Cutaneous Squamous Cell Carcinoma Patients Research Articles

Cutaneous Squamous Cell Carcinoma in Patients with Solid-Organ-Transplant-Associated Immunosuppression.

The management of advanced cutaneous squamous cell carcinoma (CSCC) has been revolutionized by the introduction of immunotherapy. Yet, successful treatment with immunotherapy relies on an adequate antitumor immune response. Patients who are solid-organ transplant recipients (SOTRs) have a higher incidence of CSCC compared to the general population. This review discusses the current knowledge of epidemiology, pathophysiology, and management of patients with CSCC who are immunocompromised because of their chronic exposure to immunosuppressive medications to prevent allograft rejection. First, we discuss the prognostic impact of immunosuppression in patients with CSCC. Next, we review the risk of CSCC development in immunosuppressed patients due to SOT. In addition, we provide an overview of the biological immune disruption present in transplanted immunosuppressed CSCC patients. We discuss the available evidence on the use of immunotherapy and provide a framework for the management approach with SOTRs with CSCC. Finally, we discuss potential novel approaches that are being investigated for the management of immunosuppressed patients with CSCC.

Aberrant expression of B7-H4 and B7-H5 contributes to the development of cutaneous squamous cell carcinoma

Cutaneous squamous cell carcinoma (CSCC) is the second most common malignant tumor of the skin. B7 homolog 4 (B7-H4) and B7-H5 (B7 homolog 5) are associated with a variety of tumors. Investigate the potential role of B7-H4 and B7-H5 in regulating the tumorigenesis and progression of CSCC. B7-H4 and B7-H5 transcriptome data were collected from GEO and TCGA databases and subjected to bioinformatical analysis by protein–protein interaction (PPI) network, functional enrichment analysis, immune analysis, and drug–gene interaction prediction analysis. We characterized the expression of B7-H4 and B7-H5 in carcinoma tissues of CSCC patients by immunohistochemistry. Meanwhile, the clinical correlation of B7-H4 and B7-H5 in CSCC was explored by statistical analysis. B7-H4 and B7-H5 genes were under-expressed in CSCC and correlated with tumor staging. According to GO and KEGG Pathway enrichment analysis, B7-H4, and B7-H5 can regulate the proliferation and activation of T cells, lymphocytes, and monocytes, and the expression of cytokines, such as IL-6 and IL-10, in CSCC. B7-H4 and B7-H5 are also jointly involved in the occurrence and development of CSCC via the JAK-STAT and Notch signaling pathways. We found that B7-H4 and B7-H5 proteins were abnormally highly expressed in CSCC tissue and correlated with tumor size and stage. Our findings offer new insights into the pathogenesis of CSCC and suggest that B7-H4 and B7-H5 are novel tissue biomarkers and promising therapeutic targets for CSCC.

PTCH1 Gene Variants, mRNA Expression, and Bioinformatics Insights in Mexican Cutaneous Squamous Cell Carcinoma Patients.

Skin cancer is one of the most frequent types of cancer, and cutaneous squamous cell carcinoma (cSCC) constitutes 20% of non-melanoma skin cancer (NMSC) cases. PTCH1, a tumor suppressor gene involved in the Sonic hedgehog signaling pathway, plays a crucial role in neoplastic processes. An analytical cross-sectional study, encompassing 211 cSCC patients and 290 individuals in a control group (CG), was performed. A subgroup of samples was considered for the relative expression analysis, and the results were obtained using quantitative real-time PCR (qPCR) with TaqMan® probes. The functional, splicing, and disease-causing effects of the proposed variants were explored via bioinformatics. cSCC was predominant in men, especially in sun-exposed areas such as the head and neck. No statistically significant differences were found regarding the rs357564, rs2236405, rs2297086, and rs41313327 variants of PTCH1, or in the risk of cSCC, nor in the mRNA expression between the cSCC group and CG. A functional effect of rs357564 and a disease-causing relation to rs41313327 was identified. The proposed variants were not associated with cSCC risk in this Mexican population, but we recognize the need for analyzing larger population groups to elucidate the disease-causing role of rare variants.

Sex as a Predictor of Response to Immunotherapy in Advanced Cutaneous Squamous Cell Carcinoma.

Approximately 3-5% of patients with cutaneous squamous cell carcinoma (CSCC) develop advanced disease, accounting for roughly 1% of all cancer deaths in Australia. Immunotherapy has demonstrated significant clinical benefit in advanced CSCC in several key phase II studies; however, there are limited data for patients treated outside of clinical trials. This is particularly relevant in advanced CSCC, which is most often seen in elderly patients with significant comorbidities. Thus, we aim to describe our experience with immunotherapy in a cohort of patients with advanced CSCC in Australia. We retrospectively reviewed all advanced CSCC patients treated with immunotherapy within the Illawarra and Shoalhaven Local Health District. Among the 51 patients treated with immunotherapy, there was an objective response rate (ORR) of 53% and disease control rate (DCR) of 67%. Our most significant predictor of response was sex, with male patients more likely to have better responses compared to female patients (DCR 85% vs. 41%, p < 0.0001), as well as improved progression-free survival (HR 4.6, 95%CI 1.9-10.8, p = 0.0007) and overall survival (HR 3.0, 95%CI 1.3-7.1, p = 0.006). Differential expression analysis of 770 immune-related genes demonstrated an impaired CD8 T-cell response in female patients. Our observed ORR of 53% is similar to that described in current literature with durable responses seen in the majority of patients.

