Types Of Nonmelanoma Skin Cancer Research Articles

The prevalence of nonmelanoma skin cancer in a population of patients with oculocutaneous albinism in Haiti.

Multiple studies have examined the prevalence of nonmelanoma skin cancers (NMSC) in patients with oculocutaneous albinism (OCA). However, to date, no studies have examined this data in Caribbean populations. This study is a cross-sectional study of 106 patients with OCA who were seen at the Oculocutaneous Albinism Clinic in Port-au-Prince and Gros Morne, Haiti, between the dates of February 2017 and June 2018. In our population, 31/106 (29%) patients were found to have NMSC, 10/31 (32%) had BCC, 12/31 (39%) had SCC, and 9/31 (29%) had both types of NMSC. The most common age groups were 31-40 years, with the overall range of ages being 18-63 years. Also, 60/106 (57%) of the patients had actinic keratoses (AK). Our study provides new data examining the prevalence of NMSC within a population of patients with OCA in Haiti. Overall, it shows that patients with albinism develop NMSC at an earlier age compared with the rest of the population. Therefore, appropriate skin cancer screening and surveillance should be implemented within this high-risk population group.

Budget Impact of Keytruda for the Treatment of Patients with Recurrent or Metastatic (R/M) and Locally Advanced (LA) Cutaneous Squamous Cell Carcinoma (cSCC) in the United States

<h3>Purpose/Objective(s)</h3> cSCC is a type of non-melanoma skin cancer and represents 20% of skin cancer deaths. When not cured by local therapy, cSCC is associated with mortality rates exceeding 70%. KEYTRUDA, an immuno-oncology therapy, was recently approved by the FDA for the treatment of patients with R/M and LA cSCC that is not curable by surgery or radiation. The objective of this study was to estimate the budget impact of adding KEYTRUDA to a US healthcare plan formulary as a therapy in advanced cSCC. <h3>Materials/Methods</h3> A budget impact model (3-year time horizon) was developed to compare the direct costs of treating R/M and LA cSCC patients with and without the introduction of KEYTRUDA. Comparators included commonly used systemic therapies (cemiplimab-rwlc, cetuximab, cisplatin + paclitaxel and cisplatin + 5-fluorouracilMT). Market shares were estimated from market research data for comparators, and assumed for KEYTRUDA as follows: 30%, 36%, 42% in R/M; and 13%, 15%, 18% in LA for years 1-3 respectively. Costs included drug Wholesale Acquisition Cost, administration, monitoring and Grade 3-5 adverse event management costs. A one-way sensitivity analysis and two scenario analyses (including Q6W schedule for KEYTRUDA, and equal KEYTRUDA and cemiplimab-rwlc treatment durations) were conducted. <h3>Results</h3> In a hypothetical 1 million member health plan, the number of R/M and LA cSCC patients were 60/60/61 and 52/52/53, respectively in years 1-3. Of these, 18/22/25 (R/M) and 7/8/9 (LA) patients receive KEYTRUDA in years 1-3. In R/M cSCC, KEYTRUDA was associated with cost savings of $1.967m over 3 years. In LA cSCC, KEYTRUDA resulted in a 3-year budget impact of $0.425m. In total, the adoption of KEYTRUDA in cSCC population was projected to lead to cost savings of $1.541m over 3 years (7% decrease). The cost saving was driven by the shorter treatment duration of KEYTRUDA versus cemiplimab-rwlc resulting in decreased drug acquisition, administration, and monitoring costs, and a less costly safety profile of KEYTRUDA versus chemotherapies. Sensitivity and scenario analyses indicate sensitivity to time on treatment assumptions. <h3>Conclusion</h3> The introduction of KEYTRUDA for R/M and LA cSCC patients in a hypothetical plan of 1 million members is projected to lead to budgetary savings of 7% over three years. Results are most sensitive to assumed time on treatment.

Patidegib in Dermatology: A Current Review.

