Aggressive Squamous Cell Carcinoma Research Articles

Treatment benefit of electrochemotherapy for superficial squamous cell carcinoma: a systematic review and single-arm meta-analysis.

Treating aggressive superficial squamous cell carcinoma (SCC) poses challenges due to invasiveness. Palliative care is recommended for inoperable cases with extensive tumors near vital organs, risking disfigurement or functional impairment. Electrochemotherapy (ECT) is an emerging cutaneous tumor treatment, but its efficacy against superficial SCC remains uncertain. This study conducts a systematic review and single-arm meta-analysis to evaluate ECT's effectiveness against superficial SCC and provide current evidence for clinical practice. Embase, PubMed and Cochrane Library were searched for studies up to May 2023. The random effects model analyzed complete response (CR) and partial response (PR), with subgroup assessment based on drug dosage, treatment response evaluation, tumor size, primary/recurrent status, and tumor location. Ten studies involving 162 patients and 208 tumors were included. Pooled CR and PR rates for ECT-treated superficial SCC were 66.5% (95% CI 48.4%-82.5%; I2 = 84%) and 20.3% (95% CI 10.5%-32.3%; I2 = 70%), respectively. Subgroup analysis indicated ECT's superiority in treating primary tumors (PR: 70%, CR: 30%) and tumors ≤ 3cm (PR: 81.3%, CR: 10.1%) compared to recurrent tumors (PR: 56.7%, CR: 36.5%) and tumors > 3cm (PR: 45.2%, CR: 34.4%). This single-arm meta-analysis confirms ECT's efficacy against superficial SCC, especially in primary tumors and those ≤ 3cm in diameter. The study highlights the impact of tumor location and response evaluation on ECT's benefits, warranting further investigation through additional research.

P37 Drug repurposing for treatment of recessive dystrophic epidermolysis bullosa cutaneous squamous cell carcinoma

Abstract Background Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited skin disorder that leads to severe wounding and blistering of the skin. Patients with RDEB develop aggressive cutaneous squamous cell carcinoma (cSCC) with a mortality rate of approximately 90% by age 55 years. The current primary treatment is wide excision of tumours, often leading to amputations. Identifying new therapeutic avenues for RDEB cSCC remains a priority. Here, we approach this in two ways. Firstly, we identified a SMAD4-dependent sphingosine pathway response to endogenous transforming growth factor (TGF)-β, essential for RDEB cSCC proliferation which could be targeted as a potential therapeutic strategy. Secondly, we utilized a US Food and Drug Administration (FDA) screen of > 3000 drugs to identify potential druggable pathways that could be used to treat RDEB cSCC. Methods RDEB cSCC cell lines were used to test Siponimod, a sphingosine-1 receptor modulator, on proliferation, clonogenicity and invasion in vitro. Siponimod was used in vivo to test tumour growth effect of targeting the sphingosine pathway. We carried out an FDA-approved drug screen on four RDEB cSCC cell lines using the Opera Phenix high-throughput microscope to identify targets. Results Treatment of RDEB cSCC cell lines with Siponimod showed compromised proliferation compared with untreated cells in addition to significant reduction in colony formation. There was a significant decrease in the invasive capability of RDEB SCC cells. Treatment of normal human keratinocytes showed no effect on proliferation. Our FDA-approved screen identified multiple drugs that target MEK, mechanistic target of rapamycin complex, histone deacetylase, signal transducer and activator of transcription, and topoisomerase I/II in the top 50 hits. The most common target was DNA damage/repair pathways, but cytoskeletal signalling, transmembrane transporters and proteases were identified as other potential avenues for treatment of RDEB cSCC. Conclusions There is an unmet need for therapeutic options in RDEB cSCC. Here, we have demonstrated the potential of repurposing previously licensed drugs to identify treatment avenues for RDEB cSCC.

Retraction: DNA methylation-mediated repression of exosomal miR-652-5p expression promotes oesophageal squamous cell carcinoma aggressiveness by targeting PARG and VEGF pathways.

Retraction: DNA methylation-mediated repression of exosomal miR-652-5p expression promotes oesophageal squamous cell carcinoma aggressiveness by targeting PARG and VEGF pathways.

A Case of Aggressive Lung Squamous Cell Carcinoma With Aberrant Cytoplasmic p53 Aggregation.

