2,641,567 deaths [2].
Pregnant and puerperal women have been considered groups at risk of morbidity and mortality since the beginning of the COVID-19 pandemic because of the physiological and immunological changes that can increase the risk of complications in respiratory infections and the knowledge of unfavorable outcomes in pregnant women and their newborns in infections caused by other coronaviruses, SARS, Middle East respiratory syndrome, and influenza [3, 4, 5, 6].
Some adverse outcomes of SARS-CoV-2 infection observed during pregnancy include admission to the intensive care unit (ICU) or death. However, the clinical evolution of COVID-19 in most women is not serious, resembling the general population [7, 8].
Initially, there was no evidence of vertical transmission due to COVID-19 during pregnancy [3, 5, 6]. During the pandemic, several studies concluded that there was this possibility [9, 10], with one confirmed case of vertical transmission occurrence [11]. However, all of them suggested that further studies should be conducted on the subject, as it is a recent disease and the number of participants in the published studies is small.
There is strong evidence that other viral infections cause neurological and behavioral changes in the fetus, such as the influenza virus related to schizophrenia [12]. Other viral infections, such as the Zika virus (ZIKV), can cause malformations, including microcephaly [13].
Therefore, outpatient monitoring of children exposed to the SARS-CoV-2 virus during pregnancy is vital to understand the impacts of the disease on the growth and development of these children.
A narrative review was carried out using the keywords: COVID-19, SARS-CoV-2, vertical transmission, perinatal infection and offspring. In addition to the search for other viral infections: influenza, herpes simplex, rubella, cytomegalovirus and human immunodeficiency virus (HIV). The authors searched the Pubmed, Medline, and Google Scholar databases, reviewed the available articles, and determined which articles were most relevant to the project.
Pregnancy is a risk factor for infection by the influenza virus. During the 1918 (Spanish flu) and 1957 (Asian flu) pandemics, mortality in pregnant women was high. During the 1918 pandemic, a 27% mortality rate was recorded, and in 1957, it corresponded to 50% of deaths in women of reproductive age [14]. In seasonal influenza periods, an increased risk of hospitalization was observed in pregnant women at any stage of pregnancy, even without associated comorbidities [15].
There were higher rates of premature births, small for gestational age newborns, and stillbirths in hospitalized pregnant women than those in outpatient treatment [16]. Regarding the occurrence of malformations in the fetuses, the possibility of its teratogenic effect with the occurrence of neural tube defects, cleft lip and palate, and congenital heart disease was evaluated. A direct effect of the virus was unlikely to be the cause of these malformations, since control of fever with antipyretics, and the use of periconceptional folic acid in pregnant women with influenza reduced the risk of these malformations in their offspring (Table 1) [17].
Viral disease | Clinical manifestation |
---|---|
Influenza | Premature birth, small for gestational age newborns, stillbirths, pregnant woman hospitalization, fetus malformation, schizophrenia |
Rubella | Congenital rubella syndrome (CRS), abortion, stillbirth, restricted urterine growth |
Herpes simplex | Triad: cutaneous, neurological and ophthalmic symptoms |
CMV | Intrauterine growth restriction, hepatosplenomegaly, microcephaly, chorioretinitis, petechiae, jaundice, thrombocytopenia, anemia |
HIV infection | Miscarriages, stillbirths, perinatal mortality, intrauterine growth restriction, low birth weight, chorioamnionitis |
Zika virus | Intrauterine growth restriction, small for gestational age, brain malformation, microcephaly, eye and hearing abnormalities, hypospadias, cryptorchidism, micropenis |
COVID-19 | Intense inflammatory response and placenta hypoxia can lead to abortions, pre-eclampsia, prematurity, IUGR |
Clinical manifestations of conceptuses resulting from the infection of pregnant women by viral disease.
Influenza infection in the first trimester of pregnancy increased the risk of schizophrenia by seven times. There was no increased risk in the other trimesters of pregnancy, according to a nested case–control study of 64 participants who were born from 1959 to 1966 and had psychiatric disorders 30 to 38 years later [12].
A cohort study of 196,929 children conducted in California did not find an increased risk of autism spectrum disorder (ASD) in offspring of pregnant women with influenza. In addition, there was no statistically significant relationship of ASD in children whose mothers received influenza vaccination in the first trimester [18].
There are two types of herpes viruses: HSV-1 and HSV-2. The latter is predominantly sexual and the etiologic agent of 70–85% of neonatal infections. Although transplacental or upward transmembrane transmission of HSV from the mother to the fetus during pregnancy is uncommon (about 5%), the rate of perinatal transmission during labor and delivery is 80–90%. The risk of neonatal infection is higher in HSV infections that start in late pregnancy (30–50%) than in early pregnancy (1%) [19, 20].
Intrauterine infection is clinically present in the fetus as a characteristic triad of cutaneous (vesicles, erosions, and scars), neurological (intracranial calcifications, microcephaly, and meningoencephalitis), and ophthalmic symptoms (microphthalmia and chorioretinitis). The clinical manifestations of neonatal peripartum and postpartum infection are found in the skin, eyes, and/or mouth (45%) and central nervous system (CNS; 30%) or as disseminated infection (25%). Regarding mortality and neurological prognosis, mortality is higher in disseminated infection cases (approximately 30%), and a worse neurological prognosis occurs in cases with CNS involvement (50%). In the treatment of neonatal HSV, high doses of intravenous acyclovir are indicated, which improves the prognosis and reduces the occurrence of neurological sequelae and delayed child development (Table 1) [19, 21].
It is an acute viral disease caused by the RNA Rubella virus of the Togaviridae family. Its clinical characteristics in healthy adults are often self-limited and include low fever, maculopapular rash, lymphadenomegaly, and oropharyngeal pain. The rates of asymptomatic cases range from 25–50% [22].
