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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Since their introduction&#44; targeted therapies have radically changed the treatment of cancer&#46; These drugs target specific molecules implicated in tumor growth and proliferation &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; They represent a change in approach for combating cancer&#44; given that they act more specifically than traditional cytotoxic agents&#46; The introduction of these agents has also led to a change in the management of these patients and the adverse effects resulting from cancer therapy&#46; Although the new targeted therapies are generally less toxic for hair&#44; they also have side effects that may impact hair&#44; whether it is the follicular cycle&#44; form&#44; or color&#44; or cause immune disorders leading to hair loss&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">EGFR Inhibitors&#58; Afatinib&#44; Cetuximab&#44; Erlotinib&#44; Gefitinib&#44; Necitumumab&#44; Osimertinib&#44; Panitumumab&#44; Vandetanib</span><p id="par0010" class="elsevierStylePara elsevierViewall">The role of epidermal growth factor receptors &#40;EGFR&#41; in tumor formation and development of skin and skin appendages is well known&#46; Moreover&#44; we know that this molecule plays an important role in the equilibrium of the follicular cycle&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">1</span></a> For this reason&#44; the main adverse effects of these treatments are dermatological&#46; These effects are essentially divided into those that affect the skin &#40;follicular or acneiform eruption&#44; xerosis&#44; and pruritus&#41;&#44; which usually have an early onset&#44; and those that affect the appendages &#40;paronychia and hair changes&#41;&#44; which have a later onset&#46;<a class="elsevierStyleCrossRefs" href="#bib0515"><span class="elsevierStyleSup">2&#8211;4</span></a> Hair changes occur in almost 80&#37; of patients after 6 months of treatment&#46; Several types of impact on hair have been reported&#58; alopecia&#44; hair growth&#44; and changes in rate of growth&#44; hair thickness&#44; and even form&#44; with hair taking on a curly or straight appearance&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">2</span></a> Rarer are changes in hair pigmentation&#46; Two types have been reported&#58; poliosis<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">5</span></a> and repigmentation of grey hair&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">6</span></a> One of the most characteristic effects is&#44; without doubt&#44; persistent or accelerated hair growth&#44; an effect known as trichomegaly&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">7</span></a> Hypertrichosis of the eye lashes is particularly striking and characteristic&#44;<a class="elsevierStyleCrossRefs" href="#bib0530"><span class="elsevierStyleSup">5&#44;7&#44;8</span></a> and usually occurs between 2 and 5 months of treatment &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; This abnormal growth&#44; in addition to the cosmetic impact&#44; leads to an aberrant form of eyelashes with the possibility&#44; in some cases&#44; of causing corneal trauma&#46; For this reason&#44; it is recommended to trim them carefully&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">4</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">Alopecia related to these drugs occurs at different rates according to the drug&#58; 11&#46;9&#37; with afatinib and 8&#46;9&#37; with cetuximab and erlotinib&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">9</span></a> In addition&#44; less frequently&#44; EGFR inhibitors can induce the onset of inflammatory alopecia&#46; This may present as inflammatory nonscarring alopecia<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">10</span></a> or as follicular pustules on the scalp&#44; leading to scarring alopecia&#44;<a class="elsevierStyleCrossRefs" href="#bib0525"><span class="elsevierStyleSup">4&#44;11</span></a> which may correspond to scalp involvement in typical follicular reaction &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; However&#44; some authors are of the opinion that this is a form of erosive pustular dermatosis of the scalp because of the trichoscopic findings&#44; characteristic of such processes&#46;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">12</span></a> In any case&#44; treatment is with topical corticosteroids&#44; while addition of antibiotics with antistaphylococcal action may be useful as <span class="elsevierStyleItalic">Staphylococcus aureus</span> infection has been reported in some cases&#46;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">11</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">HER-2 Inhibitors&#58; Trastuzumab&#44; Lapatinib&#44; Neratinib</span><p id="par0020" class="elsevierStylePara elsevierViewall">Within the pharmacological class of HER-2 inhibitors&#44; trastuzumab is the most widely used drug as an adjuvant treatment for HER-2 positive breast cancer&#46; Alopecia due to this drug does not appear to be a common adverse reaction&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">13</span></a> Lapatinib&#44; in contrast&#44; is an inhibitor of both HER-2 and EGFR&#44; and so can show effects characteristic of this latter group of inhibitors&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">14</span></a> Clinical trials conducted with neratinib to date have not reported any effects on hair&#46;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">15</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Moreover&#44; anecdotally&#44; there have been 2 cases of tufted-hair folliculitis induced by HER-2 inhibitors&#44; one with trastuzumab<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">16</span></a> and the other with lapatinib&#46;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">17</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Anti-PD-1&#47;PD-L1&#47;CTLA-4&#58; Nivolumab&#44; Pembrolizumab&#47;Atezolizumab&#44; Durvalumab&#47;Ipilimumab</span><p id="par0030" class="elsevierStylePara elsevierViewall">PD-1&#44; PD-L1&#44; and CTLA-4 inhibitors are a heterogeneous group of drugs familiar to dermatologists because they are used in the treatment of metastatic melanoma&#46; In the case of ipilimumab&#44; the onset of vitiligo-like hypopigmentation is common &#40;particularly in patients with melanoma&#41;&#44; and in initial studies&#44; up to 14&#37; of patients experienced hypopigmentation of hair of the scalp&#44; eyebrows&#44; or eye lashes&#46;<a class="elsevierStyleCrossRefs" href="#bib0595"><span class="elsevierStyleSup">18&#44;19</span></a> Subsequently&#44; there have been 2 reports of poliosis with this class of drugs&#44; 1 with ipilimumab<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">20</span></a> and the other with pembrolizumab&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">21</span></a> However&#44; the reverse effect seems more frequent with PD-1&#47;PD-L1 inhibitors&#44; as a series of 14 patients was recently published of scalp repigmentation after receiving treatment with 1 of these PD-1&#47;PD-L1 agents for nonsmall