Examples of molecular targeted therapeutic anticancer agents with their main target.
\\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:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{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"}]},book:{item:{type:"book",id:"79",leadTitle:null,fullTitle:"Multi-Agent Systems - Modeling, Control, Programming, Simulations and Applications",title:"Multi-Agent Systems",subtitle:"Modeling, Control, Programming, Simulations and Applications",reviewType:"peer-reviewed",abstract:"A multi-agent system (MAS) is a system composed of multiple interacting intelligent agents. 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A recent article estimated the incidence and mortality of cancer in 20 world regions (using the GLOBOCAN 2018 estimates), and suggested approximately 18 million new cases and 9.6 million deaths in the year of 2018. Lung cancer was most commonly diagnosed, and the leading cause of cancer-related death followed by breast, prostate, colorectal, stomach, and liver cancer [1]. Although surgery and radiation therapy are considered the primary treatment for localized forms of cancers, chemotherapeutic agents must be used when cancer cells metastasize to the regional lymphatic vessels and bloodstream. This placed more emphasis on the development of drugs and biological molecules as chemotherapeutic agents to minimize the risk of cancer metastasis to other organs, which will lead to organ failure and death [2, 3].
The era of cancer drug development was pioneered in the 1940s after using nitrogen mustard as a toxic treatment for cancer [2]. Traditional chemotherapeutic agents mediate cytotoxicity by interrupting processes or inhibiting molecules required for rapid cellular division and DNA synthesis at the cell cycle level. They are categorized as either cell cycle specific (they target a specific phase in the cell cycle) or cell cycle non-specific (they target all cell cycle phases) agents [4]. Their main disadvantage relies on their relative non-selectivity in targeting rapidly dividing non-cancerous cells such as hair follicles, bone marrow and gastrointestinal epithelial cells. This commonly manifests as serious adverse effects on patients such as hair loss, anemia, infections (due to low white blood cell count), infertility, nausea and vomiting. As a result, the effective therapeutic dose is unattained and the efficacy of conventional chemotherapeutic agents is compromised. This is commonly experienced in the clinic, when a chemotherapy regimen is administered for a delimited period, but the dose has to be reduced or treatment is postponed as a safety precaution despite tumor responsiveness [5, 6]. Furthermore, many conventional chemotherapeutics do not accumulate in the tumor mass at effective therapeutic concentrations, thereby cannot effectively inhibit their proliferation and metastasis. This is particularly true at the core micro-regions of tumors; due to the disorganized intratumoral vasculature and high interstitial fluid pressure as a consequence of aberrant angiogenesis and poor lymphatic drainage. Some types of cancers such as brain gliomas, are also difficult to reach with traditional chemotherapeutics, as they are unable to penetrate the blood brain barrier. These factors play a paramount role in drug resistance [7]. Chemotherapeutic agents with inadequate bioavailability and pharmacokinetic profiles are more inclined to metabolism and excretion before reaching cancerous cells [8]. Cancerous cells not killed during treatment are likely to acquire resistance and eventually lead to a more aggressive form of tumors with high probability of organ damage and death [4]. In addition, various oncogenes and oncoproteins in a variety of cancers are able to inactivate chemotherapeutic agents and/or eliminate them from tumor cells (e.g., through the activity of multi-drug resistance; MDR) [7, 8].
Mechanisms that mediate resistance have been studied abundantly, and many are attributed to mutations of various oncogenes. They include altered transport of chemotherapeutics across the plasma membrane by ATP-dependent multidrug transporters or upregulation of multidrug resistant gene, which encodes P-glycoprotein responsible for xenobiotic efflux out of cells [7]. Another example are defects in the apoptotic pathways leading to a loss of function in the tumor suppressor gene p53, allowing cells with damaged DNA to continue replicating and hence be unresponsive to DNA damaging effects of chemotherapeutics such as pyrimidine antagonist 5-fluorouracil and the mitotic spindle inhibitor paclitaxel [7, 8]. Enhanced action of DNA repair proteins in cancer cells also contributes to acquired forms of chemoresistance. This phenomenon has been observed with chemotherapeutics causing direct damage to the structural integrity of DNA such as intercalating agents like cisplatin and alkylating agents [7, 8]. While chemotherapeutics that mediate their action by binding to the topoisomerase-DNA complex to prevent DNA synthesis, such as doxorubicin, etoposide and camptothecin are rendered inactive by the altered activity of topoisomerase I and II, hence resistance facilitates the repair of topoisomerase-DNA complex [7, 8].
The design and development of conventional chemotherapeutics is prehistoric relative to recent findings in the complex cancer pathophysiology and tumor microenvironment. Recently, the heterogeneity of tumors is widely established as a challenge for traditional forms of cancer therapy. It is recognized to result from the higher genetic instability of uncontrolled cell division; increasing the likelihood of multiple mutations and replications errors. Ultimately it manifests as phenotypic and functional tumor heterogeneity that can occur within and between tumors [9]. Dynamic and regional variations in the tumor microenvironment in blood, lymphatic vasculature, extracellular matrix metalloproteases and cellular secretions in the tumor stroma may greatly influence the diverse development of cancer cells. Furthermore, a distinct population of cells within tumors termed cancer stem cells with a capacity for self-renewal and differentiation are recognized to be responsible for cancer relapse, also contributing to this factor [9]. The heterogeneity of tumors has proved to be a limitation to treatment with traditional chemotherapeutics and restricts their use for a variety of cancer types, it also supports intrinsic resistance to cancer therapy. In order to combat these limitations which ultimately lead to cancer progression and reduces the survival rates of patients, more selective/targeted/efficient therapies are required. This lead to the discovery of new agents which are based on the investigation of molecular behavior, biomarkers, oncogenes and biological pathways used by cancer cells to determine specific key distinctions between them and normal cells, that are responsible for tumor cell proliferation, survival and progression. Once identified these distinctions are targeted “with precision” while sparing normal cells. This concept has been renowned the “magic bullet” of cancer therapy and is the fundamental principle behind targeted cancer therapy [10].
The advent of targeted cancer therapy was established by the development of molecular targeted therapeutics, also recognized as mechanistic or direct-targeted cancer therapy [11]. This strategy utilizes small molecules or monoclonal antibodies (MAb) designed to interfere with specific molecular targets that have a relatively specific or higher expression profile in cancer cells and are critical for their growth and metastasis [11, 12]. Small molecule targeted therapies are usually low molecular weight organic compounds (<800 Daltons), that have a higher rate of cell entry relative to MAb, and so are designed to interfere with the expression/activity of intracellular signaling molecules [4]. On the other hand, MAbs generally have high binding affinities to extracellular domains expressed on cancer cells and are commonly designed to target the extracellular surface of cancerous cells; they mediate their mode of action through receptor ligand interactions [4].
Various types of molecular target mechanisms have been identified for cancer therapy; these include signal transduction inhibitors, hormone therapies, gene expression modulators, apoptosis inducers, angiogenesis inhibitors, immunotherapies and toxin delivery molecules. Many of these mechanisms overlap and with the advancement in cancer research a single anticancer therapeutic agent can encompass multiple molecular mechanisms. This is further elaborated in the subsequent paragraphs of this chapter.
Signal transduction is considered the link between a ligand mediated activation of a receptor to the resultant cellular responses such as metabolism, gene expression, cell division and apoptosis, and motility/migration, etc. [13]. Hence it is a vital route to explore for molecular-targeted therapies. Many remarkably successful agents have been developed under this category, owning to the understanding of signal transduction pathways in cancer cells. Genetic and epigenetic changes that occur in cancer cells lead to uncontrolled cellular functions (such as proliferation) in part through aberrant/modulated activity of various signaling and metabolic networks [13]. While normal cells have redundant overlapping pathways that allow for alternative signal transduction when one is inhibited, cancer cells have placed more emphasis on distinct signaling pathways owning to various mutations [13]. As a result, they have a diminished signaling network with “hyper-active” pathways to sustain cell proliferation and survival [13]. These “hyper-active” pathways are reflected in the overexpression of certain proteins in cancer cells. Together, these characteristics make cancerous cells more sensitive to stress and mutagens [13]. This forms the basis of signal transduction targeted molecular therapy. Therefore, theoretically depriving cancer cells from essential signaling elements needed for survival will lead to apoptosis and growth arrest [13]. Furthermore, some cancer cells are “addicted” to specific signaling proteins, as they are dependent on their activity for survival; a prime example is in chronic myeloid leukemia (CML) cancer. CML cells particularly in the early stage of cancer have absolute dependency on the kinase activity of Bcr-Abl fusion protein [13]. Bcr-Abl fusion protein results from an abnormal translocation in the Philadelphia chromosome (Ph) in 95% of CML patients. Fusion of Bcr and Abl genes leads to constitutive activation of Bcr-Abl tyrosine kinase, causing CML cells to grow and divide excessively [13]. Protein kinases are enzymes that regulate the biological activity of proteins by phosphorylation of specific amino acids with adenosine triphosphate (ATP) to induce conformational changes from the inactive to the active form [14]. Protein Kinases have been implicated in cell proliferation and many have transforming capacity making them oncoproteins [14]. Consequently, protein kinases have been extensively studied as a signal transduction inhibitor pathway in targeted drug therapy [13, 14, 15].
One of the most successful molecular targets of anticancer agents is the protein tyrosine kinase inhibitor imatinib (Gleevec®), for the treatment of Ph positive CML [4, 9, 10, 12, 13, 14, 15]. Its success is based on the extreme “addiction” of CML cells to Bcr-Abl fusion pathway. Imatinib is designed as an ATP mimic which acts by blocking tyrosine phosphorylation, it competitively binds to the ATP binding site on Bcr-Abl fusion protein to disrupt tyrosine kinase activity [14]. It is reported to have up to 80% response rate in Ph positive CML patients [14]. This protein kinase inhibitor is also indicated for a subset of patients with gastrointestinal stromal (GIST) tumors, which have activated point mutations in the c-Kit proto-oncogene or platelet derived growth factor receptor (PDGFR)-α kinase [4, 12, 13]. Constitutive activation of kinase, as in the Bcr-Abl fusion protein, inhibits apoptosis and stimulates cell proliferation [3, 12, 13]. Although imatinib is a highly selective agent, it has been responsive for the inhibition of Bcr-Abl, PDGFR, cKit and FIt3 protein kinases [13]. Unfortunately, long term use of imatinib in some late stage GIST or CML patients may cause drug resistance leading to therapeutic failure. The dynamically complex oncogenic signaling network of cancer cells is able to “escape the addiction” of the Bcr-Abl oncogene as it becomes mutated. Furthermore, tyrosine kinase inhibitors cannot completely eradicate leukemic stem cells; both of these factors facilitate the progression of tumors [13]. Luckily, next generation tyrosine kinase inhibitors are available for imatinib resistant patients [13]. The broad-spectrum protein tyrosine kinase inhibitor Dasatinib (Sprycel®) not only binds to the mutated Brc-Abl kinase but also to Src tyrosine kinase. Despite the reduced selectivity of this inhibitor, the Src kinase family is also responsible for tumor progression, and their overexpression has been linked to several malignancies [13]. Nilotinib (Tasigna®) is another tyrosine kinase inhibitor, which shares imatinib’s narrow tyrosine kinase selectivity profile, it inhibits the mutated Brc-Abl kinase activity, and is more efficient when compared to imatinib [13, 16]. Although lifelong therapy is expected with these next generation tyrosine kinase inhibitors, they are reported to achieve longer response rates [13, 16]. The FDA has approved both agents for first line use in patients with Ph positive CML in the chronic phase and for patients with resistance to imatinib [17]. Another dual Src and Bcr-Abl tyrosine kinase inhibitor called bosutinib (Bosulif®) has also been approved by the FDA for patients with Ph positive CML that have been treated with both imatinib and next generation tyrosine kinase inhibitors. It has been reported to have a superior molecular response profile relative to imatinib in terms of inhibition potency to Bcr-Abl mutated tyrosine kinase and more selectivity, thereby decreasing its toxicity profile [18]. Imatinib indicated for GIST patients has partial response rates and differs between subset populations depending on the cKit point mutation. Imatinib is able to extend patient life but resistance usually emerges due to modified point mutations in the cKit gene on GIST stem cells, or mutations in other oncogenes and enhanced drug efflux transporters. A second line broad-spectrum tyrosine kinase inhibitor Sunitinib (Sutent®) is indicated for imatinib resistant GIST patients. This is a multi-target inhibitor that affects vascular endothelial growth factor receptor (VEGFR) and PDGFR protein tyrosine kinases; it has also been approved for the treatment of advanced renal cell carcinoma [13].
