AJCC 8th edition classification of conjunctival melanoma.
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More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
\n'}],latestNews:[{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"},{slug:"oiv-awards-recognizes-intechopen-s-editors-20201127",title:"OIV Awards Recognizes IntechOpen's Editors"},{slug:"intechopen-joins-crossref-s-initiative-for-open-abstracts-i4oa-to-boost-the-discovery-of-research-20201005",title:"IntechOpen joins Crossref's Initiative for Open Abstracts (I4OA) to Boost the Discovery of Research"},{slug:"intechopen-hits-milestone-5-000-open-access-books-published-20200908",title:"IntechOpen hits milestone: 5,000 Open Access books published!"},{slug:"intechopen-books-hosted-on-the-mathworks-book-program-20200819",title:"IntechOpen Books Hosted on the MathWorks Book Program"}]},book:{item:{type:"book",id:"5182",leadTitle:null,fullTitle:"Lab-on-a-Chip Fabrication and Application",title:"Lab-on-a-Chip Fabrication and Application",subtitle:null,reviewType:"peer-reviewed",abstract:"The necessity of on-site, fast, sensitive, and cheap complex laboratory analysis, associated with the advances in the microfabrication technologies and the microfluidics, made it possible for the creation of the innovative device lab-on-a-chip (LOC), by which we would be able to scale a single or multiple laboratory processes down to a chip format. 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\r\n\tBisphenols, particularly bisphenol-A are one of the most abundant industrial chemicals. Humans are mainly exposed to bisphenols orally, by inhalation, or through medical devices. These chemicals are used to harden polycarbonate plastics. Plastic bottles, food storage containers, baby bottles, medical devices, and thermal papers contain a high amount of bisphenols. Bisphenols are suggested to cause endocrine disruption and bisphenol A is evaluated as an estrogenic compound. Although the use of bisphenol A is limited or banned in different products, like baby bottles, other bisphenol derivatives like bisphenol F and S are now being used instead of bisphenol A. Therefore, the toxicity of these chemicals should be evaluated carefully.
\r\n\r\n\tThe book "Bisphenols" will be on the uses, environmental effects, and toxic effects of different bisphenol derivatives. The topics in the book will include but are not limited to the environmental toxicity and adverse effects of bisphenols (hepatotoxicity, reproductive/developmental toxicity, neurotoxicity, etc.).
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Dr. Erkekoglu has published more than 150 papers in national and international peer-reviewed journals. She is a European Registered Toxicologist (ERT) since 2014.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"109978",title:"Prof.",name:"Pınar",middleName:null,surname:"Erkekoglu",slug:"pinar-erkekoglu",fullName:"Pınar Erkekoglu",profilePictureURL:"https://mts.intechopen.com/storage/users/109978/images/system/109978.JPG",biography:"Pınar Erkekoglu was born in Ankara, Turkey. She graduated with a BS from Hacettepe University Faculty of Pharmacy. Later, she received an MSci and Ph.D. in Toxicology. She completed a part of her Ph.D. studies in Grenoble, France, at Universite Joseph Fourier and CEA/INAC/LAN after receiving a full scholarship from both the Erasmus Scholarship Program and CEA. She worked as a post-doc and a visiting associate in the Biological Engineering Department at Massachusetts Institute of Technology. She is currently working as a full professor at Hacettepe University, Faculty of Pharmacy, Department of Pharmaceutical Toxicology. Her main study interests are clinical and medical aspects of toxicology, endocrine-disrupting chemicals, and oxidative stress. She has published more than 150 papers in national and international journals. Dr. Erkekoglu has been a European Registered Toxicologist (ERT) since 2014.",institutionString:"Hacettepe University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"5",totalChapterViews:"0",totalEditedBooks:"5",institution:{name:"Hacettepe University",institutionURL:null,country:{name:"Turkey"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"19",title:"Pharmacology, Toxicology and Pharmaceutical Science",slug:"pharmacology-toxicology-and-pharmaceutical-science"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"347258",firstName:"Marica",lastName:"Novakovic",middleName:null,title:"Dr.",imageUrl:"//cdnintech.com/web/frontend/www/assets/author.svg",email:"marica@intechopen.com",biography:null}},relatedBooks:[{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3621",title:"Silver Nanoparticles",subtitle:null,isOpenForSubmission:!1,hash:null,slug:"silver-nanoparticles",bookSignature:"David Pozo Perez",coverURL:"https://cdn.intechopen.com/books/images_new/3621.jpg",editedByType:"Edited by",editors:[{id:"6667",title:"Dr.",name:"David",surname:"Pozo",slug:"david-pozo",fullName:"David Pozo"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"42668",title:"Hematopoietic Stem Cells in Chronic Myeloid Leukemia",doi:"10.5772/54651",slug:"hematopoietic-stem-cells-in-chronic-myeloid-leukemia",body:'Chronic Myeloid Leukemia (CML) is a clonal disease, originated at the level of Hematopoietic Stem Cells (HSC) and characterized by the presence of the Philadelphia (Ph) chromosome and its oncogenic product p210Bcr-Abl. Such a protein has been shown to be essential for malignant transformation, since it is capable of altering cell adhesion, proliferation and apoptosis.
Current treatment options in CML include tyrosine kinase inhibitors (Imatinib, Nilotinib and Dasatinib), compounds that inhibit the activity of the BCR-ABL protein. However some patients will develop resistance or intolerance to these drugs and resistance has been associated with different mechanism including the quiescence of leukemic stem cells and Pgp or Src kinase overexpression.
In this chapter we focus on the basic biology of hematopoietic stem and progenitor cells from CML and analyze the most relevant and current concepts in this area.
Chronic myeloid leukemia (CML) is a lethal hematological malignancy characterized by the abnormal amplification of the myeloid (mainly granulocityc) compartment of the hematopoietic system. It originates from the transformation of a primitive hematopoietic cell that suffers a t(9;22) (q34; q11) balanced reciprocal translocation that results in the generation of the Philadelphia chromosome (Ph). Ph produces BCR-ABL, a constitutively active tyrosine kinase that drives a wide variety of physiological alterations [1].
CML was initially described in 1845 by John Hughes Bennett, who reported the case of a patient with “milky” blood and suggested that it was an infectious disease that caused hypertrophy of the liver and spleen, leading to the patient’s death. A few weeks later, Rudolf Virchow reported a similar case, but, in contrast to Bennett, he suggested that the disease was not infectious and implied an increase in the number of blood cells. He coined the term leukemia (from the Greek leukos, white, and “Aemia”, blood). In 1870, Neumann described that leukemia cells originate in the bone marrow; almost one hundred years later, in 1960, Nowel and Hungerford reported that in all cases of this malignancy there was a small, abnormal chromosome 22. However, was until 1973 that Janet Rowley described that the abnormal chromosome was caused by a reciprocal translocation between the long arms of chromosomes 9 and 22, designating the name of Philadelphia (Ph) chromosome[2, 3].
Chronic myelogenous leukemia has a worldwide incidence of 1-2 cases per 100,000 individuals [4]. The average age at diagnosis is 60 years; it occurs less frequently in young people and a tendency to increase exponentially with age has been observed. There is no geographic or genetic predisposition to acquire this condition, although some authors have associated it with exposure to high doses of ionizing radiation. The current CML prevalence of 24,000 affected patients in the United Sates is relatively low; it is expected to increase significantly over the next 20 years as a result of widespread use of BCR-ABL tyrosine kinase inhibitor therapy [5]. In Mexico, there are no official data on the incidence of such a disease, however, it has been estimated that there are about 80,000 cases of leukemia and 10% corresponds to CML [6].
The clinical presentation often includes granulocytosis, spenomegaly and marrow hypercellularity; however about 40% of patients are asymptomatic and their diagnosis is based on abnormal blood cell counts [1]. The natural course of the disease involves three sequential phases, namely chronic, accelerated and blast crises. Ninety percent of patients are diagnosed in chronic phase and they remain in it for 3 to 8 years. In this phase, the blood cells retain their ability to differentiate until the illness progresses to the accelerated phase, which is characterized by the egress of immature cells into the bloodstream. Finally, the disease progresses to the blast crisis, defined by the presence of 30 percent or more leukemic cells in peripheral blood or marrow or extramedullary infiltrates of blast. During this phase the survival of patients is reduced to months and even weeks [7].
