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OBJECTIVE: To assess the influence of geographies and race on the survival outcomes in patients diagnosed with cervical squamous cell carcinoma (CSCC) across three continents. METHODS: This multicontinental retrospective study was conducted in 8 hospitals across Asia, Europe, and North America (NA). Clinicopathologic data of 595 patients with presumed early stages of CSCC, treated surgically, with curative intent was collected. Descriptive analysis and Cox regression models were produced. RESULTS: A total of 595 patients, consisting of 445 (74.8 %) white, 75 (12.6 %) Blacks, and 75 (12.6 %) Asian patients were included. Geographical distribution comprised 69 % of patients from NA, 22 % from Europe, and 9 % from Asia. The median age at diagnosis was 46 years. The median overall survival (OS) and relapse-free survival (RFS) were 22.09 years and 21.19 years, respectively. Patient characteristics varied significantly across geographical regions, except for consensus tumor grade. Patients in Europe from middle-income countries with limited CC screening had a substantially higher risk of death than those in NA (HR, 1.79; 95 % CI, 1.13 to 2.79; p = 0.015). Patients from single center in Japan had higher risk of relapse than those from the four heterogeneous NA centers (sub-distribution hazard ratio, 2.19; 95 % CI, 1.22 to 3.95; p = 0.009), although OS did not differ significantly. Race remained statistically insignificant for survival outcomes across the three continents but seemed to influence survival outcomes in NA centers. CONCLUSION: Our study highlights impact of geographies and races on CSCC survival outcomes, emphasizing the need of considering these factors when developing targeted interventions against CSCC.
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Aim: To independently confirm that the 40-gene expression profile (40-GEP) test can identify patients with high-risk cutaneous squamous cell carcinoma who are more or less likely to benefit from adjuvant radiation therapy (ART).Materials & methods: Primary cutaneous squamous cell carcinoma tumors from two academic centers received retrospective 40-GEP testing and were analyzed for 5-year metastasis-free survival and projected time to event.Results: Random sampling of matched patient pairs (n = 52 ART-treated; 371 no ART) showed a median 50% decrease in 5-year progression rate for ART-treated patients (vs no ART) with 40-GEP Class 2B. Class 2A was associated with a modest ART benefit, but not Class 1.Conclusion: The 40-GEP identified patients most likely to benefit from ART (Class 2B) and those that can consider deferring treatment (Class 1).
Independent validation study: 40-GEP identifies patients with cutaneous squamous cell carcinoma who would be most likely to benefit from adjuvant radiation therapy.
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Cemiplimab has demonstrated relevant clinical activity in cutaneous squamous cell carcinoma (cSCC) but mechanisms of primary and acquired resistance to immunotherapy are still unknown. We collected clinical data from locally advanced and/or metastatic cSSC patients treated with cemiplimab in two Italian University centers. In addition, gene expression analysis by using Nanostring Technologies platform to evaluate 770 cancer- and immune-related genes on 20 tumor tissue samples (9 responders and 11 non-responders to cemiplimab) was performed. We enrolled 81 patients with a median age of 82 years. After 16.4 months of median follow-up, 12- and 24-months PFS were 53% and 42%, respectively; while 12- and 24-months OS were 71% and 61%, respectively. Treatment was well tolerated. Overall response rate (ORR) was 58%, with a disease control rate (DCR) of 77.8%. The difference between genes expressed in responder versus non-responder patient samples was substantial, particularly for genes involved in immune system regulation. Cemiplimab-resistant tumors were associated with over-expression of CCL-20 and CXCL-8. Cemiplimab confirmed efficacy and safety data in real-life cSCC patients. Overexpression of CCL-20 and CXCL-8 could represent biomarkers of lack of response to immunotherapy.