In pregnancy, maternal infections can determine a poor prognosis for the conceptus, especially when it occurs in the first trimester of pregnancy, which can result in congenital rubella syndrome (CRS), abortion, stillbirth, congenital malformations, and restricted uterine growth of the conceptus. The chances of malformation are 81% and 25% in the first and second trimesters, respectively. Rubella immunization is considered the best measure to combat this infection in the world. CRS has already been significantly eliminated in the USA; however, it cannot be said that it has been completely controlled, since outbreaks are still reported around the world [14].
Rubella virus infection findings can be found from prenatal life to later manifestations after the child’s birth and development. Among them, it can cause ocular alterations (cataract, microphthalmia, glaucoma, pigmentary retinopathy, and chorioretinitis), cardiac malformations (peripheral pulmonary artery stenosis, patent duct artery, or ventricular septal defects), and CNS alterations (microcephaly). Children who survive the neonatal period may have severe developmental disabilities (e.g., visual and hearing impairments) and an increased risk of developmental delay, even autism. In the long term, congenital rubella infection may determine an increased risk of endocrinopathies, such as thyroiditis and insulin-dependent diabetes mellitus (Table 1) [23, 24].
CMV, like other viruses in the Herpesviridae family, causes a primary infection and remains latent in the body. Primary infection is generally harmless, but it can be fatal in immunocompromised patients and cause serious fetal damage due to vertical transmission, which can occur intrauterine during childbirth through cervical and blood secretions and postnatally through breastfeeding. Thus, identifying infection in pregnant women is important [25].
In 1–4% of pregnant women, seroconversion to CMV occurs, with most women being seropositive before pregnancy, which does not prevent the infection in about 60% of babies during pregnancy. In newborns, 0.2%–2.5% are infected in utero, and most are asymptomatic (90–80%). About 10–20% of neonates have symptoms at birth, such as intrauterine growth restriction (IUGR), hepatosplenomegaly, microcephaly, chorioretinitis, petechiae, jaundice, thrombocytopenia, and anemia. Of them, 20–30% progress to death, mainly from disseminated intravascular coagulation, liver dysfunction, or bacterial infection. Even asymptomatic children at birth can present sequelae of neurological development, such as mental retardation, motor impairment, sensorineural hearing loss, or visual impairment (Table 1) [26, 27].
Vertical transmission by HIV can occur during pregnancy, childbirth, and during breastfeeding. Test implementation for HIV detection in prenatal care, antiretroviral therapy (ART) use during pregnancy and by the newborn after birth, elective cesarean delivery indication, and breastfeeding contraindication reduce the risk of HIV transmission to the baby from 40% to less than 1% in the USA [28].
Children exposed but not infected to HIV during pregnancy have a worse prognosis than those who are not since their mothers are more likely to have low CD4+ cell counts, detectable viremia, and higher morbidity. In addition, the effects on fetal development due to maternal immune dysfunction and the potential dysfunction of hereditary mitochondria in the fetus due to the exposure of women with HIV in early childhood to ART are unknown [29]. Adverse results in pregnancy associated with HIV infection can result in miscarriages, stillbirths, increased perinatal mortality, IUGR, low birth weight, and chorioamnionitis [30]. In symptomatic pregnant women, an increase in premature births has been observed (Table 1) [28].
ZIKV is a flavivirus transmitted by mosquitoes, mainly by
One cohort study evaluated 244 pregnant women with confirmed ZIKV infection during pregnancy and reported that 223 (91.4%) babies were born alive. Of these, 216 babies had clinical follow-up after birth, of which 130 (60%) children had blood and/or urine samples obtained for ZIKV detection using the real-time polymerase chain reaction (RT-PCR) technique. Results revealed that 13% of the children who underwent brain imaging exams had structural brain abnormalities such as microcephaly, 5.5% who underwent ophthalmological evaluation had ocular changes, and 12.1% who underwent additive evaluation had an abnormal result. In addition, 7.7% were born small for gestational age, which may be associated with IUGR. Meanwhile, 19% who underwent neurological exams had an abnormality in the first 6 months of life. Neurodevelopment assessments carried out after 1 year of age showed that 13.2% had severe developmental delay (Table 1) [33].
At the beginning of the pandemic, the clinical manifestations of COVID-19 in pregnant women and babies were unknown. Some studies concluded that the evolution of SARS-CoV-2 infection in pregnant and nonpregnant women was similar [6, 34]. A case–control study compared the clinical evolution of COVID-19 between pregnant women with and without COVID-19 and observed that pregnant women with mild symptoms of COVID-19 have a similar evolution to those without the disease. However, pregnant patients with severe or critical illness have worse results. The risk factors for a worse maternal and neonatal outcome include black and Hispanic race, advanced maternal age, obesity, comorbidities (diabetes mellitus and chronic hypertension), and admission to the COVID-19-related antepartum [35].
Immune responses in pregnancy induce that pregnancy is a risk factor for SARS-CoV-2 infection. In both normal and COVID-19-infected pregnancies, maternal immune responses occur as a result of decreased lymphocytes, inhibitory natural killer cell receptor activation such as NKG2A, and increased inflammatory cytokines (interferon-ɣ, interleukin (IL)-2, IL-6, IL-7, IL-10, and tumor necrosis factor-α) [36, 37]. In addition, the angiotensin-converting enzyme 2 is the receptor for SARS-CoV-2 and is widely expressed in the female reproductive system (ovary, uterus, vagina, and placenta) and fetal tissues; therefore, vertical transmission of COVID-19 is possible [38, 39].
