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5 fluorouracil &#40;5-FU&#41;&#44; diclofenac&#44; imiquimod&#44; and photodynamic therapy &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">1&#8211;13</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0010" class="elsevierStylePara elsevierViewall">The effectiveness of the above treatments&#44; however&#44; is limited by treatment resistance&#46; Tumor cell resistance is defined as an absence of sensitivity to anticancer drugs and it has multiple&#44; complex causes&#46; Resistance is the main reason why anticancer drugs fail and it has an important role in tumor progression and poor prognosis&#46; Although resistance to chemotherapy and radiotherapy has been extensively studied&#44; we are still far from understanding the mechanisms involved&#46; Generally speaking&#44; the first treatment a patient receives destroys the majority of tumor cells&#44; 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such as increased expression of the therapeutic target and activation of alternative compensatory signaling pathways&#46; Cross-resistance is another problem&#44; as once treated&#44; tumors can develop resistance to other drugs&#44; as occurs in multidrug resistance&#46; Finally&#44; certain tumors are highly heterogeneous and contain cells with different phenotypic&#44; genetic&#44; and&#47;or epigenetic characteristics&#44; meaning that sensitivity to treatment will vary according to the area of the tumor&#46;<a class="elsevierStyleCrossRefs" href="#bib0430"><span class="elsevierStyleSup">16&#8211;18</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">In this article we offer an overview of resistance to nonsurgical treatments in NMSC based on a review of case reports and series and research into the possible mechanisms involved&#46; Studies of resistance will contribute to a better understanding of tumor biology and will help to determine how best to combine treatments to improve response rates and reduce adverse effects&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">19</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">In the first of 2 articles&#44; we will review work on possible mechanisms of resistance to the following topical treatments for NMSC&#58; 5-FU&#44; imiquimod&#44; diclofenac&#44; and ingenol mebutate&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Resistance to 5-FU</span><p id="par0035" class="elsevierStylePara elsevierViewall">5-FU is a fluoropyrimidine that acts as an antimetabolite by binding to the enzyme thymidylate synthase&#44; which is responsible for the synthesis of nucleotides&#46; The resulting inhibition of thymidylate synthase leads to a reduction in DNA synthesis and cell proliferation&#44; inducing cell death&#46; These effects are particularly evident in cells with high mitotic rates&#44; such as neoplastic cells&#46; 5-FU is also incorporated into DNA or RNA&#44; interfering with their normal functioning &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0450"><span class="elsevierStyleSup">20&#8211;22</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">Topical 5-FU is approved for the treatment of AK at concentrations of 0&#46;5&#37;&#44; 1&#37;&#44; 2&#37;&#44; and 5&#37;&#46; The 5&#37; formulation&#44; applied twice daily for at least 6 weeks&#44; is indicated for superficial basal cell carcinoma &#40;BCC&#41; and is associated with an approximate cure rate of 93&#37;&#46; Topical 5-FU is not indicated for the treatment of Bowen disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0460"><span class="elsevierStyleSup">22&#8211;24</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">In the largest series to date supporting the efficacy of topical 5-FU in the treatment of superficial BCC&#44; a histologic cure rate of 90&#37; was reported after 3 weeks for 31 superficial lesions treated twice daily for 11 weeks&#46; Although the follow-up time was short&#44; a treatment resistance rate of 10&#37; was observed&#46;<a class="elsevierStyleCrossRefs" href="#bib0465"><span class="elsevierStyleSup">23&#44;25</span></a> Topical 5-FU is much less effective in nodular BCCs&#44; and its use in this setting has had limited success&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">26</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">In the case of AK&#44; 5&#37; 5-FU cream applied for 2 to 4 weeks produced a clinical cure rate of 96&#37; and a histological cure rate of 67&#37;&#44; although 54&#37; of tumors had relapsed at 12 months&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">27</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Although 5-FU is not approved for the treatment of squamous cell carcinoma &#40;SCC&#41;&#44; its efficacy in this setting has been analyzed in several studies&#46; In one of these&#44; 29 patients with SCC in situ were treated with 5-FU cream &#40;Efudix&#41; for 4 weeks&#46; The cream was applied once a day for the first week and twice a day for the remaining weeks&#46; Three months after the last treatment&#44; a complete response rate of 83&#37; was observed but at the 12-month follow-up&#44; this had fallen to 69&#37; and was accompanied by a recurrence rate of 17&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">28</span></a> In another study of 26 patients with Bowen disease treated with 5&#37; 5-FU cream twice a day for 9 weeks&#44; 92&#37; of patients achieved complete clearance over a mean follow-up period of 55 months&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">26</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">The above results clearly show that numerous NMSC lesions are resistant to treatment with 5-FU&#46; However&#44; in order to be able to predict&#8212;and resolve&#8212;resistance problems&#44; it is essential to understand the mechanisms by which 5-FU induces apoptosis and why certain tumors do not respond&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">20</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">One study described the case of a patient with severe dihydropyrimidine dehydrogenase &#40;DPD&#41; deficiency who developed severe gastrointestinal and hematological toxicity following treatment with a standard dose of 5-FU for BCC&#46; DPD is the first enzyme involved in the degradation of 5-FU&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">29</span></a> Approximately 10&#37; of topical 5-FU is absorbed through the skin while over 80&#37; is inactivated in the liver by DPD&#44; explaining why its deficiency causes toxicity&#46; In the case of colorectal cancer&#44; however&#44; patients with low DPD levels respond better to 5-FU&#44; suggesting that DPD alterations and polymorphisms could be one cause of resistance&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">29</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">Increased expression of the Bag-1 protein has been observed in progressive&#44; metastatic oral SCC&#46; This protein has an antiapoptotic function associated with the 70-kDa heat shock protein &#40;Hsp70&#41;&#44; indicating that overexpression of these 2 proteins would increase tumor cell resistance to apoptosis&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">30</span></a> In one study&#44; the elimination of Bag-1 from the cutaneous SCC cell line SCC-13 was found to increase sensitivity to 5-FU-induced apoptosis&#46;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">31</span></a> The same study demonstrated overexpression of both Bag-1 and Hsp70 in a series of tumors&#44; leading the authors to hypothesize that resistance to 5-FU in SCC might be mediated through a cytoplasmic Hsp70-dependent mechanism&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">A final theory on 5-FU resistance is related to cancer stem cells in tumors of epithelial origin&#46; According to this theory&#44; malignant tumors&#44; just like normal epidermis&#44; would contain &#8220;stem cells&#8221; responsible for proliferation that would give rise to more differentiated tumor cells that would form the bulk of the tumor&#46; Like regular stem cells&#44; cancer stem cells have a slow cell cycle&#46; It is therefore considered that they might be responsible for resistance to classic chemotherapy drugs that typically target proliferating cells&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">32</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Key point</span></span><span class="elsevierStyleBold">&#58;</span> PDP alterations and polymorphisms and overexpression of Bag-1 and Hsp70 could influence sensitivity to 5-FU treatment&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Resistance to Imiquimod</span><p id="par0085" class="elsevierStylePara elsevierViewall">Imiquimod is a synthetic compound of the imidazoquinoline family that acts as an immunomodulator&#44; stimulating both innate and acquired immune responses&#46; The immune response is modified through the toll-like receptor 7 &#40;TLR7&#41; and TLR8 pathways&#59; these receptors are located on the surface of antigen-presenting cells&#44; such as dendritic cells&#44; macrophages&#44; Langerhans cells&#44; etc&#46; The activation of these pathways triggers the production and release of numerous cytokines and chemokines&#44; tumor necrosis factor &#40;TNF&#41; &#945;&#44; interferon &#40;IFN&#41; &#947;&#44; certain interleukins &#40;ILs&#41;&#44; and granulocyte-macrophage colony-stimulating factor&#44; and attracts natural killer &#40;NK&#41; cells&#44; thereby eliciting an innate and acquired immune response &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; Imiquimod is