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Anticuerpos Monoclonales Humanizados , Carcinoma de Células Escamosas , Resistencia a Antineoplásicos , Interleucina-8 , Neoplasias Cutáneas , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/administración & dosificación , Masculino , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Femenino , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Anciano , Anciano de 80 o más Años , Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Interleucina-8/genética , Interleucina-8/metabolismo , Escape del Tumor/efectos de los fármacos , Escape del Tumor/genética , Persona de Mediana Edad , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Antineoplásicos Inmunológicos/uso terapéutico , Antineoplásicos Inmunológicos/farmacologíaRESUMEN
Cutaneous squamous cell carcinoma (cSCC) manifests through the complex interactions of UV-induced DNA damage, genetic mutations, and alterations in the tumor microenvironment. A high mutational burden is present in cSCC, as well as both cSCC precursors and normal skin, making driver genes difficult to differentiate. Despite this, several key driver genes have been identified, including TP53, the NOTCH family, CDKN2A, PIK3CA, and EGFR. In addition to mutations, the tumor microenvironment and the manipulation and evasion of the immune system play a critical role in cSCC progression. Novel therapeutic approaches, such as immunotherapy and EGFR inhibitors, have been used to target these dysregulations, and have shown promise in treating advanced cSCC cases, emphasizing the need for targeted interventions considering both genetic and microenvironmental factors for improved patient outcomes.
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Cutaneous squamous cell carcinoma (cSCC) is the second most prevalent form of skin cancer. An increasing number of cSCCs are associated with dysregulation of key molecules that control skin homeostasis. These observations have increased interest in the role of neurotrophins and their receptors in the pathogenesis of cSCC. They have been demonstrated to have a considerable impact on the aggressiveness potential of skin cancer by both in vitro and in vivo models. In this context, mouse models are classically used to dissect proliferation versus differentiation balance, but they have some limitations in terms of time, space, and costs. Recently, zebrafish models have been implemented as a new tool to obtain information regarding the invasive capacity and metastasis of neoplastic cells. By xenotransplantation technique, cSCC cells from a patient's biopsy or cell line can be successfully characterized, with or without the presence of genetic manipulation or treatments. In addition, the evaluation of the immune microenvironment contributes to potentially identifying connections and homologies with humans. In this review, we retrace the role of the neurotrophin network in healthy and pathological skin, particularly in cSCC. We review how zebrafish models can be important tools for studying cSCC development, growth, and potential treatments.
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BACKGROUND: Early cutaneous squamous cell carcinomas (cSCCs) generally show epithelial differentiation features and good prognosis, whereas advanced cSCCs present mesenchymal traits associated with tumor relapse, metastasis, and poor survival. Currently, the mechanisms involved in cSCC progression are unclear, and the established markers are suboptimal for accurately predicting the clinical course of the disease. METHODS: Using a mouse model of cSCC progression, expression microarray analysis, immunofluorescence and flow cytometry assays, we have identified a prognostic biomarker of tumor relapse, which has been evaluated in a cohort of cSCC patient samples. Phosphoproteomic analysis have revealed signaling pathways induced in epithelial plastic cancer cells that promote epithelial-mesenchymal plasticity (EMP) and tumor progression. These pathways have been validated by genetic and pharmacological inhibition assays. RESULTS: We show that the emergence of epithelial cancer cells expressing integrin αV (ITGAV) promotes cSCC progression to a mesenchymal state. Consistently, ITGAV expression allows the identification of patients at risk of cSCC relapse above the currently employed clinical histopathological parameters. We also demonstrate that activation of insulin-like growth factor-1 receptor (IGF1R) pathway in epithelial cancer cells is necessary to induce EMP and mesenchymal state acquisition in response to tumor microenvironment-derived factors, while promoting ITGAV expression. Likewise, ITGAV knockdown in epithelial plastic cancer cells also blocks EMP acquisition, generating epithelial tumors. CONCLUSIONS: Our results demonstrate that ITGAV is a prognostic biomarker of relapse in cSCCs that would allow improved patient stratification. ITGAV also collaborates with IGF1R to induce EMP in epithelial cancer cells and promotes cSCC progression, revealing a potential therapeutic strategy to block the generation of advanced mesenchymal cSCCs.