Most cell surface growth factor receptors have tyrosine kinase activity, and play an important role in cancer pathogenesis. One of the most notable for molecular targeted signal transduction cancer therapy is epidermal growth factor receptor (EGFR/ ErbB1/ HER1). It is a member of the epidermal growth factor receptors family (ErbB) of protein tyrosine kinases, which also include ErbB2/HER2, ErbB3/ Her3, and ErbB4/ Her4. Binding of a complementary ligand to these receptors induces receptor homo/hetero dimerization and subsequent tyrosine auto-phosphorylation, leading to activation of various downstream signaling molecules. In various types of cancers, the expression/activity profile of these receptors is increased leading to enhanced cell proliferation. Oncogenic mutations within the receptor kinases of this family have also been found in epithelial tumors, breast carcinomas, gliomas (glioblastoma multiforme) and in the case of EGFR in 10% of patients with non-small cell lung carcinoma (NSCLC) [13]. Currently, there are two FDA approved selective EGFR tyrosine kinase inhibitors gefitinib (Iressa®) and erlotinib (Tarceva®) and are indicated as first line therapy for NSCLC patients [13]. Initially, the response rates in patients after administration were not as efficient as expected, and it was later determined that the presence of EGFR overexpression alone does not predict effective therapy [13]. Instead, patients with particular types of EGFR substitution mutation, such as L858R mutation in the kinase domain are more likely to benefit from anti-EGFR therapy [13]. This was concluded from several clinical trials carried out on NSCLC patients comparing the administration of gefitinib to docetaxel in patients pretreated with platinum-based chemotherapy [19, 20]. Results of the trial concluded that gefitinib was either equally effective [19] or more effective [20] than docetaxel. A latter trial was conducted on patients of non-smoker Asian origin, and it was determined that they had a higher incidence of harboring the specific activating mutations in the EGFR kinase domain [13, 20]. Docetaxel is a well-established conventional chemotherapeutic agent which reversibly binds to microtubules with high affinity leading to inhibition of mitotic cell division. It is administered intravenously, and has been reported to cause dose-limiting toxicity and adverse effects of grade 3 and 4 neutropenia in 30% of patients, as well as edema and other common side effects shared by conventional chemotherapies [21]. Gefitinib, on the other hand, is administered orally, with reported adverse effects of grade 1 and 2 diarrhea and skin rash [22]. Therefore, in terms of patient compliance, therapy with gefitinib has greater efficiency than chemotherapy with docetaxel even if they provide the same therapeutic efficacy, since there is a lower incidence of severe adverse effects and oral administration is preferred over intravenous administration. Another important aspect is that not all EGFR mutations in the kinase domain are sufficient to determine patient response and instead only patients with specific EGFR mutations can benefit from certain molecular targeted treatments. In the case of gefitinib, the use of genetic screening is required prior to treatment. This prerequisite highlights the application of precision medicine in targeted cancer therapy and the need for diagnostic strategies involving prognostic biomarkers and tumor genotyping to determine the choice of targeted therapeutic. Manufacturer AstraZeneca, of gefitinib as Iressa® had partnered with Qiagen to provide FDA-approved Therascreen® EGFR companion diagnostic test to identify eligible patients for this treatment, once they test positive for the specific EGFR substitution mutations [22].
Another member of the ErbB receptor family, HER2, has received wide recognition as a target for breast carcinoma, since it has been found to be upregulated in 20–30% of breast cancers [23]. HER2 tyrosine kinase activation is initiated by homo or hetero dimerization with other ErbB receptors, in turn phosphorylation leads to signaling through two main downstream cascades, phosphatidylinositol 3 kinase (PI3K)/Akt and mitogen- activated protein kinase (MAPK); both predominantly involved in promoting cell growth and survival [13, 23]. The first FDA approved targeted monoclonal antibody (Mab) for cancer was transtuzumab (Herceptin®), which interacts with the extracellular domain of HER2 (with high affinity) and is known to be one of the most successful recombinant humanized anti-ErbB- receptor family antibodies [13]. The advantage of transtuzumab as an antibody, over previously mentioned small molecular targeted therapies, is that it exerts its cytotoxicity by several mechanisms as well as binding to the extracellular domain of HER2 on cancer cells with high affinity. Antibodies generally bind to their complementary receptor with higher selectivity or even specificity compared to small molecule therapeutics. Transtuzumab binds HER2 on the surface of cancer cells with high affinity to hinder HER2 dimerization. This also leads to degradation of the receptor and prevents HER2 recycling. As a result, downstream signaling cascades of PI3K and MAPK are diminished, promoting cell-cycle arrest and apoptosis. Furthermore, transtuzumab is able to modulate the immune system by inducing antibody-dependent cellular cytotoxicity (ADCC) through its Fc domain [13]. It can also bind to Fc receptors on various immune cells, markedly natural killer cells, but also neutrophils, mononuclear phagocytes, macrophages and dendritic cells leading to immune cell recruitment to the tumor tissue. Cytotoxicity is mediated in various ways, natural killer cells inhibit cell proliferation and intratumoral angiogenesis by the secretion of cytokines and chemokines, and they also promote tumor immunogenicity by inducing the expression of major histocompatibility antigen on cancer cells [13]. Macrophages and phagocytes carry out phagocytosis by engulfing and eliminating tumor cells [13]. Complement dependent cytotoxicity is mediated after an antibody bound to the surface of a tumor cell also binds to a nearby complement protein C1q. This activates a series of enzymatic cascades in the classical complement pathway, ultimately facilitating the formation of a cytolytic membrane attack complex on the surface of tumor cells in the form of pores that generate an influx of ions and water molecules leading to tumor cell lysis [13]. Transtuzumab has also been identified to play a role in the inhibition of angiogenesis by interfering with pro-angiogenic and anti-angiogenic factors, and reverting tumor vasculature back into normal vasculature [13]. This is supported by the enhanced localization of paclitaxel in tumors during combination therapy with transtuzumab [24]. Unfortunately, one of the limitations of transtuzumab is that it is only able to block the dimerization of HER2 with unbound HER3. Consequently, dimerization of HER2 with EGFR and ligand-bound HER3 proceeds despite transtuzumab therapy, serving as one of the reasons of acquired resistance to transtuzumab. Concurrent therapy with another Mab pertuzumab (Perjeta®) is sometimes administered as it targets dimerization of HER2 with neuregulin ligand bound HER3 [13]. Resistance may also develop by mutations that prevent the complementary binding of transtuzumab to the HER2 extracellular domain. For instance, proteolysis leading to mutated isoforms of HER2 kinases, or elevation in the expression of Mucin-4 an O-glycosylated membrane protein that dimerizes with HER2 [23]. Overexpression of other ErbB members such as EGFR that are able to dimerize with HER2 is also common, in this case a small molecule tyrosine kinase inhibitor lapatinib (Tykerb®), with dual action against HER2 and EGFR has been used [13, 23]. This further reinforces the challenges to treat patients with different molecular subtypes of breast carcinoma. As a result, transtuzumab is indicated for women that have been diagnostically found to strongly overexpress HER2 on their tumor cells and successful treatment response is more likely with early therapy. Transtuzumab has also been indicated as an adjuvant therapeutic particularly after surgery in order to eliminate micrometastases. It is also used in combination with various anticancer agents [13, 23, 24].
Various hormones are implicated in the pathogenesis of many forms of tumors such as breast, ovarian, and prostate. Hyperplasia and neoplasia can develop from excessive hormonal stimulation or loss of tumor suppressor genes that dictate hormonal secretions as they have a proliferating effect on target cells. Steroid hormone such as estrogen binds to estrogen receptors (ER) that belong to a superfamily of nuclear receptors. Upon binding, the receptor complex homo-dimerizes and interacts with sequence specific estrogen response elements in corresponding genes, leading to the activation of nuclear transcription factors that produce complementary mRNA. Elevated mRNA levels increase protein production in the endoplasmic reticulum, which ultimately result in various effector responses such as enhanced cell proliferation [25, 26]. While estrogen activity mainly regulates growth, development and physiology of reproductive systems in both sexes, ERs are also found in neuroendocrine, skeletal, adipose and cardiovascular systems [25]. Estrogen signaling pathways are complex due to its nuclear and non-genomic influences, and downstream transcriptional activities affect the biological function of different tissues expressing ERs [25]. Two types of ER have been identified ERα and ERβ, where ERα expression is considered the hallmark of hormone dependent tumor growth [25, 26, 27]. About 70% of breast cancer patients express the hormone receptors ER and/ or progesterone, making them susceptible to endocrine therapy [25, 26, 27]. These receptors have categorized breast cancer as intrinsic and molecular subtypes based on the genes the cancer cell expresses, and act as a blueprint for targeted breast cancer therapy [27]. The aim of hormone-receptor positive breast cancer therapy is to reduce the growth stimulatory effects of estrogen on breast cancer cells. A primary way to do this is by interfering with the ability of estrogen to bind to its receptor, via targeting estrogen receptors on breast cancer tumors that overexpress ER and competitively binding ERs to reduce the capacity for estradiol to bind. This concept actually paved the way for targeted cancer therapy, and was first demonstrated by the renowned non-steroidal derivative tamoxifen (Nolvadex®) [25, 26, 27, 28]. After FDA approval in the 1970s, tamoxifen became one of the world’s best-selling hormonal cancer drugs largely relating to its efficacy and short-term safety profile relative to traditional chemotherapeutics at the time [28].