COVID-19 and Cutaneous Squamous Cell Carcinoma-Impact of the Pandemic on Unequal Access to Healthcare.

Most skin tumors are not fatal, but if not treated in a timely manner, they can lead to significant morbidity. Due to the COVID-19 pandemic and in order to create more capacities for the treatment of COVID-19-positive patients as well as to contain the spread of the virus, the healthcare system was reorganized worldwide, leading to decreased access to preventive screening programs. The aim of this study was to evaluate the impact of the pandemic on healthcare accessibility to cutaneous squamous cell carcinoma patients in Serbia. This retrospective study was conducted at the Clinic for Burns, Plastic, and Reconstructive Surgery, University Clinical Center of Serbia in Belgrade. Patient demographics and pathohistological findings of tumors of patients living in and outside the capital in the period before, during, and after the pandemic were compared. The two groups did not show any differences regarding the largest tumor diameter prior and during the pandemic; however, this difference became extremely noticeable after the pandemic (15 mm vs. 27 mm; p < 0.001). While cSCCs are commonly slow-growing tumors, the impact of the COVID-19 pandemic is not negligible. This study found a population at a significant risk of cSCC metastasis, with additional evidence likely to emerge in the upcoming years.

NEO-CESQ study: Neoadjuvant plus adjuvant treatment with cemiplimab in surgically resectable, high risk stage III/IV (M0) cutaneous squamous cell carcinoma.

9576 Background: In the last years, the treatment of locally advanced and/or metastatic cutaneous squamous cell carcinoma (CSCC) has been revolutionized by the introduction of cemiplimab, an anti-PD-1 antibody, which showed a 50% overall response rate and long term benefit (1). Recently, a phase II trial of neoadjuvant cemiplimab in resectable CSCC patients (2), showed a major pathological response (MPR) rate of 63.3%. In the current multicenter, phase II trial we evaluated the efficacy of neoadjuvant plus adjuvant immune checkpoint inhibitor in patients with surgically resectable, high-risk stage III/IV (M0) CSCC. Methods: Patients with surgically resectable high-risk stage III/IV (M0) CSCC received cemiplimab at a dosage of 350 mg every 3 weeks for two cycles prior surgery and for one year after surgery. The study primary endpoint was MPR [pathological complete response (pCR) or near pCR ( &lt; 10% remaining viable tumour cells in the surgical pathology sample)] per independent central pathology review. Key secondary endpoints included recurrence-free survival (RFS), overall survival (OS), safety and the analysis of predictive biomarkers. Results: From May 2021 to October 2022 twenty-three patients were enrolled in 6 centers. pCR was observed in 9 (39%) patients and near pCR in 2 (8%) patients, while pathological partial response (10-50% remaining viable tumour cells) and no pathologic response was observed in 1 patient and 11 patients, respectively. At data lock of 31st January 2023, only one patient was discontinued due to clinical progression. Furthermore, it was observed n = 60 (57%) any adverse events (AE) and n = 29 (30%) treatment-related AE. No any G3/G4 AE were observed. Conclusions: Neoadjuvant cemiplimab induced a pathological response in 52% of stage III/IV (M0) CSCC patients with a MPR in 48%. The study is still ongoing to evaluate the impact of combined neoadjvuant and adjuvant immunotherapy on RFS and biomarkers analysis. Clinical trial information: NCT04632433 .

Long-term outcomes of PD-1 blockade in metastatic or unresectable cutaneous squamous cell cancer.