As mentioned before, the Philadelphia chromosome, which defines CML, is a shortened chromosome 22 originated from the reciprocal translocation between the long arms of chromosomes 9 and 22 [t (9; 22)] and involves addition of 3\' segments of the abl gene (9q34) to 5\' segments of the bcr gene (22q11) given rise to a bcr-abl fusion gene that transcribes a chimeric mRNA of 8.5 kb that, in turn, gives rise to a BCR-ABL fusion protein [7]. t(9;22) is evident in more than 95% of CML patients; between 5% and 10% of CML patients also present complex rearrangements that may involve one or more chromosomes in addition to 9 and 22 [8].
The normal human ABL gene encodes for a non-receptor tyrosine kinase that is ubiquitously expressed. Such a 145 kDa protein is involved in the regulation of the cell cycle, the response to genotoxic stress, and intracellular signaling mediated by the integrin family [9]. There are three isoforms of the BCR-ABL fusion protein all of which encode the same portion of the ABL tyrosine kinase, but differ in the length of the BCR sequence at the N-terminus. p185/p190 BCR-ABL is expressed in Acute Lypmphoblastic Leukaemia (ALL), p210 BCR-ABL is characteristic of Chronic Myeloid Leukemia, and p230 BCR-ABL has been associated with a subgroup of CML patients with a more indolent disease (Figure 1) [4].
Structure of the Bcr-Abl gene. It is formed by a reciprocal translocation between chromosomes 22 (Bcr gene) and 9 (Abl gene). Ther M-BCR breakpoint resulting in a P210 BCR/ABL fusion transcripts b2a2 or b3a2 and they encode a protein of 210 kDa (BCR-ABLp210) present in almost all patients with Chronic Mieloid Leukemia (modified to [9]).
BCR-ABL fusion protein localizes in the cytoplasm and shows an increased and constitutive tyrosine kinase activity as a result of oligomerization of its coiled region and deletion of the SH domain of ABL. It activates a number of cytoplasmic and nuclear signal-transduction pathways involved in cell adherence, migration, inhibition of apoptosis, and induction of cell proliferation through activation of signaling proteins such as p21RAS, c-Myc, lipid kinasse PI3k, MAPk (mitogen-activated protein kinase family), tyrosine phosphatases, and signal transducer and activator of transcription (STATs) factors [9, 10].
There is an increasing body of evidence indicating that, similar to normal hematopoiesis, a quiescent stem cell population -within the CD34+ cell compartment- exists in the bone marrow of CML patients. Such Leukemic Stem Cells (LSC) seem to be the ones driving CML progression, following a similar pattern to the one observed in normal hematopoiesis. That is to say, LSC give rise to CML progenitor cells, which, in turn, give rise to more mature cells.
Just like normal hematopoietic stem cells (HSC), CML stem cells express high levels of CD34, and lack the cell surface markers CD38, CD45RA, or CD71, as well as lineage-specific markers. However, LSC are Ph+/BCR-ABL+, which is not present in their normal counterparts. Interestingly, it has recently been shown that a novel population of lineage-negative, CD34-negative hematopoietic stem cells from CML patients also correspond to BCR-ABL+ leukemic stem cells capable to engraft immunodeficient mice [13]. Thus, it seems that most LSC are CD34+ but a subpopulation may be CD34-. Importantly, despite the predominance of LSC in CML, a residual population of normal hematopoietic stem cells (BCR-ABL- CD34+) persists in the marrow’s patient, which seems to be responsible for hematopoietic recovery after a successful treatment using Tyrosine Kinase Inhibitors (TKIs).
As mentioned before, LSC are in a quiescent state, however, they can spontaneously exit G0 to enter a proliferating state and are capable of engrafting inmmunodeficient mice [11]. In this regard, several studies have shown that TKIs, like Imatinib, Nilotinib, Dasatinib, Bosutinib, and Lonafarnib, have antiproliferative or apoptotic effects in almost all dividing CML cells; however, the population of stem cells remains viable in a quiescent state [16-21].
In vitro studies indicate that LSCs are capable of surviving for several weeks in the absence of added growth factors due to autocrine mechanisms involving production of granulocyte colony-stimulating factor (G-CSF) and Interleukin 3 (IL-3) [12]. This, in fact, is an important difference between normal and CML HSC, since the former depends on the presence of exogenous cytokines for their growth, whereas the latter, as just mentioned, can utilize autocrine mechanisms. Although there is strong evidence that Bcr-Abl is sufficient to induce CML-like disease in transduction and transgenic murine models [14], it is still unclear whether Bcr-Abl is always the first hit in CML, since in some patients with a complete cytogenetic response after treatment, BCR-ABL transcripts are still detectable by RT-PCR, which indicates that leukemic cells persist even when the disease is reduced below detectable limits [15].
Proliferation of leukemic stem and progenitor cells is regulated by Bcr-Abl. Such a tyrosine kinase activates the Ras/Raf/MEK/ERK and JAK/STAT signal transduction pathways, and this results in an amplified proliferative state [22]. Bcr-Abl causes hyperactivity of Ras, Raf and JAK/STAT, which can occur by multiple mechanisms; i.e., by Bcr-Abl activating these pathways directly, or by the induction of autocrine cytokines, which in turn activate these pathways [23]. Bcr-Abl autophosphorylation of tyrosine 177 provides a docking site for the adapter molecule Grb-2. Grb-2, after binding to the Sos protein, stabilizes Ras in its active GTP-bound form. Two other adapter molecules, Shc and Crkl, can also activate Ras [9, 24]. Ras activates Raf, and finally, Raf initiates a signaling cascade through the serine–threonine kinases Mek1/Mek2 and Erk, which ultimately leads to the transcription of genes involved in cell proliferation and survival (Figure 1), such as c-Myc, Cyclin D, Cyclin A, Bcl-2, cytokines, etc [22].
The JAK/STAT pathway has been demonstrated to be constitutively activated In CML. Among all the molecules participating in these pathways, STAT1 and STAT5 have been found to be the two major STATs phosphorilated by Bcr-Abl. STAT5 has pleiotropic physiologic functions, and its main effect in Bcr-Abl-transformed cells appears to be primarily anti-apoptotic, involving transcriptional activation of Bcl-xL [25]. Also, in some experimental systems there is evidence that Bcr-Abl induces an IL-3 and G-CSF autocrine loop in early progenitor cells [12].
Leukemic Stem Cells acquire the ability for long-term survival primarily by deregulation of apoptosis. In CML, blocking of apoptosis is mediated by Bcr-Abl. Bcr-Abl may block the release of cytochrome C from mitochondria and thus activation of caspases. This effect upstream of caspase activation might be mediated by the Bcl-2 family of proteins [26]. Bcr-Abl has been shown to up-regulate anti-apoptotic protein Bcl-xL in a STAT5-depend manner, as mention above [27]. Another link between Bcr-Abl and the inhibition of apoptosis might be the phosphorylation of the pro-apoptotic protein Bad through PI3k pathway. Bcr-Abl forms multimeric complexes with PI3 kinase, Cbl, and the adapter molecules Crk and Crkl, in which PI3 kinase is activated. The next substrate in this cascade appears to be the serine-threonine kinase Akt. This kinase had previously been implicated in antiapoptotic signaling and protein Bad as a key substrate of Akt (Figure 1). Phosphorylated Bad is inactive because it is no longer able to bind anti-apoptotic proteins such as Bcl-xL and it is trapped by cytoplasmic 14-3-3 proteins [28].
In CML, progenitor cells exhibit decreased adhesion to bone marrow stroma cells and extracellular matrix. From this point of view, adhesion to stroma negatively regulates cell proliferation, and CML cells escape this regulation by virtue of their perturbed adhesion properties. Bcr-Abl directly phosphorylates Crkl, a protein involved in the regulation of cell motility and in integrin-mediated cell adhesion by association with other focal adhesion proteins such as paxillin, the focal adhesion kinase Fak, p130 Cas and Hef1 [29, 30] (Figure 1). In addition to this, it has been demonstrated that the activity of Bcr-Abl promotes expression of integrin β1, a variant not found in the normal counterpart that inhibits adhesion to stroma and cell matrix, together with the effect of expansion and premature exit of myeloid progenitors and precursors to bloodstream [31].
Deregulation of self-renewal has been recognized as an important event in disease progression. In normal hematopoietic stem cells, self-renewal capacity involves several signaling pathways: Notch, Wnt, Sonic Hedgehog (Shh), FoxO and Alox5 [32-34].
Notch pathway
Notch receptors are an evolutionarily conserved family of trans-membrane receptors that are known to be expressed and activated in normal HSC. Binding to their physiological ligands, which are part of the Delta and Serrata families, leads to separation of an intracellular portion of Notch. This fragment is capable of entering the nucleus where it binds transcriptional repressor CBF-1. Interconnection of Notch, CBF-1 and the co-factor MAML-1 (mastermind-like-1) leads to transcriptional activation of target genes [35]. Constitutively active Notch is able to mediate multilineage potential in vivo. Differentiation of cells leads conversely to downregulation of Notch [36].