The fetuses of mothers infected with SARS-CoV-2 may be exposed to an intense inflammatory response, which can induce placental or fetal damage. Nonspecific anatomopathological changes were observed in SARS-CoV-2 infected placentas, and the most common finding was poor placental perfusion on the maternal side due to maternal hypoxia secondary to severe pulmonary infection by COVID-19. Both maternal immune response and poor placental perfusion can result in abortions, pre-eclampsia, prematurity, and IUGR [37, 40].
A study that evaluated the fetal inflammatory response in newborns of mothers infected with COVID-19 in the third trimester observed an increase in IL-6 in the fetuses, which may determine adverse sequelae of neurological development, including autism, psychosis, and long-term sensorineural deficits. However, longitudinal studies are needed to validate these associations (Table 1) [37, 41].
Only one study confirmed the vertical intrauterine transmission. In the case report described by Vivanti et al., the pregnant woman was in her last trimester of pregnancy (35 weeks) when she developed symptoms and was diagnosed with COVID-19. Cesarean delivery was indicated because of fetal distress. The conceptus was resuscitated at birth and transferred in invasive mechanical ventilation to the ICU. The virus was investigated and detected by RT-PCR from the amniotic fluid, placental tissue, bronchoalveolar lavage fluid, blood, and nasopharyngeal and anal swabs. The conceptus evolved with neurological manifestations similar to those described in adult patients with COVID-19 [11].
A review study evaluated 108 pregnant women confirmed with COVID-19 and found that 86 had pregnancy resolution. Of the newborns, 75 were tested for SARS-CoV-2 using RT-PCR, and only one was positive (1.3%). The test was collected at 36 h of life. The patient presented a good clinical evolution with reports of lymphopenia and increased liver enzymes in laboratory tests. The average gestational age of the 86 pregnancies evaluated was 36 weeks and 1 day. One baby died at birth (1.1%), and one pregnancy resulted in intrauterine death (1.1%). In both cases, the mothers had severe COVID-19. Seven babies (8.1%) required admission to the neonatal ICU [42].
A study of nine case series and two case reports evaluated 65 mothers confirmed for COVID-19 and 57 newborns. The report revealed that 31% of cases had fetal distress, and 38% of pregnant women had a premature birth. Neonatal complications were breathing difficulties or pneumonia (18%), low birth weight (13%), skin rash (3%), disseminated intravascular coagulation (3%), asphyxia (2%), and perinatal death (3%). Twenty-seven newborns underwent RT-PCR for SARS-CoV-2 by nasopharyngeal swab. Of them, four were positive: one newborn was healthy, and three had pneumonia and positive results on nasopharynx and anal swabs on days 2 and 4 of life. The question remains whether some of the maternal and neonatal complications reported are due to the virus and not iatrogenic, for example, the indication for cesarean delivery determining premature birth [43].
The infection by the SARS-CoV-2 virus presents neurological manifestations, which can be a consequence of cardiorespiratory failure and metabolic abnormalities triggered by the infection, direct invasion of the virus, or an autoimmune response to the virus. Among the neurological symptoms observed were headache, ageusia, anosmia, dizziness, myalgia/myositis, and stroke [44, 45]. The effects of this neurotropism of the virus should be investigated in children, especially in newborns whose mothers were infected during pregnancy, since its consequences on children’s neurological development are unknown. In addition, the effects of infection according to the trimester of pregnancy are unknown, leaving doubt about the prognosis of children of mothers infected in the first trimester, in relation to other periods of pregnancy (Table 2).
COVID-19 study | Neonate clinical manifestation |
---|---|
Wong YP, Khong TY, Tan GC, 2021 | Poor placenta perfusion: abortions, pre-eclampsia, prematurity and IUGR |
Cavalcante M, Cavalcante C, Sarno M, Barini R, Kwak-kim J, 2021 | |
Wong YP, Khong TY, Tan GC, 2021 | Increase in IL-6: autism, psychosis and long-term sensorineural deficits |
Liu P, Zheng J, Yang P, Wang X, Wei C, Zhang S, et al., 2020 | |
Vivanti AJ, Vauloup-Fellous C, Prevot S, Zupan V, Suffee C, Do Cao J, et al., 2020 | Conceptus evolved with neurological manifestations similar to those described in adults patients with COVID-19 |
Zaigham M, Andersson O, 2020 | Outcome of death at birth and intrauterine death of fetuses from mothers confirmed for COVID-19 |
Zimmermann P, Curtis N, 2020 | Fetal distress, premature birth, breathing difficulties, pneumonia, low birth weight, skin rash, disseminated intravascular coagulation, asphyxia and perinatal death |
Studies that evaluated the clinical manifestations in newborns born to mothers confirmed with COVID-19.
International Health Security, also called “global health security” or “public health security”, has as its main objective to maintain humanity’s well-being through prevention. Its focus is not only on diseases (infectious, chronic), it also encompasses social determinants of health, bioterrorism, climate change, cybersecurity in health and other situations.
COVID-19 is a threat to international health security, as it has repercussions in all aspects of human health, physical, social and mental well-being, as the disease causes death, sequelae, compromised mental health and social of individuals.
In children, in addition to the impact of the absence of face-to-face classes in schools and social interaction, the impact of intrauterine SARS-CoV-2 infection on their neurological and body development is still uncertain. Being an item of extreme importance to International Health Security.
It is vital to monitor the growth and proper development of children exposed to COVID-19 during pregnancy since whether or not vertical transmission occurs is still uncertain, and if confirmed, fetal prognosis should be improved through diagnosis to determine early consequences. Several viral infections during pregnancy can compromise the health of the fetuses in the short, medium, and long term.
The authors declare no conflict of interest.