thus a potent antiviral and antitumor agent&#44; and is used widely in the field of dermatology&#44; particularly in the treatment of malignant cutaneous lesions&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">2&#44;26&#44;33&#8211;37</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall">Numerous studies have shown that imiquimod also inhibits the growth of new blood vessels thanks to its antiangiogenic properties&#46; It induces an increase in IL-10 and IL-12 levels&#44; which inhibit angiogenesis&#44; reduce cell production of proangiogenic factors &#40;such as fibroblast growth factor and IL-8&#41;&#44; inhibit vascular motility&#44; and induce endothelial apoptosis&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">26</span></a> There is also evidence that imiquimod induces keratinocyte apoptosis&#44; thereby favoring cytochrome C release and caspase 3 activation&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">38</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Imiquimod 5&#37; cream is approved by the US Food and Drug Administration &#40;FDA&#41; and the European Medicines Agency &#40;EMA&#41; for the treatment of external genital warts&#44; superficial BCC&#44; and AK&#46;<a class="elsevierStyleCrossRefs" href="#bib0515"><span class="elsevierStyleSup">33&#44;39</span></a> It is applied 3 to 5 times a week for 4 to 16 weeks depending on whether it is used to treat AK or BCC&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">40</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Imiquimod has also been used to treat other types of NMSC&#44; such as Bowen disease&#44; Bowenoid papulosis&#44; extramammary Paget disease&#44; melanoma in situ&#44; and keratoacanthoma&#44; among others&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">38</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Because surgery generally produces better results than topical treatments in skin lesions&#44; imiquimod is mainly used in patients who are not candidates for surgery&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">33</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">Gupta et al&#46;<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">41</span></a> undertook a meta-analysis of 4 studies involving 393 patients to evaluate the effectiveness of imiquimod 5&#37; for the treatment of AK&#44; and described an average efficacy rate of 70&#37; &#40;with a 95&#37; confidence interval of &#177;<span class="elsevierStyleHsp" style=""></span>12&#37;&#41;&#46; A later study of 479 patients investigated the efficacy of the 2&#46;5&#37; and 3&#46;75&#37; formulations applied once a day for two 2-week periods separated by 2 weeks with no treatment&#46; After 8 weeks of follow-up&#44; the respective complete and partial response rates were 30&#46;6&#37; and 48&#46;1&#37; for imiquimod 2&#46;5&#37; and 35&#46;6&#37; and 59&#46;4&#37; for imiquimod 3&#46;5&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">42</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Waalboer-Spuij et al&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">37</span></a> undertook a clinical trial in which 118 patients with AK were treated with imiquimod 5&#37; once daily for 3 days a week over a month&#46; After this period&#44; 58&#37; of patients required a second monthly cycle due to a lack of response&#46; After 16 weeks of follow-up&#44; the complete and partial response rates were 46&#37; and 35&#37;&#44; respectively&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Very little is known about the efficacy of imiquimod in SCC&#44; as it is not approved for this condition&#46; In one study&#44; curettage followed by application of imiquimod resulted in a 95&#37; response rate at 12 weeks&#46;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">43</span></a> In another study in which imiquimod only was applied for 9 to 12 weeks&#44; the response rates were 71&#37; for SCC and 57&#37; to 80&#37; for Bowen disease&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">40</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Numerous studies have analyzed the use of imiquimod 5&#37; in BCC using different application regimens&#44; ranging from twice-daily to twice-weekly application&#44; with follow-up times of 1 to 5 years&#46; The cure rates oscillated between 42&#37; and 100&#37; and the most effective regimen was the twice-daily application&#46; Most recurrences were seen in the first or second year after treatment&#46;<a class="elsevierStyleCrossRefs" href="#bib0570"><span class="elsevierStyleSup">44&#44;45</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Cure rates for imiquimod are lower in the case of nodular BCC&#44; with one study reporting a rate of 85&#46;6&#37; at 12 months for a regimen in which imiquimod was applied daily for 12 weeks&#46;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">46</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">TLR7</span> gene&#44; located on chromosome X&#44; has been investigated as a possible factor in resistance to imiquimod&#46; In a study of 34 patients with BCC &#40;28 responders and 6 nonresponders&#41;&#44; Piaserico et al&#46;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">47</span></a> reported that the presence of the T allele for the <span class="elsevierStyleItalic">TLR7</span> polymorphism rs179008&#47;Gln11Leu might be a resistance factor&#46; Hemizygous males carrying this polymorphism have been found to have lower levels of TNF-&#945; following imiquimod stimulation&#46;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">48</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Key point</span></span><span class="elsevierStyleBold">&#58;</span> Certain polymorphisms in the <span class="elsevierStyleItalic">TLR7</span> gene might cause resistance to imiquimod&#44; and reduced TNF-&#945; levels have been proposed as a possible mechanism&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resistance to Diclofenac</span><p id="par0145" class="elsevierStylePara elsevierViewall">Diclofenac is a nonsteroidal anti-inflammatory drug that reduces the production of prostaglandins through inhibition of cyclooxygenase 2 &#40;COX-2&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46; There is evidence that COX-2 has an important role in the development and progression of NMSC&#46; COX-2 permits the formation of prostaglandin E<span class="elsevierStyleInf">2</span> &#40;PGE<span class="elsevierStyleInf">2</span>&#41;&#44; which in turn enhances tumor proliferation&#44; angiogenesis&#44; and inflammation&#44; and inhibits apoptosis&#46; COX-2 inhibition is thought to achieve the opposite effect&#44; but its mechanism of action in skin cancer cells is unknown&#46; Diclofenac 3&#37; in hyaluronic acid 2&#46;5&#37; &#40;Solaraze&#41; is available as a topical gel approved by the FDA and EMA for the treatment of AK&#46; It is applied twice daily for 60 to 90 days&#46; Although there are studies supporting the use of topical diclofenac in AK&#44;<a class="elsevierStyleCrossRefs" href="#bib0595"><span class="elsevierStyleSup">49&#8211;52</span></a> and to a lesser extent Bowen disease&#44;<a class="elsevierStyleCrossRefs" href="#bib0615"><span class="elsevierStyleSup">53&#44;54</span></a> there are no data on its effectiveness in the treatment of BCC or invasive SCC&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">40</span></a></p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0150" class="elsevierStylePara elsevierViewall">Complete response rates for AK treated with diclofenac vary widely&#44; with figures ranging from 33&#37; to 81&#37; depending on the study&#44; and there is even one study in which diclofenac failed to produce clinically significant improvements in 130 patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0625"><span class="elsevierStyleSup">55&#8211;59</span></a> There are therefore patients who do not respond to diclofenac and&#47;or who develop recurrences&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">The mechanisms of action underlying diclofenac resistance in AK are not clear&#46; Considering the similarities between AK and SCC &#40;mutated <span class="elsevierStyleItalic">p53</span> and overexpression of COX-2&#41;&#44; Rodust et al&#46;<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">60</span></a> used 4 cutaneous SCC cell lines as a model to study resistance to diclofenac in AK&#46; Three of the lines were sensitive to the proapoptotic effects associated with diclofenac-induced caspase activation&#44; while the fourth was resistant&#46; Treatment of diclofenac-sensitive cells produced the characteristic proapoptotic effects at the level of the B-cell lymphoma proteins &#40;Bcl-2&#41; and resulted in the increased expression of Bad &#40;proapoptotic&#41; and the decreased expression of myeloid cell leukemia 1 &#40;Mcl-1&#41; and Bcl-w &#40;both antiapoptotic&#41;&#46; However&#44; in the resistant line&#44; the lack of COX-2 prior to treatment with diclofenac was already associated with low levels of Mcl-<span class="elsevierStyleSmallCaps">1</span> and Bcl-w and high levels of Bad&#44; possibly due to the lack of PEG<span class="elsevierStyleInf">2</span> in the cells&#46; In such a situation&#44; diclofenac would be unable to exert its proapoptotic effects&#46; However&#44; these resistant cells were also seen to contain underexpressed levels of Noxa and Puma&#44; 2 proapoptotic members of the Bcl-2 family&#44; overall&#44; possibly favoring a COX-2-independent antiapoptotic response to diclofenac&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Key