Notch signaling may also be important in advanced stages of CML. Hes1, a key Notch target gene, was found to be highly expressed in 8 out of 20 patients with CML in blast crisis, but was not seen in the chronic phase. In mice, the combination of Hes1 and BCR-ABL expression in myeloid lineage progenitor cells resulted in an acute leukemia resembling blast crisis CML [37]. This suggests that Notch inhibitors may be useful in strategies aimed at eradicating CML LSC.
Wnt pathway
In normal hematopoiesis, Wnt pathway activity is required in the bone marrow niche to regulate HSC proliferation and to preserve self-renewal capacity [38]. Activation of the canonical Wnt/β-catenin pathway consists of binding of Wnt proteins to members of the Frizzled and low-density lipoprotein receptor related (LPR) families on the cell surface. In the absence of Wnt signals, β-catenin is associated with a large multiprotein complex that includes Axin, APC, and glycogen synthase kinase 3β (GSK3β), among others. Through a mechanism not entirely understood, when Wnt proteins bind to their target, Axin facilitates phosphorylation of β-catenin by GSK3β. Phosphorylation, in turn, results in ubiquitination, targeting β-catenin for degradation. Thus, axin serves as an inhibitor of β-catenin activity. Binding of Wnt proteins to their receptors leads to activation of Disshevled (Dsh), which inhibits phosphorylation of β-catenin by GSKβ, so it accumulates in the cytoplasm and translocates to the nucleus, where it activates transcription factors, such as LEF/TEF and allows expression of target genes [39].
This pathway has been implicated in CML. Indeed, in blast crisis CML, the LSC, which resemble granulocyte-macrophage progenitor cells (GMP), have aberrant activation of β-catenin via the canonical Wnt signaling pathway. In a proportion of these cases, the pathway is activated through abnormal missplicing of GSK3β [40].
Sonic Hedgehog (Shh) pathway
The Hedgehog (Hh) pathway is a highly conserved developmental pathway, which regulates the proliferation, migration and differentiation of cells during development [41]. It is typically active during development, but silenced in adult tissues, except during tissue regeneration and injury repair [42]. Three distinct ligands, i.e., Sonic (Shh), Indian (Ihh) and Desert (Dhh) Hedgehog exist in humans. Upon ligand binding to the receptor patched (Ptch), inhibition of smoothened (Smo) receptor is relieved. Smo then activates members of the Gli family of zinc-finger transcription factors, which translocate to the nucleus to regulate the transcription of Hh target genes, including Gli1, Gli2, Ptch and regulators of cell proliferation and survival [43].
Based on murine embryonic stem cell studies, it has been found that Hh signaling plays major roles during primitive hematopoiesis. Ihh is a primitive endoderm-secreted signal and is sufficient to activate embryonic hematopoiesis and vasculogenesis [44]. Furthermore, a study of zebrafish showed that the mutations of the Hh pathway members or inhibition of the Hh pathway with the Hh inhibitor cyclopamine can cause a developmental defect in adult HSC [45]. In addition, activation of Hh pathway has been observed in different human cancers. In CML patients, more than four-fold induction of the transcript levels of Gli1 and Ptch was observed in CD34+ cells in both chronic phase and blast crisis. In two studies using a CML mouse model, recipients of the Bcr-Abl transduced bone marrow cells from Smo-/- donor mice developed CML significantly slower than recipients of Bcr-Abl transduced bone marrow cells from wild-type donor mice. When the frequency and function of the LSCs were examined, Smo deletion caused a significant reduction of the percentage or LSCs [46]. By contrast, over expression of Smo led to an increased percentage of LSC and accelerated the progression of CML [47].
FoxO pathway
The FoxO (Forkhead-O) subfamily of transcription factors regulate cell cycle, stress resistance, differentiation, and long-term regenerative potential of HSC [48], and protect integrity of the stem cell pool. There are four members (FoxO1, FoxO3, FoxO4 and FoxO6) and are known to be effectors of the PI3k/AKT pathway, which is frequently mutated or hyperactivated in hematologic malignancies, and are abundantly expressed in the hematopoietic system. Akt directly phosporylates the FoxO members from the nucleus and promotes its degradation in the cytoplasm. FoxO members localize to the nucleus and regulate apoptosis, cell cycle progression and oxidative stress responses [49]. In a model of deficient FoxO mice it was shown a defect in the long-term expansion capacity of the HSC pool. Such a defect has been correlated with increased cell division and apoptosis of HSCs.
FoxO transcription factors have also been shown to have essential roles in the maintenance of CML LSCs [50]. FoxO3 localizes to the cell nucleus and it causes a decrease in Akt phosphorylation in the LSC population. In addition, serial CML transplantation showed that FoxO3 deficiency severely impairs the ability of LSCs to induce CML. Furthermore, transforming growth factor-β (TGF-β) is a crucial regulator of Akt activation and controls FoxO3 localization in LSCs of CML. A combination strategy of TGF-β inhibition, FoxO3 deficiency and Bcr-Abl kinase inhibition results in efficient LSCs depletion and suppression of CML development [51].
Alox5 pathway
The Alox5 pathway is the only one signaling pathway not shared by LSC with normal HSC. The Alox5 gene encoding arachidonate 5-lipoxygenase (5-LO) is involved in numerous physiological and pathological processes, including oxidative stress response, inflammation and cancer [52]. 5-LO is responsible for producing leukotrienes, a group of inflammatory substances that cause human asthma [53]. Altered arachidonate metabolism by leukocytes and platelets was reported in association with myeloproliferative disorders [54]. Several selective 5-LO inhibitors were found to reduce proliferation and induce apoptosis of CML cells in vitro [55]. Recently, human CML microarray studies have shown that Alox5 is differentially expressed in CD34+ CML cells suggesting a role for Alox5 in human CML stem cells. However, the function of Alox5 in LSCs needs to be tested. Other microarray analysis of gene expression in LSCs in CML mice showed that the ALox5 gene was up-regulated by Bcr-Abl and that this up-regulation was not inhibited by Imatinib treatment, providing a possible explanation of why LSCs are not sensitive to inhibition by Bcr-Abl kinase inhibitors [56].
Signaling pathways involved in the signaling of BCR-ABL. A) Schematic representation of principal molecules that participate in proliferation, adhesion and apoptosis. B) Pathways involved in self-renewal.
The first effective treatment for CML was the solution of Fowler\'s, which contained arsenic as active component and was used in the early 20th century. Later between 1920 y1930 irradiation to the spleen was the main therapeutic option, since it offered patients the decrease of symptoms, although it did not prolong their lives. In 1953, busulfan was included in CML treatment. This compound provided benefit in terms of survival, although it was shown to be extremely toxic for hematopoietic progenitor cells. The next drugs effective in the treatment of CML were hydroxyurea and cytosine arabinoside, both less toxic than busulfan and able to block proliferation of cells, but unable to induce specific damage to leukemic cells; thus, patients usually progressed to the accelerated and blast crisis phases [57].
Interferon-α (IFNα) was the first drug capable of extending the chronic phase of the disease and retarding the evolution to the accelerated phase. IFNα is a nonspecific stimulant of the immune system that regulates T-cell activity and produces a complete hematologic response (CHR) in 40-80% of patients, and a complete cytogenetic response (CCR) in 6-10% of patients with a median survival of 89 months [58].
In vitro studies have indicated that IFNα might function via selective toxicity against the leukemic clone, since it is able to inhibit long-term cultures from patients with CML in chronic phase and reduces the percentage of Ph+ cells [59]. It also inhibits CML myeloid progenitors while sparing normal myeloid progenitors [60]. In vivo, IFNα enhances immune regulation through the activation of dendritic, natural killer, and cytotoxic T cells, all of them capable of generating anti-tumor responses. In Bcr-Abl+ cells, IFNα induces a state of tumor dormancy and delays progression to advanced phase [61], and is able to modulate hematopoiesis through enhanced adhesion of CML progenitor cells to stromal cells, whereas adhesion of normal progenitors was unaffected. This enhanced adhesion by CML progenitor cells has been associated with a reduction in neuraminic acid levels and by enhanced hematopoietic cell-microenvironmental cell interactions, which is achieved by the induction of molecules such as β2-Integrin, L-selectin, ICAM-1 and ICAM352 [58, 62].
Because IFNα is a nonspecific immunostimulant, it produces secondary symptoms and toxicities and many patients discontinue therapy. However there are evidence that a significant proportion of IFNα-treated patients in prolonged CCR were able to discontinue treatment without disease relapse [63], and it was recently reported that in a specific group of patients treated with monotherapy there are increased numbers of NK cells and clonal γδ T cells [64].