Tamoxifen is non-steroidal triphenylethylene derivative; it is classified as a prodrug, since its metabolites have a more pronounced effect on ERs [25, 28]. Tamoxifen and its metabolites act as selective estrogen receptor modulators (SERM) since they have both anti-estrogenic and pro-estrogenic activity contingents on the target tissue [25, 28]. On mammary epithelia, tamoxifen is able to bind competitively to ERα thereby disrupting the binding of estrogen and inhibiting the transcription of estrogen responsive genes that ultimately antagonize hormone dependent breast cancer cell proliferation and tumor development [25, 28]. Tamoxifen is metabolized hepatically by cytochrome P450 (CYP450) isoforms into pharmacologically active metabolites 4-hydroxytamoxifen (4-OHT), N-desmethyl tamoxifen and endoxifen. These metabolites have a higher affinity for ERs. 4-OHT binds to ERs in breast tissue with an affinity similar to that of estradiol and inhibits ER-mediated gene transcription by recruiting co-repressors that modulate gene expression [29]. Their anti-tumorigenic activity is attributed to induction of apoptosis by downstream ER signaling pathways, inhibition of mitogenic growth factors activity and reduction of angiogenesis [30, 31]. Literature has demonstrated the complex mechanisms of action for tamoxifen and its metabolites and the difficulty in determining the molecule responsible for each mechanism, it is also hypothesized that the response to tamoxifen therapy is an aggregate of the parent and metabolites actions [29]. Pro-estrogenic activities of tamoxifen and its metabolites are demonstrated on bone density, as it decreases bone loss and inhibits osteoclasts in post-menopausal women but causes deleterious effects on bone density in healthy pre-menopausal women [32]. Another pro-estrogenic activity of tamoxifen and its metabolites is found in uterine epithelia, and it has been linked to endometrial cancer in some women restricting its use to 5 years and labeling tamoxifen as a carcinogen [25, 28]. Tamoxifen has been indicated for pre- and post-menopausal women and men diagnosed with hormone-responsive ER positive early stage breast cancer after surgery and as a chemopreventative for high-risk women [25, 27, 28].
Alternatives to SERMs exist, particularly for patients with advanced breast cancer or as a second line therapy to tamoxifen resistant tumors. These include selective estrogen receptor down regulators such as Fluvestrant (Faslodex®) [33]. Their molecular activity is also mediated by binding to ER, however, they function entirely as ER antagonists, causing downregulation and degradation of ER and ultimately inhibiting proliferation of estrogen dependent breast cancer cells. An advantage to the use of fluvestrant over tamoxifen as it is devoid of ER endometrial adverse effects [33]. It has been used in combination with docetaxel as it enhances the sensitization of breast cancer cells to chemotherapy [33].
Another group of endocrine therapy that has been indicated for postmenopausal women with hormone responsive ER breast cancer is aromatase inhibitor (AI) [26]. Their principle mode of action is to decrease circulating levels of estrogen and function by targeting and interfering with the enzyme responsible for the conversion of androgens to estradiol. CYP450 enzyme complex aromatase is responsible for catalyzing the final step in the biosynthesis of estradiol in both pre and post-menopausal women. In premenopausal women, the primary source of estrogen is from the ovaries, while in post-menopausal women adrenal and ovarian androgens are converted to estrogen by enzyme aromatase in peripheral tissues [26, 33, 34]. AIs have been categorized into two main groups, Type I and Type II inhibitors. Type I AIs are irreversible inhibitors of aromatase, they are also known as mechanism based inactivators [26, 34]. These AIs are designed to mimic the substrate of aromatase androstenedione and are recognized by the enzyme as alternate substrates. Hence they undergo irreversible chemical reactions and are converted into intermediates during catalysis; the intermediate however, is reactive and causes inactivation of the enzyme [26, 33, 34]. A successful example of a steroidal AI inhibitor is exemestane (Aromasin) [26, 33, 34]. It is an inhibitor of human placental aromatase and has shown relatively prolonged reduction of estrogen levels (4-5 days) in postmenopausal women with breast cancer due to irreversible binding to aromatase [34]. Exemestane has been found to decrease hormone dependent mammary tumors in hormone receptor positive metastatic breast cancer [34]. Type II inhibitors act by non-covalent competitive binding to the active site of aromatase to decrease the amount of estrogen formed. These inhibitors are designed to target aromatase selectively in order to avoid binding to other CYP450 enzymes [26, 34]. They contain a triazole ring, which aids in their selective binding to the haeme iron of aromatase [26]. As the binding is non-covalent it is reversible, hence therapy with these inhibitors must be continued [26, 34]. Non-steroidal examples of these AI include anastrazole (Arimidex®) and letrozole (Femara®), they are found to inhibit more than 95% of estrogen biosynthesis in post-menopausal women with advanced breast cancer [26, 34]. The FDA has approved the use of AI for postmenopausal women diagnosed with hormone receptor positive breast cancer in the early stage as adjuvant therapy and for advanced and metastatic stages after tamoxifen treatment [26, 34].
Angiogenesis is a physiological process where new blood vessels are formed from preexisting mature vasculature [35]. This process allows the surrounding tissues to be supplied with nutrients and oxygen and simultaneously gets rid of metabolic waste products and carbon dioxide. In healthy tissue, angiogenesis is a temporary process and occurs during mensuration and embryogenesis, it is also an attribute of wound healing [35]. Prolonged angiogenesis however, is usually an indication of a pathogenic state such as cancer [35, 36]. The aberrant proliferation of cells during tumor formation in many types of cancers requires an extensive capacity of vasculature to manage the high demand in oxygen and nutrients and eliminate accumulated metabolic waste for tumor cells to grow and survive. Hypoxia in the tumor microenvironment leads to the production of hypoxia-inducible factor 1α; a stimulus for angiogenic switch, inducing the overexpression of pro-angiogenic factors mainly vascular endothelial growth factor (VEGF)- A, as well as fibroblast growth factor (FGF), placental growth factor (PlGF) and platelet derived growth factor (PDGF) by tumor and host cells [13, 35, 36]. Subsequently, proliferation of endothelial cells is stimulated and chemotaxis to tumor tissue facilitates the formation of the vascular lumen architecture and simultaneous disruption of surrounding vascular membrane structure [13, 36]. These factors contribute to the defective heterogeneous vasculature surrounding and within the tumor microenvironment, differentiating it from normal vasculature [35, 36]. Tumor vasculature has fenestrated blood vessels, with diminished pericyte coverage, and intratumoral blood vessels resemble immature perforated capillaries. As a result, vasculature is highly permeable, leaky, has poor blood perfusion and interrupted blood flow [35, 36]. Furthermore, the enhanced microvascular permeability leads to the aggregation of fibrin and other plasma proteins in the stroma of tumors, increasing the interstitial fluid pressure within tumors particularly in the absence of adequate lymphatic drainage [35]. This dynamically chaotic tumor microenvironment favors tumor progression in multiple ways. The high interstitial fluid pressure prompts the dissemination of tumor cells into intratumoral capillaries and neo-vessels providing a route for metastasis [36]. Elevated pressure in the tumor core resists the delivery of chemotherapeutics into these micro-regions of the tumor [35, 36]. The heterogeneous vascularization of the tumor microenvironment is dependent on the degree of angiogenesis inflected by tumor cells, so it can be different within and between tumor tissues, and obviously for different types of cancers [36]. These variations are amplified because intratumoral neo-vessel formation is mediated when pro-angiogenic factors outweigh anti-angiogenic factors within the tumor microenvironment. Luckily, the differential activation of angiogenesis in normal tissue compared to tumor tissue provides a means of targeting this pathophysiology selectively, based on the phenotypic and functional differences between intratumoral vasculature and normal vasculature. Therefore, anti-angiogenic strategies serve as attractive cancer therapy; with the aim of terminating the blood supply to tumor tissues and micro-regions in order to impose widespread hypoxia and necrosis selectively within solid tumors while sparing normal cells.
The most extensively studied target to inhibit the angiogenesis process is the VEGF and its receptor (VEGFR). VEGF is a soluble glycoprotein with pro-angiogenic activity, which is overexpressed in tumor tissue, and also by host fibroblasts and inflammatory cells. It is a ligand for the soluble and membrane bound tyrosine kinase VEGFR expressed on endothelial cells. Upon binding, a signaling cascade is activated leading to endothelial cell proliferation, maturation and migration to tumor tissue and neo-vessel formation. Different isoforms of VEGFR and ligands of VEGF exist; the most influential interaction for intratumoral angiogenesis is VEGF-A/VEGFR-2. The first and currently most successful anti-angiogenic cancer therapeutic approved by the FDA is the humanized monoclonal anti-VEGF-A antibody bevacizumab (Avastin®). It contains complimentary-determining regions of a mice antibody that selectively binds to circulating VEGF-A to neutralize it and inhibit its interaction with VEGFR2 [13, 35, 36]. Hence a unique feature of bevacizumab is that unlike most antibodies that bind to receptors, it binds and traps the ligand VEGF-A, limiting its availability to bind to VEGFR2. This initially leads to vascular normalization, which involves reduction in the overall intratumoral vasculature and hence limits the blood supply to tumors. The interstitial fluid pressure is lowered, hypoxia decreases and intratumoral perfusion is enhanced in the core of tumor tissues. Combination therapy is usually administered with bevacizumab to take advantage of the localization of chemotherapeutics deep into the micro-regions of solid tumors [35, 36]. Bevacizumab has been approved for the treatment of renal cell carcinoma, metastatic colorectal cancer, advanced NSCLC and recurrent glioblastoma [35, 36].
Another anti-angiogenic agent which has a similar mode of action to bevacizumab is ziv-aflibercept (Zaltrap®), acts as a decoy receptor. It is a recombinant fusion protein designed by fusion of extracellular VEGF-A binding domain portions of two isoforms of VEGFR (VEGFR1 & VEGFR2) with Fc portion of human IgG1 immunoglobulin [37]. Incorporation of the two VEGFR isoform binding domains in aflibercept allows this angiogenesis inhibitor to trap VEGF-A, VEGF-B and PlGF [36]. Although VEGF-B is not implicated in the stimulation of angiogenesis, it is overexpressed in metastatic tumors and findings suggest it has a role tumor progression by maintaining existing vasculature, while PlGF is required for inflammation-associated angiogenesis in cancer progression. The FDA approves ziv-aflibercept for metastatic colorectal cancer in combination with chemotherapeutic agents 5-Fluorouracil, irinotecan and leucovorin.
Many receptors that mediate angiogenesis are activated by the tyrosine kinase motif attached to their intracellular domain, most prominently is VEGFR, but also FGF and PDGR. Therefore, small molecule receptor tyrosine kinase inhibitors have been utilized as angiogenesis inhibitors; these include sunitinib (mentioned previously) and sorafenib (Nexavar®). Like sunitinib, sorafenib has multiple receptor tyrosine kinase inhibition activity, so its mode of action is not limited to the inhibition of angiogenesis, which it does by binding to VEGFR-1, VEGFR-2 and PDGF-B receptors, leading to morphological vascular normalization of tumor tissue [35, 36]. It also inhibits activation of signaling pathway Raf kinase (Raf/MEK/ERK) which is found to be activated in renal cell carcinoma among other cancer types, and c-KIT and Flt-3 kinases; also implicated in different cancer types [35, 36]. Multiple receptor tyrosine kinase inhibitors can be prescribed as mono-therapy since they act on multiple targets in cancer cells. In fact, their co-administration with chemotherapeutics was not found to improve the drug accumulation in tumor tissues [35]. However, it was found less likely to develop resistance to multiple tyrosine kinase inhibitors compared to selective single targeted anti-angiogenic therapies [36]. The opposite is true for bevacizumab and is the reason why it is co-administered with chemotherapeutic agents [35, 36]. During the initial phases of anti-angiogenic therapy, the intratumoral vasculature undergoes vascular normalization. However, continuous administration of bevacizumab and several other anti-angiogenic therapies causes vascular shutdown and regional tumor tissue necrosis, leaving tumor cells adjacent to normal vasculature viable and prone to resistance [35, 36]. The turning point between vascular normalization and vascular shutdown for anti-angiogenic therapies is called the normalization window and it is this duration that is found to provide optimal intratumoral drug accumulation of chemotherapeutics [35, 36]. Therefore, several factors are taken into account to maximize cancer therapy using angiogenic inhibitors. These include the type of cancer; whether it is dependent on angiogenesis, type of angiogenic inhibitor; hypertension is a common adverse effect for bevacizumab while multi-tyrosine kinase inhibitors can cause more adverse effects. The type of chemotherapeutic agent to insure it will be effective once accumulated in tumor tissues and will not counteract the angiogenic inhibitor. In addition to their temporal sequence and the time lapse between administrations that would define the normalization window; so that the chemotherapeutic agent will be able to localized and accumulate within the tumor core after vascular normalization is induced by the angiogenic inhibitor to increase the overall tumor cell exposure to cytotoxic drugs [35, 36].