e21551 Background: Cutaneous squamous cell carcinoma (CSCC) is the 2nd most common malignancy in the US. Approximately 10% of patients will experience either recurrent or metastatic disease, leading to worsened morbidity and mortality. In 2019, anti-PD1 therapy was FDA approved for metastatic or unresectable CSCC, and has been established as the standard frontline systemic therapy for this disease. Here we present our long-term, follow-up data investigating the efficacy, safety, and durability of PD-1 therapy for CSCC. Methods: This is a retrospective cohort study of metastatic or unresectable CSCC patients treated with PD-1 therapy at the University of Southern California Norris Comprehensive Cancer Center and the Scripps MD Anderson Cancer Center between June 2016 and January 2023. Patient demographics, tumor characteristics, and treatment related variables were collected. Objective response (ORR) was collected per RECIST criteria. Kaplan-Meier curves were used to estimate progression free survival (PFS) and overall survival (OS). For patients receiving salvage therapy post-PD1, progression free survival 2 (PFS2) and objective response rate 2 (ORR2) were also calculated. Toxicities were graded per CTCAE v5.0. Results: A total of 39 patients diagnosed with CSCC received at least one cycle of PD-1 therapy; among these 8 were excluded from efficacy analysis. Patients were on average 68 years old (range 22-97), predominantly male (69.2%) and Caucasian (74.4%). The most common primary tumor location was head/neck (64.1%), followed by extremity (15.4%). The mean tumor diameter was 6.0 cm (4.5-7.5, 95% CI). The majority of tumors were either moderately (33.3%) or poorly (28.2%) differentiated. The most common sites of metastatic disease included lymph node (41.0%), skin/soft tissue (33.3%) and bone (25.6%). Patients received on average 7 cycles of PD-1 therapy (range 1-26) and were followed for median 13.8 months. ORR for all patients was 39.0%, including CR and PR in 7 (22.6%) and 4 (13.0%) patients, respectively; 10 patients (32.2%) achieved stable disease (SD), while 7 patients (22.6%) had progression of disease (PD). Median PFS was 6.8 months, while OS was 26.7 months. Among 10 patients receiving salvage therapy after PD-1, 6 (60.0%) received a platinum-containing regimen. Median PFS2 was 4.4 months, while ORR2 was 10.0% with 1 PR, 4 SD, and 5 with PD. PD-1 therapy was well tolerated with 13 patients (33.3%) experiencing Grade 1-2 toxicity and 2 patients (5.2%) experiencing Grade 3-4. Conclusions: In this study of long-term outcomes of CSCC patients treated with PD-1 blockade, we found that initial responses to PD-1 therapy were durable, although PFS2 was less durable for patients who required salvage therapy and ORR2 was low. Novel treatment options are needed for patients with advanced CSCC who do not achieve durable responses to PD-1 based therapy.

Radiotherapy for cutaneous squamous cell carcinoma: current standards and outlooks

Cutaneous squamous cell carcinoma accounts for 20 % of all malignant non-melanoma skin tumors, which is one of the most common cancers worldwide. Antitumor treatment is usually very effective: cure rate reaches 90 %, while local recurrence rate is 25 %. The main treatment option for primary skin cancers is surgery. The most significant risk factors for locoregional recurrence include tumor location (head and neck), size (&gt;2 cm), depth of invasion (&gt;4 mm), tumor differentiation grade, perineural invasion, immune system disorders (immunosuppression), severe concomitant diseases, and previous treatment.In patients with advanced cutaneous squamous cell carcinoma, 1-year, 2-year, and 3-year survival rates are 50–80, 30–35 and 15–16 %, respectively. Radiotherapy is a radical treatment option that increases the 5-year survival rate to 90 % and ensures good cosmetic results in 80 % of cases. There are 3 main variants of radiotherapy for cutaneous squamous cell carcinoma: sole radiotherapy according to a radical program, adjuvant radiotherapy in combination with surgery, and palliative radiotherapy. most frequently, radiotherapy is used as part of adjuvant postoperative treatment and is not initially considered as a sole conservative treatment for cutaneous squamous cell carcinoma patients below 45 years of age with resectable tumors, especially high-risk tumors. palliative radiotherapy is an affordable and effective method for combating painful symptoms; moreover, it often provides long-term local control.

Whole genome analysis reveals the genomic complexity in metastatic cutaneous squamous cell carcinoma.

Metastatic cutaneous squamous cell carcinoma (CSCC) is a highly morbid disease requiring radical surgery and adjuvant therapy, which is associated with a poor prognosis. Yet, compared to other advanced malignancies, relatively little is known of the genomic landscape of metastatic CSCC. We have previously reported the mutational signatures and mutational patterns of CCCTC-binding factor (CTCF) regions in metastatic CSCC. However, many other genomic components (indel signatures, non-coding drivers, and structural variants) of metastatic CSCC have not been reported. To this end, we performed whole genome sequencing on lymph node metastases and blood DNA from 25 CSCC patients with regional metastases of the head and neck. We designed a multifaceted computational analysis at the whole genome level to provide a more comprehensive perspective of the genomic landscape of metastatic CSCC. In the non-coding genome, 3′ untranslated region (3′UTR) regions of EVC (48% of specimens), PPP1R1A (48% of specimens), and ABCA4 (20% of specimens) along with the tumor-suppressing long non-coding RNA (lncRNA) LINC01003 (64% of specimens) were significantly functionally altered (Q-value < 0.05) and represent potential non-coding biomarkers of CSCC. Recurrent copy number loss in the tumor suppressor gene PTPRD was observed. Gene amplification was much less frequent, and few genes were recurrently amplified. Single nucleotide variants driver analyses from three tools confirmed TP53 and CDKN2A as recurrently mutated genes but also identified C9 as a potential novel driver in this disease. Furthermore, indel signature analysis highlighted the dominance of ID signature 13 (ID13) followed by ID8 and ID9. ID9 has previously been shown to have no association with skin melanoma, unlike ID13 and ID8, suggesting a novel pattern of indel variation in metastatic CSCC. The enrichment analysis of various genetically altered candidates shows enrichment of “TGF-beta regulation of extracellular matrix” and “cell cycle G1 to S check points.” These enriched terms are associated with genetic instability, cell proliferation, and migration as mechanisms of genomic drivers of metastatic CSCC.

