Good clinical response to cemiplimab in a young patient with locally advanced cutaneous squamous cell carcinoma on preexisting recessive dystrophic epidermolysis bullosa.

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic skin disease caused by mutations in the type VII collagen gene (COL7A1; 3p21.31). Mutations in this gene lead to an alteration in function or reduced amounts of collagen VII. This alteration of collagen VII leads to skin fragility and lesions at minor injuries with difficult healing. Cutaneous squamous cell carcinoma (cSCC) is more frequent in patients with RDEB than in the general population because of chronic wound formation; it constitutes a major cause of morbidity and is often cited as a cause of death for these patients. There is little experience with the treatment of cSCC in patients with RDEB. We report the case of a 19-year-old female patient with RDBE and inoperable locally advanced cSCC of the left arm. Because of the lack of therapy options, therapy with cemiplimab was started at a dose of 350 mg administered intravenously every 3 weeks. A confirmed clinical response was observed after the second cycle of treatment with no toxicity. During follow-up, the patient had a notable clinical response with no auto-immune adverse reactions. This shows that cemiplimab has a good safety profile for cSCC in patients with RDEB and is a valuable therapy option.

PLAU, transcriptionally negatively regulated by GATA6, promotes lung squamous carcinoma cell proliferation and migration.

BACKGROUND: Lung squamous cell carcinoma (LUSC) is associated with high mortality and has limited therapeutic treatment options. Plasminogen activator urokinase (PLAU) plays important roles in tumor cell malignancy. However, the oncogenic role of PLAU in the progression of LUSC remains unknown. GATA-binding factor 6 (GATA6), a key regulator of lung development, inhibits LUSC cell proliferation and migration, but the underlying regulatory mechanism remains to be further explored. Moreover, the regulatory effect of GATA6 on PLAU expression has not been reported. The aim of this study was to identify the role of PLAU and the transcriptional inhibition mechanism of GATA6 on PLAU expression in LUSC. METHODS: To identify the potential target genes regulated by GATA6, differentially expressed genes (DEGs) obtained from GEO datasets analysis and RNA-seq experiment were subjected to Venn analysis and correlation heatmap analysis. The transcriptional regulatory effects of GATA6 on PLAU expression were detected by real-time PCR, immunoblotting, and dual-luciferase reporter assays. The oncogenic effects of PLAU on LUSC cell proliferation and migration were evaluated by EdU incorporation, Matrigel 3D culture and Transwell assays. PLAU expression was detected in tissue microarray of LUSC via immunohistochemistry (IHC) assay. To determine prognostic factors for prognosis of LUSC patients, the clinicopathological characteristics and PLAU expression were subjected to univariate Cox regression analysis. RESULTS: PLAU overexpression promoted LUSC cell proliferation and migration. PLAU is overexpressed in LUSC tissues compared with normal tissues. Consistently, high PLAU expression, which acts as an independent risk factor, is associated with poor prognosis of LUSC patients. Furthermore, the expression of PLAU is transcriptionally regulated by GATA6. CONCLUSION: In this work, it was revealed that PLAU is a novel oncogene for LUSC and a new molecular regulatory mechanism of GATA6 in LUSC was unveiled. Targeting the GATA6/PLAU pathway might help in the development of novel therapeutic treatment strategies for LUSC.

RICTOR amplification is associated with Rictor membrane staining and does not correlate with PD-L1 expression in lung squamous cell carcinoma.

RICTOR gene, which encodes the scaffold protein of mTORC2, can be amplified in various tumor types, including squamous cell carcinoma (SCC) of the lung. RICTOR amplification can lead to hyperactivation of mTORC2 and may serve as a targetable genetic alteration, including in lung SCC patients with no PD-L1 expression who are not expected to benefit from immune checkpoint inhibitor therapy. This study aimed to compare RICTOR amplification detected by fluorescence in situ hybridization (FISH) with Rictor and PD-L1 protein expression detected by immunohistochemistry (IHC) in SCC of the lung. The study was complemented by analysis of the publicly available Lung Squamous Cell Carcinoma (TCGA, Firehose legacy) dataset. RICTOR amplification was observed in 20% of our cases and 16% of the lung SCC cases of the TCGA dataset. Rictor and PD-L1 expression was seen in 74% and 44% of the cases, respectively. Rictor IHC showed two staining patterns: membrane staining (16% of the cases) and cytoplasmic staining (58% of the cases). Rictor membrane staining predicted RICTOR amplification as detected by FISH with high specificity (95%) and sensitivity (70%). We did not find any correlation between RICTOR amplification and PD-L1 expression; RICTOR amplification was detected in 18% and 26% of PD-L1 positive and negative cases, respectively. The TCGA dataset analysis showed similar results; RICTOR copy number correlated with Rictor mRNA and protein expression but showed no association with PD-L1 mRNA and protein expression. In conclusion, the correlation between RICTOR amplification and Rictor membrane staining suggests that the latter can potentially be used as a surrogate marker to identify lung SCC cases with RICTOR amplification. Since a significant proportion of PD-L1 negative SCC cases harbor RICTOR amplification, analyzing PD-L1 negative tumors by RICTOR FISH or Rictor IHC can help select patients who may benefit from mTORC2 inhibitor therapy.

Significance of NKX2-1 as a biomarker for clinical prognosis, immune infiltration, and drug therapy in lung squamous cell carcinoma.