Immunohistochemistry for p53 was a well-established method for cancer diagnosis in pathology. Aberrant cytoplasmic p53 positivity reflects the accumulation of p53 aggregates, which has been shown to be associated with chemoresistance and to be a predictive marker of a worse clinical course in ovarian cancer. A 65-year-old Japanese man was diagnosed with lung cancer, and surgical resection was performed. Multiple metastasis were found 21 months post-surgery. The lesions were resistant to chemotherapy, and he succumbed to the disease 29 months post-surgery. The resected primary lesion was pathologically diagnosed as squamous cell carcinoma, with notable cytoplasmic p53 positivity indicated by immunohistochemistry. Notable aberrant cytoplasmic accumulation of p53 aggregate was observed in the cancer cells of this case. Chemotherapy was ineffective for the recurrent lesions, suggesting a role of p53 aggregates in chemoresistance. Pathological analysis of p53 via immunohistochemistry may be useful in predicting chemoresistance of lung squamous cell carcinoma.

A Sub-Group of Kidney-Transplant Recipients with Highly Aggressive Squamous Cell Carcinoma Expressing Phosphorylated Serine392p53.

Cutaneous squamous cell carcinomas in kidney-transplant recipients are frequent, with an increasing incidence linked to long immunosuppression durations and exposure to ultraviolet radiation. p53 is at the cornerstone of ultraviolet-induced DNA damage, but the role of p53 post-translational modifications in this context is not yet deciphered. Here, we investigated the phosphorylation status of p53 at Serine 392 in 25 cutaneous squamous cell carcinomas in kidney-transplant recipients, compared with 22 non-transplanted patients. Cutaneous squamous cell carcinomas in transplanted patients occurred after a median period of 19 years of immunosuppression, with a median number of 15 cutaneous squamous cell carcinomas and more aggressive histological and clinical characteristics. There was no significant difference between Ki67, p53, and pSer392p53 expression in the two groups. Using principal component analysis, we identified a cluster of exclusively transplanted patients with a median of 23 years of immunosuppression duration, significantly more aggressive biological characteristics, and higher pSer392p53 expression. pSer392p53 was expressed in the whole tumor, suggesting an early carcinogenic event in the course of prolonged immunosuppression. This high, diffuse pSer392p53 expression, corresponding to a high level of DNA damage, might be useful to identify aggressive cutaneous squamous cell carcinomas in kidney-transplant recipients to treat them more aggressively.

A-286 - Examining the Association Between Ruxolitinib and Aggressive Cutaneous Squamous Cell Carcinoma: Is There a Justified Need for Screening Programs?

A-286 - Examining the Association Between Ruxolitinib and Aggressive Cutaneous Squamous Cell Carcinoma: Is There a Justified Need for Screening Programs?

Metformin shows anti-neoplastic properties by inhibition of oxidative phosphorylation and glycolysis in epidermolysis bullosa-associated aggressive cutaneous squamous cell carcinoma.

While most cutaneous squamous cell carcinomas (cSCCs) are treatable, certain high-risk cSCCs, such as those in recessive dystrophic epidermolysis bullosa (RDEB) patients, are particularly aggressive. Owing to repeated wounding, inflammation and unproductive healing, RDEB patients have a 68% cumulative risk of developing life-threatening cSCCs by the age of 35, and a 70% risk of death by the age of 45. Despite aggressive treatment, cSCC represents the leading cause of premature mortality in these patients, highlighting an unmet clinical need. Increasing evidence points to a role of altered metabolism in the initiation and maintenance of cSCC, making metabolism a potential therapeutic target. We sought to determine the feasibility of targeting tumour cell energetics as a strategy to selectively hinder the growth advantage of aggressive cSCC. We evaluated the cell energetics profiles of RDEB-SCC cells by analysing available gene expression data against multiple gene signatures and single-gene targets linked to metabolic reprogramming. Additionally, we employed real-time metabolic profiling to measure glycolysis and respiration in these cells. Furthermore, we investigated the anti-neoplastic properties of the metformin against human and murine high-risk cSCCs in vitro and in vivo. Gene expression analyses highlighted a divergence in cell energetics profiles between RDEB-SCC and non-malignant RDEB keratinocytes, with tumour cells demonstrating enhanced respiration and glycolysis scores. Real-time metabolic profiling supported these data and additionally highlighted a metabolic plasticity of RDEB-SCC cells. Against this background, metformin exerted an anti-neoplastic potential by hampering both respiration and glycolysis, and by inhibiting proliferation in vitro. Metformin treatment in an analogous model of fast-growing murine cSCC resulted in delayed tumour onset and slower tumour growth, translating to a 29% increase in median overall survival. Our data indicate that metformin exerts anti-neoplastic properties in aggressive cSCCs that exhibit high-risk features by interfering with respiration and glycolytic processes.