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Montenegro, María L. Boiero, Lorena Valle and Claudio D. Borsarelli",authors:[{id:"97039",title:"Prof.",name:"Claudio Darío",middleName:null,surname:"Borsarelli",slug:"claudio-dario-borsarelli",fullName:"Claudio Darío Borsarelli"},{id:"99668",title:"Dr.",name:"Mariana A.",middleName:null,surname:"Montenegro",slug:"mariana-a.-montenegro",fullName:"Mariana A. Montenegro"},{id:"135406",title:"BSc.",name:"María L.",middleName:null,surname:"Boiero",slug:"maria-l.-boiero",fullName:"María L. 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Turick, A.S. Knox, J.M. Becnel, A.A. Ekechukwu and C.E. Milliken",authors:null}],mostDownloadedChaptersLast30Days:[{id:"64746",title:"HyStem®: A Unique Clinical Grade Hydrogel for Present and Future Medical Applications",slug:"hystem-a-unique-clinical-grade-hydrogel-for-present-and-future-medical-applications",totalDownloads:4393,totalCrossrefCites:2,totalDimensionsCites:3,abstract:"Medicine needs targeted, minimally-invasive delivery of protein-based and cell-based therapeutics to increase efficacy and reduce occurrence and severity of side effects. Local delivery requires a matrix to sequester and protect the medicine until its effect can be realized. The problem is, unlike stable small molecule drugs, proteins and cells cannot be co-packaged with a matrix in a prefilled syringe—they must be mixed with their matrix at the point of care. HyStem hydrogels fix this problem: They are arguably the first commercially available, GMP-qualified biodegradable hydrogels both with the ability to formulate with either proteins or cells in the hospital/surgical suite and with a history of safe use in humans. HyStem is designed to be protein, cell-friendly and in situ crosslinkable, permitting homogeneous mixing of therapeutics. One HyStem formulation is 510(k) cleared and another the subject of two European clinical trials. Key applications include localized delivery of therapeutic growth factors, antibodies, and cells. In the future, we envision HyStem’s flexibility and clinical use history forming the basis for a new generation of therapeutics. Two examples described here include HyStem’s use for patient-derived organoid culture to develop new drugs as well as for bioprinting to manufacture new organs.",book:{id:"8353",slug:"hydrogels-smart-materials-for-biomedical-applications",title:"Hydrogels",fullTitle:"Hydrogels - Smart Materials for Biomedical Applications"},signatures:"Thomas I. Zarembinski and Aleksander Skardal",authors:[{id:"262573",title:"Dr.",name:"Thomas",middleName:null,surname:"Zarembinski",slug:"thomas-zarembinski",fullName:"Thomas Zarembinski"},{id:"270426",title:"Dr.",name:"Aleksander",middleName:null,surname:"Skardal",slug:"aleksander-skardal",fullName:"Aleksander Skardal"}]},{id:"63420",title:"Stimuli-Responsive Hydrogels: An Interdisciplinary Overview",slug:"stimuli-responsive-hydrogels-an-interdisciplinary-overview",totalDownloads:2231,totalCrossrefCites:4,totalDimensionsCites:18,abstract:"Stimuli-responsive hydrogels formed by various natural and synthetic polymers are capable of showing distinctive changes in their properties with external stimuli like temperature, pH, light, ionic changes, and redox potential. Some hydrogels are developed to exhibit dual responsiveness with external stimuli such as pH and temperature. The stimuli-responsive hydrogels find a wide variety of biomedical applications including drug delivery, gene delivery, and tissue regeneration. The advanced functionalities can be imparted to textile materials by integrating stimuli-responsive hydrogels into them and stimuli-responsive hydrogels including thermoresponsive, pH-responsive, and dual-responsive improve moisture and water retention property, environmental responsiveness, esthetic appeal, display, and comfort of textiles. Stimuli-responsive hydrogels loaded with various kinds of drugs are applied for textile-based transdermal therapy as these hydrogels as drug carriers show controlled and sustained drug release. In this chapter, drug delivery and textile applications of thermoresponsive, pH-responsive, and dual-responsive (pH and temperature) hydrogels are discussed and analyzed.",book:{id:"8353",slug:"hydrogels-smart-materials-for-biomedical-applications",title:"Hydrogels",fullTitle:"Hydrogels - Smart Materials for Biomedical Applications"},signatures:"Sudipta Chatterjee and Patrick Chi-leung Hui",authors:[{id:"19338",title:"Dr.",name:"Hui",middleName:null,surname:"Chi Leung",slug:"hui-chi-leung",fullName:"Hui Chi Leung"},{id:"267430",title:"Dr.",name:"Sudipta",middleName:null,surname:"Chatterjee",slug:"sudipta-chatterjee",fullName:"Sudipta Chatterjee"}]},{id:"64338",title:"Hydrogels Based on Chitosan and Chitosan Derivatives for Biomedical Applications",slug:"hydrogels-based-on-chitosan-and-chitosan-derivatives-for-biomedical-applications",totalDownloads:2236,totalCrossrefCites:3,totalDimensionsCites:15,abstract:"Chitosan (CS) is a polymer obtained from chitin, being this, after the cellulose, the most abundant polysaccharide. The fact of (i) CS being obtained from renewable sources; (ii) CS to possess capability for doing interactions with different moieties being such capability dependent of pH; (iii) plenty of possibilities for chemical modification of CS; and (iv) tuning the final properties of CS derivatives makes this polymer very interesting in academic and technological points of view. In this way, hydrogels based on CS and on CS derivatives have been widely used for biomedical applications. Other important technological applications can be also cited, such as adsorbent of metals and dyes in wastewater from industrial effluents. In pharmaceutical field, hydrogels based on CS are often used as drugs’ and proteins’ carrier formulations due to the inherent characteristics such as the biocompatibility, nontoxicity, hydrophilicity, etc. This chapter is an attempt for updating and joining the plenty of available information regarding the preparation, characterization, and biomedical application of hydrogels based on chitosan and chitosan derivatives. More than 260 references are provided, being the majority of them published in the last 10 