Having identified that tyrosine kinase activity of Bcr-Abl is a major factor in the pathophysiology of CML, it was clear that such a molecule was an attractive target for designing a selective kinase inhibitor. In 1996, Buchdunger et al, synthesized several compounds that inhibit the activity of platelet-derived growth factor receptor (PDGF-R) and ABL kinase. One of these was the 2- phenylaminopyrimidine, which served as a starting point for the development of other related compounds [65]. The activity of the 2-phenylaminopyrimidine series was optimized and gave rise to STI571 (also named imatinib mesylate, CGP57148B or Gleevec®, Novartis Pharmaceuticals).
Imatinib
Imatinib is a highly selective inhibitor of the protein tyrosine kinase family, which includes BCR-ABL protein, PDGF-R and the c-kit receptor. It competitively binds to the ATP-binding site of BCR.ABL and inhibits protein tyrosine phosphorylation in vitro and in vivo [66]. In vitro studies had shown that Imatinib is capable to inhibit cell proliferation of cell lines expressing Bcr-Abl [67-69], effect accomplished through JAK5-STAT and PI3 kinase signaling inhibition [70, 71]. It has also been shown that STI571 can inhibit CML MNC, obtained both in chronic phase and blast crisis [71] and reduces the colony forming cells from Mobilized Peripheral Blood (MPB) and Bone Marrow from patients with CML in chronic phase [60]. Furthermore, Imatinib inhibits proliferation and cell cycle of stem (CD34+CD38-) and progenitor (CD34+CD38+) cells without altering the behavior of normal cells [72].
Studies in CML marrow by Holyoake and her colleagues have demonstrated the presence of a rare, highly quiescent, CD34+ cell subpopulation in which most of the cells are Ph+ with the ability to proliferate upon specific induction [11]. These cells are insensitive to the effects of STI571 and remain quiescent and viable even in the presence of growth factors [16]. This tumor resistance feature was also reported by Bathia, who mention that STI571 suppressed but does not eliminate primitive cells even after patients remain in CCR [73]. These primitive Ph+ cells could not be detected by nested PCR, when they are obtained from Imatinib-treated patients; however, when the cells are cultured in liquid cultures for a couple of weeks, the Ph+ population becomes detectable, indicating that they were able to remain even after Imatinib treatment [74].
In clinical trials, Imatinib has been shown remarkably effective as a single agent in IFNα-resistant CML chronic phase patients. It induces complete cytogenetic responses in more than 80% of newly diagnosed patients; however, the persistence of detectable leukemic cells in a quiescent state and the presence of patients with resistance or intolerance to Imatinib, lead to the development of a second generation of Tyrosine Kinase Inhibithors.
Nilotinib
Nilotinib (Tasigna, Novartis Pharmaceutical), is an oral aminopyrimidine that is a structural derivative of Imatinib. It was designed to be more selective against the Bcr-Abl tyrosine kinase than imatinib. Like imatinib, it acts through competitive inhibition of the ATP site in the kinase domain [75]. Clinically Nilotinib showed activity in imatinib-resistant patients in all phases of the disease. In chronic phase, it induced 92% of CHR and in accelerated phase and blast crisis the hematological responses were achieved in 72% of cases [76].
In vitro, Nilotinib is 20 times more potent than imatinib against cells expressing wild type Bcr-Abl, and similar results have been observed in studies of mutants cell lines, with the exception of the T315I mutation, which is resistant to both TKIs [77]. In primary CML CD34+ cells, Imatinib-induced apoptosis is preceded by Bim accumulation; this effect was decreased when cells were cultured in a cytokine-containing medium [78]. In contrast to Imatinib, whose main effect on CML cells seems to be induction of apoptosis, the predominant effect of nilotinib seems to be antiproliferative -rather than apoptotic [17]. Indeed, it has been suggested that Nilotinib can induce a G0/G1 cell cycle blockade in cells expressing wild type Bcr-Abl, which could result in disease persistence [79].
Dasatinib
Dasatinib (Sprycel, Bristol-Myers Squibb) is a potent, orally bioavailable thiazolecarboxamide. It is structurally unrelated to imatinib; it has the ability to bind to multiple conformations of the Abl kinase domain and it also inhibits SRC family kinases. In vitro, Dasatinib demonstrated 325-fold greater activity against native Bcr-Abl, as compared with imatinib, and it has shown efficacy against all imatinib-resistant Bcr-Abl mutants with the exception of T351I. Dasatinib is also active against PDGFR, C-Kit and ephrin A receptor [75, 76].
Dasatinib is very effective at inducing apoptosis in CML cells –either, in the presence or absence of added growth factors- and in contrast to Imatinib, that kills those cells destined to move from G0/G1 cell cycle phases, but is unable to act on those cells destined to remain quiescent in culture, Dasatinib can act on quiescent CD34+ cells. As expected, based on its structure and mode of action, it has selective cytotoxic activity for leukemic cells over normal cells [80].
Other tyrosine kinase inhibitors
Several TKIs have been developed that exhibit a target spectrum similar to the approved drugs, although they are distinct in terms of off-target effects [81].
SKI-606 (Bosutinib)
Bosutinib (Wyeth) is a 4 anilino-3-quinolinecarbonitrile dual inhibitor of Src and Abl kinases without effect in c-Kit or PDGFR. It has 200-fold grater potency for Bcr-Abl than imatinib and has activity against a number of mutations, but not T315I [76]. In clinical trials, Bosutinib induced 73% of complete hematological response in patients pretreated with Imatinib followed by Dasatinib [82]. In vitro, Bosutinib effectively inhibits Bcr-Abl kinase activity and Src phosphorylation, and reduces the proliferation and CFC growth in CML CD34+ cells; however, it does not seem to induce apoptosis [19].
AP24534 (Ponatinib)
Ponatinib, is a mulitargeted kinase inhibitor that is active against all BCR-ABL mutants, including T315I. This drug also inhibits FLT3, FGFR, VEGFR, c-Kit, and PDGFR and is able to reduce the proliferation of different cell lines and prolong survival of mice that have been injected intravenously with BCR-ABL. Ponatinib showed significant activity in a phase I study of patients with Ph+ cells who had failed to other TKIs [81, 83].
Although molecular therapy for CML is highly effective and generally non-toxic, it is unclear whether long-term outcomes with the different therapies (IFNα or TKIs) will be equivalent to cases treated with allogeneic stem cell transplantation, which has shown the highest percentage of long-term disease-free survival of any therapy [75].
In patients younger than 50 years of age and who receive a transplant before 1 year after diagnosis, 5 years survival rates superior to 70% have been attained. However, the application of this procedure is limited by the availability of matched donors and by the toxicity of the procedure in older patients. Moreover, outcomes deteriorate with disease duration [76]. This information associated with the knowledge that quiescent leukemic stem cells remain in patients after treatment, several other agents has been reported.
Danusertib (PHA 739358) is a small molecule with activity against BCR-ABL and aurora kinases and it is able to block the proliferation of leukemia cell lines as well as CD34+ cells from newly diagnosed CML patients including the mutation T315I. However, similarly to other tyrosine kinase inhibitors, no induction of apoptosis in quiescent hematopoietic stem cells could be achieved and resistant BCR-ABL positive clones emerged in the course of Danusertib treatment. This latter observation is related to Abcg2 proteins over-expression [84].
Lonafarnib (SCH66336) is an orally bioavailable non peptidomimetic farnesyl trransferase inhibitor with significant activity against Bcr-Abl+ cell lines and primary CML cells. It can enhance the toxicity of Imatinib in K562 cell line and can inhibit the proliferation of imatinib-resistant cells and increases imatinib-induced apoptosis. However it is unable to kill quiescent CD34+ leukemic cells [20]. In a clinical phase 1 study, it was shown that the combination of Lonafarnib and Imatinib is well tolerated in patients with CML who failed Imatinib, with some patients achieving a complete hematologic response and a complete cytogenetic response [85].
INNO 406 is a 2 phenylaminopyrimidine Bcr-Abl inhibitor with activity against PDGF, c-kit and Lyn that have shown to be 25-55 times more potent than Imatinib in Bcr-Abl+ cell lines. In contrast to other molecules INNO406 does not inhibit all SRC kinases, but it induces programmed cell death in chronic myelogenous leukemia (CML) cell lines through both caspase-mediated and caspase-independent pathways [86].
MK0457 is an aurora kinase inhibitor with activity against Bcr-Abl. This agent was observed to inhibit autophosphorylation of T315I mutant and demonstrate antiproliferative effects in CML cells derived from patients with this mutation, an event that may lead to its use as a combination partner with the approved and established TKI [76].