point</span></span><span class="elsevierStyleBold">&#58;</span> The lack of response to diclofenac in SCC cells appears to be independent of pathways that modulate apoptosis through COX-2 in SCC cells&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Resistance to Ingenol Mebutate</span><p id="par0165" class="elsevierStylePara elsevierViewall">Ingenol mebutate is a natural extract of <span class="elsevierStyleItalic">Euphorbia peplus</span> that has been used for many years to treat different skin conditions&#44; such as viral warts and tumors&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">61</span></a> It has a dual mechanism of action&#46; On the one hand&#44; it rapidly induces apoptosis &#40;in a matter of hours&#41; by necrosis of dysplastic keratinocytes through mitochondrial damage and plasma membrane disruption&#44;<a class="elsevierStyleCrossRef" href="#bib0660"><span class="elsevierStyleSup">62</span></a> and on the other hand&#44; several days later&#44; it triggers an inflammatory response through protein kinase C &#948; &#40;PKC&#41;&#44; with the production of proinflammatory cytokines and tumor-specific antibodies that cause neutrophil-mediated antibody-dependent cellular cytoxicity &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0665"><span class="elsevierStyleSup">63</span></a></p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0170" class="elsevierStylePara elsevierViewall">Topical ingenol mebutate gel is approved for the treatment of AK in 2 concentrations&#58; 0&#46;015&#37; applied once daily for 3 days for lesions on the head and 0&#46;05&#37; applied once daily for just 2 days for lesions on the trunk&#46;<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">64</span></a> The gel has also been used to treat other cutaneous disorders such as BCC&#44;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">6</span></a> Bowen disease&#44;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">7</span></a> giant porokeratosis &#40;1 case&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0675"><span class="elsevierStyleSup">65</span></a> anogenital warts&#44;<a class="elsevierStyleCrossRef" href="#bib0680"><span class="elsevierStyleSup">66</span></a> and even recurrent melanoma in situ&#46;<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">67</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">In the case of AK&#44; ingenol mebutate has resulted in complete response rates of 42&#46;2&#37; for lesions on the face and neck and 34&#46;1&#37; for lesions on the trunk and extremities&#46;<a class="elsevierStyleCrossRef" href="#bib0690"><span class="elsevierStyleSup">68</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">Regarding factors that might influence resistance to the acute cytotoxic effects of ingenol mebutate&#44; it has been postulated that this substance might trigger the release of calcium from the endoplasmic reticulum rather than an influx of calcium from outside the cell&#46; Differentiated human keratinocytes have high calcium levels&#44; and are significantly less sensitive to ingenol mebutate&#8211;mediated cell death than undifferentiated&#44; proliferating keratinocytes with lower calcium content&#46;<a class="elsevierStyleCrossRefs" href="#bib0660"><span class="elsevierStyleSup">62&#44;69</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">Neutrophil recruitment might also have a role in resistance to ingenol mebutate&#46; Preclinical studies have investigated the inflammatory effect of ingenol mebutate in neutrophil-depleted Foxn1<span class="elsevierStyleSup">nu</span> mice &#40;nude mice with an autosomal recessive mutation in the <span class="elsevierStyleItalic">FOXN1</span> &#91;forkhead box N1&#93; gene associated with T-cell immunodeficiency&#44; alopecia&#44; and onychodystrophy&#41; and in CD18-deficient mice &#40;mice with deficient leukocyte cell adhesion molecule expression&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0700"><span class="elsevierStyleSup">70</span></a> Both groups of mice were injected with cells from the UV-induced murine SCC line LK2&#44; and a significant increase in tumor relapse rates &#40;&#62;<span class="elsevierStyleHsp" style=""></span>70&#37;&#41; was observed after several weeks in the absence of neutrophil-mediated killing of residual tumor cells&#46; The authors concluded that an individual&#39;s immune status could contribute to resistance to ingenol mebutate treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0700"><span class="elsevierStyleSup">70</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Key point</span></span>&#58; An immune state characterized by T cell&#8211;deficiency&#44; polymorphic neutrophil deficiency&#44; and other factors such as intracellular calcium levels could influence sensitivity to treatment with ingenol mebutate&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Conclusions</span><p id="par0195" class="elsevierStylePara elsevierViewall">In recent years&#44; we have witnessed an increase in the number of topical treatments available for NMSC&#44; largely due to the introduction of a new class of drugs known as topical immunomodulators&#46; The use of these immunomodulators has given rise to studies of resistance mechanisms showing that resistance could depend on the patient&#39;s immune status and on the biochemical and molecular features of the tumor cells&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conflicts of Interest</span><p id="par0200" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A wide range of treatments is now available for nonmelanoma skin cancer &#40;NMSC&#41;&#44; including 5-fluorouracil&#44; ingenol mebutate&#44; imiquimod&#44; diclofenac&#44; photodynamic therapy&#44; methotrexate&#44; cetuximab&#44; vismodegib&#44; and radiotherapy&#46; All are associated with high clinical and histologic response rates&#46; However&#44; some tumors do not respond due to resistance&#44; which may be primary or acquired&#46; Study of the resistance processes is a broad area of research that aims to increase our understanding of the nature of each tumor and the biologic features that make it resistant&#44; as well as to facilitate the design of new therapies directed against these tumors&#46; In this article we review resistance to the authorized topical treatments for NMSC&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0015" class="elsevierStyleSection elsevierViewall"><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">En la actualidad existe una amplia variedad de tratamientos para el c&#225;ncer cut&#225;neo no melanoma &#40;CCNM&#41;&#44; como son 5-fluorouracilo&#44; mebutato de ingenol&#44; imiquimod&#44; diclofenaco&#44; terapia fotodin&#225;mica &#40;TFD&#41;&#44; metotrexato&#44; cetuximab&#44; vismodegib&#44; radioterapia&#44; todos ellos con altas tasas de respuesta cl&#237;nica e histol&#243;gica&#46; Sin embargo&#44; algunos tumores no responden al tratamiento&#44; debido a la aparici&#243;n de resistencias&#44; tanto primarias como adquiridas&#46; El estudio de los procesos de resistencia es un campo extenso de investigaci&#243;n que conlleva ampliar los conocimientos de la naturaleza de cada tumor&#44; las caracter&#237;sticas biol&#243;gicas que lo hacen resistente y el dise&#241;o de nuevas terapias dirigidas contra los mismos&#46; En el presente art&#237;culo se revisan las resistencias a los tratamientos t&#243;picos autorizados para el CCNM&#46;</p></span>"
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Gracia-Caza&#241;a T&#44; Gonz&#225;lez S&#44; Gilaberte Y&#46; Resistencias al tratamiento no quir&#250;rgico en c&#225;ncer cut&#225;neo no melanoma&#46; Parte I&#58; tratamientos t&#243;picos&#46; Actas Dermosifiliogr&#46; 2016&#59;107&#58;730&#8211;739&#46;</p>"
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Mechanism of action of 5-fluorouracil &#40;5-FU&#41;&#44; which binds to and inhibits the enzyme thymidylate synthase &#40;TS&#41;&#44; thereby reducing DNA synthesis and cell proliferation and inducing cell death&#46;</p>"
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Mechanism of action of imiquimod&#46; This immunomodulator acts by blocking TLR7 and TLR8&#44; triggering the release of proinflammatory and antimicrobial cytokines and stimulating innate and acquired immunity&#44; with antitumor effects&#46; APCs indicates antigen-presenting cells&#59; G-CSF&#44; granulocyte colony-stimulating factor&#59; GM-CSF&#44; granulocyte-macrophage colony-stimulating factor&#59; IL&#44; interleukin&#59; INF&#44; interferon&#59; NK&#44; natural killer&#59; T<span class="elsevierStyleInf">H</span>1&#44; type 1 helper T cells&#59; TLR&#44; toll-like receptor&#59; TNF&#44; tumor necrosis factor&#46;</p>"
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Inhibition of COX-2 by diclofenac&#44; leading to decrease in PGE<span class="elsevierStyleInf">2</span> and its functions &#40;e&#46;g&#46;&#44; angiogenesis&#44; tumor proliferation&#44; and inflammation&#41;&#44; favoring apoptosis&#46; COX indicates cyclooxygenase&#59; PGE<span class="elsevierStyleInf">2</span>&#44; prostaglandin E<span class="elsevierStyleInf">2</span>&#46;</p>"
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          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Mechanisms possibly involved in resistance to IM treatment are intracellular Ca<span class="elsevierStyleSup">&#43;&#43;</span> levels&#44; at the level of receptor binding and immune status of the patient&#46; AK indicates actinic keratosis&#59; Ca<span class="elsevierStyleSup">&#43;&#43;</span>&#44; calcium&#59; IM&#44; ingenol mebutate&#44; PKC&#44; protein kinase C&#46;</p>"