years.",book:{id:"8353",slug:"hydrogels-smart-materials-for-biomedical-applications",title:"Hydrogels",fullTitle:"Hydrogels - Smart Materials for Biomedical Applications"},signatures:"Kessily B. Rufato, Juliana P. Galdino, Kamila S. Ody, Antonio G.B. Pereira,\nElisangela Corradini, Alessandro F. Martins, Alexandre T. Paulino,\nAndré R. Fajardo, Fauze A. Aouada, Felipe A. La Porta, Adley F. Rubira\nand Edvani C. Muniz",authors:[{id:"262082",title:"Prof.",name:"Edvani",middleName:null,surname:"Muniz",slug:"edvani-muniz",fullName:"Edvani Muniz"},{id:"271484",title:"Prof.",name:"Fauze",middleName:null,surname:"Aouada",slug:"fauze-aouada",fullName:"Fauze Aouada"},{id:"271485",title:"Dr.",name:"Alexandre",middleName:null,surname:"Paulino",slug:"alexandre-paulino",fullName:"Alexandre Paulino"},{id:"271496",title:"MSc.",name:"Kessily",middleName:null,surname:"Rufato",slug:"kessily-rufato",fullName:"Kessily Rufato"},{id:"271497",title:"Mrs.",name:"Juliana",middleName:null,surname:"Galdino",slug:"juliana-galdino",fullName:"Juliana Galdino"},{id:"271498",title:"Dr.",name:"Antonio",middleName:null,surname:"Pereira",slug:"antonio-pereira",fullName:"Antonio Pereira"},{id:"271499",title:"Dr.",name:"Elisangela",middleName:null,surname:"Corradini",slug:"elisangela-corradini",fullName:"Elisangela Corradini"},{id:"271500",title:"Dr.",name:"Alessandro",middleName:null,surname:"Martins",slug:"alessandro-martins",fullName:"Alessandro Martins"},{id:"271501",title:"Dr.",name:"Andre",middleName:null,surname:"Fajardo",slug:"andre-fajardo",fullName:"Andre Fajardo"},{id:"271502",title:"Prof.",name:"Felipe",middleName:"De Almeida",surname:"La Porta",slug:"felipe-la-porta",fullName:"Felipe La Porta"},{id:"271503",title:"Prof.",name:"Adley",middleName:null,surname:"Rubira",slug:"adley-rubira",fullName:"Adley Rubira"},{id:"271504",title:"Ms.",name:"Kamila",middleName:null,surname:"Ody",slug:"kamila-ody",fullName:"Kamila Ody"}]},{id:"62030",title:"Decellularized ECM-Derived Hydrogels: Modification and Properties",slug:"decellularized-ecm-derived-hydrogels-modification-and-properties",totalDownloads:1633,totalCrossrefCites:6,totalDimensionsCites:12,abstract:"Extracellular matrix (ECM) hydrogels are water-swollen fibrillary three-dimensional (3D) networks where collagen type I is the major component. The hierarchical network formed by the polymerization of tropocollagen molecules with enhanced properties is an attractive template for generating biomaterials. The mammalian tissue source from which collagen is extracted and its consequent modification are variables that impact the physicochemical and biological properties of the collagen network. This chapter has the purpose to provide a review of the research of different strategies to modify and characterize the properties of decellularized ECM-derived hydrogels in the context of safe biomaterials with immunomodulatory properties.",book:{id:"6241",slug:"hydrogels",title:"Hydrogels",fullTitle:"Hydrogels"},signatures:"Jesús A. Claudio-Rizo, Jorge Delgado, Iraís A. Quintero-Ortega, José\nL. 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Many of these hydrophilic polymers have been already approved by the US Food and Drug Administration (FDA) for various applications. However, many of their potential uses required for many biomedical applications often are hindered by their low mechanical strength, antimicrobial and/or antifouling activity, biological interactions, water sorption and diffusion, porosity, electrical and/or thermal properties, among others. Thus, new advanced hydrogels have been developed as multicomponent systems in the form of composite or nanocomposite materials, which are expected to exhibit superior properties to increase the potential uses of these materials in the biomedical industry. 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MS, Ph.D., is currently with the Department of Research and Evaluation, Kaiser Permanente Southern California. He has both an MS and Ph.D. in Biomedical Engineering. He was previously a research scientist at the University of California Los Angeles (UCLA) and visiting professor and researcher at the University of North Dakota. He is currently working in artificial intelligence and its applications in medical signal processing. In addition, he is using digital signal processing in medical imaging and speech processing. Dr. Asadpour has developed brain-computer interfacing algorithms and has published books, book chapters, and several journal and conference papers in this field and other areas of intelligent signal processing. He has also designed medical devices, including a laser Doppler monitoring system.",institutionString:"Kaiser Permanente Southern California",institution:null},{id:"169608",title:"Prof.",name:"Marian",middleName:null,surname:"Găiceanu",slug:"marian-gaiceanu",fullName:"Marian Găiceanu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/169608/images/system/169608.png",biography:"Prof. Dr. Marian Gaiceanu graduated from the Naval and Electrical Engineering Faculty, Dunarea de Jos University of Galati, Romania, in 1997. He received a Ph.D. (Magna Cum Laude) in Electrical Engineering in 2002. Since 2017, Dr. Gaiceanu has been a Ph.D. supervisor for students in Electrical Engineering. He has been employed at Dunarea de Jos University of Galati since 1996, where he is currently a professor. Dr. Gaiceanu is a member of the National Council for Attesting Titles, Diplomas and Certificates, an expert of the Executive Agency for Higher Education, Research Funding, and a member of the Senate of the Dunarea de Jos University of Galati. He has been the head of the Integrated Energy Conversion Systems and Advanced Control of Complex Processes Research Center, Romania, since 2016. He has conducted several projects in power converter systems for electrical drives, power quality, PEM and SOFC fuel cell power converters for utilities, electric vehicles, and marine applications with the Department of Regulation and Control, SIEI S.pA. (2002–2004) and the Polytechnic University of Turin, Italy (2002–2004, 2006–2007). He is a member of the Institute of Electrical and Electronics Engineers (IEEE) and cofounder-member of the IEEE Power Electronics Romanian Chapter. He is a guest editor at Energies and an academic