The knowledge of the central role of BCR-ABL in the pathogenesis of CML has allowed the development of several drugs that inhibit the constitutive activity of such an ABL tyrosine kinase. However, although the treatment with tyrosine kinase inhibitors has proven effective in about 80% of CML patients at any stage, the remaining 20% can’t respond to it [87].
In CML, the criteria for successful response to treatment, as established by the European consortium LeukemiaNet and subsequently adopted by the National Comprehensive Cancer Network (NCCN) [88], include: complete hematologic remission (CHR), that is to say, a normal blood cell count and complete disappearance of signs and symptoms of the disease; complete cytogenetic response (CCR), which means the total absence of Ph+ metaphases; and complete molecular response, in which transcripts for BCR-ABL are no longer detectable. Using these response criteria, drug resistance is defined as the inability to achieve any of the following: a complete hematologic response (CHR) at 3 months, any cytogenetic response (CyR) at 6 months, partial cytogenetic response (PCyR) at 12 months, or a complete cytogenetic response (CCR) at 18 months of treatment with Imatinib [89].
Two types of resistance mechanisms to TKIs have been described: 1) Primary resistance, which occurs in less than 10% of cases and is defined as the failure of therapeutic effect during the chronic phase of CML without changing clones; and 2) secondary resistance, defined as the loss of the response initially obtained, and commonly occurs in accelerated phase (40-50%) and blast (80%) [90]
It is estimated that the probability of an individual to stay in CCR for 5 years after diagnosis, after treatment with Imatinib is approximately 63%; however, this percentage may represent a sub-estimation since in a significant proportion of cases there is discontinuation of treatment and this, of course, may underestimate the efficacy of the drug [91].
The molecular mechanisms of acquired drug resistance can be divided into two categories: BCR-ABL-dependent and BCR-ABL-independent.
The inhibition of the activity of tyrosine kinase turned out to be an ideal target for molecular therapy in CML [67]. However, shortly after the introduction of Imatinib, in vitro studies demonstrated that some cell lines became refractory to the drug, suggesting a possible inherent or acquired resistance to therapy [92]. This was quickly followed by the clinical description of patients resistant to Imatinib.
BCR-ABL mutations
The most common mechanism against TKIs therapy are point mutations within the kinase domain, which make conformational changes that decrease the affinity of the TKIs to BCR-ABL kinase domain. These point mutations in the BCR-ABL kinase domain are a major cause of Imatinib resistance, and may be identified in approximately 50% or more of the cases. Many more than 100 different mutations affecting more than 70 amino acids have so far been identified, with varying degrees of clinical relevance [93].
The first point mutation reported in TKI resistance was in the region coding for the ATP-binding site of the ABL kinase domain resulting in a threonine to isoleucine substitution at amino acid 315 (Th315→Ile315; T315I) preventing the formation of a hydrogen bond between the oxygen atom provided by the side chain of threonine 315 and the secondary amino group of Imatinib. Moreover, isoleucine contains an extra hydrocarbon group on its side chain, and this inhibits the binding of Imatinib [94]. T315I confers resistance to all currently approved BCR–ABL kinase inhibitors. Recent reports have shown that T315I mutation can be found in approximately 15% of patients after failure of imatinib therapy [85].
Other important TKI’s resistant mutations are frequently mapped to the P-loop region (residues 244 to 256) of the kinase domain, which serves as a docking site for phosphate moieties of ATP and interacts with imatinib through hydrogen and van der Waals bonds. These mutations modify the flexibility of the P-loop and destabilize the conformation required for Imatibib binding [95]. Clinical relevance of P-loop mutations is that imatinib treated patients who harbor them have been suggested to have a worse prognosis than those with non-P-loop mutations [96]. Another study identified BCR/ABL mutations in CD34+ cells from CML patients in CCR following Imatinib treatment and suggested that these mutations could lead to imatinib resistance in a small population of progenitors, which consequently could expand and cause the relapse [97].
Several additional mutations that disrupt the interaction between TKIs and BCR-ABL have been characterized, including the P-loop, C-helix, SH2 domain, substrate binding site, A-loop, and C-terminal lobe, some even prior to the initiation of therapy [98]. Most of the reported mutants are rare, however seven mutated sites constitute two thirds of all detected mutations: G250, Y253, E255 (P loop), T315I (gatekeeper), M351, F359, and H396 (activation loop or activation loop backbone) and are frequently evident in the later disease stages [99]. Recently a pan-BCR-ABL inhibitor active against the native enzyme and all tested resistant mutants, including the uniformly resistant T315I mutation has been developed [100].
BCR-ABL kinase domain mutations are not induced by the drug, but rather, just like antibiotic-resistance in bacteria, arise through a process whereby rare pre-existing mutant clones are self-selected due to their capacity to survive and expand in the presence of the drug thus gradually outgrowing drug-sensitive cells [101].
BCR-ABL gene amplification
Overexpression of Bcr-Abl leads to resistance by increasing the amount of target protein needed to be inhibited by the therapeutic dose of the drug. Amplification of the BCR–ABL gene was first described in resistant CML cell lines generated by serial passage of the cells in Imatinib containing media and demonstrated elevated Abl kinase activity due to a genetic amplification of the Bcr–Abl sequence [102, 103].
Cells expressing high amounts of Bcr-Abl in CD34+ CML cells, as in blast crisis, are much less sensitive to Imatinib and, more significantly, take a substantially shorter time for yielding a mutant subclone resistant to the inhibitor than cells with low expression levels, as in chronic phase [104]. However overexpression and amplification of the BCR-ABL gene itself accounts for Imatinib failure in a smaller percentage of patients with an overall percentage of 18% [94].
Drug efflux
HSC are characterized by their ability to pump-out fluorescent dyes, and this led to isolation of stem cells based on this property. In fact, such an efflux capacity has become one of the most efficient methods to purify stem cells from different sources [105]. In this regard, ATP-binding cassette (ABC) transmembrane transporters have shown to be responsible for most of the efflux of the fluorescent dyes in HSCs [106].
In cancer cell lines, multidrug resistance is often associated with an ATP-dependent decrease in cellular drug accumulation, which is attributed to the overexpression of ABC transporter proteins [107]. The first studies on imatinib-resistance showed increased levels of the multidrug resistance protein MDR1 (ABCB1) in Imatinib resistant BCR-ABL+ cell lines [108]. Later on, it was confirmed that Imatinib is a substrate of membrane ABC transporters, such as ABCB1 (MDR1, P-gp), and that variations in the activity or expression of P-gp affects the pharmacokinetics of Imatinib, reducing or increasing its bioavailability [109]. P-gp-positive leukemic cells have low intracellular levels of Imatinib; decreased Imatinib levels, in turn, were associated with a retained phosphorylation pattern of the Bcr-Abl target Crkl and loss of effect of Imatinib on cellular proliferation and apoptosis. The modulation of P-gp by Ciclosporin A readily restored imatinib cytotoxicity in these cells [110].
Another drug efflux pump, the breast cancer resistance protein BRCP encoded by ABCG2, has also been implicated in Imatinib resistance. Imatinib has been variably reported to be a substrate and/or an inhibitor for the BCRP/ABCG2 drug efflux pump, which is overexpressed in many human tumors and also found to be functionally expressed in CML stem cells [111, 112].
CML stem cells have been shown to express the ATP dependent transporter cassette protein ABCG2, which could decrease the intracellular accumulation of Imatinib in CML LSC [103]. Thus, overexpression of ABC transporters gives protection to tumor cells from TKIs [114].
Drug intake
Inversely to the drug efflux pump proteins, the human organic cation transporter 1 (OCT1) mediates the active transport of Imatinib into cells, and inhibition of OCT1 decreases the intracellular concentration of Imatinib [115]. OCT1 was also found to be expressed in significantly higher levels in patients who achieved a CCR to Imatinib than in those who were more than 65% Ph chromosome positive after 10 months of treatment [116]. Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) trial suggested that patients with lower hOCT1 levels had reduced MMR rates at 12 months when receiving the standard dose of Imatinib, compared with high-dose Imatinib [117].
Recently Engler and cols. found that the intracellular uptake and retention (IUR) of imatinib, OCT-1 activity and OCT-1 mRNA expression are all significantly lower in CML CD34+ cells. However, no differences in IUR or OCT-1 activity were observed between these subsets in healthy donors. Low Imatinib accumulation in primitive CML cells, mediated through reduced OCT-1 activity may be a critical determinant of long-term disease persistence [118].