        ]
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          "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; AK&#44; actinic keratosis&#59; BCC&#44; basal cell carcinoma&#59; sBCC&#44; superficial basal cell carcinoma&#59; SCC&#44; squamous cell carcinoma&#46;</p>"
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                  <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="" valign="top" scope="col" style="border-bottom: 2px solid black">&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">Imiquimod 5&#37;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">1&#44;2</span></a>&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">5-Fluorouracil<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">1&#44;3&#44;4</span></a>&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">Topical 3&#37; diclofenac gel and 2&#46;5&#37; hyaluronic acid<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">1&#44;5</span></a>&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">Ingenol Mebutate<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">1&#44;6&#44;7</span></a>&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">Photodynamic Therapy<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">1&#44;8</span></a>&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">Vismodegib<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">1&#44;9</span></a>&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">Cetuximab<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">10&#44;11</span></a>&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">Intralesional Chemotherapy<a class="elsevierStyleCrossRefs" href="#bib0410"><span class="elsevierStyleSup">12&#44;13</span></a>&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">Approved uses &#40;SPC&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Clinically typical nonhyperkeratotic&#44; nonhypertrophic AKs on the face or scalp in immunocompetent adult patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Slightly palpable and&#47;or moderately thick hyperkeratotic AK &#40;grade I&#47;II&#41; in immunocompetent adults &#40;at concentration of 5<span class="elsevierStyleHsp" style=""></span>mg of fluorouracil and 100<span class="elsevierStyleHsp" style=""></span>mg of salicylic acid&#41;<br>Multiple AKs &#40;at concentration of 5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AK&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nonhyperkeratotic and nonhypertrophic AKs in adults&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AK&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><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" 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">sBCC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">sBCC&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><td class="td" title="table-entry  " align="left" valign="top">sBCC<br>Nodular BCC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Symptomatic metastatic BCC<br>Locally advanced BCC inappropriate for surgery or radiotherapy&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" 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><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><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">Bowen disease&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><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">Other conditions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AKs in other locations and in immunodepressed patients<br>Nodular BCC<br>Bowen disease<br>Keratoacanthoma<br>Paget disease<br>Erythroplasia of Queyrat<br>SCC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bowen disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bowen disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">BCC<br>Bowen disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SCC<br>Keratoacanthoma<br>Erythroplasia of Queyrat<br>Paget disease<br>Gorlin syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Gorlin syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Locally advanced&#44; unresectable&#44; or metastatic SCC<br>Unresectable BCC in monotherapy or associated with smoothened inhibitors to reduce resistance&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Methotrexate&#58; keratoacanthoma&#44; SCC<br>Bleomycin&#58; AK&#44; sBCC&#44; and Bowen disease<br>Interferon alfa-2&#44; alfa-2a&#44; and alfa-2b&#58; BCC&#44; SCC&#44; and AK<br>Interferon &#946; and &#947;&#58; BCC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Indications for Different Treatments Available for Nonmelanoma Skin Cancer&#44; Including Approved and Off-Label Uses&#46;</p>"
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                  "referenciaCompleta" => "European Medicines Agency &#91;accessed 2 Oct 2015&#93;&#46; Available at&#58; <a id="intr0010" class="elsevierStyleInterRef" href="http://www.ema.europa.eu/">http&#58;&#47;&#47;www&#46;ema&#46;europa&#46;eu</a>"
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            1 => array:3 [
              "identificador" => "bib0360"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Imiquimod &#8212;its role in the treatment of cutaneous malignancies"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "A&#46;K&#46; Bubna"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.4103/0253-7613.161249"
                      "Revista" => array:6 [
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                        "fecha" => "2015"
                        "volumen" => "47"
                        "paginaInicial" => "354"
                        "paginaFinal" => "359"
                        "link" => array:1 [
                          0 => array:2 [
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                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0365"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "Fluoracil &#91;accessed 5 Oct 2015&#93;&#46; Available at&#58; <a id="intr0015" class="elsevierStyleInterRef" href="http://www.cancer.gov/about-cancer/treatment/drugs/fluorouracil">http&#58;&#47;&#47;www&#46;cancer&#46;gov&#47;about-cancer&#47;treatment&#47;drugs&#47;fluorouracil</a>"
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0370"
              "etiqueta" => "4"
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                0 => array:2 [
                  "contribucion" => array:1 [
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                      "titulo" => "Topical imiquimod or fluorouracil therapy for basal and squamous cell carcinoma&#58; A systematic review"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "W&#46;E&#46; Love"
                            1 => "J&#46;D&#46; Bernhard"
                            2 => "J&#46;S&#46; Bordeaux"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1001/archdermatol.2009.291"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arch Dermatol&#46;"
                        "fecha" => "2009"
                        "volumen" => "145"
                        "paginaInicial" => "1431"
                        "paginaFinal" => "1438"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20026854"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Successful treatment of sequential therapy in digital Bowen&#39;s disease with methyl aminolevulinate photodynamic therapy and topical diclofenac 3&#37; in hyaluronan 2&#46;5&#37; gel"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "T&#46; Gracia-Caza&#241;a"
                            1 => "M&#46;T&#46; L&#243;pez"
                            2 => "R&#46; Oncins"
                            3 => "Y&#46; Gilaberte"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/dth.12270"
                      "Revista" => array:6 [
                        "tituloSerie" => "Dermatol Ther&#46;"
                        "fecha" => "2015"
                        "volumen" => "28"
                        "paginaInicial" => "341"
                        "paginaFinal" => "343"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26291609"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Superficial basal cell carcinoma successfully treated with ingenol mebutate gel 0&#46;05&#37;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "C&#46; Cantisani"
                            1 => "G&#46; Paolino"
                            2 => "F&#46; Cantoresi"
                            3 => "V&#46; Faina"
                            4 => "A&#46;G&#46; Richetta"
                            5 => "S&#46; Calvieri"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/dth.12148"
                      "Revista" => array:6 [
                        "tituloSerie" => "Dermatol Ther&#46;"
                        "fecha" => "2014"
                        "volumen" => "27"
                        "paginaInicial" => "352"
                        "paginaFinal" => "354"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25052730"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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Review
Resistance of Nonmelanoma Skin Cancer to Nonsurgical Treatments. Part I: Topical Treatments
Resistencias al tratamiento no quirúrgico en cáncer cutáneo no melanoma. Parte I: tratamientos tópicos
T. Gracia-Cazañaa,b,
Autor para correspondencia
, S. Gonzálezc,d, Y. Gilaberteb,e
a Unidad de Dermatología, Hospital de Barbastro, Barbastro, Huesca, Spain
b Instituto Aragonés de Ciencias de la Salud, Zaragoza, Spain
c Servicio de Dermatología, Memorial Sloan-Kettering Cancer Center. Nueva York, EE. UU.