The efficacy and safety of cemiplimab in locally advanced or metastatic cutaneous squamous cell carcinoma: A comparative analysis of retrospective studies versus prospective studies.

Cemiplimab has been widely recommended by international guidelines to treat patients with locally advanced or metastatic cutaneous squamous cell carcinoma (CSCC). In this study, we conducted a comparative analysis to integrate the efficacy and safety data in the published prospective and retrospective studies for better understanding the application of cemiplimab. The online databases (PubMed, Cochrane CENTRAL, Web of Science, and EMBASE) were searched to find out eligible studies from inception to November 4, 2021. The "R" software and the "meta" package were used to synthesize the objective response rates (ORRs), disease control rates (DCRs), and the incidences of treatment-related adverse events (TRAEs). Overall, three retrospective studies with 398 patients and three prospective studies with 219 patients were enrolled. The pooled ORR and DCR were 53% (95% confidence interval [CI] 46-59) and 70% (95% CI 57-82) for retrospective studies versus 45% (95% CI 39-52) and 68% (95% CI 56-79) for prospective studies. In regard of toxicities, prospective studies reported much higher incidences of any grade (99% vs. 47%) and grade 3-4 TRAEs (43% vs. 15%) against retrospective studies. The most reported TRAE was fatigue, followed by diarrhea and pruritus. In addition, nine treatment-related deaths (four in retrospective studies vs. five in prospective studies) were documented. In both retrospective and prospective clinical practices, cemiplimab could be an effective regimen for locally advanced or metastatic CSCC patients, but toxicities during the treatment deserve further attention.

Advanced or Metastatic Cutaneous Squamous Cell Carcinoma: The Current and Future Role of Radiation Therapy in the Era of Immunotherapy.

Simple SummaryNodal and distant metastases of cutaneous squamous cell carcinomas are very rare and lead to dismal prognoses. Immunotherapy is approved only for cutaneous squamous cell carcinoma patients not amenable to surgery or curative radiation therapy. Radiation therapy has a clear role as an adjuvant treatment for locally advanced disease. Radiation therapy may also have an important role in inoperable and metastatic disease. Oligometastatic disease is a condition that needs to be defined for this carcinoma. This review aims to offer to the readers a comprehensive overview of studies about the role of radiotherapy in the management of advanced or metastatic cutaneous squamous cell carcinomas, also assuming possible further developments in the light of the recent discoveries about tumor biology. The present paper has the merit of re-focusing great attention on the efficacy and cost-effectiveness of radiotherapy in these not yet properly explored scenarios.Radiation therapy (RT) is an effective therapeutic option for small localized cutaneous squamous cell carcinoma (cSCC) among patients who are not eligible for or refuse surgery. RT also has a defined role as an adjuvant treatment in cases of adverse features that predispose to tumor recurrence after local excision. Since the development of cSCC is often a late consequence of chronic sun exposure, its occurrence is more common among elderly patients whose comorbidities may contraindicate surgical procedures. These could be impeded not only by frail medical conditions but also by technical issues. Indeed, an aggressive locoregional behavior of cSCC may culminate in unresectability due to widespread invasion of neighboring tissues. Moreover, cSCC could develop distant metastases. Both locally advanced and metastatic cSCCs carry a poor prognosis. In these scenarios, recent discoveries of tumor molecular targets are promoting the use of promising systemic therapies, especially immunotherapy, over RT. However, the results from using immunotherapy and, even more so, of chemotherapy are still not optimal. By contrast, advances in radiation delivery equipment can safely treat even large and complex-shaped cSCC targets in challenging body sites. In addition, RT could also have a role in metastatic cSCC settings by enhancing the effectiveness of concomitant immunotherapy. The aim of this review is to summarize and comment on the body of literature about the use of radiotherapy for operable and inoperable locally advanced cSCCs and for metastatic ones in an attempt to define its current and future role.

Clinicopathological characteristics and clinical morbidity in high-risk head and neck cutaneous squamous cell carcinoma patients in Western Australia.