Differential interactions between drug efflux/influx pumps and kinase inhibitors might be a possible means to tailor drug selection for individual patients, because OCT-1 expression is a key determinant of intracellular availability of Imatinib but not of Nilotinib [119]. Other TKIs, such as Dasatinib and, as just mentioned, Nilotinib, do not appear to be substrates for hOCT1, but whether this difference alone will lead to reduced resistance rates with these second-generation TKIs remains unknown [120]. An adequate balance between influx (hOCT1) and efflux (MDR1, ABCG2) transporters may be a critical determinant of intracellular drug levels and, hence, resistance to Imatinib.
Quiescence
One feature of CML is the presence of a population of highly quiescent primitive cells [11], which, as their normal counterparts, is capable of regenerating hematopoiesis and reconstitutes the disease in immunocompromised mice [121]. These stem cells are Ph+, express high levels of CD34 and do not express CD38, CD45RA and CD71, and may spontaneously exit the G0 phase and enter a state of constant proliferation [122]. Several reports have documented that quiescent cells from CML patients are insensitive to in vitro treatment with Imatinib and Dasatinib [16, 123].
A possible cause of insensitivity to TKIs is that BCR-ABL mRNA transcript levels are 300-fold higher in the most primitive CD34+CD38-Lin- population than in terminally differentiating CD34-Lin+ CML cells [124]. It has been reported that elevated levels of Bcr-Abl confer reduced sensitivity to Imatinib [125]. Moreover, the quiescent state of CML stem cells allows them to evade chemotherapy treatments, which are designed to eliminate metabolically active cell population as well as targeted therapies, thus contributing to relapse when treatment with tyrosine kinase inhibitors is discontinued.
Activation of BCR-ABL alternative signaling
BCR-ABL activates different signaling pathways that promote the growth and survival of hematopoietic cells, thus inducing cell transformation. These pathways include Ras, mitogen activated protein kinase (MAPK), c-jun N-terminal kinase (JNK), stress-activated protein kinase (SAPK), nuclear factor kappa B(NF-kB), signal transducers and activators of transcription (STAT), phosphoinositide 3- (PI-3) kinase, and c-Myc [126]. A well characterized pathway involves the Src Family Kinases (SFKs), which are activated by BCR-ABL and the subsequent inhibition of BCR-ABL by Imatinib may not result in the complete inhibition of Src family kinases elucidating a Bcr-Abl independent mechanism of imatinib resistance [127]. Phosphorylation of the Bcr-Abl SH2 and SH3 domains by the SFK may increase the activity of the Abl kinase and may alter its susceptibility to Imatinib [128].
Activation of the Janus kinase (Jak) and subsequent phosphorylation of several Signal Transducer and Activator of Transcription (STAT) family members has been identified in both Bcr–Abl–positive cell lines and in primary CML cells and may contribute to the transforming ability of Bcr–Abl [129].
The tyrosine residue at position 177 within the BCR portion is essential for the binding of adaptor proteins, including Growth Factor Receptor-Bound Protein 2 (GRB2) GRB10, 14-3-3, and the SH2 domain of ABL1 [130]. Bcr-Abl protein is able to activate the Ras/Raf/Mek kinase pathway and the phosphatidylinositol 3′ kinase (PI3K)/Erk pathways through GRB2 [131, 132].
Autocrine loops could contribute to resistance. It has been demonstrated that IL-3 and granulocyte-colony G-CSF are produced within primitive CD34+ cells from patients with CML-CP, both of these cytokines stimulate cellular proliferation in an autocrine manner and protect cells from Imatinib-induced apoptosis [122].
Resistance mechanism in Chronic Myeloid Leukemia. Principal mechanisms involved in dependent and independent BCR-ABL mechanisms are shown (modified to [99]).
The presence of a rare population of cells capable of initiating and sustaining leukemia in CML (LSC) has major implications for the biology of the disease and the development of new and more effective treatments. As recognized by several investigators, LSC are key players in the origin and progression of CML, as well as in the reappearance of the disease after treatment. Thus, it is evident that novel therapies must be directed towards the elimination of such cells. However, since their numbers within the marrow microenvironment are extremely low, as compared to the bulk of the malignant cells, and their biology is quite different from that of the rest of the CML cells, the task of finding solutions to this problem is a rather difficult one. It is a great challenge, but significant advances will surely be achieved in the years to come.
Antonieta Chàvez-González is recipient of funding from the National Council of Science and Technology CONACYT (grant CB 2008-01-105994) and from the Mexican Institute for Social Security IMSS (grant IMSS/PROT/G11/946). Dafne Moreno-Lorenzana and Socrates Avilés-Vazquez are scholarship holders from CONACYT and IMSS. Héctor Mayani is a scholar of FUNDACION IMSS (Mexico) and his research is supported by grants from the National Council of Science and Technology-CONACYT (grant SALUD-69664).
The incidence of melanoma continues to rise globally with significant mortality in spite of modern treatment protocols [1]. Ocular melanoma is the most common type of melanoma in adults after the cutaneous melanoma. It constitutes 3.7% of all melanomas [2]. It results due to the abnormal proliferation of the melanocytes in the eye. Based on the location, the ocular melanoma can be broadly classified as follows:
Eyelid melanoma
Conjunctival melanoma
Uveal melanoma
Iris melanoma
Trabecular meshwork melanoma
Iridotrabeculociliary or iridociliary melanoma
Ciliary body melanoma
Choroidal melanoma
Ciliochoroidal melanoma
Eyelid melanoma is relatively and comprises less than 1% of all eyelid cancers. Serial documentation and close monitoring of suspicious lesions play a very important role in early diagnosis. Variable pigmentation, rapid increase in size, change in color, abnormal vascularity, and tendency to bleed are the typical features of eyelid melanoma [3].
\nThe clinical spectrum of melanocytic tumors of the conjunctiva constitutes about 53% of all conjunctival tumors. The reported incidence is two cases per million per year, but the incidence is increasing. It usually occurs at a median age of 62 years and is very rare in children [4, 5].
\n\n
\n\n\n
Fleshy, variably pigmented (tan to dark brown) placoid, or modular elevated lesion located on the limbal, bulbar, forniceal, or palpebral conjunctiva. The lesions which are localized, bulbar, thin, and limbal have a good prognosis where as those which are large, diffuse, forniceal, on caruncle and tarsus have poorer prognosis (Figure 1).
Prominent feeder vessels (conjunctival and scleral)
It can develop secondarily in contiguity with an eyelid margin which is called as implantation melanoma [9].
Conjunctival melanoma.
\n
A careful dissection of the mass with “no-touch technique,” wide excision with frozen section margin control is ideal.
Alcohol keratoepitheliectomy for the corneal involvement.
Double freeze thaw cryotherapy of the resection edge and the clinically suspected involved base if it is less than 3 clock hours.
Episcleral plaque brachytherapy if base is involved for more than 3 clock hours. Plaque rotation can be customized depending on the tumor extent.
Interferon and interleukin-2 in combination can be administered in disseminated melanoma [8].
Sentinel lymphangiography is indicated in tumors more than 2 mm and helps in complete removal of the lymph nodes.
Abnormal proliferation of the melanocytes, spindle, or the epitheloid cells.
\n\n
Metastasis to ipsilateral facial lymph nodes, brain, lung, skin, bone, and liver are the most common.
Multiple recurrences, especially those within the orbit, might require orbital exenteration [4].
Intraocular and intraorbital involvement may require modified enucleation and orbital exenteration, respectively.
Recurrences after the therapy are 50–70% at 10 years.
Overall mortality rate is 25% at 10 years and more than 30% in 15 years [9, 10].
The 10 year rate of metastasis is PAM 25%, Nevus 26%, De novo 49% [11]
The prognosis can be predicted by the AJCC-TNM staging of conjunctival melanoma (Table 1).
The factors predictive of metastasis or death are de novo origin, tarsal or forniceal location, nodular mass, and orbital invasion [11].