In order to define the vascular normalization window and success of anti-angiogenic therapy, predictive detection of vascular parameters is required to enable precision and personal therapy for each patient. Microvascular density analysis is significant to determine vascular integrity during patient treatment and the sensitivity of the cancer to anti-angiogenic therapy; it can be monitored
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Examples of molecular targeted therapeutic anticancer agents with their main target.
The previous sections discussed targeted therapeutics based on their molecular mechanisms of action. Although many have proved successful and more efficient than conventional chemotherapeutics, there still remained limitations in terms of toxicity and resistance. The next section addresses a new field in targeted cancer therapy that aims to improve on molecularly targeted therapies by embedding further selectivity into therapeutics. The general principle behind this new and growing field is utilizing the selective delivery of therapeutics to target tumor tissue as well as the selective molecular mechanisms observed in molecularly targeted therapeutics. Targeted delivery therapeutics can be classified into passive targeting which takes advantage of the enhanced permeation and retention effects of the tumor microenvironment or active targeting, which is based on incorporating targeting moieties that will guide the cancer agents to their targets. The following section discusses these two categories in more detail.
Chemotherapeutic agents are often low molecular weight molecules, with characteristically unfavorable pharmacokinetic profiles usually having short half-lives, large volumes of distribution in healthy tissue but suboptimal biodistribution in tumors. The systemic circulation also influences their plasma protein binding strength limiting the free drug available for therapeutic action. Polar, and low molecular weight chemotherapeutic molecules (less than 30 kDa) generally have short systemic circulation exposure as they are cleared by glomerular filtration in the kidneys. On the contrary, macromolecules are commonly recognized by macrophages and cleared from the circulation by the reticuloendothelial (RES) system in the liver. Both of these mechanisms of clearance pose a threat to the drug concentration required to produce the desired therapeutic effect in tumor tissue. In turn, higher concentrations of these drugs that usually have a low therapeutic index, need to be administered making non-selective toxicity inevitable. Furthermore, the inability of conventional chemotherapeutics to sufficiently localize and accumulate in the core of tumors contributes to severe adverse effects and therapeutic resistance, rendering many incompetents for cancer therapy.
Passive targeting of cancer therapeutics aims to improve the pharmacokinetic properties of anticancer agents and tailor them to take advantage of the characteristics and architecture of the tumor microenvironment. The principle behind passively targeted chemotherapeutics is to design delivery systems with improved pharmacokinetic profiles complimentary to the tumor microenvironment. So that encapsulated chemotherapeutics can be transported in the circulation safely for longer durations with minimal toxicity to surrounding healthy tissue. Once they reach the tumor microenvironment they passively accumulate in tumor tissues and are released at therapeutic concentrations to exert their cytotoxicity against cancer cells. As mentioned previously, tumor vasculature is different from normal vasculature. These variations have a unique impact on the behavior of substances in the vicinity of the tumor microenvironment; the phenomenon is known as the enhanced permeation and retention (EPR) effect of tumors. It is attributed to the abnormal vasculature and impaired lymphatic drainage in the tumor microenvironment [37]. The imbalance in angiogenic factors and matrix metalloproteinases leads to the formation of highly disorganized dilated vessels with fenestrations, due to pores and wide gap junctions between endothelial cells that lack sufficient pericytes and a basement membrane [37]. Intratumoral vessels usually lack the smooth muscle layer surrounding endothelial cells and hence remain dilated [37]. As a result, intratumoral vasculature is leaky enough to extravasate macromolecules >600 nM in diameter into tumor tissues as opposed to normal vasculature where tight junctions restrict the permeability of molecules sized >4 nM [37]. Furthermore, the impaired lymphatic system in the tumor microenvironment retains extravasated molecules allowing them to accumulate [37]. Therefore, the enhanced permeation of macromolecules in neoplastic vasculature and their retention and accumulation into tumor tissues lead to the application of nanotherapeutics as delivery systems for targeted cancer therapy.
The design of delivery systems with improved pharmacokinetic profiles and biodistribution that complement the pathophysiology of the tumor microenvironment is made possible by utilizing nanocarriers. The field of nanomedicine, derived from nanotechnology is extremely broad with a deluge of components synthesized and investigated for various diseased states. Nanocarriers are colloidal drug delivery systems with sizes in the nanometer range (generally <500 nM) imparting a high surface to volume ratio to them and their cargo. This is a significant feature for their characteristics. Variations in size, shape, and synthetic constituents have been investigated to determine the ideal nanocarriers for enhanced bioavailability and therapeutic efficiency of anticancer agents. The principle behind nanocarriers is to allow drugs to behave as though they have a larger molecular weight. Much research has gone into determining the ideal size of nanocarriers for cancer therapy and it was found to range from 10 to 100 nM [38]. Justified as nanocarriers >10 nM are more likely to escape rapid excretion by glomerular filtration in the kidneys. While nanocarrier >100 nM are more likely to be absorbed by proteins for opsonization prior to hepatic uptake and clearance by RES [38]. Surface charge of nanocarriers is another modifiable property to manipulate the pharmacokinetic profiles of therapeutics. It is attributable to the various types of nanomaterial formulations available to synthesis these carriers. Neutral and anionic nanocarriers are favorable in evading renal elimination whereas cationic nanocarriers form better interactions with the negatively charged cell membrane and enhances their cellular uptake [38]. Another way to modify the surface of nanoparticles is by a process called PEGylation. It involves coating the surface of nanoparticles with an inert polymer polyethylene glycol (PEG) so that they are shielded from interactions during systemic circulation, particularly from protein blood components and even aggregation with one another. This imparts stealth properties to nanoparticles and has been effective in increasing circulation times of nanoparticles as they avoid surface absorption and opsonization, reducing the frequency of clearance by phagocytosis and the RES system [39].
Nanocarriers can be categorized into 3 types based on their constituents, organic, inorganic, and hybrid [40]. Organic carriers include liposomes, solid lipid nanoparticles, dendrimers, polymer nanoparticles and polymeric micelles. Inorganic nanocarriers include carbon nanotubes and mesoporous silica nanoparticles, while hybrids are a combination of both. This part of the chapter discusses the most prevalent organic nanocarriers as only two have been approved by the FDA to date for anticancer use.
These microscopic lipid bilayers have become very popular after the success of the reformulated anticancer drug Doxil (Caelyx®) [41]. They are spherical vesicles with an aqueous core surrounded by single or multiple lipid bilayers, composed from natural or synthetic lipids such as phospholipids and cholesterol that can enter cells by endocytosis. The structure of liposomes allows them to encapsulate both water and lipid soluble drug payloads [41]. Schematic of liposome arrangement is shown in Figure 1. Hence liposomes can improve the pharmacokinetic properties of a range of drugs with different solubilities. Moreover, they can be coated with polymers or PEGylated to provide stealth properties. Doxil for instance is a polyethylene glycol coated liposome with the chemotherapeutic doxorubicin as the drug payload. Currently, it is the sole liposomal cytotoxic agent approved for solid tumors, and indicated by the FDA for ovarian cancer and multiple myeloma [41]. The chemotherapeutic doxorubicin is an anthracycline, which mediates its cytotoxicity by intercalating with DNA and inhibiting topoisomerase I and II activity, leading to apoptosis induction in cancer cells [42]. However, one of its main drawbacks is cardiotoxicity which can be fatal or lead to congestive heart failure, hence patients are only permitted a limited dose in their lifetime [41, 42]. The reformulation of doxorubicin as doxil has overcome this adverse effect; in fact, it has a very different toxicity profile from doxorubicin [41, 42]. While being dose limited by mucocutaneous toxicities, its adverse effects are much less severe. Furthermore, the bioavailability of doxil is preferential to doxorubicin as it is more stable in systemic circulation, has a longer half-life and slower clearance rate [42]. It is also able to extravasate into leaky intratumoral vasculature where its concentration is low compared to normal vasculature where its concentration is higher, by passive diffusion and accumulate substantially more in solid tumors [42]. As a result, it has a better therapeutic efficacy and index compared to doxorubicin [42].
Schematic diagram of liposomal arrangement of phospholipid (not to scale).
Nanoparticles have been synthesized in a variety of forms from various constituents. Solid lipid nanoparticles constitute organic solid lipids such as mono- di- and triglycerides, free fatty acids and alcohols or waxes and steroids [40]. These lipids are dispensed in water to form a nanosized colloidal dispersion with a large size range of 50–1000 nM, an emulsifier is added to stabilize the formulation [40]. Lipid constituents offer great advantages as nanocarriers for anticancer drugs classified as class II and class IV in the Biopharmaceutical classification system, where aqueous solubility is low [40]. This is because they increase the solubilization of lipophilic drugs and enhance their bioavailability. These delivery systems also provide controlled drug delivery, they are biocompatible and biodegradable and have greater drug payloads as well as improved stability and are feasible for large-scale manufacture [40]. Another type of nanoparticles is polymeric nanoparticles these are solid nanosized colloidal particles that are formulated as nanospheres or nanocapsules depending on the structural organization [40]. They are made from both synthetic biodegradable polymers such as polylactic acid, polyglycolic acid, PEG and N-(2-hydroxypropyl) methacrylamide, or natural polymers such as albumin, alginate, collagen, chitosan and heparin [40]. The advantage of using polymeric nanoparticles is that they are usually biocompatible and biodegradable, hence reduce toxicity and are degraded in the body by normal metabolic routes [40]. They also offer greater drug stability in the circulation and during storage, are formulated to be homogenous compared to liposomes and retain the enhanced bioavailability characteristic of nanocarriers [40].
