Case and Research Letter
Interferon Eyedrops in the Treatment of Basal Cell Carcinoma of the Eyelid
Colirio de interferón y carcinoma basocelular palpebral
V.M. Leis-Dosil
, I. Prats-Caelles, C. Rubio-Flores
Corresponding author
Sección de Dermatología, Hospital Universitario Infanta Sofía, San Sebastián de los Reyes, Madrid, Spain
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Leis-Dosil, I. Prats-Caelles, C. Rubio-Flores" "autores" => array:3 [ 0 => array:4 [ "nombre" => "V.M." "apellidos" => "Leis-Dosil" "email" => array:1 [ 0 => "vmanuel.leis@salud.madrid.org" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">¿</span>" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "I." "apellidos" => "Prats-Caelles" ] 2 => array:2 [ "nombre" => "C." "apellidos" => "Rubio-Flores" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Sección de Dermatología, Hospital Universitario Infanta Sofía, San Sebastián de los Reyes, Madrid, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Colirio de interferón y carcinoma basocelular palpebral" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 629 "Ancho" => 800 "Tamanyo" => 101036 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Basal cell carcinoma on the lower margin of the left eyelid: appearance before starting treatment.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Interferons (IFN) are a family of pleiotropic cytokines that exert antiviral and antitumor effects through several different mechanisms (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> These cytokines are of interest to dermatologists mainly because of their effectiveness in the treatment of basal cell carcinoma (BCC), squamous cell carcinoma, Kaposi sarcoma, and melanoma.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0010" class="elsevierStylePara elsevierViewall">Intralesional IFN was first demonstrated to effectively treat BCC in 1986,<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> and it produced complete responses in between 67% and 80% of patients in published series. IFN can be administered as monotherapy or as an adjuvant after surgery. Here, we describe the use of IFN administered topically in ophthalmic eyedrops in the management of a BCC on the free margin of the eyelid. This formulation is used in ophthalmology to treat squamous conjunctival papillomata,<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> squamous neoplasms of the ocular surface, Kaposi sarcomas, and conjunctival melanomas.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">We report the case of an 88 year-old woman with a histologically-confirmed, solid papular BCC of 5<span class="elsevierStyleHsp" style=""></span>mm in diameter on the margin of the lower left eyelid (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). The patient refused surgical treatment. Other treatment options, such as photodynamic therapy and imiquimod cream, were considered, but were ruled out due to the characteristics and location of the lesion. The patient also refused treatment with intralesional IFN due to a fear of injections. It was decided to treat the BCC with IFN alfa-2b in ophthalmic eyedrops at a concentration of 1 million IU/mL, administered 4 times per day.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6,7</span></a> This treatment was continued for 4 months, resulting in a decrease in the size of the lesion (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). No adverse effects were observed during treatment, and there was no change in the clinical appearance of the lesion on follow-up at 39 months. The patient still refuses to undergo either surgery or a control biopsy.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">The efficacy of IFN alfa-2b eyedrops in various tumors of the conjunctiva, eyelid, and ocular surface is described in the ophthalmic literature.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,5,7,8</span></a> The recommended dose is 1 drop of IFN alfa-2b at 1 million IU/mL 4 times per day for 3 to 4 months. Some authors recommend a maintenance regimen of 1 drop every 12<span class="elsevierStyleHsp" style=""></span>hours.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Several studies have compared ophthalmic with intralesional IFN alfa-2b administration<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> in the treatment of both non-invasive and invasive ocular surface squamous neoplasia, reporting better patient compliance and lower rates of local and systemic side effects in patients treated with eyedrops. The only local side effects reported are mild and resolve upon discontinuation of treatment. They include punctate keratitis, follicular conjunctivitis, and conjunctival hyperemia.