book editor for IntechOpen. He is also a member of the editorial boards of the Journal of Electrical Engineering, Electronics, Control and Computer Science and Sustainability. Dr. Gaiceanu has been General Chairman of the IEEE International Symposium on Electrical and Electronics Engineering in the last six editions.",institutionString:'"Dunarea de Jos" University of Galati',institution:{name:'"Dunarea de Jos" University of Galati',country:{name:"Romania"}}},{id:"4519",title:"Prof.",name:"Jaydip",middleName:null,surname:"Sen",slug:"jaydip-sen",fullName:"Jaydip Sen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/4519/images/system/4519.jpeg",biography:"Jaydip Sen is associated with Praxis Business School, Kolkata, India, as a professor in the Department of Data Science. His research areas include security and privacy issues in computing and communication, intrusion detection systems, machine learning, deep learning, and artificial intelligence in the financial domain. He has more than 200 publications in reputed international journals, refereed conference proceedings, and 20 book chapters in books published by internationally renowned publishing houses, such as Springer, CRC press, IGI Global, etc. Currently, he is serving on the editorial board of the prestigious journal Frontiers in Communications and Networks and in the technical program committees of a number of high-ranked international conferences organized by the IEEE, USA, and the ACM, USA. He has been listed among the top 2% of scientists in the world for the last three consecutive years, 2019 to 2021 as per studies conducted by the Stanford University, USA.",institutionString:"Praxis Business School",institution:null},{id:"320071",title:"Dr.",name:"Sidra",middleName:null,surname:"Mehtab",slug:"sidra-mehtab",fullName:"Sidra Mehtab",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00002v6KHoQAM/Profile_Picture_1584512086360",biography:"Sidra Mehtab has completed her BS with honors in Physics from Calcutta University, India in 2018. She has done MS in Data Science and Analytics from Maulana Abul Kalam Azad University of Technology (MAKAUT), Kolkata, India in 2020. Her research areas include Econometrics, Time Series Analysis, Machine Learning, Deep Learning, Artificial Intelligence, and Computer and Network Security with a particular focus on Cyber Security Analytics. Ms. Mehtab has published seven papers in international conferences and one of her papers has been accepted for publication in a reputable international journal. She has won the best paper awards in two prestigious international conferences – BAICONF 2019, and ICADCML 2021, organized in the Indian Institute of Management, Bangalore, India in December 2019, and SOA University, Bhubaneswar, India in January 2021. Besides, Ms. Mehtab has also published two book chapters in two books. Seven of her book chapters will be published in a volume shortly in 2021 by Cambridge Scholars’ Press, UK. Currently, she is working as the joint editor of two edited volumes on Time Series Analysis and Forecasting to be published in the first half of 2021 by an international house. Currently, she is working as a Data Scientist with an MNC in Delhi, India.",institutionString:"NSHM College of Management and Technology",institution:null},{id:"226240",title:"Dr.",name:"Andri Irfan",middleName:null,surname:"Rifai",slug:"andri-irfan-rifai",fullName:"Andri Irfan Rifai",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/226240/images/7412_n.jpg",biography:"Andri IRFAN is a Senior Lecturer of Civil Engineering and Planning. He completed the PhD at the Universitas Indonesia & Universidade do Minho with Sandwich Program Scholarship from the Directorate General of Higher Education and LPDP scholarship. He has been teaching for more than 19 years and much active to applied his knowledge in the project construction in Indonesia. His research interest ranges from pavement management system to advanced data mining techniques for transportation engineering. He has published more than 50 papers in journals and 2 books.",institutionString:null,institution:{name:"Universitas Internasional Batam",country:{name:"Indonesia"}}},{id:"314576",title:"Dr.",name:"Ibai",middleName:null,surname:"Laña",slug:"ibai-lana",fullName:"Ibai Laña",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314576/images/system/314576.jpg",biography:"Dr. Ibai Laña works at TECNALIA as a data analyst. He received his Ph.D. in Artificial Intelligence from the University of the Basque Country (UPV/EHU), Spain, in 2018. He is currently a senior researcher at TECNALIA. His research interests fall within the intersection of intelligent transportation systems, machine learning, traffic data analysis, and data science. He has dealt with urban traffic forecasting problems, applying machine learning models and evolutionary algorithms. He has experience in origin-destination matrix estimation or point of interest and trajectory detection. Working with large volumes of data has given him a good command of big data processing tools and NoSQL databases. He has also been a visiting scholar at the Knowledge Engineering and Discovery Research Institute, Auckland University of Technology.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"314575",title:"Dr.",name:"Jesus",middleName:null,surname:"L. Lobo",slug:"jesus-l.-lobo",fullName:"Jesus L. Lobo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314575/images/system/314575.png",biography:"Dr. Jesús López is currently based in Bilbao (Spain) working at TECNALIA as Artificial Intelligence Research Scientist. In most cases, a project idea or a new research line needs to be investigated to see if it is good enough to take into production or to focus on it. That is exactly what he does, diving into Machine Learning algorithms and technologies to help TECNALIA to decide whether something is great in theory or will actually impact on the product or processes of its projects. So, he is expert at framing experiments, developing hypotheses, and proving whether they’re true or not, in order to investigate fundamental problems with a longer time horizon. He is also able to design and develop PoCs and system prototypes in simulation. He has participated in several national and internacional R&D projects.