MiRNAs that target amyloid precursor protein processing machinery in extracellular vesicles and particles derived from oral squamous cells carcinoma.

Considering that microRNAs (miRNAs), extracellular vesicles and particles (EVPs) and the amyloid precursor protein (APP) processing have been shown to be altered in oral squamous cells carcinoma (OSCC), it is possible that miRNAs that target APP processing pathways in EVPs are impacted in tumor cells. Our aim was to evaluate miRNAs that target APP itself or disintegrin and metalloproteinase domain 10 (ADAM10), which generate a trophic compound, sAPPα, in EVPs derived from OSCC cell lines, an aggressive and non-invasive, compared to normal keratinocytes. We used two OSCC cell lines, an aggressive human oral squamous cell carcinoma cell line (SCC09) and a less aggressive cell line (CAL27) compared with a keratinocyte lineage (HaCaT). Cells were maintained in cell media, from which we isolated EVPs. EVPs were evaluated regarding their size and concentration using Nanotracking Analysis. We measured the levels of miRNAs which had as potential downstream target APP or ADAM10, specifically miR-20a-5p, miR-103a-3p, miR-424-5p, miR-92b-3p, miR-31-5p, and miR-93-5. There were no differences on size distributions and concentration of isolated EVPs. OSCC cell lines-derived EVPs miR-20a-5p, miR-92b-3p, and miR-93-5p were upregulated in comparison to HaCaT-derived EVPs; while miR-31-5p was reduced in EVPs obtained from CAL27 cells. Our results indicate changes in miRNAs that target APP machinery processing in EVPs derived from OSCC cell lines of different aggressiveness, which may be involved with abnormal miRNA expression in OSCC tissue and/or releasing tumor suppressor miRNA.

Aggressive Cutaneous Squamous Cell Carcinoma of the Head and Neck: A Review.

Non-melanoma skin cancer of the head and neck (NMSCHN) is one of the most common malignancies worldwide, and its incidence is growing at a significant rate. It has been found to be aggressive in its spread and has the capacity to metastasize to regional lymph nodes. Cutaneous squamous cell carcinoma (cSCC) has a considerably high mortality rate. It has remarkable characteristics: diameter >2 cm, depth >5 mm, high recurrence, perineural invasion, and locoregional metastases. Aggressive cSCC lesions most commonly metastasize to the parotid gland. Also, immunocompromised patients have a higher risk of developing this aggressive cancer along with the worst prognostic outcomes. It is very important to discuss and assess the risk factors, prognostic factors, and outcomes of patients with cSCC, which will give clinicians future directives for making modifications to their treatment plans. The successful treatment of aggressive cSCC of the head and neck includes early detection and diagnosis, surgery alone or adjuvant chemotherapy, and radiotherapy as required. Multimodal therapy options should be considered by clinicians for better outcomes of aggressive cSCC of the head and neck.

P21 Tyrosine and serine STAT3 phosphorylation drives cutaneous squamous cell carcinoma in recessive dystrophic epidermolysis bullosa as demonstrated using a 3D in vitro model