<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5,8,9</span></a> Development of the flu syndrome characteristic of systemic or intralesional IFN therapy is rare.<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6,7</span></a> Comparison of IFN alfa-2b eyedrops with surgical treatment of non-invasive squamous neoplasia has revealed a comparable cure rate (total resolution in 96.4% of patients), with eyedrops producing better cosmetic results and less destruction of limbal stem cells.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">While we found no mention of this treatment in the dermatological literature, several ophthalmologic publications describe the effectiveness of topical IFN alfa-2b in cases of viral warts, intraepidermal carcinomas, and even melanomas on the eyelids and ocular surface, although these results are described in small series or isolated cases and should thus be interpreted with caution. We found no other cases in which IFN alfa-2b eyedrops have been used in the management of BCC of the eyelid. BCC is an accepted indication for IFN alfa-2b, and our findings point to a new potential route of administration. In our case the volume of the tumor decreased considerably, and the patient remains clinically stable after 3 years. However, we have no objective evidence of resolution, which requires close monitoring in a clinical setting. Our isolated experience should in no way change the standard accepted approaches used for the management of nonmelanoma skin cancer. Controlled clinical trials will be necessary to definitively determine the effectiveness of this treatment. However, given its ease of administration and its few, mild side effects, we propose the use of IFN alfa-2b eyedrops as a neoadjuvant therapy in selected cases to reduce tumor size before microscopically controlled surgical excision.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Leis-Dosil VM, Prats-Caelles I, Rubio-Flores C. Colirio de interferón y carcinoma basocelular palpebral. Actas Dermosifiliogr. 2014;105:207–208.</p>" ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 629 "Ancho" => 800 "Tamanyo" => 101036 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Basal cell carcinoma on the lower margin of the left eyelid: appearance before starting treatment.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 599 "Ancho" => 800 "Tamanyo" => 99233 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Decrease in lesion size after 4 months of treatment.</p>" ] ] 2 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Interferon subtype: a, alfa-2a; b, alfa-2b; c, alfa-n3.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">Indications</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Antiviral</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Hepatitis B<span class="elsevierStyleSup">a,b</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Hepatitis C<span class="elsevierStyleSup">a,b</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Human papilloma virus<span class="elsevierStyleSup">a,c</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Antitumor</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Hepatocarcinoma<span class="elsevierStyleSup">b</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Chronic myeloid leukemia,<span class="elsevierStyleSup">a,b</span> hairy cell leukemia,<span class="elsevierStyleSup">a,b</span> multiple myeloma<span class="elsevierStyleSup">b</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Kaposi sarcoma<span class="elsevierStyleSup">a,b</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Renal carcinoma<span class="elsevierStyleSup">a</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Basal cell carcinoma<span class="elsevierStyleSup">b</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Squamous cell carcinoma<span class="elsevierStyleSup">b</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Melanoma<span class="elsevierStyleSup">a,b</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">Mechanisms of action</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Suppression of cell proliferation</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Increased macrophage-mediated phagocytosis</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Inhibition of viral replication</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Inhibition of angiogenesis</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Increase in cellular immune response of T lymphocytes</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab465421.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Interferons: Indications and Mechanisms of Action.