\n\nAs another relevant part of his everyday research work, he usually publishes his findings in reputed scientific refereed journals and international conferences, occasionally acting as reviewer and Programme Commitee member. Concretely, since 2018 he has published 9 JCR (8 Q1) journal papers, 9 conference papers (e.g. ECML PKDD 2021), and he has co-edited a book. He is also active in popular science writing data science stories for reputed blogs (KDNuggets, TowardsDataScience, Naukas). Besides, he has recently embarked on mentoring programmes as mentor, and has also worked as data science trainer.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"103779",title:"Prof.",name:"Yalcin",middleName:null,surname:"Isler",slug:"yalcin-isler",fullName:"Yalcin Isler",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRyQ8QAK/Profile_Picture_1628834958734",biography:"Yalcin Isler (1971 - Burdur / Turkey) received the B.Sc. degree in the Department of Electrical and Electronics Engineering from Anadolu University, Eskisehir, Turkey, in 1993, the M.Sc. degree from the Department of Electronics and Communication Engineering, Suleyman Demirel University, Isparta, Turkey, in 1996, the Ph.D. degree from the Department of Electrical and Electronics Engineering, Dokuz Eylul University, Izmir, Turkey, in 2009, and the Competence of Associate Professorship from the Turkish Interuniversity Council in 2019.\n\nHe was Lecturer at Burdur Vocational School in Suleyman Demirel University (1993-2000, Burdur / Turkey), Software Engineer (2000-2002, Izmir / Turkey), Research Assistant in Bulent Ecevit University (2002-2003, Zonguldak / Turkey), Research Assistant in Dokuz Eylul University (2003-2010, Izmir / Turkey), Assistant Professor at the Department of Electrical and Electronics Engineering in Bulent Ecevit University (2010-2012, Zonguldak / Turkey), Assistant Professor at the Department of Biomedical Engineering in Izmir Katip Celebi University (2012-2019, Izmir / Turkey). He is an Associate Professor at the Department of Biomedical Engineering at Izmir Katip Celebi University, Izmir / Turkey, since 2019. In addition to academics, he has also founded Islerya Medical and Information Technologies Company, Izmir / Turkey, since 2017.\n\nHis main research interests cover biomedical signal processing, pattern recognition, medical device design, programming, and embedded systems. He has many scientific papers and participated in several projects in these study fields. He was an IEEE Student Member (2009-2011) and IEEE Member (2011-2014) and has been IEEE Senior Member since 2014.",institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",country:{name:"Turkey"}}},{id:"339677",title:"Dr.",name:"Mrinmoy",middleName:null,surname:"Roy",slug:"mrinmoy-roy",fullName:"Mrinmoy Roy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/339677/images/16768_n.jpg",biography:"An accomplished Sales & Marketing professional with 12 years of cross-functional experience in well-known organisations such as CIPLA, LUPIN, GLENMARK, ASTRAZENECA across different segment of Sales & Marketing, International Business, Institutional Business, Product Management, Strategic Marketing of HIV, Oncology, Derma, Respiratory, Anti-Diabetic, Nutraceutical & Stomatological Product Portfolio and Generic as well as Chronic Critical Care Portfolio. A First Class MBA in International Business & Strategic Marketing, B.Pharm, D.Pharm, Google Certified Digital Marketing Professional. Qualified PhD Candidate in Operations and Management with special focus on Artificial Intelligence and Machine Learning adoption, analysis and use in Healthcare, Hospital & Pharma Domain. Seasoned with diverse therapy area of Pharmaceutical Sales & Marketing ranging from generating revenue through generating prescriptions, launching new products, and making them big brands with continuous strategy execution at the Physician and Patients level. Moved from Sales to Marketing and Business Development for 3.5 years in South East Asian Market operating from Manila, Philippines. Came back to India and handled and developed Brands such as Gluconorm, Lupisulin, Supracal, Absolut Woman, Hemozink, Fabiflu (For COVID 19), and many more. In my previous assignment I used to develop and execute strategies on Sales & Marketing, Commercialization & Business Development for Institution and Corporate Hospital Business portfolio of Oncology Therapy Area for AstraZeneca Pharma India Ltd. Being a Research Scholar and Student of ‘Operations Research & Management: Artificial Intelligence’ I published several pioneer research papers and book chapters on the same in Internationally reputed journals and Books indexed in Scopus, Springer and Ei Compendex, Google Scholar etc. Currently, I am launching PGDM Pharmaceutical Management Program in IIHMR Bangalore and spearheading the course curriculum and structure of the same. I am interested in Collaboration for Healthcare Innovation, Pharma AI Innovation, Future trend in Marketing and Management with incubation on Healthcare, Healthcare IT startups, AI-ML Modelling and Healthcare Algorithm based training module development. I am also an affiliated member of the Institute of Management Consultant of India, looking forward to Healthcare, Healthcare IT and Innovation, Pharma and Hospital Management Consulting works.",institutionString:null,institution:{name:"Lovely Professional University",country:{name:"India"}}},{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/1063/images/system/1063.png",biography:"Prof. Dr. Constantin Voloşencu graduated as an engineer from\nPolitehnica University of Timișoara, Romania, where he also\nobtained a doctorate degree. He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. He has developed automation equipment for machine tools, spooling\nmachines, high-power ultrasound processes, and more.",institutionString:"Polytechnic University of Timişoara",institution:{name:"Polytechnic University of Timişoara",country:{name:"Romania"}}},{id:"221364",title:"Dr.",name:"Eneko",middleName:null,surname:"Osaba",slug:"eneko-osaba",fullName:"Eneko Osaba",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/221364/images/system/221364.jpg",biography:"Dr. Eneko Osaba works at TECNALIA as a senior researcher. He obtained his Ph.D. in Artificial Intelligence in 2015. He has participated in more than twenty-five local and European research projects, and in the publication of more than 130 papers. He has performed several stays at universities in the United Kingdom, Italy, and Malta. Dr. Osaba has served as a program committee member in more than forty international conferences and participated in organizing activities in more than ten international conferences. He is a member of the editorial board of the International Journal of Artificial Intelligence, Data in Brief, and Journal of Advanced Transportation. He is also a guest editor for the Journal of Computational Science, Neurocomputing, Swarm, and Evolutionary Computation and IEEE ITS Magazine.