d Departmento de Medicina, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain
e Unidad de Dermatología, Hospital San Jorge, Huesca, Spain
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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">There are many options available for the treatment of different types of nonmelanoma skin cancer &#40;NMSC&#41;&#44; including actinic keratosis &#40;AK&#41;&#46; This is important as surgery has its limitations and is not always feasible&#44; such as when patients have multiple and&#47;or extensive lesions or lesions in cosmetically sensitive areas&#46; The introduction of chemotherapy drugs in recent years has increased the treatment options available and produced high complete response rates&#46; Nonsurgical procedures have several advantages&#46; In particular&#44; they are noninvasive&#44; offer excellent cosmetic results&#44; and can be combined with other treatments and repeated&#46; Examples of nonsurgical options used to treat NMSC are retinoids&#44; 5 fluorouracil &#40;5-FU&#41;&#44; diclofenac&#44; imiquimod&#44; and photodynamic therapy &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">1&#8211;13</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0010" class="elsevierStylePara elsevierViewall">The effectiveness of the above treatments&#44; however&#44; is limited by treatment resistance&#46; Tumor cell resistance is defined as an absence of sensitivity to anticancer drugs and it has multiple&#44; complex causes&#46; Resistance is the main reason why anticancer drugs fail and it has an important role in tumor progression and poor prognosis&#46; Although resistance to chemotherapy and radiotherapy has been extensively studied&#44; we are still far from understanding the mechanisms involved&#46; Generally speaking&#44; the first treatment a patient receives destroys the majority of tumor cells&#44; but if the tumor does not respond adequately to this treatment&#44; resistant cancer cells will remain and may even become more aggressive after several treatment cycles&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">14</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Resistance can be generally classified as intrinsic or acquired&#46; Intrinsic resistance is characterized by the presence of pre-existing factors that influence how the tumor cells will respond to treatment&#44; while acquired resistance develops after the treatment of a priori sensitive tumors&#46; Intrinsic resistance is a complex process related to diverse biochemical and molecular features of the tumor that allow certain cells to avoid death&#46; Acquired resistance&#44; by contrast&#44; can be caused by different factors&#44; including the limited amount of drug or radiation that reaches the tumor&#44; factors in the tumor environment&#44; and possible mutations that arise in tumor cells during treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">15</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Additional adaptive responses also need to be considered&#44; such as increased expression of the therapeutic target and activation of alternative compensatory signaling pathways&#46; Cross-resistance is another problem&#44; as once treated&#44; tumors can develop resistance to other drugs&#44; as occurs in multidrug resistance&#46; Finally&#44; certain tumors are highly heterogeneous and contain cells with different phenotypic&#44; genetic&#44; and&#47;or epigenetic characteristics&#44; meaning that sensitivity to treatment will vary according to the area of the tumor&#46;<a class="elsevierStyleCrossRefs" href="#bib0430"><span class="elsevierStyleSup">16&#8211;18</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">In this article we offer an overview of resistance to nonsurgical treatments in NMSC based on a review of case reports and series and research into the possible mechanisms involved&#46; Studies of resistance will contribute to a better understanding of tumor biology and will help to determine how best to combine treatments to improve response rates and reduce adverse effects&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">19</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">In the first of 2 articles&#44; we will review work on possible mechanisms of resistance to the following topical treatments for NMSC&#58; 5-FU&#44; imiquimod&#44; diclofenac&#44; and ingenol mebutate&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Resistance to 5-FU</span><p id="par0035" class="elsevierStylePara elsevierViewall">5-FU is a fluoropyrimidine that acts as an antimetabolite by binding to the enzyme thymidylate synthase&#44; which is responsible for the synthesis of nucleotides&#46; The resulting inhibition of thymidylate synthase leads to a reduction in DNA synthesis and cell proliferation&#44; inducing cell death&#46; These effects are particularly evident in cells with high mitotic rates&#44; such as neoplastic cells&#46; 5-FU is also incorporated into DNA or RNA&#44; interfering with their normal functioning &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0450"><span class="elsevierStyleSup">20&#8211;22</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">Topical 5-FU is approved for the treatment of AK at concentrations of 0&#46;5&#37;&#44; 1&#37;&#44; 2&#37;&#44; and 5&#37;&#46; The 5&#37; formulation&#44; applied twice daily for at least 6 weeks&#44; is indicated for superficial basal cell carcinoma &#40;BCC&#41; and is associated with an approximate cure rate of 93&#37;&#46; Topical 5-FU is not indicated for the treatment of Bowen disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0460"><span class="elsevierStyleSup">22&#8211;24</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">In the largest series to date supporting the efficacy of topical 5-FU in the treatment of superficial BCC&#44; a histologic cure rate of 90&#37; was reported after 3 weeks for 31 superficial lesions treated twice daily for 11 weeks&#46; Although the follow-up time was short&#44; a treatment resistance rate of 10&#37; was observed&#46;<a class="elsevierStyleCrossRefs" href="#bib0465"><span class="elsevierStyleSup">23&#44;25</span></a> Topical 5-FU is much less effective in nodular BCCs&#44; and its use in this setting has had limited success&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">26</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">In the case of AK&#44; 5&#37; 5-FU cream applied for 2 to 4 weeks produced a clinical cure rate of 96&#37; and a histological cure rate of 67&#37;&#44; although 54&#37; of tumors had relapsed at 12 months&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">27</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Although 5-FU is not approved for the treatment of squamous cell carcinoma &#40;SCC&#41;&#44; its efficacy in this setting has been analyzed in several studies&#46; In one of these&#44; 29 patients with SCC in situ were treated with 5-FU cream &#40;Efudix&#41; for 4 weeks&#46; The cream was applied once a day for the first week and twice a day for the remaining weeks&#46; Three months after the last treatment&#44; a complete response rate of 83&#37; was observed but at the 12-month follow-up&#44; this had fallen to 69&#37; and was accompanied by a recurrence rate of 17&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">28</span></a> In another study of 26 patients with Bowen disease treated with 5&#37; 5-FU cream twice a day for 9 weeks&#44; 92&#37; of patients achieved complete clearance over a mean follow-up period of 55 months&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">26</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">The above results clearly show that numerous NMSC lesions are resistant to treatment with 5-FU&#46; However&#44; in order to be able to predict&#8212;and resolve&#8212;resistance problems&#44; it is essential to understand the mechanisms by which 5-FU induces apoptosis and why certain tumors do not respond&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">20</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">One study described the case of a patient with severe dihydropyrimidine dehydrogenase &#40;DPD&#41; deficiency who developed severe gastrointestinal and hematological toxicity following treatment with a standard dose of 5-FU for BCC&#46; DPD is the first enzyme involved in the degradation of 5-FU&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">29</span></a> Approximately 10&#37; of topical 5-FU is absorbed through the skin while over 80&#37; is inactivated in the liver by DPD&#44; explaining why its deficiency causes toxicity&#46; In the case of colorectal cancer&#44; however&#44; patients with low DPD levels respond better to 5-FU&#44; suggesting that DPD alterations and polymorphisms could be one cause of resistance&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">29</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">Increased expression of the Bag-1 protein has been observed in progressive&#44; metastatic oral SCC&#46; This protein has an antiapoptotic function associated with the 70-kDa heat shock protein &#40;Hsp70&#41;&#44; indicating that overexpression of these 2 proteins would increase tumor cell resistance to apoptosis&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">30</span></a> In one study&#44; the elimination of Bag-1 from the cutaneous SCC cell line SCC-13 was found to increase sensitivity to 5-FU-induced