Abstract The early onset of aggressive cutaneous squamous cell carcinoma (cSCC) and its rapid progression in recessive dystrophic epidermolysis bullosa (RDEB) leads to nearly 100% mortality rates in these patients. Elevated levels of phospho-STAT3 on tyrosine residue (STAT3Tyr705) have been intensively demonstrated in RDEB-derived cSCC cells, demonstrating that the constitutive activation and dysregulation of the Janus kinase (JAK)/STAT pathway plays a role in RDEB cSCC pathogenesis. We efficiently applied ruxolitinib (JAK1/2 inhibitor that blocks phosphorylation on STAT3Tyr705) to a RDEB–cSCC xenograph mouse model, reducing the size of small tumours but found that it was insufficient to reduce bigger tumours completely. Recently, phosphorylation at serine-727 (STAT3Ser727) has been shown to be relevant in the evolution of some cancers, but it has not yet been studied in RDEB cSCC. We hypothesized that phosphorylation at serine-727 of the STAT3 pathway might play a role in RDEB cSCC tumour development and progression, and could not be inhibited by ruxolitinib. To validate our hypothesis, we studied two RDEB cSCC human patient samples with different degrees of dedifferentiation (normal RDEB skin, edge of the tumour and centre of the RDEB cSCC). We demonstrated that STAT3Tyr705 was preferentially upregulated in the normal RDEB skin followed by the tumour edge skin, presenting less phosphorylation on the tumour. When we analysed STAT3 phosphorylation on STAT3Ser727, we could see that it presented the opposite phosphorylation pattern, being more phosphorylated in the tumour and less in normal RDEB skin. Furthermore, we validated the STAT3Ser727residue pattern across other cSCC cell lines and found that serine phosphorylation is present in other SCCs, demonstrating its crucial role in tumour development. To further investigate and analyse cancer progression in more detail, an easy and robust RDEB cSCC model is instrumental. Therefore, we generated RDEB cSCC spheroids in vitro, which has four key advantages over the previous models developed: (i) it is easy to generate; (ii) small amounts of cells are required; (iii) it is suitable for drug testing; and (iv) it can be used to recapitulate different stages of tumour development. We have been able to control their size and use them for drug testing, observing a 20% size decrease after 6 days of ruxolitinib treatment. Taken together, this three-dimensional RDEB cSCC in vitro model, along with analysis of human samples, will allow us to better understand RDEB cSCC progression at different stages, allowing us to investigate new treatments for RDEB cSCC.

A pilot, open study to assess efficacy and safety of ON-01910 (rigosertib) in patients with recessive dystrophic epidermolysis bullosa associated locally advanced/metastatic squamous cell carcinoma.

TPS9604 Background: Recessive Dystrophic Epidermolysis Bullosa (RDEB) is an extremely rare, severe blistering disease driven by mutations in collagen seven (COL7A1). Besides the skin and mucosal blistering, this genodermatosis is also characterized by aggressive cutaneous squamous cell carcinomas (cSCCs) arising from patients’ chronic wounds. The cumulative risk of death from these cSCCs is 70% by age 45. There are limited effective treatment options for advanced (unresectable/metastatic) RDEB-associated cSCCs. While the standard of care for any advanced cSCC is immune checkpoint inhibitors, only half of the treated patients had responses in clinical trials. Their use for RDEB-associated SCCs been limited to case reports, and our own experience has not been positive. Conventional chemotherapy in RDEB-associated cSCC is another proposed treatment strategy, however, case reports demonstrated limited response rates without lasting effects. Currently it is recommended palliatively, although there are concerns about adverse effects. Other existing options are tyrosine kinase inhibitors, resulting in mixed responses to treatment for advanced cSCCs of any type, and epidermal growth factor receptor inhibitors, demonstrating limited effectiveness in a small number of case reports on RDEB-associated cSCCs. More effective therapeutic modalities for advanced/metastatic RDEB-associated cSCCs are needed. We previously demonstrated that RDEB SCC keratinocytes are specifically affected by polo-like kinase-1 (PLK-1) siRNA. Eight PLK-1 inhibitors were screened for cytotoxicity. Of the 8 candidates, ON-01910 was superior as it demonstrated the largest therapeutic window for distinguishing between tumor versus normal cells. The ON-01910 clinical trial is in progress in patients with RDEB with advanced/metastatic cSCCs. Methods: ON-01910 is being evaluated in both oral and intravenous formulations in an open-label, non-randomized phase 2 study in RDEB patients with advanced, treatment resistant cSCC. The trial explores the anti-tumor activity of ON-01910 and evaluates its safety and tolerability. Secondary objectives are to assess the impact on quality of life and to perform biomarker analysis on patient tissue. This study began in August 2021 and is ongoing. One patient is currently enrolled in the oral arm at Thomas Jefferson University in the USA. Safety is assessed according to the CTCAE v5. Tumor response in lymph nodes is determined per the RECIST 1.1 and in skin via clinical examination with serial tumor measurements. Key eligibility criteria include 1) diagnosis of RDEB and associated measurable, advanced cSCC confirmed histologically 2) failure to respond to standard of care including excision for localized disease 3) no concomitant cancer therapies. Clinical trial information: NCT04177498 .

Association of Suppressive Myeloid Cell Enrichment with Aggressive Oropharynx Squamous Cell Carcinoma.