cell lung cancer &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">22</span></a> Of note is that 13 of the 14 patients were men&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">Although alopecia arising from anti-PD-1 agents occurs in 1&#37; to 2&#37; of patients&#44; there are no studies that adequately characterize this effect&#46;<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">23</span></a> With ipilimumab&#44; the proportion of patients with alopecia is around 5&#46;1&#37; &#40;ranging from 1&#46;3&#37; to 18&#46;3&#37; according to the series&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">9</span></a> Recently&#44; a series of 4 cases has been published of patients during combined treatment with PD-1&#47;PD-L1<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>ipilimumab&#44; who developed a clinical picture indicative of alopecia areata &#40;AA&#41;&#59; 3 of them in plaque form and 1 case of alopecia universalis with nail involvement&#46;<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">23</span></a> Two cases of AA related to ipilimumab use have been reported&#46;<a class="elsevierStyleCrossRefs" href="#bib0625"><span class="elsevierStyleSup">24&#44;25</span></a> In 1 of them&#44; AA was associated with extensive vitiligo and the authors argued that the presence of autoimmune phenomena could be a marker of longer survival&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Another anecdotal case involved a change to a persistent curly hair phenotype in a patient receiving treatment with nivolumab&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">26</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">BRAF Inhibitors&#58; Vemurafenib&#44; Dabrafenib</span><p id="par0045" class="elsevierStylePara elsevierViewall">BRAF inhibitors were pioneers in targeted therapy for metastatic melanoma&#46; These treatments have a complex safety profile&#44; which has been improved through combination with MEK inhibitors&#46;<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">27</span></a> The effects of BRAF inhibitors on hair are varied and common&#46; Alopecia&#44; typically of the diffuse&#44; nonscarring form of mild intensity &#40;grade <span class="elsevierStyleSmallCaps">i</span>-<span class="elsevierStyleSmallCaps">ii</span>&#41;&#44; is a common side effect&#44; present in 8&#37; in the first clinical trials of vemurafenib and up to 100&#37; in a prospective study of 11 patients&#46;<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">28</span></a> However&#44; the most reliable data probably are derived from a cohort of 3219 patients treated with vemurafenib&#44; up to 25&#37; of whom had some form of alopecia&#46;<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">29</span></a> This rate was similar to that reported in a metaanalysis &#40;23&#46;7&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">9</span></a> We have less extensive data on the percentage of dabrafenib-treated patients who develop alopecia&#46; A series of 119 patients showed an incidence of 14&#37;&#44;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">30</span></a> which in the aforementioned metanalysis increased to 18&#46;9&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">9</span></a> Furthermore&#44; of note is that this type of alopecia is often accompanied by changes in hair morphology &#40;to curly phenotype&#41;&#44; hair thickness&#44; and hair color &#40;typically grey hair may appear or&#44; occasionally&#44; repigmentation is reported&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0640"><span class="elsevierStyleSup">27&#44;31</span></a> This occurs in 16&#46;7&#37; of patients with vemurafenib and 13&#37; to 60&#37; of those with dabrafenib &#40;usually in mild form&#41;&#44; depending on the series&#46;<a class="elsevierStyleCrossRefs" href="#bib0655"><span class="elsevierStyleSup">30&#44;32</span></a> This set of findings has been denoted RASopathic alopecia by some authors&#46;<a class="elsevierStyleCrossRef" href="#bib0660"><span class="elsevierStyleSup">31</span></a> In addition&#44; the appearance of interfollicular yellow dots in the scalp is characteristically observed in association with these changes&#46;<a class="elsevierStyleCrossRef" href="#bib0665"><span class="elsevierStyleSup">32</span></a> In most cases&#44; these effects occur at the start of treatment&#44; although recently a late-onset case has been reported&#46;<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">33</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Finally&#44; the appearance of seborrheic dermatitis of the scalp is not uncommon&#44; and management can be challenging&#44;<a class="elsevierStyleCrossRef" href="#bib0675"><span class="elsevierStyleSup">34</span></a> with some of the most affected patients developing forms of pityriasis amiantecea&#46;<a class="elsevierStyleCrossRef" href="#bib0680"><span class="elsevierStyleSup">35</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">MEK Inhibitors&#58; Trametinib&#44; Cobimetinib&#44; Binimetinib&#44; Selumetinib</span><p id="par0055" class="elsevierStylePara elsevierViewall">As we have already pointed out&#44; MEK inhibitors are usually used in combination with BRAF inhibitors &#40;vemurafenib and dabrafenib&#41;&#44; not just to increase survival but to reduce side effects&#46;<a class="elsevierStyleCrossRefs" href="#bib0635"><span class="elsevierStyleSup">26&#44;27</span></a> Therefore&#44; specific reports on their side effects on hair when used as monotherapy are limited&#46; In one of the phase <span class="elsevierStyleSmallCaps">iii</span> clinical trials that included 323 patients with trametinib&#44; alopecia was reported in 19&#37;&#44; in almost all cases of grade <span class="elsevierStyleSmallCaps">i</span> severity&#46;<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">36</span></a> According to a metaanalysis&#44; the overall percentage of such events among patients treated with trametinib was close to 13&#46;3&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">9</span></a> In another small series of 11 patients&#44; selumetinib was reported to cause alopecia in 9&#37; of cases&#46;<a class="elsevierStyleCrossRef" href="#bib0690"><span class="elsevierStyleSup">37</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">However&#44; the most important aspect of these drugs is&#44; without doubt&#44; their capacity to improve the safety profile of BRAF inhibitors&#44; the agents with which they are almost always used in combination&#46; Comparative studies between BRAF inhibitors alone and a combination of BRAF and MEK inhibitors show that most of the usual side effects occur at a lower frequency with combination therapy&#46;<a class="elsevierStyleCrossRefs" href="#bib0635"><span class="elsevierStyleSup">26&#44;30&#44;37</span></a> This however is not the case with photosensitivity and keratosis pilaris&#44; whose incidence may increase with combination therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">27</span></a> With regards hair&#44; the combination does seem to improve the safety profile&#44; as shown in a comparative study in which the incidence of alopecia was compared for patients treated