apoptosis&#46;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">31</span></a> The same study demonstrated overexpression of both Bag-1 and Hsp70 in a series of tumors&#44; leading the authors to hypothesize that resistance to 5-FU in SCC might be mediated through a cytoplasmic Hsp70-dependent mechanism&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">A final theory on 5-FU resistance is related to cancer stem cells in tumors of epithelial origin&#46; According to this theory&#44; malignant tumors&#44; just like normal epidermis&#44; would contain &#8220;stem cells&#8221; responsible for proliferation that would give rise to more differentiated tumor cells that would form the bulk of the tumor&#46; Like regular stem cells&#44; cancer stem cells have a slow cell cycle&#46; It is therefore considered that they might be responsible for resistance to classic chemotherapy drugs that typically target proliferating cells&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">32</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Key point</span></span><span class="elsevierStyleBold">&#58;</span> PDP alterations and polymorphisms and overexpression of Bag-1 and Hsp70 could influence sensitivity to 5-FU treatment&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Resistance to Imiquimod</span><p id="par0085" class="elsevierStylePara elsevierViewall">Imiquimod is a synthetic compound of the imidazoquinoline family that acts as an immunomodulator&#44; stimulating both innate and acquired immune responses&#46; The immune response is modified through the toll-like receptor 7 &#40;TLR7&#41; and TLR8 pathways&#59; these receptors are located on the surface of antigen-presenting cells&#44; such as dendritic cells&#44; macrophages&#44; Langerhans cells&#44; etc&#46; The activation of these pathways triggers the production and release of numerous cytokines and chemokines&#44; tumor necrosis factor &#40;TNF&#41; &#945;&#44; interferon &#40;IFN&#41; &#947;&#44; certain interleukins &#40;ILs&#41;&#44; and granulocyte-macrophage colony-stimulating factor&#44; and attracts natural killer &#40;NK&#41; cells&#44; thereby eliciting an innate and acquired immune response &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; Imiquimod is thus a potent antiviral and antitumor agent&#44; and is used widely in the field of dermatology&#44; particularly in the treatment of malignant cutaneous lesions&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">2&#44;26&#44;33&#8211;37</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall">Numerous studies have shown that imiquimod also inhibits the growth of new blood vessels thanks to its antiangiogenic properties&#46; It induces an increase in IL-10 and IL-12 levels&#44; which inhibit angiogenesis&#44; reduce cell production of proangiogenic factors &#40;such as fibroblast growth factor and IL-8&#41;&#44; inhibit vascular motility&#44; and induce endothelial apoptosis&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">26</span></a> There is also evidence that imiquimod induces keratinocyte apoptosis&#44; thereby favoring cytochrome C release and caspase 3 activation&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">38</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Imiquimod 5&#37; cream is approved by the US Food and Drug Administration &#40;FDA&#41; and the European Medicines Agency &#40;EMA&#41; for the treatment of external genital warts&#44; superficial BCC&#44; and AK&#46;<a class="elsevierStyleCrossRefs" href="#bib0515"><span class="elsevierStyleSup">33&#44;39</span></a> It is applied 3 to 5 times a week for 4 to 16 weeks depending on whether it is used to treat AK or BCC&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">40</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Imiquimod has also been used to treat other types of NMSC&#44; such as Bowen disease&#44; Bowenoid papulosis&#44; extramammary Paget disease&#44; melanoma in situ&#44; and keratoacanthoma&#44; among others&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">38</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Because surgery generally produces better results than topical treatments in skin lesions&#44; imiquimod is mainly used in patients who are not candidates for surgery&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">33</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">Gupta et al&#46;<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">41</span></a> undertook a meta-analysis of 4 studies involving 393 patients to evaluate the effectiveness of imiquimod 5&#37; for the treatment of AK&#44; and described an average efficacy rate of 70&#37; &#40;with a 95&#37; confidence interval of &#177;<span class="elsevierStyleHsp" style=""></span>12&#37;&#41;&#46; A later study of 479 patients investigated the efficacy of the 2&#46;5&#37; and 3&#46;75&#37; formulations applied once a day for two 2-week periods separated by 2 weeks with no treatment&#46; After 8 weeks of follow-up&#44; the respective complete and partial response rates were 30&#46;6&#37; and 48&#46;1&#37; for imiquimod 2&#46;5&#37; and 35&#46;6&#37; and 59&#46;4&#37; for imiquimod 3&#46;5&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">42</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Waalboer-Spuij et al&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">37</span></a> undertook a clinical trial in which 118 patients with AK were treated with imiquimod 5&#37; once daily for 3 days a week over a month&#46; After this period&#44; 58&#37; of patients required a second monthly cycle due to a lack of response&#46; After 16 weeks of follow-up&#44; the complete and partial response rates were 46&#37; and 35&#37;&#44; respectively&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Very little is known about the efficacy of imiquimod in SCC&#44; as it is not approved for this condition&#46; In one study&#44; curettage followed by application of imiquimod resulted in a 95&#37; response rate at 12 weeks&#46;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">43</span></a> In another study in which imiquimod only was applied for 9 to 12 weeks&#44; the response rates were 71&#37; for SCC and 57&#37; to 80&#37; for Bowen disease&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">40</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Numerous studies have analyzed the use of imiquimod 5&#37; in BCC using different application regimens&#44; ranging from twice-daily to twice-weekly application&#44; with follow-up times of 1 to 5 years&#46; The cure rates oscillated between 42&#37; and 100&#37; and the most effective regimen was the twice-daily application&#46; Most recurrences were seen in the first or second year after treatment&#46;<a class="elsevierStyleCrossRefs" href="#bib0570"><span class="elsevierStyleSup">44&#44;45</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Cure rates for imiquimod are lower in the case of nodular BCC&#44; with one study reporting a rate of 85&#46;6&#37; at 12 months for a regimen in which imiquimod was applied daily for 12 weeks&#46;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">46</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">TLR7</span> gene&#44; located on chromosome X&#44; has been investigated as a possible factor in resistance to imiquimod&#46; In a study of 34 patients with BCC &#40;28 responders and 6 nonresponders&#41;&#44; Piaserico et al&#46;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">47</span></a> reported that the presence of the T allele for the <span class="elsevierStyleItalic">TLR7</span> polymorphism rs179008&#47;Gln11Leu might be a resistance factor&#46; Hemizygous males carrying this polymorphism have been found to have lower levels of TNF-&#945; following imiquimod stimulation&#46;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">48</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Key point</span></span><span class="elsevierStyleBold">&#58;</span> Certain polymorphisms in the <span class="elsevierStyleItalic">TLR7</span> gene might cause resistance to imiquimod&#44; and reduced TNF-&#945; levels have been proposed as a possible mechanism&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resistance to Diclofenac</span><p id="par0145" class="elsevierStylePara elsevierViewall">Diclofenac is a nonsteroidal anti-inflammatory drug that reduces the production of prostaglandins through inhibition of cyclooxygenase 2 &#40;COX-2&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46; There is evidence that COX-2 has an important role in the development and progression of NMSC&#46; COX-2 permits the formation of prostaglandin E<span class="elsevierStyleInf">2</span> &#40;PGE<span class="elsevierStyleInf">2</span>&#41;&#44; which in turn enhances tumor proliferation&#44; angiogenesis&#44; and inflammation&#44; and inhibits apoptosis&#46; COX-2 inhibition is thought to achieve the opposite effect&#44; but its mechanism of action in skin cancer cells is unknown&#46; Diclofenac 3&#37; in hyaluronic acid 2&#46;5&#37; &#40;Solaraze&#41; is available as a topical gel approved by the FDA and EMA for the treatment of AK&#46; It is applied twice daily for 60 to 90 days&#46; Although there are studies supporting the use of topical diclofenac in AK&#44;<a class="elsevierStyleCrossRefs" href="#bib0595"><span class="elsevierStyleSup">49&#8211;52</span></a> and to a lesser extent Bowen disease&#44;<a class="elsevierStyleCrossRefs" href="#bib0615"><span