While immune-cell infiltrated tumors, such as human papillomavirus positive (HPV+) ororpharyngeal squamous cell carcinomas (OPSCC) have been associated with an improved clinical prognosis, there is evidence to suggest that OPSCCs are also subjected to increased immunoregulatory influence. The objective of this study was to assess whether patients with clinically aggressive OPSCC have a distinct immunosuppressive immune signature in the primary tumor. This retrospective case-control study analyzed 37 pre-treatment tissue samples from HPV+ and HPV-negative OPSCC patients treated at a single institution. The cases were patients with known disease recurrence and the controls were patients without disease recurrence. An mRNA-expression immune-pathway profiling was performed, and correlated to clinical outcomes. The TCGA head and neck cancer database was utilized to make comparisons with the institutional cohort. In our cohort, HPV-negative and HPV+ patients with known disease recurrence both had significantly increased suppressive monoctyte/macrophage and granulocyte cell-expression-profile enrichment. Similar findings were found in the TCGA cohort when comparing HPV-negative to positive patients. our study demonstrates that patients with recurrent HPV+ OPSCC had suppressive monocyte/macrophage and granulocyte immune-cell enrichment, similar to those seen in the more aggressive HPV-negative OPSCC.

Abstract LB252: HPV integration events are heterogenous, clonally selected and associated with spatially distinct transcriptomic profiles in aggressive HPV positive oropharyngeal squamous cell carcinoma

Abstract HPV positive Oropharyngeal Squamous Cell Carcinoma (HPV positive OPSCC) is rising in incidence and, for patients that recur, survival is extremely poor. Recent technological advances have led to a better understanding of patterns of HPV integration in primary tumors but have not yet tested the evolution of these events in deadly forms of the disease. Therefore, we performed multi-region sequencing analysis on a cohort of 34 recurrent and metastatic patients with HPV positive OPSCC (29% survival rate) plus one recurrent HPV positive model pair, UPCI-90 and UPCI-152. We then used our recently developed capture-based sequencing HPV integration caller and assembler pipeline, SearcHPV, to identify patterns of viral integration into the host genome and Oxford Nanopore long-read whole genome sequencing to validate the integration events in selected cases. In total, 1591 HPV integrations were called and assembled. Unexpectedly, our analysis revealed that HPV integration events are heterogenous as multiple independent integration events were observed in different spatial regions of the same tumor. Further, when comparing independent and anatomically distinct regions of recurrence from the same patient, independent integration events were also observed. Heterogeneity of integration structures was found to include variation of local HPV copy number, distribution of the specific HPV integration sites within the structures as well as distinct characteristics of rearrangement breakpoints (human-HPV, HPV-HPV, human-human). Given this observation, we then evaluated the hypothesis that HPV integration events could be clonally selected by comparing the integration profiles from a cohort of matched primary and recurrent tumors. In this cohort, 64 integration events (11 exact same; 53 clustered in the same genes) were maintained throughout tumor progression to recurrence, while other integration events were lost, supporting a model of clonal evolution with driver and passenger integrations. We then explored this further using one recurrent HPV positive model pair, UPCI-90 and UPCI-152, using long-read whole genome sequencing which validated the heterogeneity and clonal selection of HPV integration events. Finally, to test if differences in HPV integration content in spatially distinct regions could drive spatially distinct phenotypic differences, we performed multi-region RNA-seq analysis on 8 HPV16 positive OPSCCs, which demonstrated spatial differences in HPV16 E7 expression, that were validated with RNAscope assays, as well as statistically significant spatial enrichment of independent oncogenic gene sets. Collectively, we report evidence showing that HPV integration events are heterogenous, clonally selected during progression and associated with distinct transcriptomic profiles. Based on this data, we now propose a new working model of disease pathogenesis in which heterogeneity and clonal evolution of HPV integration events serve as a critical driver of the disease process. Citation Format: Wenjin Gu, Apurva Bhangale, Collin V. Brummel, Elizabeth Gensterblum-Miller, Matthew E. Spector, Ryan E. Mills, Chad Brenner. HPV integration events are heterogenous, clonally selected and associated with spatially distinct transcriptomic profiles in aggressive HPV positive oropharyngeal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB252.

Enrichment and nLC-MS/MS Analysis of Head and Neck Cancer Mucinome Glycoproteins.