with dabrafenib &#40;14&#37;&#41; and those treated with a combination of dabrafenib and trametinib &#40;3&#46;3&#37;&#41;&#59; the incidences of curly hair and grey hair was also compared &#40;12&#46;6&#37; vs&#46; 3&#46;3&#37;&#44; respectively&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">30</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Recently&#44; a case of trichorrhexis nudosa was reported in a 14-year-old girl&#44; associated with treatment with trametinib&#46;<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">38</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">KIT&#47;BCR-ABL Inhibitors&#58; Axitinib&#44; Imatinib&#44; Regorafenib&#47;Bosutinib&#44; Dasatinib&#44; Nilotinib&#44; Ponatinib</span><p id="par0070" class="elsevierStylePara elsevierViewall">This heterogenous class of drugs inhibit tyrosine kinases produced by c-kit&#44; platelet growth factor receptors&#44; and BCR-ABL fusion&#46; They are mainly used for hematological malignancies&#44; such as chronic myeloid leukemia&#44; although they have a wide range of other indications&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">13</span></a> The most characteristic side effects of this group are associated with pigmentation disorders&#44;<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">19</span></a> given the role of c-kit in melanocyte physiology&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">13</span></a> Multiple patterns of skin hypopigmentation or depigmentation have been described with imatinib&#44;<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">19</span></a> with possible hair involvement<a class="elsevierStyleCrossRefs" href="#bib0700"><span class="elsevierStyleSup">39&#44;40</span></a> &#40;sometimes in form of grey hair&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0710"><span class="elsevierStyleSup">41&#44;42</span></a> These alterations are more common in patients with dark phototypes and they usually respond to decreased doses or remit on suspending the drug&#46;<a class="elsevierStyleCrossRef" href="#bib0720"><span class="elsevierStyleSup">43</span></a> Several cases have also been reported of leukotrichia caused by dasatinib&#44; whether or not associated with skin hypopigmentation&#44;<a class="elsevierStyleCrossRefs" href="#bib0725"><span class="elsevierStyleSup">44&#8211;46</span></a> and by regorafenib&#46;<a class="elsevierStyleCrossRef" href="#bib0740"><span class="elsevierStyleSup">47</span></a> The opposite effect &#40;repigmentation&#41;&#44; although less frequent&#44; has also been reported both in skin&#44; mucosas&#44; and nails<a class="elsevierStyleCrossRefs" href="#bib0600"><span class="elsevierStyleSup">19&#44;43</span></a> and in hair&#44; in 2 different series with imatinib&#58; a series of 9 cases out of 133 treated patients &#40;median duration&#44; 5&#46;7 months&#41;<a class="elsevierStyleCrossRef" href="#bib0745"><span class="elsevierStyleSup">48</span></a> and another of 8 cases &#40;out of 58&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0750"><span class="elsevierStyleSup">49</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Another adverse effect on hair observed frequently is alopecia&#44; particularly in women&#46; Regorafenib is the agent in this class with the highest rate of alopecia &#40;23&#46;7&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">9</span></a> Although nilotinib also shows high rates of alopecia &#40;6&#37;-8&#37; according to pivotal studies&#44; with one metaanalysis finding an incidence as high as 15&#46;9&#37;&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0720"><span class="elsevierStyleSup">43&#44;50</span></a> this effect is not well characterized&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">13</span></a> In one case&#44; the onset of complete diffuse alopecia of an inflammatory nature is described in detail &#40;affecting the scalp and eyebrows but not the eyelashes&#44; body hair&#44; or nails&#41; in a female patient&#44; associated with an eruption of multiple flesh-colored follicular papules on the trunk&#44; several weeks after starting nilotinib&#46;<a class="elsevierStyleCrossRef" href="#bib0760"><span class="elsevierStyleSup">51</span></a> In addition&#44; the event coincided with a recent postpartum period&#46; Given that alopecia in these cases does not resemble the usual form of onset&#44; the authors proposed the term nilotinib-induced alopecia&#46; To date&#44; there have not been any further reports on this specific type of alopecia&#46; Imatinib can also cause alopecia&#44; which is reported in 6&#46;6&#37; of patients&#44;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">9</span></a> although complete alopecia is uncommon&#46;<a class="elsevierStyleCrossRef" href="#bib0765"><span class="elsevierStyleSup">52</span></a> In a comparative study of axitinib and sorafenib &#40;both of which are indicated for metastatic renal cancer&#41;&#44; alopecia was reported in 4&#37; of patients treated with axitinib&#46;<a class="elsevierStyleCrossRef" href="#bib0770"><span class="elsevierStyleSup">53</span></a> Dasatinib has an alopecia rate of approximately 7&#46;8&#37;&#44; although this may vary from 3&#37; to 19&#46;1&#37; according to the series&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">9</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">In addition to alopecia and pigmentation disorders&#44; other types of side effects that impact hair can be observed&#46; Keratosis pilaris caused by nilotinib is common<a class="elsevierStyleCrossRef" href="#bib0775"><span class="elsevierStyleSup">54</span></a>&#59; this may be atrophic and is described as associated with plaque AA&#46;<a class="elsevierStyleCrossRef" href="#bib0780"><span class="elsevierStyleSup">55</span></a> Of note also is that lichenoid reactions are common in this group of drugs and&#44; at times&#44; this may affect hair in the form of lichen planopilaris&#46;<a class="elsevierStyleCrossRef" href="#bib0785"><span class="elsevierStyleSup">56</span></a> Moreover&#44; with some of these drugs &#40;nilotinib&#44; dasatinib&#44; and ponatinib&#41;&#44; cases have been reported in which the clinical manifestations could be mixed&#44; typically combining a finding of lichen planopilaris with skin eruptions such as keratosis pilaris&#44; reminiscent of Graham-Little syndrome&#46;<a class="elsevierStyleCrossRef" href="#bib0790"><span class="elsevierStyleSup">57</span></a> In addition&#44; anecdotally&#44; there have been reports of imatinib associated with a case of madarosis in a pediatric patient<a class="elsevierStyleCrossRef" href="#bib0795"><span class="elsevierStyleSup">58</span></a> and of nilotinib with a case of perforating folliculitis&#46;<a class="elsevierStyleCrossRef" href="#bib0800"><span class="elsevierStyleSup">59</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">VEGF&#47;VEGFR Inhibitors&#58; Bevacizumab&#44; Pazopanib&#44; Sorafenib&#44; Sunitinib&#47;Lenvatinib&#44; Ramucirumab</span><p id="par0085" class="elsevierStylePara elsevierViewall">Drugs that belong to the class of VEGF&#47;VEGFR inhibitors are also called multikinase inhibitors because&#44; in addition to inhibiting activity of