class="elsevierStyleSup">53&#44;54</span></a> there are no data on its effectiveness in the treatment of BCC or invasive SCC&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">40</span></a></p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0150" class="elsevierStylePara elsevierViewall">Complete response rates for AK treated with diclofenac vary widely&#44; with figures ranging from 33&#37; to 81&#37; depending on the study&#44; and there is even one study in which diclofenac failed to produce clinically significant improvements in 130 patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0625"><span class="elsevierStyleSup">55&#8211;59</span></a> There are therefore patients who do not respond to diclofenac and&#47;or who develop recurrences&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">The mechanisms of action underlying diclofenac resistance in AK are not clear&#46; Considering the similarities between AK and SCC &#40;mutated <span class="elsevierStyleItalic">p53</span> and overexpression of COX-2&#41;&#44; Rodust et al&#46;<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">60</span></a> used 4 cutaneous SCC cell lines as a model to study resistance to diclofenac in AK&#46; Three of the lines were sensitive to the proapoptotic effects associated with diclofenac-induced caspase activation&#44; while the fourth was resistant&#46; Treatment of diclofenac-sensitive cells produced the characteristic proapoptotic effects at the level of the B-cell lymphoma proteins &#40;Bcl-2&#41; and resulted in the increased expression of Bad &#40;proapoptotic&#41; and the decreased expression of myeloid cell leukemia 1 &#40;Mcl-1&#41; and Bcl-w &#40;both antiapoptotic&#41;&#46; However&#44; in the resistant line&#44; the lack of COX-2 prior to treatment with diclofenac was already associated with low levels of Mcl-<span class="elsevierStyleSmallCaps">1</span> and Bcl-w and high levels of Bad&#44; possibly due to the lack of PEG<span class="elsevierStyleInf">2</span> in the cells&#46; In such a situation&#44; diclofenac would be unable to exert its proapoptotic effects&#46; However&#44; these resistant cells were also seen to contain underexpressed levels of Noxa and Puma&#44; 2 proapoptotic members of the Bcl-2 family&#44; overall&#44; possibly favoring a COX-2-independent antiapoptotic response to diclofenac&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Key point</span></span><span class="elsevierStyleBold">&#58;</span> The lack of response to diclofenac in SCC cells appears to be independent of pathways that modulate apoptosis through COX-2 in SCC cells&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Resistance to Ingenol Mebutate</span><p id="par0165" class="elsevierStylePara elsevierViewall">Ingenol mebutate is a natural extract of <span class="elsevierStyleItalic">Euphorbia peplus</span> that has been used for many years to treat different skin conditions&#44; such as viral warts and tumors&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">61</span></a> It has a dual mechanism of action&#46; On the one hand&#44; it rapidly induces apoptosis &#40;in a matter of hours&#41; by necrosis of dysplastic keratinocytes through mitochondrial damage and plasma membrane disruption&#44;<a class="elsevierStyleCrossRef" href="#bib0660"><span class="elsevierStyleSup">62</span></a> and on the other hand&#44; several days later&#44; it triggers an inflammatory response through protein kinase C &#948; &#40;PKC&#41;&#44; with the production of proinflammatory cytokines and tumor-specific antibodies that cause neutrophil-mediated antibody-dependent cellular cytoxicity &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0665"><span class="elsevierStyleSup">63</span></a></p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0170" class="elsevierStylePara elsevierViewall">Topical ingenol mebutate gel is approved for the treatment of AK in 2 concentrations&#58; 0&#46;015&#37; applied once daily for 3 days for lesions on the head and 0&#46;05&#37; applied once daily for just 2 days for lesions on the trunk&#46;<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">64</span></a> The gel has also been used to treat other cutaneous disorders such as BCC&#44;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">6</span></a> Bowen disease&#44;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">7</span></a> giant porokeratosis &#40;1 case&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0675"><span class="elsevierStyleSup">65</span></a> anogenital warts&#44;<a class="elsevierStyleCrossRef" href="#bib0680"><span class="elsevierStyleSup">66</span></a> and even recurrent melanoma in situ&#46;<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">67</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">In the case of AK&#44; ingenol mebutate has resulted in complete response rates of 42&#46;2&#37; for lesions on the face and neck and 34&#46;1&#37; for lesions on the trunk and extremities&#46;<a class="elsevierStyleCrossRef" href="#bib0690"><span class="elsevierStyleSup">68</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">Regarding factors that might influence resistance to the acute cytotoxic effects of ingenol mebutate&#44; it has been postulated that this substance might trigger the release of calcium from the endoplasmic reticulum rather than an influx of calcium from outside the cell&#46; Differentiated human keratinocytes have high calcium levels&#44; and are significantly less sensitive to ingenol mebutate&#8211;mediated cell death than undifferentiated&#44; proliferating keratinocytes with lower calcium content&#46;<a class="elsevierStyleCrossRefs" href="#bib0660"><span class="elsevierStyleSup">62&#44;69</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">Neutrophil recruitment might also have a role in resistance to ingenol mebutate&#46; Preclinical studies have investigated the inflammatory effect of ingenol mebutate in neutrophil-depleted Foxn1<span class="elsevierStyleSup">nu</span> mice &#40;nude mice with an autosomal recessive mutation in the <span class="elsevierStyleItalic">FOXN1</span> &#91;forkhead box N1&#93; gene associated with T-cell immunodeficiency&#44; alopecia&#44; and onychodystrophy&#41; and in CD18-deficient mice &#40;mice with deficient leukocyte cell adhesion molecule expression&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0700"><span class="elsevierStyleSup">70</span></a> Both groups of mice were injected with cells from the UV-induced murine SCC line LK2&#44; and a significant increase in tumor relapse rates &#40;&#62;<span class="elsevierStyleHsp" style=""></span>70&#37;&#41; was observed after several weeks in the absence of neutrophil-mediated killing of residual tumor cells&#46; The authors concluded that an individual&#39;s immune status could contribute to resistance to ingenol mebutate treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0700"><span class="elsevierStyleSup">70</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Key point</span></span>&#58; An immune state characterized by T cell&#8211;deficiency&#44; polymorphic neutrophil deficiency&#44; and other factors such as intracellular calcium levels could influence sensitivity to treatment with ingenol mebutate&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Conclusions</span><p id="par0195" class="elsevierStylePara elsevierViewall">In recent years&#44; we have witnessed an increase in the number of topical treatments available for NMSC&#44; largely due to the introduction of a new class of drugs known as topical immunomodulators&#46; The use of these immunomodulators has given rise to studies of resistance mechanisms showing that resistance could depend on the patient&#39;s immune status and on the biochemical and molecular features of the tumor cells&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conflicts of Interest</span><p id="par0200" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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          "identificador" => "xres750958"
          "titulo" => "Graphical abstract"
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          "identificador" => "sec0005"
          "titulo" => "Introduction"
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        6 => array:2 [
          "identificador" => "sec0010"
          "titulo" => "Resistance to 5-FU"
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        7 => array:2 [
          "identificador" => "sec0015"
          "titulo" => "Resistance to Imiquimod"
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        8 => array:2 [
          "identificador" => "sec0020"
          "titulo" => "Resistance to Diclofenac"
        ]
        9 => array:2 [
          "identificador" => "sec0025"
          "titulo" => "Resistance to Ingenol Mebutate"
        ]
        10 => array:2 [
          "identificador" => "sec0030"
          "titulo" => "Conclusions"
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        11 => array:2 [
          "identificador" => "sec0035"
          "titulo" => "Conflicts of Interest"
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        12 => array:1 [
          "titulo" => "References"
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    "fechaRecibido" => "2016-01-11"
    "fechaAceptado" => "2016-04-30"
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          "clase" => "keyword"
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          "palabras" => array:5 [