Mucin-domain glycoproteins expressed on cancer cell surfaces play central roles in cell adhesion, cancer progression, stem cell renewal, and immune evasion. Despite abundant evidence that mucin-domain glycoproteins are critical to the pathobiology of head and neck squamous cell carcinoma (HNSCC), our knowledge of the composition of that mucinome is grossly incomplete. Here, we utilized a catalytically inactive point mutant of the enzyme StcE (StcEE447D) to capture mucin-domain glycoproteins in head and neck cancer cell line lysates followed by their characterization using sodium dodecyl-sulfate polyacrylamide gel electrophoresis (SDS-PAGE), in-gel digestion, nano-liquid chromatography-tandem mass spectrometry (nLC-MS/MS), and enrichment analyses. We demonstrate the feasibility of this workflow for the study of mucin-domain glycoproteins in HNSCC, identify a set of mucin-domain glycoproteins common to multiple HNSCC cell lines, and report a subset of mucin-domain glycoproteins that are uniquely expressed in HSC-3 cells, a cell line derived from a highly aggressive metastatic tongue squamous cell carcinoma. This effort represents the first attempt to identify mucin-domain glycoproteins in HNSCC in an untargeted, unbiased analysis, paving the way for a more comprehensive characterization of the mucinome components that mediate aggressive tumor cell phenotypes. Data associated with this study have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the data set identifier PXD029420.

Extratumoral invasion: A unique phenomenon of aggressive recurrent oropharyngeal squamous cell carcinoma

BackgroundOropharyngeal squamous carcinomas cause significant morbidity and mortality. Poor prognosticators include lymphovascular and perineural invasion. Extratumoral phenotypes of these histologic findings confer worse prognoses. MethodsWe report eight cases of recurrent oropharyngeal cancer with diffuse extratumoral lymphovascular invasion (ELVI) or extratumoral perineural invasion (EPNI) and review the existing literature. ResultsOn salvage resection for recurrence following primary radiation or chemoradiation, six patients manifested ELVI and two showed EPNI. These patterns conferred difficulty with complete surgical clearance; final pathologic analysis demonstrated positive margins for all eight patients. The six patients with ELVI were p16+ and the two with EPNI were p16-. Currently, two patients are deceased and six patients are alive at an average follow-up of 17.4 months. Of the six living patients, 2 have a new recurrence and are in hospice while 4 have no evidence of disease. ConclusionsELVI and EPNI have received little consideration in the literature as unique histopathologic features of oropharyngeal squamous carcinoma. We present the first series on these adverse extratumoral features in recurrent disease. We call attention to these unique histologic features in the setting of recurrent oropharyngeal cancer to encourage others to track the results of therapeutic intervention and to identify successful strategies for treatment.

445 Does tyrosine and serine phosphorylation of STAT3 drive cutaneous squamous cell carcinoma in recessive dystrophic epidermolysis bullosa?

The early onset of aggressive cutaneous squamous cell carcinoma (cSCC) and its rapid progression in recessive dystrophic epidermolysis bullosa (RDEB) leads to premature mortality. Elevated levels of STAT3Tyr705 (pY-STAT3) phosphorylation have been demonstrated in RDEB-derived cSCC cells, showing that constitutive activation and dysregulation of the pathway play a role in RDEB-cSCC pathogenesis. Application of Ruxolitinib (JAK1/2 inhibitor) to an RDEB-cSCC xenograph mouse model, reduces the size of small tumours but is insufficient to completely reduce bigger tumours.

Chondroitin Sulfate Proteoglycan 4 as a Marker for Aggressive Squamous Cell Carcinoma.

Chondroitin sulfate (CS) proteoglycan 4 (CSPG4) is a cell surface proteoglycan that is currently under investigation as a marker of cancer malignancy, and as a potential target of anticancer drug treatment. CSPG4 acts as a driver of tumourigenesis by regulating turnover of the extracellular matrix (ECM) to promote tumour cell invasion, migration as well as inflammation and angiogenesis. While CSPG4 has been widely studied in certain malignancies, such as melanoma, evidence is emerging from global gene expression studies, which suggests a role for CSPG4 in squamous cell carcinoma (SCC). While relatively treatable, lack of widely agreed upon diagnostic markers for SCCs is problematic, especially for clinicians managing certain patients, including those who are aged or infirm, as well as those with underlying conditions such as epidermolysis bullosa (EB), for which a delayed diagnosis is likely lethal. In this review, we have discussed the structure of CSPG4, and quantitatively analysed CSPG4 expression in the tissues and pathologies where it has been identified to determine the usefulness of CSPG4 expression as a diagnostic marker and therapeutic target in management of malignant SCC.