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Transición Epitelial-Mesenquimal , Receptor IGF Tipo 1 , Transducción de Señal , Neoplasias Cutáneas , Animales , Humanos , Ratones , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/genética , Línea Celular Tumoral , Pronóstico , Receptor IGF Tipo 1/metabolismo , Receptor IGF Tipo 1/genética , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/genética , Microambiente Tumoral , Integrina alfaV/genética , Integrina alfaV/metabolismoRESUMEN
Background: Cemiplimab was licensed in the United Kingdom (UK) in 2019 for the treatment of patients with locally advanced and metastatic CSCC not suitable for curative surgery or radiotherapy (advanced CSCC [aCSCC]). No UK multi-center studies have investigated the real-world experience of cemiplimab post marketing authorization in aCSCC. Methods: This non-interventional retrospective study (10 UK centers) involved data collection from medical records of patients with aCSCC who initiated cemiplimab treatment between 2 July 2019 and 30 November 2020. The study period was a minimum of 12 and a maximum of 36 months post cemiplimab initiation. The primary objective was to describe the real-world clinical effectiveness of cemiplimab (primary outcome: overall response rate [ORR]). Results: Of 105 patients, 70% (n=73/105) were male (median [range] age at index of 78.5 [55.4-93.2] years); most patients (63% [n=50/80]) had an Eastern Cooperative Oncology Group (ECOG) score of 1 and 62% (n=63/102) had metastatic disease. The ORR within 12 months was 42% (95% confidence interval [CI] 32%-51%) and the disease control rate was 62% (n=65/105). The median (95% CI) real-world progression-free survival and overall survival from index was 8.6 (6.0-18.7) and 21.0 (14.7-25.2) months, respectively. The median (range) number of cemiplimab infusions was 11.0 (1.0-44.0). Eighty-seven percent experienced no cemiplimab treatment interruptions; 13% (n=14/105) interrupted treatment due to immune-related adverse reactions (irARs) (47% [n=9/19] of treatment interruption events). Eighty-five percent (n=89/105) of patients had discontinued cemiplimab treatment by the end of the study; where reasons for discontinuation were recorded, 20% (n=17/87) discontinued due to the completion of their 2-year treatment course. Nineteen percent (n=20/105) of patients experienced irARs. Conclusion: Effectiveness and safety data in this study are broadly similar to previous real-world studies of cemiplimab and the EMPOWER-CSCC1 clinical trial; with our cohort representing a broader population (included immunocompromised and transplant patients). Results support the use of cemiplimab for the treatment of aCSCC in a real-world setting.
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Anticuerpos Monoclonales Humanizados , Humanos , Masculino , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Femenino , Persona de Mediana Edad , Reino Unido , Anciano , Estudios Retrospectivos , Anciano de 80 o más Años , Antineoplásicos Inmunológicos/uso terapéutico , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Resultado del TratamientoRESUMEN
Topical tirbanibulin is a highly effective and well tolerated novel treatment option for actinic keratoses (AKs). This study aimed to characterize the mode of action of tirbanibulin in keratinocytes (NHEK) and cutaneous squamous cell carcinoma (cSCC) cell lines (A431, SCC-12) in vitro. Tirbanibulin significantly reduced proliferation in a dose-dependent manner in all investigated cell lines, inhibited migration, and induced G2/M-cell cycle arrest only in the cSCC cell lines analyzed, and induced apoptosis solely in A431, which showed the highest sensitivity to tirbanibulin. In general, we detected low basal expression of phosphorylated SRC in all cell lines analyzed, therefore, interference with SRC signaling does not appear to be the driving force regarding the observed effects of tirbanibulin. The most prominent tirbanibulin-mediated effect was on ß-tubulin-polymerization, which was especially impaired in A431. Additionally, tirbanibulin induced an increase of the proinflammatory cytokines IL-1α, bFGF and VEGF in A431. In conclusion, tirbanibulin mediated anti-tumor effects predominantly in A431, while healthy keratinocytes and more dedifferentiated SCC-12 were less influenced. These effects of tirbanibulin are most likely mediated via dysregulation of ß-tubulin-polymerization and may be supported by proinflammatory aspects.