Background: Basal cell carcinoma is one of the most common types of non-melanoma skin cancers, which can be locally destructive despite low-rate metastasis. Surgery is the treatment of choice, but it lacks of efficacy on advanced cases. Hedgehog pathway inhibitors are a class of drugs providing a new therapeutic option for patients affected by advanced disease. Besides systemic therapy, such as vismodegib and sonidegib, also topical inhibitors have been developed. Patidegib is able to decrease tumor burden, reducing the adverse effects induced by systemic targeted therapies. Methods: We performed comprehensive research to summarize the use of patidegib in advanced and recurrent aggressive basal cell carcinomas. Only English language human studies were included in the search. Results: Seven trials reported the application of patidegib. Both topical and systemic patidegib demonstrated safety, tolerability, and efficacy in naïve patients with stage II and III basal cell carcinomas, while stage IV disease and not-naïve patients did not show any benefit. Conclusion: Unlike systemic Hedgehog pathway inhibitors, patidegib 2% gel is not associated with systemic adverse effects and allows a better patient management. Considering the multidisciplinary management of neoplasia, in the era of precision medicine, it is mandatory to confide in pharmacogenomics to obtain personalized combined or sequential therapies.

Methotrexate in the Treatment of Non-Melanoma Skin Cancers

Background: There are three types of non-melanoma skin cancer (NMSC): basal (BCC), keratoacanathoma (KA), and cutaneous squamous cell carcinoma (cSCC). These three malignancies account for 99 percent of all tumors in this category. Because it slows DNA synthesis in quickly proliferating cells, methotrexate (MTX) is an effective treatment for tumors that are fast developing. To prevent the production of the purine nucleotide thymidine, it inhibits the development of tetrahydrofolate by binding to the dihydrofolate reductase. Objective: To assess the efficacy and safety of MTX in the treatment of NMSCs. Conclusion: When used as a less intrusive and less expensive treatment for NMSCs, MTX has the potential to be a very effective and safe alternative treatment, especially in patients who are elderly or have other medical conditions.

Health-Related Quality of Life of Patients with Recurrent or Metastatic Cutaneous Squamous Cell Carcinoma Treated with Pembrolizumab in KEYNOTE-629.

IntroductionPembrolizumab provided durable responses and acceptable safety in recurrent or metastatic (R/M) cutaneous squamous cell carcinoma (cSCC) in the KEYNOTE-629 study. In this elderly, fragile population with disfiguring tumours, preservation of health-related quality of life (HRQoL) is critical. Here, we present pre-specified exploratory HRQoL analyses from the first interim analysis of KEYNOTE-629.MethodsPatients with R/M cSCC not amenable to surgery or radiation therapy received pembrolizumab 200 mg every 3 weeks for ≤ 24 months. HRQoL end points included change from baseline to week 12 in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) global health status (GHS)/QoL, functioning, symptom and European Quality of Life 5-Dimension 5-Level (EQ-5D-5L) scores and change from baseline through week 48 in EORTC QLQ-C30 GHS/QoL and physical functioning scores. Improvement (≥ 10-point increase post-baseline with confirmation) was assessed using the exact binomial method.ResultsAnalyses included 99 patients for EORTC QLQ-C30 and 100 for EQ-5D-5L. Compliance was > 80% at week 12. Mean scores were stable from baseline to week 12 for GHS/QoL (4.95 points; 95% confidence interval, −1.00 to 10.90) and physical functioning (−3.38 points; 95% confidence interval, −8.80 to 2.04). EORTC-QLQ-C30 functioning, symptom, and EQ-5D-5L scores remained stable at week 12. Post-baseline scores were improved in 29.3% of patients for GHS/QoL, 17.2% for physical functioning, and in a numerically higher proportion of responders versus non-responders (GHS/QoL, 55.6% versus 16.1%; physical functioning, 36.1% versus 7.1%).ConclusionsIn elderly patients with R/M cSCC, the clinical efficacy of pembrolizumab translates into a benefit validated by HRQoL preservation or improvement during treatment.Trial RegistrationClinicalTrials.gov identifier: NCT03284424.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13555-021-00598-6.

Autoantibodies against p53, MMP-7, and Hsp70 as Potential Biomarkers for Detection of Nonmelanoma Skin Cancers.

Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are two predominant histological types of nonmelanoma skin cancer (NMSC), lacking effective early diagnostic markers. In this study, we assessed the diagnostic value of autoantibodies against p53, MMP-7, and Hsp70 in skin SCC and BCC. ELISA was performed to detect levels of autoantibodies in sera from 101 NMSC patients and 102 normal controls, who were recruited from the Cancer Hospital of Shantou University Medical College. A receiver operator characteristic curve was used to evaluate the diagnostic value. The serum levels of autoantibodies against p53, MMP-7, and Hsp70 were higher in NMSCs than those in the normal controls (all P < 0.01). The AUC of the three-autoantibody panel was 0.841 (95% CI: 0.788-0.894) with the sensitivity and specificity of 60.40% and 91.20% when differentiating NMSCs from normal controls. Furthermore, measurement of this panel could differentiate early-stage skin cancer patients from normal controls (AUC: 0.851; 95% CI: 0.793-0.908). Data from Oncomine showed that the level of p53 mRNA was elevated in BCC (P < 0.05), and the Hsp70 mRNA was upregulated in SCC (P < 0.001). This serum three-autoantibody panel might function in assisting the early diagnosis of NMSC.

Role of signal transducer and activator of transcription 3 in cutaneous squamous cell carcinoma

Objective To assess the role of signal transducer and activator of transcription 3 (STAT3) in cutaneous squamous cell carcinoma (cSCC). Background cSCC is considered the second most frequent type of nonmelanoma skin cancer. The Janus kinase-STAT pathway plays a significant role in the proliferation and survival of various cancer cells. Between seven mammalian STAT proteins, continuous activation of STAT3 is commonly observed in several cancer cells. Patients and methods This prospective and retrospective case–control study was conducted on 48 cases with cSCC and 47 age-matched and sex-matched apparently healthy participants. All sections were immunohistochemically stained for the STAT3 antibody. Results All controls showed significant STAT3 nucleo-cytoplasmic localization in the epidermis and the dermis, whereas in cSCC, most cases of nonmelanoma skin cancer showed cytoplasmic STAT3 expression in the epithelium and the surrounding stroma (P < 0.001 for both). STAT3 overexpression was noted in cSCC in comparison with the control group (P = 0.007). A significant relationship between the STAT3 epithelial Histo-score and high grade (P = 0.001) and advanced stage (P < 0.001) of cSCC was noted. Conclusions Cytoplasmic localization of STAT3 could play a tumor-promoting role in the pathogenesis of cSCC. Moreover, STAT3 overexpression might be incriminated in the progression of cSCC. This could be very attractive in the development of new anticancer therapy using STAT3 inhibitors.

Swiss Recommendations for Systemic Therapies in Locally Advanced and Metastatic Cutaneous Squamous Cell Carcinoma

Cutaneous squamous cell carcinoma (cSCC) is the second most frequent type of non-melanoma skin cancer. Its incidence has been rising in recent years, with the highest rate reported in Switzerland compared to other countries in Europe. While the majority of cSCC cases are low-grade tumors with an excellent prognosis following surgical excision, a minority of cSCC lesions (approximately 5% of patients) progress to locally advanced cSCC (lacSCC) or distant metastatic disease (mcSCC), both of which have an unfavorable prognosis. Recent evidence from studies with checkpoint immunotherapy has changed the systemic treatment landscape for lacSCC and mcSCC patients. While both programmed death-1 (PD-1) receptor inhibitors cemiplimab and pembrolizumab are approved by the FDA, cemiplimab is the only approved systemic therapy for the treatment of nonresectable advanced cSCC in the EU and was recently also approved in Switzerland. Based on the latest evidence from randomized clinical trials, national consensus recommendations for the systemic treatment of advanced cSCC have been defined. For classification and optimal management of patients with lacSCC or mcSCC, an interdisciplinary tumor board discussion should be mandatory. Difficult-to-treat advanced cSCC patients should be referred to and treated by specialized centers. These Swiss recommendations provide guidance for the management of patients aged ≥18 years with lacSCC or mcSCC, specifically systemic therapy with a PD-1 inhibitor in the first-line setting. These up-to-date recommendations will also help Swiss physicians in their decision-making and address treatment variability in Swiss clinical practice. Keywords: cSCC, locally advanced, metastatic, systemic treatment, immunotherapy, cemiplimab