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:10 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => 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Chin" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Am J Ophtalmol" "fecha" => "2008" "volumen" => "145" "paginaInicial" => "124" "paginaFinal" => "129" ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0030" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Topical interferon alpha 2<span class="elsevierStyleHsp" style=""></span>b eye-drops for treatment of ocular surface squamous neoplasia: A dose comparison study" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "A. Galor" 1 => "C.L. Karp" 2 => "S. Chhabra" 3 => "S. Barnes" 4 => "E.C. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 14 | 13 | 27 |
| 2024 October | 104 | 57 | 161 |
| 2024 September | 97 | 32 | 129 |
| 2024 August | 115 | 69 | 184 |
| 2024 July | 102 | 41 | 143 |
| 2024 June | 117 | 46 | 163 |
| 2024 May | 110 | 64 | 174 |
| 2024 April | 85 | 27 | 112 |
| 2024 March | 90 | 28 | 118 |
| 2024 February | 83 | 29 | 112 |
| 2024 January | 78 | 33 | 111 |
| 2023 December | 106 | 22 | 128 |
| 2023 November | 97 | 32 | 129 |
| 2023 October | 98 | 20 | 118 |
| 2023 September | 112 | 35 | 147 |
| 2023 August | 64 | 13 | 77 |
| 2023 July | 85 | 35 | 120 |
| 2023 June | 92 | 26 | 118 |
| 2023 May | 110 | 30 | 140 |
| 2023 April | 74 | 27 | 101 |
| 2023 March | 73 | 30 | 103 |
| 2023 February | 76 | 31 | 107 |
| 2023 January | 72 | 39 | 111 |
| 2022 December | 84 | 55 | 139 |
| 2022 November | 54 | 28 | 82 |
| 2022 October | 48 | 23 | 71 |
| 2022 September | 53 | 41 | 94 |
| 2022 August | 28 | 30 | 58 |
| 2022 July | 36 | 31 | 67 |
| 2022 June | 53 | 44 | 97 |
| 2022 May | 133 | 34 | 167 |
| 2022 April | 191 | 51 | 242 |
| 2022 March | 140 | 49 | 189 |
| 2022 February | 149 | 31 | 180 |
| 2022 January | 193 | 37 | 230 |
| 2021 December | 145 | 49 | 194 |
| 2021 November | 153 | 69 | 222 |
| 2021 October | 112 | 52 | 164 |
| 2021 September | 85 | 44 | 129 |
| 2021 August | 67 | 30 | 97 |
| 2021 July | 73 | 25 | 98 |
| 2021 June | 137 | 40 | 177 |
| 2021 May | 86 | 44 | 130 |
| 2021 April | 240 | 71 | 311 |
| 2021 March | 142 | 38 | 180 |
| 2021 February | 78 | 29 | 107 |
| 2021 January | 49 | 35 | 84 |
| 2020 December | 44 | 14 | 58 |
| 2020 November | 35 | 23 | 58 |
| 2020 October | 36 | 21 | 57 |
| 2020 September | 39 | 19 | 58 |
| 2020 August | 31 | 22 | 53 |
| 2020 July | 40 | 16 | 56 |
| 2020 June | 38 | 37 | 75 |
| 2020 May | 34 | 21 | 55 |
| 2020 April | 34 | 19 | 53 |
| 2020 March | 33 | 30 | 63 |
| 2020 February | 5 | 11 | 16 |
| 2020 January | 4 | 6 | 10 |
| 2019 December | 6 | 6 | 12 |
| 2019 November | 4 | 0 | 4 |
| 2019 October | 0 | 8 | 8 |
| 2019 September | 10 | 28 | 38 |
| 2019 August | 4 | 7 | 11 |
| 2019 July | 4 | 13 | 17 |
| 2019 June | 4 | 14 | 18 |
| 2019 May | 6 | 12 | 18 |
| 2019 April | 2 | 23 | 25 |
| 2019 March | 0 | 12 | 12 |
| 2019 February | 5 | 15 | 20 |
| 2019 January | 1 | 3 | 4 |
| 2018 December | 4 | 5 | 9 |
| 2018 November | 2 | 7 | 9 |
| 2018 October | 1 | 0 | 1 |
| 2018 September | 4 | 3 | 7 |
| 2018 August | 0 | 5 | 5 |
| 2018 July | 0 | 2 | 2 |
| 2018 June | 0 | 3 | 3 |
| 2018 May | 0 | 5 | 5 |
| 2018 April | 0 | 3 | 3 |
| 2018 March | 5 | 2 | 7 |
| 2018 February | 83 | 3 | 86 |
| 2018 January | 102 | 6 | 108 |
| 2017 December | 98 | 10 | 108 |
| 2017 November | 66 | 9 | 75 |
| 2017 October | 69 | 3 | 72 |
| 2017 September | 71 | 11 | 82 |
| 2017 August | 87 | 18 | 105 |
| 2017 July | 69 | 16 | 85 |
| 2017 June | 94 | 16 | 110 |
| 2017 May | 79 | 15 | 94 |
| 2017 April | 68 | 17 | 85 |
| 2017 March | 84 | 21 | 105 |
| 2017 February | 60 | 7 | 67 |
| 2017 January | 55 | 15 | 70 |
| 2016 December | 86 | 13 | 99 |
| 2016 November | 138 | 10 | 148 |
| 2016 October | 117 | 11 | 128 |
| 2016 September | 229 | 16 | 245 |
| 2016 August | 197 | 9 | 206 |
| 2016 July | 90 | 4 | 94 |
| 2016 June | 18 | 5 | 23 |
| 2016 May | 15 | 5 | 20 |
| 2016 April | 3 | 18 | 21 |
| 2016 March | 3 | 3 | 6 |
| 2016 February | 8 | 2 | 10 |
| 2016 January | 13 | 12 | 25 |
| 2015 December | 10 | 8 | 18 |
| 2015 November | 15 | 10 | 25 |
| 2015 October | 13 | 4 | 17 |
| 2015 September | 9 | 2 | 11 |
| 2015 August | 9 | 1 | 10 |
| 2015 July | 165 | 11 | 176 |
| 2015 June | 94 | 7 | 101 |
| 2015 May | 82 | 13 | 95 |
| 2015 April | 93 | 9 | 102 |
| 2015 March | 70 | 3 | 73 |
| 2015 February | 68 | 6 | 74 |
| 2015 January | 49 | 7 | 56 |
| 2014 December | 59 | 7 | 66 |
| 2014 November | 51 | 5 | 56 |
| 2014 October | 67 | 10 | 77 |
| 2014 September | 49 | 3 | 52 |
| 2014 August | 60 | 4 | 64 |
| 2014 July | 38 | 5 | 43 |
| 2014 June | 52 | 9 | 61 |
| 2014 May | 45 | 11 | 56 |
| 2014 April | 25 | 6 | 31 |
| 2014 March | 16 | 2 | 18 |
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