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Apoptosis , Carcinoma de Células Escamosas , Movimiento Celular , Proliferación Celular , Queratinocitos , Neoplasias Cutáneas , Tubulina (Proteína) , Humanos , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/metabolismo , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Línea Celular Tumoral , Tubulina (Proteína)/metabolismo , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/metabolismo , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Antineoplásicos/farmacología , Polimerizacion/efectos de los fármacos , Queratosis Actínica/tratamiento farmacológico , Queratosis Actínica/patología , Queratosis Actínica/metabolismo , Transducción de Señal/efectos de los fármacos , Acetamidas , Morfolinas , PiridinasRESUMEN
S-phase kinase-associated protein 2 (Skp2) is an F-box protein overexpressed in human cancers and linked with poor prognosis. It triggers cancer pathogenesis, including stemness and drug resistance. In this study, we have explored the potential role of Skp2 targeting in restoring the expression of tumor suppressors in human cutaneous squamous cell carcinoma (cSCC) cells. Our results showed that genetic and pharmacological Skp2 targeting markedly suppressed cSCC cell proliferation, colony growth, spheroid formation, and enhanced sensitization to chemotherapeutic drugs. Further, western blot results demonstrated restoration of tumor suppressor (KLF4) and CDKI (p21) and suppression of vimentin and survivin in Skp2-knocked-down cSCC cells. Importantly, we also explored that Skp2 targeting potentiates apoptosis of cSCC cells through MAPK signaling. Moreover, co-targeting of Skp2 and PI3K/AKT resulted in increased cancer cell death. Interestingly, curcumin, a well-known naturally derived anticancer agent, also inhibits Skp2 expression with concomitant CDKI upregulation. In line, curcumin suppressed cSCC cell growth through ROS-mediated apoptosis, while the use of N-acetyl cysteine (NAC) reversed curcumin-induced cell death. Curcumin treatment also sensitized cSCC cells to conventional anticancer drugs, such as cisplatin and doxorubicin. Altogether, these data suggest that Skp2 targeting restores the functioning of tumor suppressors, inhibits the expression of genes associated with cell proliferation and stemness, and sensitizes cancer cells to anticancer drugs. Thus, genetic, and pharmacological ablation of Skp2 can be an important strategy for attenuating cancer pathogenesis and associated complications in skin squamous cell carcinoma.
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Apoptosis , Carcinoma de Células Escamosas , Factor 4 Similar a Kruppel , Proteínas Quinasas Asociadas a Fase-S , Neoplasias Cutáneas , Humanos , Proteínas Quinasas Asociadas a Fase-S/metabolismo , Proteínas Quinasas Asociadas a Fase-S/genética , Apoptosis/efectos de los fármacos , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/tratamiento farmacológico , Línea Celular Tumoral , Factor 4 Similar a Kruppel/metabolismo , Proliferación Celular/efectos de los fármacos , Curcumina/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacosRESUMEN
BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is one of the most common skin cancers for which effective drugs are urgently needed. Echinatin, a natural compound extracted from Glycyrrhiza plants, has shown promising antitumour effects. However, the efficacy and the direct target of echinatin in cSCC remain unclear. PURPOSE: This study conducted a systematic investigation of the antitumour effects of echinatin on cSCC and the underlying mechanisms involved. STUDY DESIGN AND METHODS: Three cSCC cell lines, a xenograft model, and a UV-induced cSCC mouse model were used to investigate the potential protective effects of echinatin. The interactions between echinatin and glutathione S-transferase mu3 (GSTM3) and between echinatin and peroxiredoxin-2 (PRDX2) were evaluated by a proteome microarray assay, pull-down LCâMS/MS analysis, surface plasmon resonance, and molecular docking. The potential mechanisms of GSTM3-mediated echinatin activity were analysed by using western blotting, lentivirus infection and small interfering RNA (siRNA) transfection. RESULTS: In this study, we found that echinatin inhibited the proliferation and migration of cSCC cells but had no cytotoxic effect on primary human keratinocytes. Furthermore, echinatin significantly inhibited tumour growth in vivo. Mechanistically, our data showed that echinatin could directly bind to GSTM3 and PRDX2. Notably, echinatin inhibited GSTM3 and PRDX2 levels by promoting their proteasomal degradation, which led to the disruption of ROS production. We then revealed that echinatin increased mitochondrial ROS production by inhibiting GSTM3. Moreover, echinatin triggered ferroptosis by inhibiting GSTM3-mediated ferroptosis negative regulation (FNR) proteins. In addition, echinatin regulated GSTM3-mediated ROS/MAPK signalling. CONCLUSION: Echinatin has good antitumour effects both in vitro and in vivo. Moreover, our findings indicate that GSTM3 and PRDX2 could function as viable targets of echinatin in cSCC. Consequently, echinatin represents a novel treatment for cSCC through the targeting of GSTM3-mediated ferroptosis.