            0 => "Skin cancer"
            1 => "Imiquimod"
            2 => "5-Fluorouracil"
            3 => "Diclofenac"
            4 => "Ingenol"
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      ]
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          "palabras" => array:5 [
            0 => "C&#225;ncer cut&#225;neo"
            1 => "Imiquimod"
            2 => "5-Fluorouracilo"
            3 => "Diclofenaco"
            4 => "Ingenol"
          ]
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    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A wide range of treatments is now available for nonmelanoma skin cancer &#40;NMSC&#41;&#44; including 5-fluorouracil&#44; ingenol mebutate&#44; imiquimod&#44; diclofenac&#44; photodynamic therapy&#44; methotrexate&#44; cetuximab&#44; vismodegib&#44; and radiotherapy&#46; All are associated with high clinical and histologic response rates&#46; However&#44; some tumors do not respond due to resistance&#44; which may be primary or acquired&#46; Study of the resistance processes is a broad area of research that aims to increase our understanding of the nature of each tumor and the biologic features that make it resistant&#44; as well as to facilitate the design of new therapies directed against these tumors&#46; In this article we review resistance to the authorized topical treatments for NMSC&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0015" class="elsevierStyleSection elsevierViewall"><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">En la actualidad existe una amplia variedad de tratamientos para el c&#225;ncer cut&#225;neo no melanoma &#40;CCNM&#41;&#44; como son 5-fluorouracilo&#44; mebutato de ingenol&#44; imiquimod&#44; diclofenaco&#44; terapia fotodin&#225;mica &#40;TFD&#41;&#44; metotrexato&#44; cetuximab&#44; vismodegib&#44; radioterapia&#44; todos ellos con altas tasas de respuesta cl&#237;nica e histol&#243;gica&#46; Sin embargo&#44; algunos tumores no responden al tratamiento&#44; debido a la aparici&#243;n de resistencias&#44; tanto primarias como adquiridas&#46; El estudio de los procesos de resistencia es un campo extenso de investigaci&#243;n que conlleva ampliar los conocimientos de la naturaleza de cada tumor&#44; las caracter&#237;sticas biol&#243;gicas que lo hacen resistente y el dise&#241;o de nuevas terapias dirigidas contra los mismos&#46; En el presente art&#237;culo se revisan las resistencias a los tratamientos t&#243;picos autorizados para el CCNM&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Gracia-Caza&#241;a T&#44; Gonz&#225;lez S&#44; Gilaberte Y&#46; Resistencias al tratamiento no quir&#250;rgico en c&#225;ncer cut&#225;neo no melanoma&#46; Parte I&#58; tratamientos t&#243;picos&#46; Actas Dermosifiliogr&#46; 2016&#59;107&#58;730&#8211;739&#46;</p>"
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Mechanism of action of 5-fluorouracil &#40;5-FU&#41;&#44; which binds to and inhibits the enzyme thymidylate synthase &#40;TS&#41;&#44; thereby reducing DNA synthesis and cell proliferation and inducing cell death&#46;</p>"
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Mechanism of action of imiquimod&#46; This immunomodulator acts by blocking TLR7 and TLR8&#44; triggering the release of proinflammatory and antimicrobial cytokines and stimulating innate and acquired immunity&#44; with antitumor effects&#46; APCs indicates antigen-presenting cells&#59; G-CSF&#44; granulocyte colony-stimulating factor&#59; GM-CSF&#44; granulocyte-macrophage colony-stimulating factor&#59; IL&#44; interleukin&#59; INF&#44; interferon&#59; NK&#44; natural killer&#59; T<span class="elsevierStyleInf">H</span>1&#44; type 1 helper T cells&#59; TLR&#44; toll-like receptor&#59; TNF&#44; tumor necrosis factor&#46;</p>"
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Inhibition of COX-2 by diclofenac&#44; leading to decrease in PGE<span class="elsevierStyleInf">2</span> and its functions &#40;e&#46;g&#46;&#44; angiogenesis&#44; tumor proliferation&#44; and inflammation&#41;&#44; favoring apoptosis&#46; COX indicates cyclooxygenase&#59; PGE<span class="elsevierStyleInf">2</span>&#44; prostaglandin E<span class="elsevierStyleInf">2</span>&#46;</p>"
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          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Mechanisms possibly involved in resistance to IM treatment are intracellular Ca<span class="elsevierStyleSup">&#43;&#43;</span> levels&#44; at the level of receptor binding and immune status of the patient&#46; AK indicates actinic keratosis&#59; Ca<span class="elsevierStyleSup">&#43;&#43;</span>&#44; calcium&#59; IM&#44; ingenol mebutate&#44; PKC&#44; protein kinase C&#46;</p>"
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          "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; AK&#44; actinic keratosis&#59; BCC&#44; basal cell carcinoma&#59; sBCC&#44; superficial basal cell carcinoma&#59; SCC&#44; squamous cell carcinoma&#46;</p>"
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                  <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="" valign="top" scope="col" style="border-bottom: 2px solid black">&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">Imiquimod 5&#37;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">1&#44;2</span></a>&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">5-Fluorouracil<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">1&#44;3&#44;4</span></a>&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">Topical 3&#37; diclofenac gel and 2&#46;5&#37; hyaluronic acid<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">1&#44;5</span></a>&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">Ingenol Mebutate<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">1&#44;6&#44;7</span></a>&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">Photodynamic Therapy<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">1&#44;8</span></a>&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">Vismodegib<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">1&#44;9</span></a>&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">Cetuximab<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">10&#44;11</span></a>&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">Intralesional Chemotherapy<a class="elsevierStyleCrossRefs" href="#bib0410"><span class="elsevierStyleSup">12&#44;13</span></a>&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">Approved uses &#40;SPC&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Clinically typical nonhyperkeratotic&#44; nonhypertrophic AKs on the face or scalp in immunocompetent adult patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Slightly palpable and&#47;or moderately thick hyperkeratotic AK &#40;grade I&#47;II&#41; in immunocompetent adults &#40;at concentration of 5<span class="elsevierStyleHsp" style=""></span>mg of fluorouracil and 100<span class="elsevierStyleHsp" style=""></span>mg of salicylic acid&#41;<br>Multiple AKs &#40;at concentration of 5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AK&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nonhyperkeratotic and nonhypertrophic AKs in adults&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AK&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><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" 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">sBCC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">sBCC&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><td class="td" title="table-entry  " align="left" valign="top">sBCC<br>Nodular BCC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Symptomatic metastatic BCC<br>Locally advanced BCC inappropriate for surgery or radiotherapy&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" 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><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><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">Bowen disease&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><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">Other conditions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AKs in other locations and in immunodepressed patients<br>Nodular BCC<br>Bowen disease<br>Keratoacanthoma<br>Paget disease<br>Erythroplasia of Queyrat<br>SCC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bowen disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Bowen disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">BCC<br>Bowen disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">SCC<br>Keratoacanthoma<br>Erythroplasia of Queyrat<br>Paget disease<br>Gorlin syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Gorlin syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Locally advanced&#44; unresectable&#44; or metastatic SCC<br>Unresectable BCC in monotherapy or associated with smoothened inhibitors to reduce resistance&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Methotrexate&#58; keratoacanthoma&#44; SCC<br>Bleomycin&#58; AK&#44; sBCC&#44; and Bowen disease<br>Interferon alfa-2&#44; alfa-2a&#44; and alfa-2b&#58; BCC&#44; SCC&#44; and AK<br>Interferon &#946; and &#947;&#58; BCC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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Información del artículo
ISSN: 15782190
Idioma original: Inglés
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