BackgroundThere is no registry data on morbidity and mortality of high‐risk cutaneous squamous cell carcinoma (cSCC) in Australia.AimTo examine the clinicopathological features, mortality and morbidity in high‐risk cSCC patients in Western Australia (WA).MethodsA retrospective cohort study was conducted through hospital record review on cSCC patients discussed at multidisciplinary meetings at the two largest WA hospitals between March 2015 and December 2016.ResultsOf 141 patients, 129 were evaluable, with median follow up of 43.9 (range 3.0–53.2) months. Patients were predominantly older males (84%) with significant comorbidities (Charlson Comorbidity Index (CCI) ≥5; 76%) and history of previous nonmelanoma skin cancer (57%) with advanced disease (57% stage IV without distant metastasis; American Joint Committee on Cancer, 7th edition). Pathological high‐risk features were common including nodal extracapsular extension (47%) and cranial nerve involvement (16%). Clinical morbidity was significant with a median of 2 (range 0–13) excisions and 2 (range 0–21) cSCC‐related hospitalisations for any cSCC event following the index case discussion. Recurrences of the primary index lesion occurred in 60% of patients and 20% had ≥2 recurrences. Median overall survival for patients with nonmetastatic disease was 39.8 (range 25.9–53.7) months and 16.1 (range 0.2–32.0) months for metastatic disease. CCI ≥5, advanced nodal stage and ≥2 recurrences were significantly associated with mortality on multivariable analyses (P < 0.05). Nodal extracapsular extension and any recurrences were identified as significant risk factors for disease‐specific mortality on multivariable analyses (P < 0.05).ConclusionHigh‐risk cSCC patients have significant health needs represented by high‐baseline comorbidities, multiplicity of cSCC events and the number of healthcare‐associated interventions. There is an unmet need for robust cancer data collection.

Immunotherapy Response in Cutaneous Squamous Cell Carcinoma Patients with Cranial Nerve Involvement

Purpose/Objective(s) Immunotherapy (IO) with cemiplimab or pembrolizumab is approved for treatment of metastatic or locally advanced cutaneous squamous cell carcinoma (cSCC). There is evidence of objective response to these anti-PD-1 agents in locally advanced cSCC. Cranial nerve (CN) involvement is seen in less than 5% of cSCC and is a poor prognostic factor. Radiotherapy (RT) can be used for locally advanced cSCC, however comprehensive delineation and eradication of perineural invasion can be challenging. To our knowledge, there are no published studies indicating how patients with CN involvement respond to IO. Materials/Methods Patients were identified and retrospectively reviewed under an Institutional Review Board approved protocol at a tertiary care center. Selection criteria included histologically proven locally advanced cSCC of the head and neck cancer with CN involvement treated with IO. Results A total of 8 patients met inclusion criteria; demographic, disease, and treatment characteristics are summarized in Table 1. Most patients were men, with a median age at diagnosis of 74 years and had a median follow-up of 8.4 months. All received cemiplimab 350 mg intravenously every 3 weeks; 1 patient was initially treated with pembrolizumab, then transitioned to cemiplimab. 2 patients received IO for recurrence of previously diagnosed locally advanced cSCC, 1 of which had prior treatment with cetuximab and RT. 6 patients presented with CN involvement at diagnosis, and the additional 2 at time of recurrence after previous non-IO therapy. 1 patient treated with IO was immunosuppressed due to CLL and also had nodal involvement. 4 patients received RT prior to IO, and 1 patient received stereotactic radiosurgery (SRS) concurrent with IO. 3 patients never received RT and all had clinical benefit with IO: 2 having stable disease (SD) and 1 partial response (PR). Overall, 4 patients had PR, 2 SD and 2 progressive disease (PD) as best response. 5 patients are alive at last follow up, 1 completed a full year of IO and is currently off treatment, and 4 remain on IO treatment. Conclusion In this limited cohort of patients with locally advanced cSCC with CN involvement, IO has shown clinical benefit in 75% of the cases. All patients treated with IO alone demonstrated a clinical response, indicating IO can be an effective monotherapy. Given the challenges of RT with extensive perineural invasion, RT can be reserved in the event of local failure after IO. Immunotherapy (IO) with cemiplimab or pembrolizumab is approved for treatment of metastatic or locally advanced cutaneous squamous cell carcinoma (cSCC). There is evidence of objective response to these anti-PD-1 agents in locally advanced cSCC. Cranial nerve (CN) involvement is seen in less than 5% of cSCC and is a poor prognostic factor. Radiotherapy (RT) can be used for locally advanced cSCC, however comprehensive delineation and eradication of perineural invasion can be challenging. To our knowledge, there are no published studies indicating how patients with CN involvement respond to IO. Patients were identified and retrospectively reviewed under an Institutional Review Board approved protocol at a tertiary care center. Selection criteria included histologically proven locally advanced cSCC of the head and neck cancer with CN involvement treated with IO. A total of 8 patients met inclusion criteria; demographic, disease, and treatment characteristics are summarized in Table 1. Most patients were men, with a median age at diagnosis of 74 years and had a median follow-up of 8.4 months. All received cemiplimab 350 mg intravenously every 3 weeks; 1 patient was initially treated with pembrolizumab, then transitioned to cemiplimab. 2 patients received IO for recurrence of previously diagnosed locally advanced cSCC, 1 of which had prior treatment with cetuximab and RT. 6 patients presented with CN involvement at diagnosis, and the additional 2 at time of recurrence after previous non-IO therapy. 1 patient treated with IO was immunosuppressed due to CLL and also had nodal involvement. 4 patients received RT prior to IO, and 1 patient received stereotactic radiosurgery (SRS) concurrent with IO. 3 patients never received RT and all had clinical benefit with IO: 2 having stable disease (SD) and 1 partial response (PR). Overall, 4 patients had PR, 2 SD and 2 progressive disease (PD) as best response. 5 patients are alive at last follow up, 1 completed a full year of IO and is currently off treatment, and 4 remain on IO treatment. In this limited cohort of patients with locally advanced cSCC with CN involvement, IO has shown clinical benefit in 75% of the cases. All patients treated with IO alone demonstrated a clinical response, indicating IO can be an effective monotherapy. Given the challenges of RT with extensive perineural invasion, RT can be reserved in the event of local failure after IO.