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Carcinoma de Células Escamosas , Ferroptosis , Glutatión Transferasa , Neoplasias Cutáneas , Ferroptosis/efectos de los fármacos , Animales , Neoplasias Cutáneas/tratamiento farmacológico , Humanos , Carcinoma de Células Escamosas/tratamiento farmacológico , Línea Celular Tumoral , Ratones , Glutatión Transferasa/metabolismo , Peroxirredoxinas/metabolismo , Antineoplásicos Fitogénicos/farmacología , Ratones Endogámicos BALB C , Proliferación Celular/efectos de los fármacos , Simulación del Acoplamiento Molecular , Ratones Desnudos , Movimiento Celular/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Queratinocitos/efectos de los fármacos , ChalconasRESUMEN
Cutaneous squamous cell carcinoma is a prevalent malignancy with a rising incidence and a notably high mutational load. Exploring the genetic nuances of cSCC and investigating molecular approaches stands as a potential avenue for improving outcomes in high-risk patients. This retrospective case-control study involved two cohorts, one of 14 patients (the "discovery cohort") and the other of 12 patients (the "validation cohort"), with cSCC located in the head/neck anatomical region and diagnosed at the pT2 stage. Overall, cases developed early local relapses of the disease, whereas controls never relapsed during the entire follow-up period. A next-generation sequencing (NGS) approach conducted on histological samples revealed that TP53 and CDKN2A were the most frequently mutated genes in our series. No specific mutations were identified as potential prognostic or therapeutic targets. Controls exhibited a tendency toward a higher mutational rate compared to cases. It is possible that an increased number of mutations could prompt the cSCC to expose more antigens, becoming more immunogenic and facilitating recognition by the immune system. This could enhance and sustain the immunological response, potentially preventing future recurrences.
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Cutaneous squamous cell carcinoma (cSCC) ranks as the second most prevalent skin tumour (excluding melanoma). However, the molecular mechanisms driving cSCC progression remain elusive. This study aimed to investigate GBP1 expression in cSCC and elucidate its potential molecular mechanisms underlying cSCC development. GBP1 expression was assessed across public databases, cell lines and tissue samples. Various assays, including clone formation, CCK8 and EdU were employed to evaluate cell proliferation, while wound healing and transwell assays determined cell migration and invasion. Subcutaneous tumour assays were conducted to assess in vivo tumour proliferation, and molecular mechanisms were explored through western blotting, immunofluorescence and immunoprecipitation. Results identified GBP1 as an oncogene in cSCC, with elevated expression in both tumour tissues and cells, strongly correlating with tumour stage and grade. In vitro and in vivo investigations revealed that increased GBP1 expression significantly enhanced cSCC cell proliferation, migration and invasion. Mechanistically, GBP1 interaction with SP1 promoted STAT3 activation, contributing to malignant behaviours. In conclusion, the study highlights the crucial role of the GBP1/SP1/STAT3 signalling axis in regulating tumour progression in cSCC. These findings provide valuable insights into the molecular mechanisms of cSCC development and offer potential therapeutic targets for interventions against cSCC.