A successful example of an anticancer polymeric nanoparticle that has been approved by the FDA is Abraxane®, for the treatment of metastatic breast cancer and NSCLC. It constitutes the chemotherapeutic taxane paclitaxel bound to the natural polymer albumin in a solvent free formulation, forming a colloidal suspension of 130 nM particles. This formulation has several advantages over the use of the traditional chemotherapeutic paclitaxel limited by its poor aqueous solubility. Previously, paclitaxel was administered in a formulation with Cremophor® a solubilizing agent to enhance its solubility in the systemic circulation, however, many patients suffered hypersensitivity reactions from Cremophor® and pretreatment with steroids or antihistamine is recommended for these cases [43]. Albumin acts as a carrier for hydrophobic paclitaxel without Cremophor®, and is found to accumulate in tumors along with its bound constituents [42]. It is also able to enhance the endothelial cellular uptake of paclitaxel by the formation of caveolaes during transcytosis, this is reflected in clinical trials where the permeation and antitumor activity of Abraxane® was higher compared to paclitaxel. It is also found to have a higher maximum tolerated dose and the adverse effects of Abraxane® were reported to be less severe and frequent than the general taxane associated adverse effects [41, 43].
The enhanced stability during systemic circulation offered by nanocarrier to their cargo has served as a key advantage to the application of targeted gene delivery for cancer therapy. Gene therapy has been implicated to replace or knock out mutations commonly detected in cancer or insert new genes into cancerous cells to induce apoptosis. Therefore, by targeting endogenous tumor gene expressions, a highly potent and specific therapeutic effect can be instigated with minimal off-target toxicity. This is widely applicable to cancer therapy due to its dependence on oncoproteins and oncogenes. Moreover, multiple genes can be targeted to inhibit tumorigenesis, recurrence and resistance [44]. However, challenges with regard to toxicity and instability have rendered gene therapeutics immature for cancer therapy. The introduction of naked genetic material such as DNA, plasmid DNA, small interfering RNA, nucleotides, and peptides in the systemic circulation is limited due to instability and degradation by serum nucleases in the plasma as well as rapid renal clearance and phagocytosis by immune cells [44]. In addition, not only is cellular uptake restricted but nuclear delivery of genes into non-dividing target cells is inefficient and discrepancies exist on long term incorporation of genetic DNA information into the host cell, as it is likely to have unforeseen implications on patient’s safety and toxic immune responses have been reported [44].
Nanocarriers have the potential to be delivery vectors for genetic material as cargo to their target tissue. Their versatility allows them to be designed in a manner that allows high gene delivery efficiency and payload capacity [44]. Genetic material can be incorporated and attached into nanocarriers by electrostatic interactions or surface conjugation [44]. Cationic nanocarriers like liposomes synthesized from cationic and neutrally charged lipids are able to condense DNA, siRNA, nucleotides, peptides and proteins to form complexes of plasmid DNA lipids that self-assemble into lipoplexes. Similarly, polymer nanocarriers are able to form polyplexes with nucleic acids [44]. These complexes protect the genetic cargo from enzymatic degradation in the systemic circulation and aid in cellular interactions that facilitate endocytosis. Hence they are able to deliver their cargo intracellularly increasing the likelihood of efficient transfection.
Moreover, nanocarrier can be synthesized from polymers that are able to respond to specific stimuli based on physiochemical differences between cancer and non-cancerous cells, leading to the development of smart drug delivery systems [45]. Their aim is to reduce dosage frequency in a spatially controlled manner and facilitate the delivery and accumulation of the therapeutic system to the target tumor tissue. Followed by the release of anticancer agent at the specific location at a precise concentration based on internal or external stimuli [45]. Smart polymer nanocarriers can respond to stimuli such as changes in pH, enzyme configurations, redox reactions and light [45]. The application of passive targeted therapy in cancer has proved to dampen down adverse effects experienced with traditional chemotherapeutics. In addition, the improved pharmacokinetic profiles and enhanced efficiency of passive targeted cancer delivery systems has increased the response and survival rates of patients. However, this strategy of targeted cancer therapy is not devoid of challenges as non-selective toxicity and resistance remains to be an issue that impedes cancer therapy. Hence a further extension to passive targeted cancer therapy was explored that pioneered the birth of a different strategy for targeted delivery it is active targeted therapy and is discussed in the final section of this chapter.
Active targeting anticancer therapeutics aims to further increase the selectivity of chemotherapeutics to tumor tissue via delivery strategies through preferentially potentiating their affinity towards cancer cells and escalating endocytic internalization. The principle mechanism of active targeted cancer therapy is based on receptor-mediated interactions. Their framework is established through targeting moieties such as small molecule ligands or antibodies that bind to receptor of proteins, sugars or lipids on the surface of target cells. As a result, these ligands act as delivery agents for the anticancer therapeutic system, prompting its tumor accumulation and enhancing its residence time.
Many of the same receptors targeted in molecular targeted therapeutics have been utilized as active targeted delivery therapeutics, imparting a second functionality to active targeted delivery cancer therapy, whereby one part of the system acts by targeted delivery and the other part mediates molecular mechanisms of cytotoxicity. Commonly targeted cell surface receptors include EGFR and HER2. Widely explored cell surface receptors include folic acid receptor, transferrin, and prostate specific membrane antigen [11]. The scope of this targeting strategy is endless and a heterogeneous array of targeting components have been utilized and reported as drug-targeting conjugates such as antibodies in antibody drug conjugates (ADC), proteins, peptiodomimetic and small molecules.
Much of the success of active targeted delivery therapeutics for cancer therapy has been achieved with ADC. They constitute extremely potent chemotherapeutic agents that are not administered alone, due to their narrow therapeutic window and extreme non-selective toxicity, examples include maytansinoids and auristatins. Maytansinoids are second-generation microtubulin polymerization inhibitors similar to vinca-alkaloid traditional chemotherapeutics, that have been modified to bind to tubulin with >100-fold higher affinity [46]. The ADC transtuzumab emtansine (Kadcyla®/T-DM1) has been synthesized with a derivative of maytansin (DM1) conjugated to transtuzumab, previously mentioned, a MAb for breast cancer patients that overexpress HER2. This design allows targeted delivery of a highly potent cytotoxic agent to tumor cells that express HER2 with a favorable therapeutic window that would otherwise not be achieved by the cytotoxic agent alone. Many factors need to be taken into account with the design of ADC, particularly the binding affinity of the targeting ligand to the receptor after conjugation with the therapeutic agent, in the case of T-DM1, it binds to HER2 with a similar binding affinity to free transtuzumab [46]. This is not always the case as conjugation and linkers connecting the targeting moiety and therapeutic agent can cause steric hindrance or altered structural configurations, which restricts or dissolves binding. Linkers are designed to stably carry the therapeutic system in systemic circulation and insure the therapeutic agent will not dissociate until it has reached the target site. This is achieved to a higher degree with non-cleavable linkers, but cleavable linkers are utilized more commonly as complete cleavage of the therapeutic agent from the system ensures efficient cytotoxic action. Binding of the targeting moiety to the receptor usually induces cellular internalization of the therapeutic system. Targeting moieties and linkers are also designed to facilitate intracellular release of the cytotoxic agent. Transtuzumab in T-DM1 aids in the internalization of DM1 into cancer cells, it contains a non-cleavable linker that keeps the system stable in circulation but may compromise the cytotoxic activity of DM1 if proteolytic lysosomal degradation of transtuzumab is inefficient [46]. In addition to the cytotoxic action of DM1 after intracellular release, T-DM1 is also able to inflect the antitumor action of transtuzumab regarding inhibition of HER2 signaling and marking HER2 overexpressing cells for ADCC [46].
Although no small molecule active targeting delivery therapeutics for cancer therapy have been approved by the FDA to date, research in this field is growing exponentially. Many of these potential therapeutics in clinical stages of development utilize nanoparticles that are decorated with targeting ligands on their surface and encapsulate anticancer drugs as payloads [11].
The origins of targeted therapy started by challenging cytotoxic chemotherapy with an alternative approach to treatment, achieved by adopting the “magic bullet” theory of selectivity between pharmacological principles of cancer and non-cancer cells. Targeted anticancer therapy is an exponentially growing class of chemotherapeutic agents with advantages over conventional anticancer drugs. The advantage is a result of selective targeting of cytotoxic agents towards cancer cells over normal cells. Selective targeting is based on variations in genes, proteins and pathophysiology of cancer cells compared to non-cancerous cells. This has been explored and achieved in molecular mechanism therapeutics as well as passive and active targeting delivery strategies for cancer therapy. The progress in cancer therapy stems from the understanding cancer biology leading to detailed distinctions between the pathophysiology of tumors and the physiology of normal tissue.
Strategies of targeted anticancer therapy have advanced by applying meticulous selectivity to chemotherapeutic. This commenced with variations in molecular mechanisms of action in mechanistic therapeutics with much success in targeting signal transduction pathways specifically tyrosine kinase proteins. Subsequently, a greater degree of selectivity is investigated by passive targeting mechanisms, which utilizes nanocarriers to take advantage of the enhanced permeation and retention effects of the tumor microenvironment. This strategy has also shown that not only is the pharmacodynamic profile of the anticancer agents significant for the success of cancer therapy but so is their pharmacokinetic profile. Further selectivity has also been explored by active targeting delivery via receptor-mediated interactions with cancer cells. All these targeting strategies can be combined and tailored to achieve efficient response rates for patients.
The application of targeted therapeutics has shifted therapy protocols for cancer patients towards precision medicine; hence various aspects need to be considered with targeting cancer therapy. This approach involves determining diagnostic biomarkers and genotyping tumors to choose the relevant targeted therapeutic for the patient. Furthermore, treatment needs to be designed and tailored for patients in terms of duration, dose and monitoring of adverse effects. Careful selection of combination therapies and dosing regimens are also critical to the success of cancer therapy.
Targeted cancer therapy has proven more effective than conventional chemotherapeutics as the maximum tolerated dose is higher so patients are able to tolerate therapeutic doses with less severe adverse effects. This resulted in improved patient response rates and survival. Although resistance is still an issue with cancer therapy, the strategies employed by targeted therapy have widened the scope of therapeutics available if resistance occurs. Although much of this field is still under development, the progress made with targeted cancer therapy is changing the perspective of cancer from a fatal disease to a chronic one that can be managed throughout the patient’s lifetime.
Considered the second most commonly performed operation after cesarean section worldwide, hysterectomy may be classified as abdominal (laparotomy, laparoscopy, or robotic assistance) and vaginal (via an incision through the superior part of the vagina).
The most common indications for hysterectomy are benign conditions such as uterine fibroids, endometriosis, genital prolapse, pelvic pain, heavy menstrual bleeding, but the technique is also used for gynecological malignancy (usually ovarian, uterine, or cervical) and risk-reducing surgery (in cases of BRCA 1 or 2 mutations or Lynch syndrome) [1, 2, 3, 4].
Actually, there are three types of hysterectomy—total hysterectomy (the uterus and cervix are removed), subtotal or partial hysterectomy (the uterus is removed, but the cervix is left in place), and total hysterectomy with bilateral salpingo-oophorectomy (uterus, fallopian tubes, ovaries, and cervix are removed) [1, 2, 3, 4]. The term radical hysterectomy (removal of the uterus, cervix, parametrium, vaginal cuff, and fallopian tubes) is used to describe a wide range of procedures universally applicable to cervical cancer. However, the degree of radicality clearly depends on preoperative estimation of tumor location, surgical margins and the risk of occult lymphatic spread. Moreover, the ovaries may or may not be removed according to the patient age [1, 2, 3, 4]. In addition, supracervical hysterectomy is sometimes preferred to diminish the intraoperative complications and surgical times, as well as to limit the possibility of lower urinary tract issues and maintain normal sexual function [1, 2, 3, 4].