Real-world Treatment Patterns and Outcomes with Systemic Therapies in Unresectable Locally Advanced and Metastatic Cutaneous Squamous Cell Carcinoma in Germany.

Advanced cutaneous squamous cell carcinoma is a challenge to treat. Conventional systemic treatment options include chemotherapy and epidermal growth factor receptor-inhibitors. The aim of this study was to assess clinical outcomes with systemic treatments in advanced cutaneous squamous cell carcinoma. Patients receiving systemic treatment at the Tübingen Dermato-Oncology centre between 2007 and 2017 were identified (n = 59). Median age was 76 years (interquartile range (IQR) 71-80 years), 83.1% of patients were male, 72.9% had metastatic cutaneous squamous cell carcinoma, and 27.1% had unresectable locally advanced cutaneous squamous cell carcinoma. During median follow-up of 52 weeks (IQR 27-97 weeks), overall response rate was 14.3%, and disease control rate was 53.6%. Median progression-free survival was 15 weeks (IQR 8-42 weeks), and median overall survival was 52 weeks (IQR 27-97 weeks). Patients receiving chemoradiation vs chemotherapy alone showed better overall survival (hazard ratio 0.41, p = 0.014,) and progression-free survival (hazard ratio 0.42, p = 0.009); no differences were observed for metastatic cutaneous squamous cell carcinoma vs locally advanced cutaneous squamous cell carcinoma patients. Although chemotherapy and/or cetuximab showed limited outcomes in advanced cutaneous squamous cell carcinoma, such therapy may still be an option when anti-PD-1 treatment is contraindicated.

The Fgl2 interaction with Tyrobp promotes the proliferation of cutaneous squamous cell carcinoma by regulating ERK-dependent autophagy.

Human fibroleukin 2 (Fgl2), a member of the fibrinogen superfamily, can cleave prothrombin to generate thrombin or is secreted in a soluble form as a new type of effector of Tregs with immunomodulatory functions. However, there is little research on the role of Fgl2 in cutaneous squamous cell carcinoma (CSCC) growth. We examined the expression of Fgl2 in samples from CSCC patients and CSCC cell lines. Then, the effect of Fgl2 on CSCC was evaluated in vitro and in animals. Regulation of autophagy by Fgl2 was explored in CSCC. Coimmunoprecipitation (Co-IP) and immunofluorescence colocalization experiments were conducted to identify the regulatory effect of Fgl2 on the downstream protein Tyrobp. Then, gain- or loss-of-function analyses and evaluation of Tyrobp expression were performed to validate its role in autophagy and proliferation promoted by Fgl2. Here, our study demonstrated that Fgl2 promoted the proliferation of CSCC cells in vitro and in vivo. Knocking down Fgl2 reduced CSCC cell proliferation and inhibited autophagy in CSCC. Mechanistically, Fgl2 interacted with Tyrobp and promoted ERK-dependent autophagy, resulting in the proliferation of CSCC cells. Our study suggested that Fgl2 could be a promising prognostic biomarker and useful therapeutic target for CSCC.