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Carcinoma de Células Escamosas , Movimiento Celular , Proliferación Celular , Proteínas de Unión al GTP , Invasividad Neoplásica , Factor de Transcripción STAT3 , Neoplasias Cutáneas , Factor de Transcripción Sp1 , Factor de Transcripción STAT3/metabolismo , Humanos , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/genética , Factor de Transcripción Sp1/metabolismo , Proteínas de Unión al GTP/metabolismo , Proteínas de Unión al GTP/genética , Línea Celular Tumoral , Animales , Ratones , Transducción de Señal , Femenino , Ratones DesnudosRESUMEN
The immune checkpoint inhibitor (ICI) cemiplimab is a human monoclonal antibody used in the treatment of locally advanced and metastatic cutaneous squamous cell carcinoma (CSCC) not amenable to surgery or radiation therapy. Although cemiplimab shows excellent efficacy with a good tolerability profile, it can cause side effects, including potentially life-threatening endocrinopathies. We discuss the case of a 77-year-old Caucasian female with CSCC treated with only three cycles of cemiplimab who presented with altered mental status and was found to have severe hyperglycemia, hyperosmolarity, ketonemia, glucosuria, and ketonuria concerning for hyperosmolar hyperglycemic syndrome (HHS) with concurrent diabetic ketoacidosis (DKA). The patient made a rapid recovery in the hospital while on standard therapies for HHS/DKA and cemiplimab was discontinued upon discharge. While there have been reports of cemiplimab-induced DKA, to our knowledge, this is the first reported case of cemiplimab-induced HHS-DKA. This report aims to shed light on cemiplimab-induced HHS-DKA and to underscore the need to elucidate the molecular mechanisms underlying ICI-induced diabetes mellitus (ICI-DM).
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According to current predictions, one-fifth of all Americans will develop skin cancer during their lifetime. Cutaneous squamous cell carcinoma (cSCC) most commonly occurs in the head and neck region, which is the area of the body with the highest level of sun exposure. High-risk head and neck cSCC (HNcSCC) is a broad category with numerous high-risk factors that are associated with unfavorable results. In cSCC staging systems, clinical and tumor traits that are likely to result in poor outcomes are identified. Metastasis occurs in ~2.5% of patients with cSCC, most often in the local lymph nodes, and there is some indication that lymph node metastasis has a distinct pattern based on the tumor site. Current findings on tumor molecular targets have suggested the use of systemic treatments, particularly immunotherapy (such as cemiplimab, pembrolizumab and nivolumab), over radiotherapy or chemotherapy for this type of metastasis. However, when used simultaneously with immunotherapy, radiotherapy may be beneficial in the treatment of metastatic HNcSCC by improving the efficacy of immunotherapy. The present review aims to assess the existing literature on metastatic HNcSCC pathways and treatment options, in order to define current and future directions. Notably, there is an urgent need to identify patients who may benefit from local or systemic cancer treatments. The treatment of lymph node metastasis presents a therapeutic challenge and requires comprehensive management.
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Squamous cell carcinoma (SCC) is the second leading form of skin cancer. In the elderly population, surgery may carry more risk and significant morbidity in comparison to less invasive forms of treatment. This case report describes the successful use of intralesional 5-fluorouracil (IL5-FU) to treat cutaneous squamous cell carcinoma (cSCC). A 98-year-old white woman presented in early May 2017 with a 3.5-cm rapidly growing crusted nodule on her left proximal-lateral arm. She had a past medical history of chronic obstructive pulmonary disease, atrial fibrillation, and heart failure. The patient also had a frail body habitus and weighed 80 pounds. Physical examination revealed a large, ulcerated, crateriform mass on the left proximal-lateral arm. A shave biopsy was performed, which revealed a well-differentiated SCC, composed of nodular masses of neoplastic squamous cells with atypical nuclei, keratin pearl formation, and scattered mitotic figures with surrounding fibrosis and inflammation. The patient was wheelchair-bound and oxygen-dependent and, thus, not considered a good surgical or radiation candidate. Treatment was decided with 5-fluorouracil. At a four-week follow-up appointment, there was no visible or palpable evidence of the tumor. There was no sign of recurrence at three months, indicating treatment success. The patient later died due to cardiac arrest in September 2017. The elderly population with cSCC can benefit from intervention and treatment with IL5-FU when surgery is not an option due to patient comorbidities. IL5-FU can potentially be used in areas where access to a dermatologist, surgeon, or surgical services is limited.
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Cutaneous squamous cell carcinoma (cSCC) arising from radiation dermatitis has a higher risk of metastasis than conventional cSCC. Immunosuppression is another risk factor for cSCC, suggesting that mycosis fungoides (MF) could be a risk factor for cSCC. Here we report a case of radiation-induced cSCC with a high level of tumor-mutation burden that developed in a patient with MF who was successfully treated with pembrolizumab. The present case suggests that pembrolizumab might be an optimal therapy for radiation-induced cSCC, even at advanced stages.