The best route for hysterectomy is multifactorial, depending not only on the surgeon’s skills and patient safety (minimally invasive procedures as vaginal, laparoscopic, laparoscopic-assisted, and robotic-assisted hysterectomies) but also on economic reasons [1, 2, 3, 4].
Hemorrhage after hysterectomy is recognized as an occasional life-threatening complication in modern gynecological surgery, assuming appropriate medical and surgical management [2, 3, 4, 5, 6, 7, 8, 9].
Classified as “reactionary” (postoperative bleeding within the first 24 hours following surgery) and secondary (bleeding occurring in the interval 3–22 days after surgery), unexpected hemorrhage may arise regardless of the route or subtype of hysterectomy [5, 6, 9]. Early recognition and prompt intervention (reoperation or arterial embolization) to arrest bleeding are essential strategies for the suitable outcome of the patient [2, 3, 4, 5, 6, 7, 8, 9, 10].
While the role of risk factors for “reactionary” hemorrhage is emerging and critical for a correct assessment of the patient, operative laparoscopy is still ideal to treat hemorrhage after vaginal hysterectomy, laparoscopic hysterectomy, laparoscopic-assisted vaginal hysterectomy, and laparotomy being necessary only in selected cases [2, 3, 4, 6, 9].
Secondary hemorrhage presents with varying degrees of severity and tends to be more common after laparoscopic hysterectomy, especially total laparoscopic hysterectomy than after the other hysterectomy approaches [5, 9]. Factors potentially responsible are vaginal vault infection, vault hematoma, a poor surgical technique including excessive thermal injury by electrocoagulation, and early resumption of physical activity, large uterus size, excessive use of an energy source for the uterine artery, and culdotomy [2, 3, 4, 5, 7, 9, 10].
Ultimately, the management of secondary hemorrhage is challenging and involves diverse approaches based on the exact cause of bleeding, comprising vaginal packing with or without vault suturing, laparoscopic coagulation of the uterine artery if the source of bleeding could not be identified vaginally or arterial embolization [6, 9, 10].
Because of elective gynecologic surgery, we encourage selective patients to donate their own blood before surgery [6, 11]. Several definitions are actually used:
autologous blood transfusion, when is done with the patient’s own blood; blood is stored and can be transfused during surgery;
homologous transfusion or transfusion from another woman;
parachute pack or umbrella pack is a useful tool for pelvic bleeding after pelvic exenteration;
peanut dissector; this tool is indicated for blunt pressure dissection of small places;
total blood volume; estimated blood volume of total body weight is 8% or 4.5–5.0 liters in the average women. When intraoperative blood loss exceeds 15% of the blood volume, blood transfusion must be taken into consideration in combating hypovolemic shock. About 15% of an adult blood volume can be calculated by amplification a patient’s weight in kg 10 times. The usual method of performing abdominal hysterectomy involved the use of clamps or forceps on vessels.
The present chapter will give an overview on different aspects of bleeding after hysterectomy such as incidence rate, risk factors, mechanisms, and management techniques aiming to expand our knowledge and skills in recognizing and treating this unexpected potentially serious complication. Furthermore, we intend to offer a guide toward standardizing treatment practice across bleeding issues following hysterectomy considering clear recommendations and algorithms.
Postoperative hemorrhage represents a significant potential complication of contemporary gynecological surgery. Despite normal hemostasis, appropriate/suitable surgical technique and close monitoring, postoperative bleeding may occur, leading to the different clinical and operative scenarios and challenging even the most experienced operative team [2, 3, 4, 9, 11, 12].
Based on their timing to surgery, two main subtypes of postoperative hemorrhage are actually recognized [5, 6, 7, 8, 9]:
Although the incidence of postoperative hemorrhage basically varies according to surgery, the difference between abdominal, laparoscopic, and vaginal hysterectomy remains statistically insignificant [5, 6, 7]. Indeed, some authors postulate that postoperative bleeding occurs more frequently after abdominal and laparoscopic than after vaginal hysterectomy, but overall, the incidence of hemorrhagic events after a hysterectomy varies from 0.2 to 3.1%, irrespective of surgical route [5, 6, 7, 8, 10, 13, 14].
On the other hand, the true frequency of delayed bleeding complications is still unknown, although the consequences can be particularly significant in women undergoing outpatient surgery [5, 6, 7, 8, 10, 13, 14]. Paul et al. reported an overall cumulative incidence of secondary hemorrhage after a total laparoscopic hysterectomy of 1.3% [5]. Although secondary hemorrhage is rare, it is more often reported after total laparoscopic hysterectomy than after other hysterectomy approaches [5, 6, 7, 8, 10, 13, 14].
Table 1 summarizes data on the incidence of postoperative hemorrhage reported by several authors.
Authors | Type of study, no of cases | Incidence postoperative hemorrhage |
---|---|---|
Makinen et al. [15] |
|
|
Wilke et al. [13] |
|
|
Holub and Jabor [7] |
|
|
Erian et al. [6] | 719 patients between November 1990 and March 2007: 476 VH, 243 LH |
|
Paul et al. [5] |
|
|
Incidence of postoperative hemorrhage in gynecological surgery.*
AH, abdominal hysterectomy; LH, laparoscopic hysterectomy; VH, vaginal hysterectomy; L-AVH, laparoscopic-assisted vaginal hysterectomy.
Hemorrhage is responsible for about half of the postoperative complications following gynecological surgery, ranging from persistent venous oozing to massive blood loss from injury to retroperitoneal vessels [5, 6, 7, 12, 13].
Main bleeding sites comprise the anterior abdominal wall (both the suprapubic and the umbilical incision), the vaginal cuff (after laparoscopic hysterectomy and laparoscopic-assisted vaginal hysterectomy), and intraabdominal bleeding. Abdominal wall vessel injury occurs with increasing frequency, as the practice of laparoscopic surgery becomes wider and trocars become sharper [2, 3, 4, 7, 9].
The source of bleeding in secondary hemorrhage can be the uterine vessels or descending cervical/vaginal vessels; occasionally, uterine artery pseudoaneurysm can cause delayed heavy vaginal bleeding after laparoscopic hysterectomy [2, 3, 4, 7, 9]; additionally, the technique of vaginal vault closure may also contribute to the occurrence of secondary hemorrhage [5, 9].
Postoperative hemorrhage can result from failure to control vascular injury during surgery. Accurate clamp placement, gentle handling of tissues, and the accuracy of dissection are all important and contribute to maximum efficiency with minimum blood loss and minimum tissue damage when abdominal hysterectomy is performed [9].
The electrosurgical instrument can be used for a precise incision of the abdominal wall with minimal tissue injury. By holding the electrode close to the tissue or touching the metal clamp and pressing the coagulation button, superficial coagulation can be achieved [2, 3, 4, 9].
Intra- and post-operative bleeding generally develops in younger women or those with a more vascular pelvis who underwent a hysterectomy, especially laparoscopic hysterectomy in the presence of fibroids [6, 16].
Possible rationales for secondary hemorrhage comprise a bleeding vessel missed at the end of the procedure, effects of pneumoperitoneum, Trendelenburg position, low intraoperative pressure, wearing off the effect of vasopressin, subacute infection, postoperative analgesia, as well as bleeding disorders [2, 3, 4, 5, 7, 9].
Other potential factors accounting for delayed postsurgical bleeding are vaginal vault infection, vault hematoma, poor surgical technique with excessive thermal injury by electrocoagulation, and early resumption of physical activity [5, 7, 9]. A large-sized uterus, high vascularity, large-sized vessels, excessive use of an energy source for the uterine artery, and culdotomy also play a role in this hemorrhagic event [5, 7, 9].
Most of the complications during or after hysterectomy are preventable or treatable. Other complications may exist as medical conditions before hysterectomy but are worsened during surgery, especially if not managed as part of holistic woman’s care.
Complications after surgery include [2, 3, 4, 9, 12]:
In Romania, the mortality rate following a hysterectomy is very low.
Contemporary management of surgical interventions includes postoperative bleeding and the possibility of blood transfusion with risks of HIV transmission (in 1.9 million cases), the transmission of hepatitis B (one in every 180.000 cases), or a febrile reaction to transfusion (1% cases) [2]. Most experts recommend acute normovolemic hemodilution and cell salvage in women undergoing hysterectomy section who will not accept blood products.
Hypovolemic shock can occur after major bleeding as a direct result of uncontrolled hemorrhage. Depending on the total blood volume lost, hypovolemic shock may be divided into four classes: I (< 75 mL or 15%), II (750–1500 mL, or 15–30%), III (1500–2000 mL or 30–40%) and IV (>2000 mL or > 40%) [6].
The clinical manifestations of class I hypovolemia are not measurable and compensatory mechanisms restore plasma volume within a day. In class II hypovolemia, tachycardia is the most frequent clinical finding as a result of inadequate circulatory volume. The distinction between class I and II hypovolemic shock is made by recording blood pressure and pulse in the standing, sitting, or reclining position. Postural hypotension is observed as result of cardiac failure. Compensatory mechanisms begin to fail with the class III hypovolemic shock. This results in an increase in the arterial and venous oxygen difference with classic signs including worked tachycardia, tachypnea, oliguria, and cold skin. With the class IV hypovolemic shock, a patient’s survival depends on rapid transfusion of blood and immediate surgical intervention before cardiovascular collapse and death or organ system failure.
After initial resuscitative measures are instituted, it is highly recommended for patients to be carried out in a critical care unit. Use of sympathomimetic agents after sufficient hydration and vasodilator is normally preferred in the management of patients with hemorrhagic shock who have arterial pressure higher than 70 mm Hg.
Once restoration of the intravascular volume has been completed, it is important to reassess the patient’s response to blood transfusion when managing women with severe blood loss, especially in those patients who have pulmonary edema, myocardial infarction, or congestive heart failure [12].
Transfusion for patients with hemoglobin of 8–10 mg/dL is no longer recommended.
When major surgery is anticipated and transfusion is massive, platelets in addition to packed cell transfusion are required. It is recommended that cryoprecipitate be reserved for patients with deficiencies in von Willebrand factor, factor VIII, and fibrinogen factor XIII.
Recognized as an uncommon complication of hysterectomy, postoperative hemorrhage represents a true challenge in routine practice [8]; irrespective of the procedure, a close follow-up of the patient in a high-dependency unit is indicated in order to exclude recurrence of bleeding [6, 7].
The key to successful management is timely intervention meaning prompt diagnosis, urgent resuscitation if necessary and rapid decision for either arterial embolization or reoperation according to the severity of bleeding and the hemodynamic stability of the patient. Both techniques are highly effective to control bleeding; nevertheless, if the patient is hemodynamically unstable or of the interval since surgery is under 24 hours suggesting rapid hemorrhage, the emergency return to the operating theater to arrest the bleeding is preferred [6, 7, 9].