Circular RNA circ-LARP1B contributes to cutaneous squamous cell carcinoma progression by targeting microRNA-515-5p/TPX2 microtubule nucleation factor axis

ABSTRACT Circular RNAs (circRNAs) have shown pivotal regulatory roles in tumorigenesis and progression. Our purpose was to analyze the role of circRNA La ribonucleoprotein 1B (circ-LARP1B; hsa_circ_0070934) in cutaneous squamous cell carcinoma (CSCC) progression and its associated mechanism. Cell viability, colony formation ability, migration, and invasion were analyzed by 3-(4, 5-dimethylthiazol-2-yl)-2, 5 diphenyltetrazolium bromide (MTT) assay, colony formation assay, wound healing assay, and transwell invasion assay. Flow cytometry was performed to analyze cell apoptosis and cell cycle progression. Cell glycolytic metabolism was analyzed using Glucose Uptake Colorimetric Assay kit, Lactate Assay Kit II, and ATP colorimetric Assay kit. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were performed to verify the interaction between microRNA-515-5p (miR-515-5p) and circ-LARP1B or TPX2 microtubule nucleation factor (TPX2). Circ-LARP1B expression was up-regulated in CSCC tissues and cell lines. Circ-LARP1B knockdown suppressed cell viability, colony formation ability, migration, invasion, cell cycle progression, and glycolysis and triggered cell apoptosis in CSCC cells. miR-515-5p was a direct target of circ-LARP1B in CSCC cells, and circ-LARP1B silencing-mediated anti-tumor effects were largely counteracted by miR-515-5p knockdown. miR-515-5p directly interacted with the 3ʹ untranslated region (3ʹUTR) of TPX2. TPX2 overexpression largely overturned miR-515-5p-mediated anti-tumor effects in CSCC cells. Circ-LARP1B could up-regulate TPX2 expression by sponging miR-515-5p in CSCC cells. Circ-LARP1B knockdown suppressed tumor growth in vivo. In conclusion, circ-LARP1B contributed to CSCC progression by targeting miR-515-5p/TPX2 axis. The circ-LARP1B/miR-515-5p/TPX2 axis might provide novel therapeutic targets for CSCC patients.

Enhanced metastatic risk assessment in cutaneous squamous cell carcinoma with the 40-gene expression profile test.

Aim: To clinically validate the 40-gene expression profile (40-GEP) test for cutaneous squamous cell carcinoma patients and evaluate coupling the test with individual clinicopathologic risk factor-based assessment methods. Patients & methods: In a 33-site study, primary tumors with known patient outcomes were assessed under clinical testing conditions (n=420). The 40-GEP results were integrated with clinicopathologic risk factors. Kaplan-Meier and Cox regression analyses were performed for metastasis. Results: The 40-GEP test demonstrated significant prognostic value. Risk classification was improved via integration of 40-GEP results with clinicopathologic risk factor-based assessment, with metastasis rates near the general cutaneous squamous cell carcinoma population for class 1 and ≥50% for class 2B. Conclusion: Combining molecular profiling with clinicopathologic risk factor assessment enhances stratification of cutaneous squamous cell carcinoma patients and may inform decision-making for risk-appropriate management strategies.

HOTAIR/Sp1/miR-199a critically regulates cancer stemness and malignant progression of cutaneous squamous cell carcinoma.

The long non-coding RNA (lncRNA), HOX antisense intergenic RNA (HOTAIR) is a well-characterized oncogene in multiple human cancers, but not in cutaneous squamous cell carcinoma (CSCC). In this study, we focused on investigating the potential role of HOTAIR in stemness of CSCC. By measuring its expression using RT-qPCR in CSCC vs. normal tissues, as well as in CSCC cell lines A431 or SCC13, A431- or SCC13-derived CSCC stem cells (CSCSCs), and normal skin fibroblasts (HSFs), we detected higher expression of HOTAIR in CSCC than in normal tissues, in recurrent than in non-recurrent CSCC tissues, in CSCCs and CSCSCs than in HSFs, and particularly, in CSCSCs than in CSCCs. Kaplan-Meier analysis suggested that higher expression of HOTAIR was positively correlated with worse overall survival of CSCC patients. Functional assays on colony formation, EdU incorporation, sphere formation, western blot on stem-cell biomarkers, and in vivo models showed that HOTAIR was essential in maintaining multiple stem cell phenotypes of CSCSCs in vitro and in vivo xenograft growth as well as metastasis. Mechanistically, HOTAIR directly interacted with and up-regulated Sp1. Sp1 then induced DNMT1-mediated promoter methylation and direct transcriptional repression of miR-199a-5p. Targeting Sp1 or DNMT1 further boosted the in vivo anti-tumor and anti-metastasis activities of targeting HOTAIR. In conclusion, HOTAIR, by up-regulating Sp1 and targeting miR-199a, promotes stemness and progression of CSCC. Targeting HOTAIR, Sp1 or the underlying mechanisms may thus benefit CSCC treatment.