Definition of primary clinical tumor (cT) | \n
TX Primary tumor cannot be assessed T0 No evidence of primary tumor T1 Tumor of the bulbar conjunctiva T1a < 1 quadrant T1b > 1 but <2 quadrants T1c > 2 but <3 quadrants T2 Tumor of nonbulbar conjunctiva (forniceal, palpebral, tarsal, caruncle) T2a Noncaruncular and < 1 quadrant nonbulbar conjunctiva T2b Noncaruncular and > 1 quadrant nonbulbar conjunctiva T2c Caruncular and < 1 quadrant nonbulbar conjunctiva T2d Caruncular and > 1 quadrant nonbulbar conjunctiva T3 Tumor of any size with local invasion T3a Globe T3b Eyelid T3c Orbit T3d Nasolacrimal duct and/or lacrimal sac and/or paranasal sinuses T4 Tumor of any size with invasion of central nervous system. | \n
Definition of regional lymph nodes (N) | \n
NX Regional lymph nodes cannot be assessed N0 Regional lymph node metastasis absent N1 Regional lymph node metastasis present | \n
Definition of distant metastasis (M) | \n
M0 Distant metastasis absent M1 Distant metastasis present | \n
Definition of primary pathological tumor (pT) | \n
TX Primary tumor cannot be assessed T0 No evidence or primary tumor Tis Tumor confined to conjunctival epithelium T1 Tumor of bulbar conjunctiva T1a Tumor with <2 mm thickness invasion of substantia propria T1b Tumor with >2 mm thickness invasion of substantia propria T2 Tumor of nonbulbar conjunctiva T2a Tumor with <2 mm thickness invasion of substantia propria T2b Tumor with >2 mm thickness invasion of substantia propria T3 Tumor of any size with local invasion T3a Globe T3b Eyelid T3c Orbit T3d Nasolacrimal duct and/or lacrimal sac and/or paranasal sinuses T4 Tumor of any size with invasion of central nervous system | \n
AJCC 8th edition classification of conjunctival melanoma.
It is the most common primary intraocular malignancy in adults. The earlier detection and prompt treatment has decreased the morbidity to some extent over the years.
\nBased on the location, they can be classified into
Iris melanoma
Trabecular meshwork melanoma
Iridotrabeculociliary or iridociliary melanoma
Ciliary body melanoma
Choroidal melanoma
Ciliochoroidal melanoma
The most common differential diagnosis of uveal melanoma is anevus. The following are the key points to differentiate the two (pneumonic: ABCDEF):
Age ≤ 40 years
Blood vessels
Clock hours inferiorly
Diffuse configuration
Ectropion uveae
Feathery margin
Iris melanoma constitutes about 4% of uveal melanomas [14]. The mean age at presentation is 40–47 years. It is very rarely seen in the pediatric age group. Males and females are equally affected. It is most commonly seen in Caucasians (97.8%) [15].
\nNodular pigmented lesion usually seen in the inferior iris. It is usually associated with tumor seeding in the adjacent iris or trabecular meshwork and secondary glaucoma.
\n\n
Circumscribed
Diffuse
\n
Observation of clinically suspicious lesions
Local resection (iridectomy/iridocyclectomy) for tumors less than 3–4 clock hours
Plaque brachytherapy—has up to 87% chance if tumor control after local resection
Proton beam therapy
Enucleation—for diffuse, recurrent tumors or eyes with intractable glaucoma
\n
Primary iris cyst
Iris nevus
Essential iris atrophy
Iris foreign body
Peripheral anterior synechiae
Iris metastasis
\n
Angle invasion
Elevated intraocular pressure
Extraocular extension
Previous surgical intervention before referral prognosis [14]
Prognosis is better than ciliary body or choroidal melanoma with a 10-year metastasis of 7% as compared to 25% in choroidal melanoma and 34% for ciliary body melanoma.
\nIt is relatively a rare uveal tumor and is reported in one of 10 cases of all intraocular melanomas [18, 19].
\n\n
Diminution of vision due to astigmatism or lens dislocation
Painless visual field loss or pain due to acute glaucoma
Episcleral sentinel vessels
Unexplained relatively low intraocular pressure
Management options include local resection, plaque brachytherapy, proton beam radiation, and enucleation.
\n\n
Spindle A and B type melanoma—best prognosis
Mixed cell melanoma
Epitheloid cell melanoma—poor prognosis
Necrotic melanoma—poor prognosis
Hematogenous metastasis is faster in ciliary body melanoma as a result of continuous contractions of the ciliary muscle and rich vascularization.
\nThe prognostic factors are listed in Table 3.
\nT Category and criteria | \n
T1—Tumor limited to the iris T1a—Tumor limited to the iris, not more than 3 clock hours in size T1b—Tumor limited to the iris, more than 3 clock hours in size T1c—Tumor limited to the iris with secondary glaucoma T2—Tumor confluent with or extending into the ciliary body, choroid, or both T2a—Tumor confluent with or extending into the ciliary body, without secondary glaucoma T2b—Tumor confluent with or extending into the ciliary body and choroid, without secondary glaucoma T2c—Tumor confluent with or extending into the ciliary body, choroid, or both with secondary glaucoma | \n
T3—Tumor confluent with or extending into the ciliary body, choroid, or both, with scleral extension | \n
T4—Tumor with extrascleral extension T4a—Tumor with extrascleral extension ≤5 mm in largest diameter T4b—Tumor with extrascleral extension >5 mm in largest diameter | \n
G Category and criteria | \n
GX—Grade cannot be assessed G1—Spindle cell melanoma (>90% spindle cells) G2—Mixed cell melanoma (>10% epitheloid cells and < 90% spindle cells) G3—Epitheloid cell melanoma (>90% epitheloid cells) | \n
N Category and criteria | \n
N1—Regional lymph node metastasis or discrete tumor deposits in the orbit N1a—Metastasis in one or more regional lymph node(s) N1b—No regional lymph nodes are positive, but there are discrete tumor deposits in the orbit that are not contiguous to the eye | \n
M Category and criteria | \n
M0—No distant metastasis by clinical classification M1—Distant metastasis M1a—Largest diameter of the largest metastasis ≤3 cm M1b—Largest diameter of the largest metastasis 3.1–8 cm M1c—Largest diameter of the largest metastasis ≥8.1 cm | \n
AJCC 8th edition classification of iris melanoma [20].
Clinical | \nMacroscopic | \nMicroscopic | \n
---|---|---|
Local/general signs Local extension Presence of metastasis Age of the patient Dysplastic nevi | \nSize of the tumor <11 mm—small 11–15 mm—medium >15 mm—large | \nEpitheloid and necrotic cellular patterns Necrosis Intense pigmentation Melanophagic, lymphocytic infiltrate | \n
The prognostic factors for ciliary body melanoma.
Choroidal melanoma is the most common uveal melanoma and constitutes about 90% of all uveal melanomas. This is usually seen in an elderly age group at around 60 years and there is no gross gender predilection. It is seen predominantly in Caucasians (98%), as compared to other races. It has a pronounced tendency to metastasize resulting in high mortality [21]. Predisposing factors are listed in Table 4.
\nIt can be incidentally detected in asymptomatic patients on routine ocular examination. Most of the patients, however, manifest with diminution of vision, floaters, photopsia, visual field loss, or pain due to impingement of posterior ciliary nerve or angle closure glaucoma. It can metastasize to liver (89%), lung (29%), and bone (17%). Median survival after metastasis is 6–12 months [22]. Males have a poor prognosis than females. The lower metastatic rate in females can be explained due to the inhibitory action of estrogen on the growth of micrometastases within the liver [23, 24].
\nChoroidal melanoma can be broadly classified into diffuse (Figure 2) and circumscribed (Figure 3). The circumscribed variant can either be dome-shaped (75%) or mushroom-shaped (20%). Diffuse choroidal melanoma is seen in 3–17% cases and has a substantial risk of metastasis despite its flat appearance. The poor prognostic factors include delayed diagnosis, greater proportion of epitheloid cells, and a tendency for extraocular extension [25].
\nDiffuse choroidal melanoma.
Circumscribed choroidal melanoma.
AJCC Classification has already been mentioned under the section of iris melanoma (Table 2).
\nThe most common precursor lesion for choroidal melanoma is the preexisting choroidal nevus (Figure 4), followed by oculodermal melanocytosis.
\nChoroidal nevus.
The following are used to differentiate a choroidal nevus from a melanoma (pneumonic: to find small ocular melanoma using helpful hints daily):
Thickness > 2 mm
Fluid
Symptoms
Orange pigmentation
Margin <3 mm to disk
Ultrasound hollow
Absent halo
Absent grusen
It has 95% accuracy and is useful to estimate tumor size for periodic observation and to evaluate for extraocular extension.
\nThe characteristic features on A-scan are:
Initial prominent spike
Low to medium internal reflectivity with diminishing amplitude
Fine oscillation of internal spiking pattern (vascular pulsations)
The characteristic features on B-scan are:
Low to medium internal reflectivity
Choroidal excavation
Shadowing of subadjacent soft tissue
Internal vascularity
Acoustic hallowing
Hyperautofluorescence of orange-colored lipofuscin pigment.