Long-term safety and efficacy of gene-corrected autologous keratinocyte grafts for recessive dystrophic epidermolysis bullosa

BackgroundRecessive dystrophic epidermolysis bullosa (RDEB) is a rare, devastating blistering genodermatosis caused by mutations in the COL7A1 gene, which encodes for type VII collagen and is necessary for dermal-epidermal adhesion and integrity. Disease manifestations include severe and debilitating wounds, aggressive squamous cell carcinomas, and premature death; however, there are currently no approved therapies. This Phase 1/2a, open-label study evaluated the long-term efficacy and safety of gene-corrected autologous keratinocyte grafts (EB-101) for chronic RDEB wounds.MethodsAutologous keratinocytes were harvested from participants with severe RDEB, transduced with a retrovirus containing the full-length COL7A1 gene, and grown into 5 × 7 cm (35 cm2) sheets. Gene-corrected keratinocyte sheets were then transplanted onto chronic RDEB wounds present for ≥ 12 weeks.ResultsSeven adult participants with severe RDEB were grafted with six sheets each (42 total sheets) onto wounds and followed for a mean of 5.9 years (range 4–8 years). Long-term improvements in wound healing and symptoms were observed. At year five, 70% (21/30) of treated sites demonstrated ≥ 50% wound healing compared to baseline by investigator global assessment. No sites with ≥ 50% wound healing were painful or pruritic, compared to 67% (6/9) of sites with < 50% wound healing (p < 0.001) at year five. Grafts were well-tolerated throughout long-term follow-up. No serious adverse events related to treatment were reported over a mean of 5.9 years of follow-up. No persistent systemic autoimmunity against type VII collagen or replication-competent retrovirus infections were identified, and no participants developed squamous cell carcinomas related to treatment during long-term follow-up.ConclusionsTreatment with EB-101 appears safe and efficacious, and produces long-term improvements in wound healing, pain, and itch for RDEB patients. Results from the Phase 3 randomized controlled trial are forthcoming.Trial registrationClinicalTrials.gov, NCT01263379. Registered December 15, 2010. https://clinicaltrials.gov/ct2/show/NCT01263379

34954 Cutaneous microbial markers of squamous cell carcinoma risk in solid organ transplant recipients

Solid organ transplant recipients (SOTRs) are 100-times more prone to aggressive cutaneous squamous cell carcinoma (SCC) compared with the general population. Despite this increased mortality, our ability to prognosticate risk of cancer in SOTRs is still poor. Accumulating evidence suggests a detrimental influence of microbial dysbiosis on transplant outcomes and immunosuppressant metabolism. Additionally, altered skin microbiome, specifically excessive colonization of the skin by Staphylococcus aureus, has been found in cutaneous SCCs of immunocompetent individuals. We hypothesized that cutaneous dysbiosis is a potential modifier to the risk of SCC in SOTRs and that the microbiome of SOTRs with a history of SCC (>4 instances) is distinct from the microbiome of SOTRs without a history of SCC. To investigate this theory, we generated microbial genomic data from the skin samples of 2 matched cohorts: SOTRs with and without history of SCC. Analyses included testing for differences in microbial diversity measures and differentially relatively abundant microbiome species between cohorts. In the cutaneous microbiomes of SOTRs with SCC history, we identified a significantly reduced abundance of Roseomonas mucosa, which is a S aureus–suppressive species. This suggests a protective effect of R mucosa against the development of SCC through suppression of a bacterial species hypothesized to initiate inflammation-related signaling involved in SCC-genesis. Overall, these findings not only point to a potential role of cutaneous microbiomes as predictive biomarkers for the development of SCC in SOTRs but also suggest that the microbiome can be used for potential preventive and interventional strategies.

34993 Aggressive squamous cell carcinoma in setting of Huriez syndrome

A 63-year-old man presented for a painful mass on his right thumbnail that had been present for several months. On examination, he had nail dystrophy and several ventral pterygia. Most interestingly, scleroatrophy of the distal upper extremities were noted on all 10 digits and the palms had marked keratoderma. Further history revealed that he had had keratoderma since childhood. History also noted conical dentition that led to dentures at the age of 17, and nail abnormalities. His condition went undiagnosed in childhood, and he did not follow up with a dermatologist.