the intracellular portion of the VEGF receptor&#44; they act on many other tyrosine kinases either directly or indirectly&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">13</span></a> For this reason&#44; they exhibit a wide range of adverse effects and many of these coincide with adverse effects characteristic of other classes of drug&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">The most frequent adverse effect on hair is alopecia&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">13</span></a> Several studies support this affirmation&#58; different metaanalyses cite the percentage of patients with alopecia at 6&#37; &#40;5&#37;-21&#37;&#41; with sunitinib&#44;<a class="elsevierStyleCrossRef" href="#bib0805"><span class="elsevierStyleSup">60</span></a> 10&#37; &#40;3&#46;3&#37;-26&#46;8&#37;&#41; with bevacizumab&#44;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">9</span></a> 12&#46;3&#37; &#40;9&#37;-16&#37;&#41; with pazopanib&#44;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">9</span></a> and 25&#46;5&#37;-29&#37; with sorafenib&#44;<a class="elsevierStyleCrossRef" href="#bib0810"><span class="elsevierStyleSup">61</span></a> the drug with the highest percentage of affected patients&#46; Furthermore&#44; sorafenib-associated alopecia has its own distinctive characteristics&#46; Onset usually occurs between week 3 and week 15 of treatment and may at times be accompanied by slow growth of facial hair&#46;<a class="elsevierStyleCrossRef" href="#bib0815"><span class="elsevierStyleSup">62</span></a> Another study reported that up to 19&#37; of patients experienced loss of body hair&#44; not always associated with alopecia of scalp hair&#46;<a class="elsevierStyleCrossRef" href="#bib0820"><span class="elsevierStyleSup">63</span></a> Management is complex&#44; as there is no specific treatment available&#44; but the disorder is not usually permanent and the patient regains hair density once treatment is complete &#40;and sometimes even before completion&#41;&#46; When hair regrows&#44; it may appear brittle and curly&#46;<a class="elsevierStyleCrossRef" href="#bib0825"><span class="elsevierStyleSup">64</span></a> Other authors have reported that the event in some patients may have characteristics that overlap with AA&#46;<a class="elsevierStyleCrossRef" href="#bib0830"><span class="elsevierStyleSup">65</span></a> With regards the VEGFR inhibitors lenvatinib and ramucirumab&#44; limited data are currently available&#46; Ramucirumab&#44; according to a metaanalysis of 6 randomized clinical trials&#44; does not show an increase in the proportion of patients with alopecia compared with placebo&#44;<a class="elsevierStyleCrossRef" href="#bib0835"><span class="elsevierStyleSup">66</span></a> whereas with lenvatinib&#44; 11&#37; of patients had alopecia in a phase <span class="elsevierStyleSmallCaps">iii</span> clinical trial with 261 patients&#46;<a class="elsevierStyleCrossRef" href="#bib0840"><span class="elsevierStyleSup">67</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Through direct or indirect activity on c-kit&#44; these drugs are also often associated with skin and hair pigmentation disorders&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">13</span></a> In this case&#44; sunitinib is typically the most widely implicated drug&#44;<a class="elsevierStyleCrossRef" href="#bib0815"><span class="elsevierStyleSup">62</span></a> with depigmentation of the hair&#44; eyebrows&#44; and eyelashes in up to 8&#37; to 14&#37; of cases&#46;<a class="elsevierStyleCrossRefs" href="#bib0715"><span class="elsevierStyleSup">42&#44;68&#8211;70</span></a> Onset usually occurs after 5 to 6 weeks of treatment&#44; with hair acquiring a greyish color&#46; The effect usually remits within 2 to 3 weeks of finishing treatment&#44; and so it is possible that there are intermittent cases of depigmentation&#44; depending on the periodicity of treatment &#40;due to transient inhibition of c-kit&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0815"><span class="elsevierStyleSup">62&#44;69</span></a> Although this effect is usually attributed to sunitinib&#44; in some series&#44; the proportion of hair depigmentation with pazopanib is even higher&#44; reaching 38&#37;<a class="elsevierStyleCrossRef" href="#bib0860"><span class="elsevierStyleSup">71</span></a> at high doses&#44; with rapid onset<a class="elsevierStyleCrossRef" href="#bib0865"><span class="elsevierStyleSup">72</span></a> and an odds ratio of 4&#46;54&#46;<a class="elsevierStyleCrossRef" href="#bib0870"><span class="elsevierStyleSup">73</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Hedgehog Inhibitors&#58; Vismodegib&#44; Sonidegib&#44; Erismodegib</span><p id="par0100" class="elsevierStylePara elsevierViewall">Hedgehog inhibitors are primarily indicated for advanced and metastatic basal cell carcinoma&#46;<a class="elsevierStyleCrossRef" href="#bib0660"><span class="elsevierStyleSup">31</span></a> In this case&#44; alopecia is&#44; without doubt&#44; the most frequent adverse effect involving hair &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46; The rates are very high&#44; reaching 63&#37; in the first pivotal clinical trials with vismodegib&#46;<a class="elsevierStyleCrossRef" href="#bib0875"><span class="elsevierStyleSup">74</span></a> In fact&#44; vismodegib is the cancer drug with the highest rate of alopecia according to a comparative metaanalysis&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">9</span></a> Furthermore&#44; of note is that 10&#37;-14&#37; have grade <span class="elsevierStyleSmallCaps">ii</span> alopecia &#40;&#62;<span class="elsevierStyleHsp" style=""></span>50&#37; hair loss&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0875"><span class="elsevierStyleSup">74</span></a> Another important study published recently of 694 patients with advanced and metastatic basal cell carcinoma treated with vismodegib reported a percentage of patients with alopecia of 62&#37;&#44; with the event occurring constantly throughout the first 12 months of treatment&#58; it was responsible for withdrawal from treatment in 3&#37; of patients&#46;<a class="elsevierStyleCrossRef" href="#bib0880"><span class="elsevierStyleSup">75</span></a> Of note is that this alopecia resolves spontaneously on stopping treatment &#40;usually during the first year&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0880"><span class="elsevierStyleSup">75</span></a> 4 cases have been reported of persistent alopecia &#40;mean duration of follow-up of 15 months&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0885"><span class="elsevierStyleSup">76</span></a> In addition&#44; other authors report 2 cases in which spontaneous improvement in this process during treatment was accompanied by treatment failure&#44; and they speculate whether this could be an early marker of therapeutic failure and disease progression&#46;<a class="elsevierStyleCrossRef" href="#bib0890"><span class="elsevierStyleSup">77</span></a> Alopecia associated with sonidegib&#44; although not as common&#44; is still present in more than 10&#37; of cases&#46;<a class="elsevierStyleCrossRef" href="#bib0895"><span class="elsevierStyleSup">78</span></a> The Hedgehog