Predictors of Recurrence and Survival in High-Stage Primary Cutaneous Squamous Cell Carcinoma: A Recursive Partitioning Analysis

<h3>Purpose/Objective(s)</h3> High stage cutaneous squamous cell carcinoma (CSCC) has an elevated risk of recurrence (5-25%). Current staging systems stratify patients rely on tumor factors only. We sought to develop an RPA incorporating patient-, tumor-, disease-, and treatment-related factors to identify prognostic subgroups for high-stage CSCC patients receiving definitive therapy. <h3>Materials/Methods</h3> All high-stage CSCCs, defined as Brigham & Women's Hospital (BWH) tumor (T) staging system T2B and T3, treated with curative intent were included. Recurrence-free survival (RFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared by log rank test. Recursive partitioning analysis (RPA) was performed to identify prognostic factors for RFS and OS. <h3>Results</h3> A total of 444 patients (76% male, 95% Caucasian, median age 74 years) with 523 primary tumors were included. Median follow up was 31 months (range 1-194). 31% of patients were immunosuppressed (organ transplant 13%, chronic lymphocytic leukemia (CLL) 14%, and other reasons 3%). 432 tumors were BWH T2b and 91 were BWH T3, of whom 12% were node-positive, 32% node-negative, and 56% unknown nodal status. 33% of patients experienced recurrence. Immunosuppression, recurrent tumor, perineural invasion (PNI), and lymphovascular space invasion (LVSI) were associated with significantly worse RFS (median RFS 23 months, 95% CI, 19-28), while immunosuppression, lymph node positivity, and extranodal extension (ENE) were associated with significantly worse OS (median OS 40 months, 95% CI, 33-46). RPA identified 4 prognostic subgroups with distinct RFS patterns (<i>P</i> < 0.0001): class I included age < 77 years without LVSI (N = 212, 2-year RFS: 63%; 95% CI, 56-70%), class II included age ≥ 77 years without PNI (N = 132, 2-year RFS: 44%, 95% CI, 36-55%), class III included age < 77 years with LVSI (N = 36, 2-year RFS: 29%; 95% CI, 17-50%), and class IV included age ≥ 77 years with PNI (N = 60, 2-year RFS: 25%; 95% CI, 15-41%). RPA identified 4 prognostic subgroups with distinct OS patterns (<i>P</i> < 0.0001): class I included age < 78 years and ≤ 1 lymph node positive (N = 221, 2-year OS: 84%; 95% CI, 79-90%), class II included age ≥ 78 years and no or immunosuppression other than CLL (N = 141, 2-year OS: 64%; 95% CI, 55-73%), class III included age < 78 years and > 1 lymph node positive (N = 48, 2-year OS: 54%; 95% CI, 41-71%), and class IV included age ≥ 78 years and immunosuppression from CLL (N = 34, 2-year OS: 37%; 95% CI, 23-57%). <h3>Conclusion</h3> An RPA classification system was created for patients with high-stage primary CSCC treated with definitive intent that identifies 4 prognostic subgroups associated with recurrence-free survival and overall survival based on age, LVSI, PNI, burden of nodal metastasis, and immunosuppression status. This has implications for patient counselling, clinical trial design and post-treatment surveillance.

Serum Sialylation Changes in Actinic Keratosis and Cutaneous Squamous Cell Carcinoma Patients.

Cutaneous squamous cell carcinoma (cSCC), a malignant proliferation of the cutaneous epithelium, is the second most common skin cancer after basal cell carcinoma (BCC). Unlike BCC, cSCC exhibits a greater aggressiveness and the ability to metastasize to any organ in the body. Chronic inflammation and immunosuppression are important processes linked to the development of cSCC. The tumor can occur de novo or from the histological transformation of preexisting actinic keratoses (AK). Malignant cells exhibit a higher amount of sialic acid in their membranes than normal cells, and changes in the amount, type, or linkage of sialic acid in malignant cell glycoconjugates are related to tumor progression and metastasis. The aim of our study was to investigate the sialyation in patients with cSCC and patients with AK. We have determined the serum levels of total sialic acid (TSA), lipid-bound sialic acid (LSA), beta-galactoside 2,6-sialyltransferase I (ST6GalI), and neuraminidase 3 (NEU3) in 40 patients with cSCC, 28 patients with AK, and 40 healthy subjects. Data analysis indicated a significant increase in serum levels of TSA (p < 0.001), LSA (p < 0.001), ST6GalI (p < 0.001), and NEU3 (p < 0.001) in the cSCC group compared to the control group, whereas in patients with AK only the serum level of TSA was significantly higher compared to the control group (p < 0.001). When the cSCC and AK groups were compared, significant differences between the serum levels of TSA (p < 0.001), LSA (p < 0.001), ST6GalI (p < 0.001) and NEU3 (p < 0.001) were found. The rate of synthesis of sialoglycoconjugates and their rate of enzymatic degradation, expressed by the ST6GalI/NEU3 ratio, is 1.64 times lower in the cSCC group compared to the control group (p < 0.01) and 1.53 times lower compared to the AK group (p < 0.01). The tumor diameter, depth of invasion, and Ki67 were associated with higher levels of TSA and LSA. These results indicate an aberrant sialylation in cSCC that correlates with tumor aggressiveness.