Large Basal Cell Carcinoma Defect Closure on The Lateral Cheek Using Multiple Advancement Flaps

Basal cell carcinoma (BCC) is the most common type of nonmelanoma skin cancer (NMSC). It grows slowly and very rarely metastasizes but can cause substantial morbidity due to its tendency to relapse and locally invasive nature, especially when located on the face. Excision surgery is still the gold standard treatment for primary BCC and is usually followed by reconstruction procedure. Skin flap techniques vary widely, one of which is flap advancement technique. The main benefit of flap advancement technique is the ability to hide the excision line, thus resulting in an aesthetically sound outcome. We report a case of 72-year-old female with hyperpigmented plaque brownish lump on the left lateral cheek. A diagnosis of igmented basal cell carcinoma had been confirmed through histopathological examination. The patient was treated with wide excision surgery and the defect was closed by multiple advancement flaps. Follow-up after three months showed excellent cosmetic and functional outcome.

Role of cytoplasmic localization of discoidin domain receptor 1 in basal-cell carcinoma

Objective The objective of this study was to investigate the role of discoidin domain receptors (DDR1) in the pathogenesis of basal-cell carcinoma (BCC) through its immunohistochemical expression and to correlate its expression with clinicopathological parameters. Background BCC is the most common type of nonmelanoma skin cancer. The pathogenesis is usually combined with environmental factors, mainly ultraviolet irradiation through long-term sun exposure. Patients and methods This retrospective case–control study was carried out on 77 patients presented with BCC and 20 age-matched and gender-matched apparently healthy volunteers. Skin biopsies from controls and BCC cases were retrieved from the archives of Pathology Department, Faculty of Medicine, Menoufia University for histopathological and immunohistochemical DDR1 evaluation. Results Cytoplasmic localization of DDR1 could be incriminated in the development and progression of BCC. DDR1 offers potential targeted therapy in cancer, as none of the control groups showed cytoplasmic epithelial localization DDR1, whereas (90.9%) cytoplasmic epithelial localizations were demonstrated in BCC (P 0.001 and 0.005, respectively). Conclusion Cytoplasmic localization of DDR1 has a role in the pathogenesis of BCC which can be a new therapeutic target in BCC.

Optical coherence tomography for fast bedside imaging, assessment and monitoring of autoimmune inflammatory skin diseases?

Optical coherence tomography (OCT) is a non-invasive, high-resolution imaging technique with a growing impact in dermatology. The principle of OCT is comparable to that of sonography, except that it uses infrared laser light instead of ultrasound waves. It has been clinically demonstrated that OCT is suitable for discriminating between different types of non-melanoma skin cancer at an early stage of disease. Optical coherence tomography generates two- or three-dimensional images of up to 2mm penetration depth, a field of view of 6mm × 6mm, and an acquisition time of seconds. The resolution capability of OCT is more than 3 to 100 times higher than that of ultrasound imaging. It is of particular interest that the additional information on vasculature provided by OCT angiography enables the assessment and monitoring of inflammatory skin diseases. The use of OCT to locate exact blister levels was demonstrated for diagnosing autoimmune bullous diseases. It is anticipated that detection of subclinical lesions could indicate a relapse of the disease. In the future, this could enable intervention and early treatment. Furthermore, the development of high-speed OCT could allow fast scanning and bedside imaging of large body sites.

The use of cisplatin electrochemotherapy in nonmelanoma skin cancers: A single-center study.