pathway shows high signaling levels in growing follicles&#44; which would explain the high rates of alopecia when this pathway is inhibited&#46;<a class="elsevierStyleCrossRef" href="#bib0900"><span class="elsevierStyleSup">79</span></a> In fact&#44; agonists of the Hedgehog pathway have been studied as potential treatments for androgenic alopecia &#40;and have been ruled out due to their numerous adverse effects&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0905"><span class="elsevierStyleSup">80</span></a> A recent study characterized in detail the pattern of alopecia associated with these drugs in 5 patients &#40;4 with vismodegib and 1 with sonidegib&#47;erismodegib&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0910"><span class="elsevierStyleSup">81</span></a> In all cases&#44; the authors describe the cases as a diffuse&#44; noninflammatory alopecia &#40;without an androgenic pattern&#41;&#44; with slow and gradual onset&#44; and regrowth of increasingly fine and weak hair&#46; This process occurred between 2 and 9 months &#40;median of 3&#46;1 months&#41; of treatment and often affected body hair and eyebrows &#40;in 4 out of 5 cases&#41; and nails &#40;3 out of 5&#41;&#46; In no case were signs of AA observed&#46; The only histopathological findings were an increase in the telogen to anagen ratio&#44; consistent with telogen effluvium&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">Another curious effect associated with vismodegib treatment&#44; reported once anecdotally&#44; is trichodysplasia spinulosa&#46;<a class="elsevierStyleCrossRef" href="#bib0915"><span class="elsevierStyleSup">82</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Proteasome Inhibitors&#58; Bortezomib&#44; Carfilzomib&#44; Ixazomib</span><p id="par0110" class="elsevierStylePara elsevierViewall">Proteasome inhibitors are drugs used mainly in the treatment of hematological malignancies&#46; Alopecia caused by bortezomib is considered uncommon&#44;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">9</span></a> with incidences ranging from 0&#46;4&#37; to 10&#46;9&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0920"><span class="elsevierStyleSup">83&#44;84</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">mTOR Inhibitors&#58; Everolimus&#44; Temsirolimus&#44; Sirolimus</span><p id="par0115" class="elsevierStylePara elsevierViewall">mTOR inhibitors are drugs with many wide-ranging indications that generally have limited impact on hair&#46;<a class="elsevierStyleCrossRefs" href="#bib0660"><span class="elsevierStyleSup">31&#44;85</span></a> These agents are considered as an uncommon cause of hair loss&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">9</span></a> The percentage of patients with alopecia is 5&#46;3&#37; &#40;1&#46;9&#37;-14&#46;3&#37;&#41; with everolimus and 5&#46;2&#37; &#40;0&#46;9&#37;-25&#46;9&#37;&#41; with temsirolimus&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">9</span></a> With sirolimus&#44; the prevalence of alopecia&#44; usually mild and diffuse&#44; is 9&#37;&#44; and occasionally&#44; it may also affect body hair&#46;<a class="elsevierStyleCrossRef" href="#bib0935"><span class="elsevierStyleSup">86</span></a> The following effects have also been reported for sirolimus&#58; hypertrichosis &#40;face and body&#41;&#44; 2 cases of AA&#44; and folliculitis of the scalp in up to 25&#37; of patients&#46;<a class="elsevierStyleCrossRef" href="#bib0935"><span class="elsevierStyleSup">86</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">PI3K Inhibitors&#58; Idelalisib&#44; Copanlisib&#44; Dactolisib</span><p id="par0120" class="elsevierStylePara elsevierViewall">PI3K is a promising target for hematological malignancies and brain tumors&#44; with limited data on capillary reactions&#46; The presence of high PI3K activity in hair follicle cells would seem to indicate that inhibition of this pathway could lead to a high percentage of alopecia&#46;<a class="elsevierStyleCrossRef" href="#bib0940"><span class="elsevierStyleSup">87</span></a> In fact&#44; in murine models with dactolisib&#44; alopecia was the most frequently observed adverse effect&#46;<a class="elsevierStyleCrossRef" href="#bib0945"><span class="elsevierStyleSup">88</span></a> However&#44; the data available to date with idelalisib &#40;the PI3K inhibitor for which most clinical experience is available&#41; suggest that the percentage of patients with alopecia is low&#46;<a class="elsevierStyleCrossRef" href="#bib0950"><span class="elsevierStyleSup">89</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Anti-CD52&#58; Alemtuzumab</span><p id="par0125" class="elsevierStylePara elsevierViewall">Alemtuzumab is an anti-CD52 agent with a range of indications&#46; Characteristically&#44; it is associated with several autoimmune adverse effects&#46;<a class="elsevierStyleCrossRef" href="#bib0955"><span class="elsevierStyleSup">90</span></a> In this context&#44; there have been reports of AA associated with alemtuzumab&#44; both in plaque form and the universalis form&#44; which can be accompanied by other events of autoimmune origin &#40;<a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0960"><span class="elsevierStyleSup">91</span></a> Furthermore&#44; the rate of alopecia is 5&#46;3&#37; &#40;0&#46;7&#37;-29&#46;4&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">9</span></a></p><elsevierMultimedia ident="fig0025"></elsevierMultimedia></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">ALK Inhibitors&#58; Alectinib&#44; Ceritinib&#44; Crizotinib</span><p id="par0130" class="elsevierStylePara elsevierViewall">ALK inhibitors are indicated mainly for nonsmall cell lung cancer&#46; The rate of alopecia caused by crizotinib is 8&#37; &#40;4&#46;9&#37;-13&#46;2&#37;&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0550"><span class="elsevierStyleSup">9&#44;92</span></a> Data for other ALK inhibitors are limited&#44; although a case of diffuse alopecia caused by alectinib has been reported in a patient who had already received crizotinib without alopecia occurring&#46;<a class="elsevierStyleCrossRef" href="#bib0970"><span class="elsevierStyleSup">93</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">HDAC Inhibitors&#58; Belinostat&#44; Panobinostat&#44; Romidepsin&#44; Vorinostat</span><p id="par0135" class="elsevierStylePara elsevierViewall">There are limited data on HDAC inhibitors to date&#46; A study of 6 patients with advanced cutaneous T-cell lymphoma who received treatment with vorinostat detected 2 cases of mild alopecia and 1 case of moderate alopecia&#44; with no other effects of note on hair&#46;<a class="elsevierStyleCrossRef" href="#bib0975"><span class="elsevierStyleSup">94</span></a></p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">RANKL Inhibitors&#58; Denosumab</span><p id="par0140" class="elsevierStylePara elsevierViewall">Denosumab is the main drug in this class and is indicated for the treatment of osteoporosis and bone metastases&#46; Alopecia has not been reported among the common adverse effects after 10 years of use&#46;<a class="elsevierStyleCrossRef" href="#bib0980"><span class="elsevierStyleSup">95</span></a> One case of AA universalis has been reported related