Current options for managing hemorrhage include [6, 7, 9]:
every patient should be carefully monitored postoperatively for signs of bleeding (hypotension, tachycardia, tachypnea, abdominal distension);
ultrasound can confirm intraperitoneal bleeding; more ways to determine intraabdominal hemorrhage include abdominal and pelvic CT scan; a routine coagulation profile should be done immediately for the patient with a rapid pulse, low blood pressure, and/or low urine output. The surgeon must take charge of the problem and execute the technical steps necessary to treat hemorrhagic shock in the operating room. Intraperitoneal bleeding can be hidden by incisional pain and analgesic medications. Despite adequate dissection, a small vessel may bleed or the suture may cut through tissue. Skeletonized vessels and small sutures should be used for significantly reducing the incidence of postoperative hemorrhage. Venous bleeding can be more life-threatening than arterial hemorrhage which can be clearly seen and controlled with fast small sutures or clamps.
the presence of unexpected drop in hematocrit or hemoglobin postoperatively.
A simplified algorithm to describe steps after gynecological surgery and potential post-surgery bleeding is provided in Figure 1.
A simplified algorithm of post-surgery bleeding approach.
A closer look at the holistic management of postoperative blood should also underpin the following [9]:
to assess blood value and coagulation mechanisms;
to identify changes in the coagulation components, and to initiate replacement therapy in order to achieve adequate hemostasis. In assessing the patient’s coagulation status, it is very important to avoid such a situation known as the trauma triad of death consisting of—hypothermia, metabolic acidosis, and coagulopathy. In some patients with benign disease, blood transfusion is rarely indicated. Experience has shown that blood transfusion may be significant in women with malignant disease;
to establish the therapeutic strategy by measuring the level of prothrombin time < 14 sec, activated partial thromboplastin time (aptt) < 40 sec, fibrinogen >100 mg/dL, platelets >80 × 103 mL.
In hemodynamically unstable women (rapid pulse, falling blood pressure, with or without renal impairment) or if the bleeding occurs shortly in post-surgery (the so-called reactionary hemorrhage), it is desirable to return to the operating room [5, 6, 7, 8, 9].
A preoperative abdominal and pelvic ultrasound or CT scan is routinely required to visualize the source of bleeding as being intra- or retro-peritoneal, as well as adequate local examination without or under anesthesia. Moreover, the operative procedure should be mentally revised to identify any potential bleeding issue [9].
Surgical revision for postoperative bleeding may be performed transvaginally, laparoscopically, or both [5, 6, 7, 8, 9, 13, 14].
Postoperative hemorrhage from the vaginal vault recurrently originates from the vaginal artery in the lateral vaginal fornix or from one of its branches, since the lateral vaginal angle which includes the vaginal artery may not be accurately protected or turn into disligated [9, 13, 14]. Excessive vaginal bleeding needs to be objectively measured; since the vagina is a distensible organ, clots obstructing the vaginal introitus may lead to a large amount of blood accumulating and distending the vagina, subsequently covering the true significance of hemorrhage [9, 13, 14]. Vaginal bleeding can be controlled by clamping and ligating the bleeding point as well as by delayed-absorbable transfixion suturing of the vaginal mucosa and paravaginal tissue [9, 13, 14]. If such techniques are not enough or bleeding vessels have retracted, other tactics should be intended [8].
When no noticeable vaginal source, bleeding after abdominal or vaginal hysterectomy is traditionally treated by laparotomy or laparoscopy [7, 9]. While laparotomy is recommended in cases of intraperitoneal bleeding or unsuccessful conservative transvaginal treatment, operative laparoscopy is clearly indicated if the source of bleeding cannot be identified by the means of vaginal examination and/or if an intraabdominal bleeding source is suspected [7, 9, 13].
Post-surgery bleeding requires laparotomy in two situations.
Firstly, if the surgical hemostasis cannot be achieved transvaginally, laparotomy may be necessary [9].
Secondly, if the patient underwent an abdominal hysterectomy, the incision should be reopened, succeeding the following steps (i) clots and blood evacuation from the abdomen and pelvic area; (ii) searching of the potential bleeding sites, commencing with the most expected places; (iii) ligating, suturing, or clipping of the identified bleeding sites; (iv) verifying the ureteral integrity as high risk of ureteral damage during reoperation; and (v) closing second time after a completely dry abdomen and pelvis [9].
The laparoscopic approach to postoperative bleeding following laparoscopic hysterectomy, vaginal hysterectomy, or laparoscopic-assisted vaginal hysterectomy is an attractive alternative to the abdominal surgical approach in the majority of patients [6, 7, 9, 13]. The procedure can be used to adequately evaluate the pelvis and the abdominal wall, which is occasionally the source of hemorrhage after laparoscopic hysterectomy. Moreover, whether the bleeding is from the abdominal wall, the surgical pedicles, or the vaginal cuff, it can be managed laparoscopically [8, 9]. Evidently, hemostasis can be more easily obtained in laparoscopic surgery because of magnification, close inspection, routine use of suction irrigation, and bipolar coagulation [7, 9]. Besides, bipolar coagulation, a Foley catheter introduced in the port-site bleeding, or a collagen-fibrin agent can be used to achieve local hemostasis during laparoscopy [7, 9].
Following laparoscopic irrigation/suction using Ringer’s solution to clear the operative field, a combination of laparoscopic suturing using absorbable suture material and laparoscopic bipolar coagulation is commonly recommended [6, 8, 9]. Also, electrosurgery is effective in controlling bleeding during laparoscopic surgery. Furthermore, different forms of fibrin adhesive are tested in gynecologic open surgery in order to stop oozing hemorrhages after primary hemostatic treatment with a high efficacy rate (98%) [6]. Holub and Kliment reported successful treatment of hemorrhage from damaged tissue near important pelvic structures using the laparoscope to apply collagen fleece combined with fibrin glue [7, 17].
To avoid further risk of injury to the abdominal wall and to improve the recovery time from surgery,
Conversely, if the patient is reasonably stable and there is not abrupt early bleeding (based on the volume of blood in the abdomen or retroperitoneal space as estimated by ultrasound and the time from surgery), it seems realistic to try to identify the bleeding artery and embolize it by transcatheter interventional radiological techniques [2, 3, 4, 9, 10].
Arterial embolization remains an important minimally invasive option for the management of delayed postoperative hemorrhage [2, 3, 4, 8, 9, 18]. Transcatheter arterial embolization has been shown to be an effective tool for the management of postoperative hemorrhage after gynecologic laparoscopy, but also after abdominal and vaginal hysterectomy [8, 9]. Selective angiographic arterial embolization is a quite simple and safe procedure with a clinical success rate up to 90% in routine practice and usually a low complication rate less than 10%, including a mild postembolization syndrome with pain, fever, high leucocyte count related to vascular thrombosis and tissue necrosis [8, 9]. Bladder necrosis, vesicovaginal fistula, neuropathies as well as renal toxicity are uncommon, isolated side effects [9].
Arterial embolization technique comprises the following main steps—(i) identification of the site of bleeding by angiofluoroscopy if more than 2–3 mL/min bleeding rate; (ii) percutaneous catheterization of the femoral artery or, uncommonly, brachial artery under local anesthesia with retrograde direct access to the hypogastric artery; (iii) canulation of the hypogastric artery or specific collateral vessel if appropriate; (iv) injection of the embolization material under angiographic observation (metal coins, autologous clot, small pieces of gelfoam, small silastic spheres, subcutaneous tissue, or other hemostatic materials; (v) repeat angiography to demonstrate the occlusion of the bleeding vessel; (vi) remove of the catheter followed by careful monitoring for further bleeding [8, 9, 10].
Although second surgery is often the initial choice for postoperative hemorrhage, for a patient who is hemodynamically stable but is experiencing postoperative hemorrhage, transcatheter arterial embolization is a welcome alternative to a second surgery [8, 9]. However, if rapid access to interventional radiology is not available or if transcatheter arterial embolization is unsuccessful, laparoscopy can still be considered [8, 9]. Besides, a potential advantage of surgical management of postoperative hemorrhage over transcatheter arterial embolization is the ability to evacuate the hemoperitoneum, which may decrease postoperative pain, the risk of infection, and the risk of ileus [8, 9].
It is typical to expect some bleeding after hysterectomy in the 6–8 weeks following the procedure; the discharge may be red, brown, or pink. Bleeding should steadily decrease in the days and weeks following the surgery and should never be excessive at any point of recovery [18]. The exception is menstruation in women who have undergone a subtotal hysterectomy [18, 19]. In case of bleeding after hysterectomy, it is more likely to be of some pathologic cause instead of menstruation which needs to be ruled out [19].
However, a sudden and significant increase in bleeding during recovery should be considered abnormal. Points of concern comprise but are not limited to—bright red vaginal bleeding (indicating active bleed), temperature over 100.4°F, severe nausea or vomiting, increasing pelvic pain, a local complication such as redness, swelling, or drainage at the incision site as well as difficulty in urinating or pain with urination suggesting either an infection or a neurogenic bladder [18].
Delayed vaginal hemorrhage after laparoscopic supracervical hysterectomy usually requires emergent reoperation. Several studies have described continued cyclical bleeding from the cervical stump after supracervical hysterectomy in 0–25% of cases [20].
Effective interventions addressing hemorrhage after hysterectomy are needed to reduce women’s mortality worldwide.
Prior to hysterectomy, these women should be offered specific counseling and have a prospective plan for the management of their disease, developed by gynecologists of how their condition and hysterectomy interact. Prehysterectomy counseling services starting for all women planning this surgical intervention are a key part of hospital services and should be an integral part of the local health services network. They could be provided by general practitioners or specialist clinicians or surgeons, all of whom should be suitably trained or may require different management or specialized services before hysterectomy. There are special circumstances as congenital or acquired coagulation disorders that should be considered to evaluate by a thorough history and lab tests.
Professional interpretation services for women who do not speak English.
It is not clear how much the specific medical terminology is conveyed to the patient. Healthcare providers have to invest in technology, security, specialists, and translators to ensure healthcare becomes world-class. Medical tourism is growing each year. Romania provides the highest quality healthcare at the lowest price. Also, the cost of hysterectomy in Romania is lower than the same treatment in UK or UE. In developed countries as the USA, UE countries or Canada patients have to wait a long time for major surgeries. The cost involved in treating a patient depends upon factors like—type of hysterectomy needed, hospital and physician selected for it, and duration of staying.
Communication and referrals among professionals.
Good communication among professionals is essential. Referral between specialties involved should be rapid. They can use a variety of communication methods including—mobile phone, email, fax, Whatsapp, Instagram, Tik Tok, Facebook, etc. In many cases, junior trainees in the front line did not have proper support and need to have clear guidelines about when to seek senior help.
Women with serious medical conditions
They require immediate and appropriate multidisciplinary specialist care; women will require referral to tertiary or specialist medical centers for their preexisting medical or mental conditions before hysterectomy. Conditions that require prehysterectomy counseling and advice include—epilepsy, diabetes, asthma, congenital or known acquired cardiac disease, autoimmune disorders, renal and liver disease, obesity (BMI > 30), severe mental illness, or psychiatric conditions that require a change of medication, HIV infection. Women with potential serious underlying preexisting medical on mental health conditions should be immediately referred to appropriate specialist centers of expertise as soon as their symptoms develop.
Clinical training
All clinical staff must undertake regular training for the identification and management of serious disease conditions or potential emergencies or signs and symptoms of potentially life-threatening conditions, circulatory failure, severe hypertension or major hemorrhage, pyrexia >38°C, tachycardia >100 bpm, breathlessness. The local clinicians may be excellent at the management of severely ill women but must also accept written, documented, and audited courses. There should be a well-trained team of doctors for recording and charting investigations performed, obtaining quick results, ensuring that abnormal results are followed up promptly and have resulted in a better outcome.