\nSmall melanoma: Hypofluorescence (blocked fluorescence)
\nLarge melanoma: Patchy pattern of early hypofluorescence and hyperfluorescence followed by late intense staining. Double circulation—internal vascularity
\nIt helps to differentiate anterior tumors from those of ciliary body origin. Although the tumor margins and extent is well delineated by UBM, the resolution of internal tumor details is limited.
\nDome-shaped choroidal mass with overlying outer retinal thickening and subretinal fluid.
\nOptical coherence tomography angiography shows reduced capillary density in the affected eye.
\nPigmented melanomas can be seen as T1 Hyperdense and T2 hypodense intraocular masses.
\nAlthough reliable, it is technically challenging and requires expertise.
\nThe most common treatment modality is the episceral plaque brachytherapy. Plaque brachytherapy is suitable for tumors up to 16 mm in diameter and up to 6 mm thickness with Ruthenium-106 and up to 8 mm thickness with Iodine-125. The dose to the tumor apex should be 10,000 cGy and almost up to 90% tumor control can be achieved. Enucleation is an option for tumors beyond the scope of plaque brachytherapy. Orbital exenteration might be required in tumors with orbital invasion. The proton beam irradiation has a higher chance of eye salvage but the availability and affordability are the considerable limitations. The other treatment modalities include laser photocoagulation, transpupillary thermotherapy, chemotherapy, and immunotherapy.
\nThe various newer treatment modalities under evaluation are:
Chemotherapy with dacarbazine+interferon alpha, cisplatin, tamoxifen+sunitinib, and fotemustine.
Targeted therapy with crizotinib, sunitinib, and valproic acid.
Immunotherapy with Ipilimumab with nivolumab.
Modified Callenders’s classification describes various patterns on histopathology.
Spindle cell nevi
Spindle cell melanoma
Necrotic melanoma
Epitheloid cell melanoma
Mixed cell melanoma
The epitheloid cell and the mixed cell melanoma have the poorest prognosis among all the subtypes (Table 5). Immunohistochemical markers characteristic of choroidal melanoma are S-100, HMB-45.
\n\n\n\nHost factors | \nEnvironment factors | \n
---|---|
Light colored eyes Fair skinned | \nIntermittent ultraviolet exposure to arc welding Chronic UV exposure Occupational sunlight exposure | \n
Predisposing factors.
Clinical features | \nHistopathologic features | \nCytogenetic features | \nTranscriptomic feature | \n
---|---|---|---|
Older age at presentation | \nEpithelioid cytology | \nChromosome 3 loss (monosomy 3) | \nGene expression profile class 2 | \n
Male gender | \nHigh mitotic activity/PC-10/Ki-67 | \nChromosome 8q gain or 8p loss | \n\n |
Larger tumor basal diameter | \nHigh values of mean diameter of 10 largest nucleoli | \nChromosome 1p loss | \n\n |
Thicker tumor | \nHigh microvascular density | \nChromosome 6q loss | \n\n |
Ciliary body tumor location | \nMicrovascular loops and patterns | \nChromosome 9q loss | \n\n |
Diffuse tumor configuration | \nTumor-infiltrating lymphocytes, macrophages | \nBAP1 loss | \n\n |
Association with ocular/oculodermal melanocytosis | \nLoss of nuclear immunostaining for BAP1 | \n\n | \n |
Extraocular tumor extension | \nHigh expression of insulin-like growth factor 1 receptor | \n\n | \n |
Advanced AJCC category and staging | \nHigh expression of HLA class I and II | \n\n | \n |
The poor prognostic factors include [26].
The risk factors for metastasis include (Table 7):
Thickness > 2 mm
Symptoms
Margin <3 mm to disk
Documented growth
The presence of four risk factors has a metastatic rate of 20% but the absence of risk factors has only <1% risk of systemic metastasis. Also, each millimeter increase in thickness adds 5% risk for metastasis at 10 years and a hazard ratio of 1.08 [27]. Doubling time of untreated metastases ranged from 34 to 220 days (median, 63 days). The metastasis from tumors as small as 3 × 3 × 1.5 mm has been noted in a study [28]. Based on the estimated growth rates, a rational follow-up interval to detect metastatic uveal melanoma would be 4–6 months. Primary uveal melanomas that develop clinically detectable metastasis after conservative therapy may have micrometastasized several years before treatment.
\nDamato’s classification of metastasis [26]:
Metastasizing melanomas, which have already metastasized by the time of ocular treatment even though the metastases may not be detectable.
Pre-metastasizing melanomas, which develop metastatic capability and disseminate if treatment is delayed.
Non-metastasizing melanomas, which do not metastasize even if never treated.
This is the largest study ever to be performed in Ocular oncology with 43 participating centers and more than 2000 patients [29, 30].
\nObjectives of the study:
To evaluate the therapeutic interventions for patients with choroidal melanoma
To determine which of the two, enucleation or brachytherapy prolongs the lifetime of an individual, and if both have a similar survival, then which offers the longer cancer-free survival and better prognosis for vision.
Inclusion and exclusion criteria:
Primary choroidal melanoma in one eye
Less than 50% involvement of ciliary body
Age 21 years or older
Ability to give informed consent
Ability to return for treatment and scheduled follow-up
No primary cancer (except noninvasive nonmelanotic skin cancer/CIS cervix)
No coexisting disease threatening survival (5 years or longer)
No metastatic melanoma
No contraindication for surgery/RT
No previous FNAB
No previous treatment
No extrascleral extension of 2 mm or more
No diffuse, ring or multifocal tumor
No iris/angle involvement
No use of immunosuppressive therapy that cannot be discontinued
Outcome measures:
Primary outcome: Time to death from all-cause mortality
Secondary outcome: Metastasis-free survival, cancer-free survival, and years of useful vision
Trial design and treatment groups:
Small <3 (1.5–2.4) mm, 5 mm (observational group)
Medium 3–8 (2.5–10) mm, 16 mm (randomized group)
Large >8 (10 mm), >16 mm (randomized group)
Results:
Pre-enucleation EBRT for large melanoma has no advantage over enucleation group. Five-year Kaplan–Meier estimates for survival were 57% for the enucleation group and 62% for the pre enucleation radiation group.
Enucleation versus brachytherapy for medium melanoma were comparable. The cumulative all-cause mortality at 12 years was 43% for patient in the plaque radiotherapy group versus 41% for those in enucleation group.
The small tumor trial showed that small choroidal melanomas managed by observation showed tumor growth in 21% by 2 years and 31% by 5 years. Observation for small melanoma is not acceptable now and is treated appropriately.
The mitogen-activated protein kinase (MAPK) pathway is one of the main regulatory pathways involved in choroidal melanoma development, particularly through mutations in BRAF, NRAS, and KIT. Choroidal melanoma with BRAF mutation is common in younger patients and the ones associated with preexisting nevi. KIT mutations are the least common choroidal melanoma mutation in MAPK pathway. NRAS mutation is very rare in choroidal melanoma [21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33]. Disomy 3 and chromosome 6p gain are associated with a good prognosis.
\nChromosome 3 loss, 8q gain, 1p loss and 6q loss = Class 1 associated with poor prognosis.
\nBased on gene expression prolifes (GEP), uveal melanoma is now classified into three prognostic categories for metastasis (Table 6).
\n\n | \n | Systemic metastasis at 5 years | \n
---|---|---|
Class 1A | \nLow risk | \n2% | \n
Class 1B | \nIntermediate risk | \n21% | \n
Class 2 | \nHigh risk | \n72% | \n
Prognostic categories for metastasis.
The GEPs are playing a major role at present in prognosticating the risk of metastasis. The tumor as such is constantly evolving at the genetic and molecular level which is described as intratumoral genetic heterogeneity. The term cresendo malignancy is described which explains the transformation of a small tumor which is slow growing over years but acquires Class 2 genetic changes over time (Table 6).
\nTumor size | \nMonosomy 3 | \nIf M3, metastasis by 3 years | \n
---|---|---|
Small 0–3 mm | \n23% | \n0% | \n
Med 3–8 mm | \n35% | \n24% | \n
Large >8 mm | \n>50% | \n58% | \n
Metastasis depends on several factors: Size, markers-BAPI, and genetics [34].
A periodic follow-up with systemic investigations is mandatory in view of high metastatic rates of choroidal melanoma. An annual PET-CT scan is ideal, however, the monitoring of the liver function tests, ultrasonography of the abdomen and the chest X-Ray are reasonably good.
\nOcular melanoma is being effectively managed currently. A protocol-based management of the patient can lead to good local tumor control and careful systemic monitoring can decrease the morbidity and mortality to a great extent. The ongoing research in genetics will probably help us understand and prognosticate ocular melanoma in a better way.
\nThe authors acknowledge this chapter to their patients.
\nThe authors declare no conflict of interest.
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