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"275829",title:"Dr.",name:"Esther",middleName:null,surname:"Villar-Rodriguez",slug:"esther-villar-rodriguez",fullName:"Esther Villar-Rodriguez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/275829/images/system/275829.jpg",biography:"Dr. Esther Villar obtained a Ph.D. in Information and Communication Technologies from the University of Alcalá, Spain, in 2015. She obtained a degree in Computer Science from the University of Deusto, Spain, in 2010, and an MSc in Computer Languages and Systems from the National University of Distance Education, Spain, in 2012. Her areas of interest and knowledge include natural language processing (NLP), detection of impersonation in social networks, semantic web, and machine learning. Dr. Esther Villar made several contributions at conferences and publishing in various journals in those fields. Currently, she is working within the OPTIMA (Optimization Modeling & Analytics) business of TECNALIA’s ICT Division as a data scientist in projects related to the prediction and optimization of management and industrial processes (resource planning, energy efficiency, etc).",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49813/images/system/49813.png",biography:"Prof. Dr. Javier Del Ser received his first PhD in Telecommunication Engineering (Cum Laude) from the University of Navarra, Spain, in 2006, and a second PhD in Computational Intelligence (Summa Cum Laude) from the University of Alcala, Spain, in 2013. He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. He is a Senior Member of the IEEE, and a recipient of the Biscay Talent prize for his academic career.",institutionString:"Tecnalia Research & Innovation",institution:null},{id:"278948",title:"Dr.",name:"Carlos Pedro",middleName:null,surname:"Gonçalves",slug:"carlos-pedro-goncalves",fullName:"Carlos Pedro Gonçalves",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRcmyQAC/Profile_Picture_1564224512145",biography:'Carlos Pedro Gonçalves (PhD) is an Associate Professor at Lusophone University of Humanities and Technologies and a researcher on Complexity Sciences, Quantum Technologies, Artificial Intelligence, Strategic Studies, Studies in Intelligence and Security, FinTech and Financial Risk Modeling. He is also a progammer with programming experience in:\n\nA) Quantum Computing using Qiskit Python module and IBM Quantum Experience Platform, with software developed on the simulation of Quantum Artificial Neural Networks and Quantum Cybersecurity;\n\nB) Artificial Intelligence and Machine learning programming in Python;\n\nC) Artificial Intelligence, Multiagent Systems Modeling and System Dynamics Modeling in Netlogo, with models developed in the areas of Chaos Theory, Econophysics, Artificial Intelligence, Classical and Quantum Complex Systems Science, with the Econophysics models having been cited worldwide and incorporated in PhD programs by different Universities.\n\nReceived an Arctic Code Vault Contributor status by GitHub, due to having developed open source software preserved in the \\"Arctic Code Vault\\" for future generations (https://archiveprogram.github.com/arctic-vault/), with the Strategy Analyzer A.I. module for decision making support (based on his PhD thesis, used in his Classes on Decision Making and in Strategic Intelligence Consulting Activities) and QNeural Python Quantum Neural Network simulator also preserved in the \\"Arctic Code Vault\\", for access to these software modules see: https://github.com/cpgoncalves. He is also a peer reviewer with outsanding review status from Elsevier journals, including Physica A, Neurocomputing and Engineering Applications of Artificial Intelligence. Science CV available at: https://www.cienciavitae.pt//pt/8E1C-A8B3-78C5 and ORCID: https://orcid.org/0000-0002-0298-3974',institutionString:"University of Lisbon",institution:{name:"Universidade Lusófona",country:{name:"Portugal"}}},{id:"241400",title:"Prof.",name:"Mohammed",middleName:null,surname:"Bsiss",slug:"mohammed-bsiss",fullName:"Mohammed Bsiss",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241400/images/8062_n.jpg",biography:null,institutionString:null,institution:null},{id:"276128",title:"Dr.",name:"Hira",middleName:null,surname:"Fatima",slug:"hira-fatima",fullName:"Hira Fatima",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/276128/images/14420_n.jpg",biography:"Dr. Hira Fatima\nAssistant Professor\nDepartment of Mathematics\nInstitute of Applied Science\nMangalayatan University, Aligarh\nMobile: no : 8532041179\nhirafatima2014@gmal.com\n\nDr. Hira Fatima has received his Ph.D. degree in pure Mathematics from Aligarh Muslim University, Aligarh India. Currently working as an Assistant Professor in the Department of Mathematics, Institute of Applied Science, Mangalayatan University, Aligarh. She taught so many courses of Mathematics of UG and PG level. Her research Area of Expertise is Functional Analysis & Sequence Spaces. She has been working on Ideal Convergence of double sequence. She has published 17 research papers in National and International Journals including Cogent Mathematics, Filomat, Journal of Intelligent and Fuzzy Systems, Advances in Difference Equations, Journal of Mathematical Analysis, Journal of Mathematical & Computer Science etc. She has also reviewed few research papers for the and international journals. 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