Identifying and managing very sick women with critical illness before, during or after hysterectomy
In very acute situations, a team approach can be very healthful. The management of patients with an acute severe illness with circulatory failure, arterial hypertension, and major hemorrhage requires a team approach and help from the anesthetic and critical care services. There are some healthcare professionals who failed to manage crisis situations outside their immediate area of expertise; therefore, it is crucial to recognize their limitations and to know when and whom to call for another opinion once the patient was admitted to the hospital.
Coagulation factors, hematocrit, serum calcium, glucose, and electrolytes could be assessed every 120 minutes or after 10 U of transfusion; these lab tests are very helpful for the diagnosis of postoperative bleeding.
RCOG guidelines of the responsibilities of the consultant on call should be followed.
Bilateral hypogastric artery ligation can reduce blood loss to a minimum during hysterectomy [9].
Hypotensive anesthesia is also a safe and effective technique in reducing the circulation to the operative field [9].
Serious incident and women death reporting
Health professionals, senior or junior, must recognize an act on the signs and symptoms of potentially life-threatening conditions.
The evaluation of such a report must include clinicians from relevant disciplines (including anesthetics) who were not involved with the deaths. This report is recommended to be a requirement in the future.
The identification and act on women’s death should be reviewed as a serious incident and disseminated to all health professionals, junior or senior. Women’s deaths are generally underreported because of incorrect classification of cause.
Fatal hemorrhage can result from laceration of the external iliac vein or the hypogastric vein where they join together which are at risk of injury when the surgeon dissects between the distal common iliac artery, the psoas muscle, and the area of lumbosacral nerve trunks [9]. These vessels cannot be clamped and ligated with clips or sutures [9].
Dissection around the aorta and vena cava done with inadequate exposure performed in order to remove lymph nodes around them can result in serious hemorrhage. Bleeding usually can be avoided by placing a finger over the laceration and a vascular needle is used to close the laceration from side to side. The same technique may be used for common and external iliac veins [9].
Also, bleeding can occur by dissecting pararectal space and presacral space as well as obturator fossa [9].
Pathology
Patient death autopsy must be improved and require more expertise.
In Romania, the number of women death after hysterectomy (death rate) is very small and many of the autopsies reviewed were considered adequate. When an autopsy is needed, the body can be taken to another area for more expert examination. Despite evaluation by many examiners in the different specialties, the final diagnosis could not be resolved because of inadequate clinical data, poor autopsy quality, or the unmanageable nature of some death.
The lack of routine observation in the postoperative period or a failure to appreciate blood loss or recognition of abnormal vital signs such as oxygen saturation and respiratory rate can lead to death after hysterectomy. The patient should be evaluated before hysterectomy for risk factors and the medical conditions of the women should be diagnosed by a careful history and lab tests in order to decrease the possibility of hemorrhage.
The risks of blood transfusion, the transmission of HIV or hepatitis B should be discussed before surgical procedure.
The peace of surgical intervention should be governed by good exposure of the tissue, accuracy of dissection, and clamping or suturing the vessels in a precise manner. The skills and experiences of the surgeon without wasting time with unnecessary hesitation or indecision will reduce the risk of uncontrolled hemorrhage after a hysterectomy.
The surgeon should control the life-threatening hemorrhage by judgment, knowledge, and technical skills. The patient’s medical history for vital signs, blood loss volume, and levels of coagulation factors will determine how quickly blood transfusion is initiated. Careful postoperative clinical evaluation of the patient by the surgeon and surgical team with abdominal or pelvic ultrasound or CT scanning will help to prevent or minimize significant blood loss after hysterectomy and localize the site of bleeding.
No funding was received for this chapter.
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Science",value:19,count:5}],publicationYearFilters:[{group:"publicationYear",caption:"2022",value:2022,count:3},{group:"publicationYear",caption:"2021",value:2021,count:3},{group:"publicationYear",caption:"2020",value:2020,count:3},{group:"publicationYear",caption:"2019",value:2019,count:1},{group:"publicationYear",caption:"2018",value:2018,count:1}],authors:{paginationCount:148,paginationItems:[{id:"165328",title:"Dr.",name:"Vahid",middleName:null,surname:"Asadpour",slug:"vahid-asadpour",fullName:"Vahid Asadpour",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/165328/images/system/165328.jpg",biography:"Vahid Asadpour, 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:{name:"Association for Computing Machinery",country:{name:"United States of America"}}},{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:"310576",title:"Prof.",name:"Erick Giovani",middleName:null,surname:"Sperandio Nascimento",slug:"erick-giovani-sperandio-nascimento",fullName:"Erick Giovani Sperandio Nascimento",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y00002pDKxDQAW/ProfilePicture%202022-06-20%2019%3A57%3A24.788",biography:"Prof. Erick Sperandio is the Lead Researcher and professor of Artificial Intelligence (AI) at SENAI CIMATEC, Bahia, Brazil, also working with Computational Modeling (CM) and HPC. He holds a PhD in Environmental Engineering in the area of Atmospheric Computational Modeling, a Master in Informatics in the field of Computational Intelligence and Graduated in Computer Science from UFES. He currently coordinates, leads and participates in R&D projects in the areas of AI, computational modeling and supercomputing applied to different areas such as Oil and Gas, Health, Advanced Manufacturing, Renewable Energies and Atmospheric Sciences, advising undergraduate, master's and doctoral students. He is the Lead Researcher at SENAI CIMATEC's Reference Center on Artificial Intelligence. In addition, he is a Certified Instructor and University Ambassador of the NVIDIA Deep Learning Institute (DLI) in the areas of Deep Learning, Computer Vision, Natural Language Processing and Recommender Systems, and Principal Investigator of the NVIDIA/CIMATEC AI Joint Lab, the first in Latin America within the NVIDIA AI Technology Center (NVAITC) worldwide program. He also works as a researcher at the Supercomputing Center for Industrial Innovation (CS2i) and at the SENAI Institute of Innovation for Automation (ISI Automação), both from SENAI CIMATEC. He is a member and vice-coordinator of the Basic Board of Scientific-Technological Advice and Evaluation, in the area of Innovation, of the Foundation for Research Support of the State of Bahia (FAPESB). He serves as Technology Transfer Coordinator and one of the Principal Investigators at the National Applied Research Center in Artificial Intelligence (CPA-IA) of SENAI CIMATEC, focusing on Industry, being one of the six CPA-IA in Brazil approved by MCTI / FAPESP / CGI.br. He also participates as one of the representatives of Brazil in the BRICS Innovation Collaboration Working Group on HPC, ICT and AI. He is the coordinator of the Work Group of the Axis 5 - Workforce and Training - of the Brazilian Strategy for Artificial Intelligence (EBIA), and member of the MCTI/EMBRAPII AI Innovation Network Training Committee. He is the coordinator, by SENAI CIMATEC, of the Artificial Intelligence Reference Network of the State of Bahia (REDE BAH.IA). He leads the working group of experts representing Brazil in the Global Partnership on Artificial Intelligence (GPAI), on the theme \"AI and the Pandemic Response\".",institutionString:"Manufacturing and Technology Integrated Campus – SENAI CIMATEC",institution:null},{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:'"Politechnica" University Timişoara',institution:null},{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:{name:"Tecnalia",country:{name:"Spain"}}},{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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Possible contributions can address (but are not limited to) the following research topics: Bioinspired design and control of exoskeletons, orthoses, and prostheses; Experimental evaluation of the effect of assistive devices (e.g., influence on gait, balance, and neuromuscular system); Bioinspired technologies for rehabilitation, including clinical studies reporting evaluations; Application of neuromuscular and biomechanical models to the development of bioinspired technology.',annualVolume:11404,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/8.jpg",editor:{id:"144937",title:"Prof.",name:"Adriano",middleName:"De Oliveira",surname:"Andrade",fullName:"Adriano Andrade",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRC8QQAW/Profile_Picture_1625219101815",institutionString:null,institution:{name:"Federal University of Uberlândia",institutionURL:null,country:{name:"Brazil"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"49517",title:"Prof.",name:"Hitoshi",middleName:null,surname:"Tsunashima",fullName:"Hitoshi Tsunashima",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYTP4QAO/Profile_Picture_1625819726528",institutionString:null,institution:{name:"Nihon University",institutionURL:null,country:{name:"Japan"}}},{id:"425354",title:"Dr.",name:"Marcus",middleName:"Fraga",surname:"Vieira",fullName:"Marcus Vieira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003BJSgIQAX/Profile_Picture_1627904687309",institutionString:null,institution:{name:"Universidade Federal de Goiás",institutionURL:null,country:{name:"Brazil"}}},{id:"196746",title:"Dr.",name:"Ramana",middleName:null,surname:"Vinjamuri",fullName:"Ramana Vinjamuri",profilePictureURL:"https://mts.intechopen.com/storage/users/196746/images/system/196746.jpeg",institutionString:"University of Maryland, Baltimore County",institution:{name:"University of Maryland, Baltimore County",institutionURL:null,country:{name:"United States of America"}}}]},{id:"9",title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering",keywords:"Biotechnology, Biosensors, Biomaterials, Tissue Engineering",scope:"The Biotechnology - Biosensors, Biomaterials and Tissue Engineering topic within the Biomedical Engineering Series aims to rapidly publish contributions on all aspects of biotechnology, biosensors, biomaterial and tissue engineering. We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics can include but are not limited to: Biotechnology such as biotechnological products and process engineering; Biotechnologically relevant enzymes and proteins; Bioenergy and biofuels; Applied genetics and molecular biotechnology; Genomics, transcriptomics, proteomics; Applied microbial and cell physiology; Environmental biotechnology; Methods and protocols. Moreover, topics in biosensor technology, like sensors that incorporate enzymes, antibodies, nucleic acids, whole cells, tissues and organelles, and other biological or biologically inspired components will be considered, and topics exploring transducers, including those based on electrochemical and optical piezoelectric, thermal, magnetic, and micromechanical elements. Chapters exploring biomaterial approaches such as polymer synthesis and characterization, drug and gene vector design, biocompatibility, immunology and toxicology, and self-assembly at the nanoscale, are welcome. Finally, the tissue engineering subcategory will support topics such as the fundamentals of stem cells and progenitor cells and their proliferation, differentiation, bioreactors for three-dimensional culture and studies of phenotypic changes, stem and progenitor cells, both short and long term, ex vivo and in vivo implantation both in preclinical models and also in clinical trials.",annualVolume:11405,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",institutionString:null,institution:{name:"Autonomous University of Baja California",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"35539",title:"Dr.",name:"Cecilia",middleName:null,surname:"Cristea",fullName:"Cecilia Cristea",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYQ65QAG/Profile_Picture_1621007741527",institutionString:null,institution:{name:"Iuliu Hațieganu University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"40735",title:"Dr.",name:"Gil",middleName:"Alberto Batista",surname:"Gonçalves",fullName:"Gil Gonçalves",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYRLGQA4/Profile_Picture_1628492612759",institutionString:null,institution:{name:"University of Aveiro",institutionURL:null,country:{name:"Portugal"}}},{id:"211725",title:"Associate Prof.",name:"Johann F.",middleName:null,surname:"Osma",fullName:"Johann F. 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