Electrochemotherapy (ECT) is a well-known nonconventional skin cancer ablative method that was shown to be safe and effective for treating both locoregional disease spreading and disseminated cutaneous and subcutaneous lesions from different types of cancer. The most common medications used are bleomycin and cisplatin. In the last years many studies were performed on ECT, lead it to be a valid therapeutic option in many international guidelines. Nevertheless, there are still no clear indications regarding timing of its use. The main aim of this study was first to assess the safety and effectiveness of intralesional cisplatin ECT for treating different types of nonmelanoma skin cancer in a group of eligible patients. The second endpoint was to assess patients' tolerability and symptoms improvement through the treatment. A single-center prospective study was performed. Patients with squamous cell carcinoma, basal cell carcinoma, or skin metastases were selected during 1 month. The ideal setting was the presence of two or three lesions with a maximum diameter of 2 cm. Both primary, recurrent, and metastatic lesions were included. Before and 8 weeks after treatment, all patients were evaluated to assess the number, measurement, and anatomical site of skin lesions using photography and metric notation. The medical device for membrane electroporation was the CLINIPORATOR EPS02 model. The cisplatin concentration was at least 1 mg/mL. The dose for each single lesion was calculated based on its volume, as is the standard procedure for ECT. Local or systemic adverse events and changes in symptoms were evaluated with a questionnaire based on a visual analog scale that was administrated before and after ECT. Eight patients with a total of 18 lesions underwent the procedure (six men and two women). Four out of eight (50%) patients had a complete response to the treatment. However, all eight patients had an overall tumor response (100%), experiencing an improvement in symptoms including less pain and bleeding from the tumor. Our study clearly show that ECT with intralesional cisplatin is a valuable and safety procedure for nonmelanoma skin cancer and cutaneous tumor metastasis. ECT with cisplatin was able to achieve a good local disease control leading to complete response in an half of cases. The results were stable after 1 year of follow-up. The outer ear area displayed a really good response, due to both ear's anatomical configuration and intralesional cisplatin pharmacological characteristics.

Epigallocatechin Gallate Enhances MAL-PDT Cytotoxic Effect on PDT-Resistant Skin Cancer Squamous Cells.

Photodynamic therapy (PDT) has been used to treat certain types of non-melanoma skin cancer with promising results. However, some skin lesions have not fully responded to this treatment, suggesting a potential PDT-resistant phenotype. Therefore, novel therapeutic alternatives must be identified that improve PDT in resistant skin cancer. In this study, we analyzed the cell viability, intracellular protoporphyrin IX (PpIX) content and subcellular localization, proliferation profile, cell death, reactive oxygen species (ROS) detection and relative gene expression in PDT-resistant HSC-1 cells. PDT-resistant HSC-1 cells show a low quantity of protoporphyrin IX and low levels of ROS, and thus a low rate of death cell. Furthermore, the resistant phenotype showed a downregulation of HSPB1, SLC15A2, FECH, SOD2 and an upregulation of HMBS and BIRC5 genes. On the other hand, epigallocatechin gallate catechin enhanced the MAL-PDT effect, increasing levels of protoporphyrin IX and ROS, and killing 100% of resistant cells. The resistant MAL-PDT model of skin cancer squamous cells (HSC-1) is a reliable and useful tool to understand PDT cytotoxicity and cellular response. These resistant cells were successfully sensitized with epigallocatechin gallate catechin. The in vitro epigallocatechin gallate catechin effect as an enhancer of MAL-PDT in resistant cells is promising in the treatment of difficult skin cancer lesions.

Cytoplasmic Increase in Hsp70 Protein: A Potential New Biomarker of Early Infiltration of Cutaneous Squamous Cell Carcinoma Arising from Actinic Keratosis.

Background: Cutaneous squamous skin cell carcinoma (SCC) is the second most frequent type of non-melanoma skin cancer and is the second leading cause of death by skin cancer in Caucasian populations. However, at present it is difficult to predict patients with poor SCC prognosis. Objective: To identify proteins with expression levels that could predict SCC infiltration in SCC arising from actinic keratosis (SCC-AK). Methods: A total of 20 biopsies from 20 different patients were studied; 10 were SCC-AK samples and 10 were taken from normal skin. Early infiltrated SCC-AK samples were selected based on histological examination, and to determine the expression of proteins, fresh skin samples were processed by two-dimensional electrophoresis. Results: The expression levels of three proteins, namely alpha hemoglobin and heat shock proteins 27 and 70 (Hsp27 and Hsp70, respectively) were significantly increased in SCC-AK samples with respect to normal control skin. However, only the expression level of Hsp70 protein positively correlated with the level of SCC-AK dermis infiltration. Immunohistological examination suggested that increased expression of Hsp70 proteins seemed to mainly occur in the cytoplasm of keratinocytes. The increased cytoplasmic Hsp70 expression in SCC-AK was confirmed by Western blot experiments. Conclusion: Cytoplasmic expression of Hsp70 could be a potential biomarker of early infiltration of SCC arising from AK.