to use of denosumab after only 2 weeks of treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0985"><span class="elsevierStyleSup">96</span></a> The authors discussed whether the fact that RANKL belongs to the TNF-&#945; family might bear some relation on the appearance of this effect&#44; given that anti-TNF-&#945; agents have been frequently associated with onset of paradoxical AA&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">PARP Inhibitors&#58; Olaparib&#44; Rucaparib&#44; Veliparib&#44; Talazoparib&#44; Iniparib</span><p id="par0145" class="elsevierStylePara elsevierViewall">PARP inhibitors are drugs in development mainly for metastatic ovarian cancer&#46; In a clinical trial of 306 patients&#44; it was shown that there was no increase in the proportion of patients with alopecia in the veliparib arm compared with placebo&#46;<a class="elsevierStyleCrossRef" href="#bib0990"><span class="elsevierStyleSup">97</span></a> Another trial also showed a statistically significant decrease in the percentage of patients with alopecia who received veliparib&#47;temozolomide instead of the traditional chemotherapy regimen with carboplatin&#47;paclitaxel&#46;<a class="elsevierStyleCrossRef" href="#bib0995"><span class="elsevierStyleSup">98</span></a> Olaparib was also able to reduce the rate of alopecia when combined with traditional chemotherapy in comparison with a chemotherapy-only regimen&#46;<a class="elsevierStyleCrossRef" href="#bib1000"><span class="elsevierStyleSup">99</span></a></p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Anti-CD30&#58; Brentuximab</span><p id="par0150" class="elsevierStylePara elsevierViewall">Brentuximab is any anti-CD30 agent indicated mainly for refractory Hodgkin lymphoma&#46;<a class="elsevierStyleCrossRef" href="#bib1005"><span class="elsevierStyleSup">100</span></a> The proportion of patients with alopecia after receiving brentuximab is 14&#37; &#40;9&#46;9&#37;-19&#46;6&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">9</span></a> Furthermore&#44; anecdotally&#44; there is a case report of complete hair repigmentation in a 72-year-old man after 6 months of treatment with brentuximab&#46;<a class="elsevierStyleCrossRef" href="#bib1010"><span class="elsevierStyleSup">101</span></a></p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Conclusions</span><p id="par0155" class="elsevierStylePara elsevierViewall">Hair-related side effects are common with new targeted therapies used in cancer &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; All dermatologists should be aware of the most important ones to enable appropriate management of these patients&#44; who are seen increasingly frequently in our clinics &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; Several different types of hair reactions have been reported depending on the pharmacological class&#46; These can be associated with the morphology of the hair&#44; such as characteristic trichomegaly with EGFR inhibitors&#46; Pigmentary changes are also frequent and range from typical depigmentation with c-kit or VEGF&#47;VEGFR inhibitors to surprising repigmentation associated with PD-1&#47;PDL-1 inhibitors&#46; Even the most typical reactions&#44; such as alopecia with Hedgehog inhibitors&#44; show specific and differentiated characteristics according to the drug used&#46; Other effects reported less often include entities that resemble classic hair diseases&#44; such as AA&#44; lichen planopilaris&#44; and erosive pustular dermatosis of the scalp&#46; Although the rapid advance of targeted therapy does not afford any rest&#44; this review may serve as an initial guide for consultation and study of adverse effects on hair related with these drugs so far&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Conflicts of Interest</span><p id="par0160" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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          "identificador" => "xres1174024"
          "titulo" => "Graphical abstract"
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              "identificador" => "abst0005"
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        1 => array:3 [
          "identificador" => "xres1174022"
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            0 => array:1 [
              "identificador" => "abst0010"
            ]
          ]
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        2 => array:2 [
          "identificador" => "xpalclavsec1097943"
          "titulo" => "Keywords"
        ]
        3 => array:3 [
          "identificador" => "xres1174023"
          "titulo" => "Resumen"
          "secciones" => array:1 [
            0 => array:1 [
              "identificador" => "abst0015"
            ]
          ]
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        4 => array:2 [
          "identificador" => "xpalclavsec1097944"
          "titulo" => "Palabras clave"
        ]
        5 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
        ]
        6 => array:2 [
          "identificador" => "sec0010"
          "titulo" => "EGFR Inhibitors&#58; Afatinib&#44; Cetuximab&#44; Erlotinib&#44; Gefitinib&#44; Necitumumab&#44; Osimertinib&#44; Panitumumab&#44; Vandetanib"
        ]
        7 => array:2 [
          "identificador" => "sec0015"
          "titulo" => "HER-2 Inhibitors&#58; Trastuzumab&#44; Lapatinib&#44; Neratinib"
        ]
        8 => array:2 [
          "identificador" => "sec0020"
          "titulo" => "Anti-PD-1&#47;PD-L1&#47;CTLA-4&#58; Nivolumab&#44; Pembrolizumab&#47;Atezolizumab&#44; Durvalumab&#47;Ipilimumab"
        ]
        9 => array:2 [
          "identificador" => "sec0025"
          "titulo" => "BRAF Inhibitors&#58; Vemurafenib&#44; Dabrafenib"
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        10 => array:2 [
          "identificador" => "sec0030"
          "titulo" => "MEK Inhibitors&#58; Trametinib&#44; Cobimetinib&#44; Binimetinib&#44; Selumetinib"
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        11 => array:2 [
          "identificador" => "sec0035"
          "titulo" => "KIT&#47;BCR-ABL Inhibitors&#58; Axitinib&#44; Imatinib&#44; Regorafenib&#47;Bosutinib&#44; Dasatinib&#44; Nilotinib&#44; Ponatinib"
        ]
        12 => array:2 [
          "identificador" => "sec0040"
          "titulo" => "VEGF&#47;VEGFR Inhibitors&#58; Bevacizumab&#44; Pazopanib&#44; Sorafenib&#44; Sunitinib&#47;Lenvatinib&#44; Ramucirumab"
        ]
        13 => array:2 [
          "identificador" => "sec0045"
          "titulo" => "Hedgehog Inhibitors&#58; Vismodegib&#44; Sonidegib&#44; Erismodegib"
        ]
        14 => array:2 [
          "identificador" => "sec0050"
          "titulo" => "Proteasome Inhibitors&#58; Bortezomib&#44; Carfilzomib&#44; Ixazomib"
        ]
        15 => array:2 [
          "identificador" => "sec0055"
          "titulo" => "mTOR Inhibitors&#58; Everolimus&#44; Temsirolimus&#44; Sirolimus"
        ]
        16 => array:2 [
          "identificador" => "sec0060"
          "titulo" => "PI3K Inhibitors&#58; Idelalisib&#44; Copanlisib&#44; Dactolisib"
        ]
        17 => array:2 [
          "identificador" => "sec0065"
          "titulo" => "Anti-CD52&#58; Alemtuzumab"