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Cutaneous squamous cell carcinoma (cSCC) is the second most common malignancy worldwide, with most deaths caused by locally advanced and metastatic disease. Treatment of resectable metastases is typically limited to invasive surgery with adjuvant radiotherapy; however, many patients fail to respond and there is minimal data to predict response or propose effective alternatives. Precision medicine could improve this, though genomic biomarkers remain elusive in the high mutational background and genomic complexity of cSCC. A phenotypic approach to precision medicine using patient-derived ex vivo tumour models is gaining favour for its capacity to directly assess biological responses to therapeutics as a functional, predictive biomarker. However, the use of ex vivo models for guiding therapeutic selection has yet to be employed for metastatic cSCC. This review will therefore evaluate the existing experimental models of metastatic cSCC and discuss how ex vivo methods could overcome the shortcomings of these existing models. Disease-specific considerations for a prospective methodological pipeline will also be discussed in the context of precision medicine.
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Carcinoma de Células Escamosas , Medicina de Precisión , Neoplasias Cutáneas , Humanos , Neoplasias Cutáneas/terapia , Neoplasias Cutáneas/patología , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/secundario , Medicina de Precisión/métodos , Metástasis de la NeoplasiaRESUMEN
BACKGROUND: THOC7-AS1 and FSTL1 expression are frequently upregulated in cutaneous squamous cell carcinoma (cSCC). However, their molecular biological mechanisms remain elusive and their potential as therapeutic targets needs urgent exploration. METHODS: Human tissue samples were used to evaluate clinical parameters. In vitro and in vivo experiments assessed biological functions. Quantitative PCR, western blot, immunohistochemistry, immunocytochemistry, immunoprecipitation, RNA fluorescence in situ hybridization, RNA pull-down, RNA immunoprecipitation, silver staining, chromatin immunoprecipitation, dual luciferase reporter assays etc. were utilized to explore the molecular biological mechanisms. RESULTS: We found FSTL1 is an oncogene in cSCC, with high expression in tumor tissues and cells. Its elevated expression closely associates with tumor size and local tissue infiltration. In vitro and in vivo, high FSTL1 expression promotes cSCC proliferation, migration and invasion, facilitating malignant behaviors. Mechanistically, FSTL1 interacts with ZEB1 to promote epithelial-to-mesenchymal transition (EMT) in cSCC cells. Exploring upstream regulation, we found THOC7-AS1 can interact with OCT1, which binds the FSTL1 promoter region and promotes FSTL1 expression, facilitating cSCC progression. Finally, treating tumors with THOC7-AS1 antisense oligonucleotides inhibited cSCC proliferative and migratory abilities, delaying tumor progression. CONCLUSIONS: The THOC7-AS1/OCT1/FSTL1 axis regulates EMT and promotes tumor progression in cSCC. This study provides clues and ideas for cSCC targeted therapy.
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Carcinoma de Células Escamosas , Proteínas Relacionadas con la Folistatina , Neoplasias Cutáneas , Humanos , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Proteínas Relacionadas con la Folistatina/genética , Proteínas Relacionadas con la Folistatina/metabolismo , Regulación Neoplásica de la Expresión Génica , Hibridación Fluorescente in Situ , ARN , ARN Largo no Codificante/genética , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patologíaRESUMEN
Cutaneous squamous cell carcinoma (CSCC) accounts for â¼20%-25% of all skin tumors. Its precise incidence is often challenging to determine due to limited statistics and its incorporation with mucosal forms. While most cases have a favorable prognosis, challenges arise in patients presenting with locally advanced or metastatic forms, mainly appearing in immunocompromised patients, solid organ transplantation recipients, or those facing social difficulties. Traditionally, chemotherapy and targeted therapy were the mainstays for advanced cases, but recent approvals of immunotherapeutic agents like cemiplimab and pembrolizumab have revolutionized treatment options. These guidelines, developed by the Italian Association of Medical Oncologists (AIOM) using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach, aim to guide clinicians in diagnosing, treating, and monitoring patients with CSCC, covering key aspects from primitive tumors to advanced stages, selected by a panel of experts selected by AIOM and other national scientific societies. The incorporation of these guidelines into clinical practice is expected to enhance patient care and address the evolving landscape of CSCC management.