Glyciphon ointment for local treatment of basal cell cancer: clinical and pharmacological aspects

Introduction.Basal cell cancer (BCC) accounts for up to 80 % of all types of non-melanoma skin cancers. In 97 % of cases, BCC develops on bare facial skin, especially at the nose-forehead border, nose wings, corners of eyes and lips. Surgery can lead to gross cosmetic defects, therefore more and more specialists prefer conservative methods, among which local drug therapy holds a special place.The study objectiveis to evaluate the effectiveness and safety of glyciphon ointment for BCC local treatment as well as the economic costs.Materials and methods.The study included 114 patients who underwent BCC local drug therapy with 30 % Glyciphon ointment, where 111 (97.4 %) patients had primary BCC, and 3 (2.6 %) ones – recurrent BCC.Results.The study recorded 115 cases of use of glyciphon ointment in 114 patients. Doctors were fully satisfied with the treatment results in 101 (88.6 %) cases. In 11 (9.6 %) cases, satisfaction was partial due to severe adverse events (edema and hyperemia of the facial skin, pain), and in 2 (1.7 %) cases the treatment was found unsatisfactory. Eighty-six (93.5 %) patients with adverse events continued Glyciphon ointment therapy. The relapse rate after local drug therapy was 4.4 %, indicating its high efficacy and good tolerance. According to the study, most patients required 1 treatment course with 1 package of Glyciphon. Total cost of the treatment is approximately 17,000 rubles. Total budget expenditures are estimated at 1 billion 190 million rubles. Local BCC therapy with Glyciphon comparing to surgery may save more than 1 billion rubles for the state budget.Conclusion.Local chemotherapy with 30 % Glyciphon ointment is an effective and safe method to treat BCC. Its use increases treatment availability for patients and can significantly reduce federal expenditures.

Kidney Transplant Modifies the Architecture and Microenvironment of Basal Cell Carcinomas

Background/Aims: Basal cell carcinoma (BCC) is a frequent type of nonmelanoma skin cancer, which shows a greater prevalence in kidney-transplanted (KT) patients than in the general population. The study of this tumor in KT patients may allow us to understand the influence of the tumor inflammatory microenvironment on cancer behavior, and to design new image analysis methods to determine prognosis and apply personalized medicine. The major hypothesis of the present work is that antirejection drugs, by modifying the B-cell/T-cell balance, induce measurable differences in tumoral cell microarchitecture and in the inflammatory microenvironment in KT patients compared to nontransplanted controls. Methods: In this retrospective study in an Italian cohort including 15 KT patients and 15 control subjects from the general population who developed BCC, we analyzed tissue microarchitecture and inflammatory infiltrates of BCC using state-of-the-art nonlinear image analysis techniques such as fractal dimension and sample entropy of internuclear distances. Results: KT patients showed a nonsignificant trend to a greater number of nuclei in the basal cell layer compared to non-KT controls and subtle changes in the intact skin compared to controls. Similarly, the number of mitoses per unit length was almost doubled in the patients with KT compared to controls. However, when the number of mitotic cells was normalized by the total number of cells in the basal layer (mitotic index), these differences were not significant, although a clear trend was still present. Finally, KT patients showed a nonsignificant trend to an increased ­density of inflammatory cells close to the tumoral cell layer. When considering the intact skin, this difference was significant, with a 70% increase in the density of inflammatory cells. Conclusion: Data comparing the microarchitecture of BCC in normal subjects and KT patients are scanty, and the present study is the first to use nonlinear image analysis techniques to this aim. The observed differences underscore the relevance of T-cell suppression in cancer behavior. These data suggest that BCC develops in treated patients with specific biological characteristics which should be further analyzed in terms of therapeutic response.