        ]
        18 => array:2 [
          "identificador" => "sec0070"
          "titulo" => "ALK Inhibitors&#58; Alectinib&#44; Ceritinib&#44; Crizotinib"
        ]
        19 => array:2 [
          "identificador" => "sec0075"
          "titulo" => "HDAC Inhibitors&#58; Belinostat&#44; Panobinostat&#44; Romidepsin&#44; Vorinostat"
        ]
        20 => array:2 [
          "identificador" => "sec0080"
          "titulo" => "RANKL Inhibitors&#58; Denosumab"
        ]
        21 => array:2 [
          "identificador" => "sec0085"
          "titulo" => "PARP Inhibitors&#58; Olaparib&#44; Rucaparib&#44; Veliparib&#44; Talazoparib&#44; Iniparib"
        ]
        22 => array:2 [
          "identificador" => "sec0090"
          "titulo" => "Anti-CD30&#58; Brentuximab"
        ]
        23 => array:2 [
          "identificador" => "sec0095"
          "titulo" => "Conclusions"
        ]
        24 => array:2 [
          "identificador" => "sec0100"
          "titulo" => "Conflicts of Interest"
        ]
        25 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2018-02-12"
    "fechaAceptado" => "2018-10-13"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1097943"
          "palabras" => array:6 [
            0 => "Cancer treatment"
            1 => "Trichology"
            2 => "Hair"
            3 => "Alopecia"
            4 => "Targeted therapies"
            5 => "Hair reactions"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec1097944"
          "palabras" => array:6 [
            0 => "Tratamiento oncol&#243;gico"
            1 => "Tricolog&#237;a"
            2 => "Pelo"
            3 => "Alopecia"
            4 => "Terapias diana"
            5 => "Alteraciones capilares"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">The advent of immune targeted therapies for cancer has radically changed the treatment and prognosis of many cancers&#46; These drugs are called <span class="elsevierStyleItalic">targeted</span> therapies because they target specific pathophysiological mechanisms of cancer&#46; This paradigm shift in cancer treatment&#44; however&#44; has resulted in new adverse dermatologic effects involving both the skin and its appendages&#46; In the case of hair&#44; targeted drugs can cause immune alterations and changes in hair growth&#44; color&#44; and shape&#46; Because most targeted therapies are new&#44; there is no single document describing all these adverse effects&#46; We performed an exhaustive review of the literature to characterize adverse hair effects associated with the use of targeted therapies&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0015" class="elsevierStyleSection elsevierViewall"><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Las nuevas terapias inmunol&#243;gicas dirigidas contra el c&#225;ncer han supuesto un cambio radical en el tratamiento y el pron&#243;stico de muchas neoplasias&#46; Estos medicamentos se dirigen de manera mucho m&#225;s espec&#237;fica contra los mecanismos fisiopatog&#233;nicos del c&#225;ncer&#44; por lo que adquieren el sobrenombre de &#171;terapias diana&#187;&#46; Este cambio de paradigma ha supuesto la aparici&#243;n de nuevos efectos adversos dermatol&#243;gicos&#44; que afectan tanto la piel como sus anejos&#46; Los efectos adversos en el pelo pueden manifestarse en alteraciones de su ciclo&#44; forma&#44; color o inmunolog&#237;a&#46; Debido a que son tratamientos nuevos en su mayor&#237;a y no existe un documento que englobe todos estos efectos adversos&#44; hemos realizado una exhaustiva revisi&#243;n bibliogr&#225;fica para caracterizar de manera concreta cu&#225;les son los efectos adversos tricol&#243;gicos que pueden inducir cada uno de estos f&#225;rmacos&#46;</p></span>"
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Mir-Bonaf&#233; JF&#44; Saceda-Corralo D&#44; Va&#241;&#243;-Galv&#225;n S&#46; Reacciones capilares de las nuevas terapias diana dirigidas contra el c&#225;ncer&#46; Actas Dermosifiliogr&#46; 2019&#59;110&#58;182&#8211;192&#46;</p>"
      ]
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">A&#44; Trichomegaly of the eyelashes and facial hypertrichosis caused by erlotinib &#40;anti-EGFR agent&#41;&#46; B&#44; Hypertrichosis of the arm of the same patient&#46; Courtesy of Dr&#46; M&#46;P&#46; Garcia-Muret&#46;</p>"
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Follicular reaction on scalp caused by cetuximab &#40;anti-EGFR agent&#41;&#44; resembling erosive pustular dermatosis of the scalp&#46;</p>"
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">A&#44; Patient with grey hair&#46; B&#44; Same patient with hair repigmentation after nivolumab &#40;anti-PD1&#41; treatment&#46; Courtesy of Dr&#46; N&#46; Rivera&#46;</p>"
        ]
      ]
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          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Diffuse alopecia caused by vismodegib &#40;Hedgehog inhibitor&#41; in patients included in the STEVIE study&#46; A&#44; Male patient before starting treatment&#46; B&#44; After 8 months of treatment&#46; C&#44; At 3 months after discontinuation of treatment&#46; D&#44; Female patient before starting treatment&#46; E&#44; After 9 months of treatment&#46; F&#44; At 3 months after discontinuation of treatment&#46; Courtesy of Dr&#46; V&#46; Ruiz-Salas&#46;</p>"
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        "tipo" => "MULTIMEDIAFIGURA"
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          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Alopecia areata &#40;AA&#41; universalis caused by alemtuzumab &#40;anti-CD52 agent&#41;&#46; A&#44; Appearance before treatment&#46; B&#44; Initial plaques of AA on the legs&#46; C and D&#44; Final phase of AA universalis&#46;</p> <p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Source&#58; Van der Zwan et al&#46;<a class="elsevierStyleCrossRef" href="#bib0960"><span class="elsevierStyleSup">91</span></a>&#46;</p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Target&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Main Agents&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">EGFR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Afatinib&#44; cetuximab&#44; erlotinib&#44; gefitinib&#44; necitumumab&#44; osimertinib&#44; panitumumab&#44; vandetanib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">HER-2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Trastuzumab&#44; lapatinib&#44; neratinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PD-1&#47;PD-L1&#47;CTLA-4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nivolumab&#44; pembrolizumab&#47;atezolizumab&#44; avelumab&#44; durvalumab&#47;ipilimumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">BRAF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Dabrafenib&#44; vemurafenib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">MEK&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Trametinib&#44; cobimetinib&#44; binimetinib&#44; selumetinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">KIT&#47;BCR-ABL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Axitinib&#44; imatinib&#44; regorafenib&#47;bosutinib&#44; dasatinib&#44; nilotinib&#44; ponatinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">VEGF&#47;VEGFR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bevacizumab&#44; pazopanib&#44; sorafenib&#44; sunitinib&#47;lenvatinib&#44; ramucirumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hedgehog&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Vismodegib&#44; sonidegib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Proteasome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bortezomib&#44; carfilzomib&#44; ixazomib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">mTOR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Everolimus&#44; temsirolimus&#44; sirolimus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CD52&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Alemtuzumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">ALK&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Alectinib&#44; ceritinib&#44; crizotinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">HDAC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Belinostat&#44; panobinostat&#44; romidepsin&#44; vorinostat&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">RANKL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Denosumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PARP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Olaparib&#44; rucaparib&#44; veliparib&#44; talazoparib&#44; iniparib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CD30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Brentuximab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Main Molecular Targets for Targeted Cancer Therapy and the Corresponding Agents&#46;</p>"
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        "tipo" => "MULTIMEDIATABLA"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Position&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Drug&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Percentage of Patients With Alopecia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Mechanism of Action&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Vismodegib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">56&#46;9 &#40;5&#46;6-63&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hedgehog inhibition&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Sorafenib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">29 &#40;23&#46;9-34&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">VEGFR inhibition&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Vemurafenib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">23&#46;7 &#40;9&#46;6-47&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">BRAF inhibition&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Regorafenib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">23&#46;5 &#40;9&#46;7-46&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">KIT inhibition&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Dabrafenib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">18&#46;9 &#40;10&#46;5-31&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">BRAF inhibition&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nilotinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">15&#46;9 &#40;12&#46;4-20&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">KIT inhibition&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Brentuximab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">14 &#40;9&#46;9-19&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Anti-CD30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Trametinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">13&#46;3 &#40;6&#46;2-26&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MEK inhibition&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pazopanib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12&#46;3 &#40;9-16&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">VEGFR inhibition&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Afatinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11&#46;9 &#40;9&#46;1-15&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">EGFR inhibition&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">The 10 Drugs With Highest Incidence of Alopecia and Their Mechanism of Action&#46;</p>"
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      7 => array:8 [
        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
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          0 => array:3 [
            "identificador" => "at3"
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        "tabla" => array:1 [
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              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Target&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Main Capillary Reactions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Secondary Capillary Reactions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">EGFR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Morphological changes&#44; trichomegaly&#44; inflammatory alopecia&#44; follicular reaction of the scalp&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Changes in pigmentation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">HER-2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Tufted-hair folliculitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PD-1&#47;PD-L1&#47;CTLA-4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Changes in pigmentation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Morphological changes&#44; AA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">BRAF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RASopathic alopecia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Seborrheic dermatitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">MEK&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Reduction of adverse effects of BRAF inhibitors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Alopecia&#44; trichorrhexis nudosa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">KIT&#47;BCR-ABL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Changes in pigmentation&#44; nilotinib-induced alopecia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Keratosis pilaris&#44; lichenoid reactions&#44; AA&#44; madarosis&#44; perforating folliculitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">VEGF&#47;VEGFR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Alopecia&#44; hair depigmentation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">All the effects of EGFR inhibitors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hedgehog&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Alopecia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Trichodysplasia spinulosa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Proteasome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">mTOR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Alopecia &#40;scalp and body&#41;&#44; hypertrichosis&#44; AA&#44; folliculitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CD52&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">RANKL&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PARP&nbsp;\t\t\t\t\t\t\n
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