Immunotherapy in Nonmelanoma Skin Cancer

Immunotherapy is emerging as a new and promising treatment for a great variety of tumors, including nonmelanoma skin cancer. Checkpoint inhibitors —antibodies that block proteins that regulate the immune system—mainly target the surface protein CTLA-4 (cytotoxic T-lymphocyte-associated antigen 4) and the PD-1/PD-L1 (programmed cell death protein 1/PD-ligand 1) axis. We review the CTLA-4 and PD-1/PD-L1 pathways and current evidence supporting checkpoint inhibitor therapy in the main types of nonmelanoma skin cancer.

149 Metformin as adjuvant in PDT in squamous cell carcinoma

Photodynamic therapy (PDT) is used for the treatment of several types of Non-Melanoma Skin Cancer (NMSC) although sometimes resistant cells responsible for the relapses may appear after treatment. Normal differentiated cells depend primarily on mitochondrial oxidative phosphorylation to generate energy, but cancer cells change this metabolism to an aerobic glycolysis (Warburg effect), which could influence in the response to antitumor drugs. Here, we have evaluated the expression of different proteins implicated in the energetic metabolism in the resistance to PDT of squamous cell carcinoma (SCC) in vitro and in vivo. In addition, we have evaluated the use of metformin, an antidiabetic type II compound, to destroy in vitro the resistant cells, alone or in combination with PDT, and in SKH-1 hairless mice exposed chronically to UV in the prevention of the development of tumors. For in vitro experiments, the cell lines SCC-13 and A431 were used. The cells, called parental (P), were subjected to 10 PDT cycles to obtain resistant cells that were inoculated in immunosuppressed mice; the induced tumors were sub-cultured by explants and a cell population called 10GT was obtained. On these cultures we have evaluated the combined treatment of PDT with metformin. For in vivo experiments, the SCC carcinomas induced in SKH-1 mice exposed to UV were treated with PDT, metformin or combination of both. The results obtained in vitro, showed a significant increase in cell death after the combined PDT-metformin treatment when compared to those obtained after PDT or metformin alone. In SCC carcinomas induced in SKH-1 hairless mice, after 28 weeks exposed to UV the number of lesions in the UV group was greater than that of the groups: UV+PDT, UV+metf or UV+metf+PDT. To analyse the molecular mechanism of metformin in combination with PDT, we have finally evaluated the expression elements that participate in the mTOR pathway after the treatments, in vitro and in tumors generated in mice.

Inmunoterapia en cáncer cutáneo no melanoma

Immunotherapy is emerging as a new and promising treatment for a great variety of tumors, including nonmelanoma skin cancer. Checkpoint inhibitors —antibodies that block proteins that regulate the immune system— mainly target the surface protein CTLA-4 (cytotoxic T-lymphocyte-associated antigen 4) and the PD-1/PD-L1 (programmed cell death protein 1/PD-ligand 1) axis. We review the CTLA-4 and PD-1/PD-L1 pathways and current evidence supporting checkpoint inhibitor therapy in the main types of nonmelanoma skin cancer.

The NLRP1 Inflammasome Pathway Is Silenced in Cutaneous Squamous Cell Carcinoma

The inflammasome protein NLRP1 is an important innate immune sensor in human keratinocytes, and, together with ASC and caspase-1, it mediates the activation and secretion of the proinflammatory cytokines IL-1β and IL-18. These cytokines and inflammasomes can have partly opposing roles during tumorigenesis in mice. In contrast, ASC expression is impaired in different types of cancer in humans. In this study, we analyzed inflammasome activation and expression of inflammasome proteins, including their downstream cytokines, in squamous cell carcinomas, a type of nonmelanoma skin cancer derived from keratinocytes. We assessed mRNA and protein levels in human primary keratinocytes and skin carcinoma-derived SCC cell lines and detected a strong down-regulation of expression of NLRP1 inflammasome components, as well as reduced expression of the proinflammatory cytokines proIL-1β and proIL-1α. Protein levels of NLRP1, ASC, caspase-1, and proIL-1β were reduced in patient-derived SCC biopsy samples compared with healthy skin. Furthermore, the results suggest that expression of PYCARD (ASC), CASP1, IL1B, and NLRP1 is silenced by methylation in SCC cell lines. In conclusion, the down-regulation of the inflammasome pathway in SCCs might favor late tumor development in human skin.