Background: This study was performed to determine the biological processes in which NKX2-1 is involved and thus its role in the development of lung squamous cell carcinoma (LUSC) toward improving the prognosis and treatment of LUSC. Methods: Raw RNA sequencing (RNA-seq) data of LUSC from The Cancer Genome Atlas (TCGA) were used in bioinformatics analysis to characterize NKX2-1 expression levels in tumor and normal tissues. Survival analysis of Kaplan-Meier curve, the time-dependent receiver operating characteristic (ROC) curve, and a nomogram were used to analyze the prognosis value of NKX2-1 for LUSC in terms of overall survival (OS) and progression-free survival (PFS). Then, differentially expressed genes (DEGs) were identified, and Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and Gene Set Enrichment Analysis (GSEA) were used to clarify the biological mechanisms potentially involved in the development of LUSC. Moreover, the correlation between the NKX2-1 expression level and tumor mutation burden (TMB), tumor microenvironment (TME), and immune cell infiltration revealed that NKX2-1 participates in the development of LUSC. Finally, we studied the effects of NKX2-1 on drug therapy. To validate the protein and gene expression levels of NKX2-1 in LUSC, we employed immunohistochemistry(IHC) datasets, The Gene Expression Omnibus (GEO) database, and qRT-PCR analysis. Results: NKX2-1 expression levels were significantly lower in LUSC than in normal lung tissue. It significantly differed in gender, stage and N classification. The survival analysis revealed that high expression of NKX2-1 had shorter OS and PFS in LUSC. The multivariate Cox regression hazard model showed the NKX2-1 expression as an independent prognostic factor. Then, the nomogram predicted LUSC prognosis. There are 51 upregulated DEGs and 49 downregulated DEGs in the NKX2-1 high-level groups. GO, KEGG and GSEA analysis revealed that DEGs were enriched in cell cycle and DNA replication.The TME results show that NKX2-1 expression was positively associated with mast cells resting, neutrophils, monocytes, T cells CD4 memory resting, and M2 macrophages but negatively associated with M1 macrophages. The TMB correlated negatively with NKX2-1 expression. The pharmacotherapy had great sensitivity in the NKX2-1 low-level group, the immunotherapy is no significant difference in the NKX2-1 low-level and high-level groups. The analysis of GEO data demonstrated concurrence with TCGA results. IHC revealed NKX2-1 protein expression in tumor tissues of both LUAD and LUSC. Meanwhile qRT-PCR analysis indicated a significantly lower NKX2-1 expression level in LUSC compared to LUAD. These qRT-PCR findings were consistent with co-expression analysis of NKX2-1. Conclusion: We conclude that NKX2-1 is a potential biomarker for prognosis and treatment LUSC. A new insights of NKX2-1 in LUSC is still needed further research.

Oncological outcomes post transoral robotic surgery (TORS) for HPV-associated oropharyngeal squamous cell carcinoma, a single-centre retrospective Australian study.

We present a cohort review of TORS resection for HPV-associated oropharyngeal squamous cell carcinoma (OPSCC) and its associated oncological outcomes spanning a 10-year period. A retrospective case series review was performed of patients undergoing primary surgical treatment for HPV-associated OPSCC through the St. Vincent's Head and Neck Cancer service from 2011 to 2022. The primary outcomes were to investigate complete resection of the primary tumour, rates of recurrence, and survival analysis. Secondary outcomes included complications, rates of adjuvant therapy, sites of recurrence and rates of percutaneous endoscopic gastrostomy (PEG). 184 patients underwent TORS-based therapy with neck dissection, and guideline-directed adjuvant therapy for HPV-associated OPSCC. Our median follow-up was 46 months. The positive margin rate on final histopathology analysis was 10.9%. Adjuvant therapy was indicated in 85 patients (46%). The local recurrence rate was 10.9% with the majority (80%) of patients recurring in the first 3 years since treatment. The disease-specific survival at 3 years was 98.6% and at 5 years was 94.4%. The 3-year and 5-year OS for the cohort was 96.7% and 92.5%, respectively. The presence of extranodal extension and positive margins were associated with increased risk of recurrence, whereas adjuvant therapy was found to be a protective factor for both overall recurrence and survival. Major complications occurred in 12 patients (6.5%), resulting in one death. This study has demonstrated that primary surgical therapy for HPV-associated OPSCC is a safe and effective treatment modality with low local recurrence and complication rates, and overall survival benefits.

FOXD2-AS1 promotes malignant cell behavior in oral squamous cell carcinoma via the miR-378 g/CRABP2 axis.

BACKGROUND: Oral squamous cell cancer (OSCC) is a prevalent malignancy in oral cavity, accounting for nearly 90% of oral malignancies. It ranks sixth among the most common types of cancer worldwide and is responsible for approximately 145,000 deaths each year. It is widely accepted that noncoding RNAs participate cancer development in competitive regulatory interaction, knowing as competing endogenous RNA (ceRNA) network, whereby long non-coding RNA (lncRNA) function as decoys of microRNAs to regulate gene expression. LncRNA FOXD2-AS1 was reported to exert an oncogenic role in OSCC. Nevertheless, the ceRNA network mediated by FOXD2-AS1 was not investigated yet. This study aimed to explore the effect of FOXD2-AS1 on OSCC cell process and the underlying ceRNA mechanism. METHODS: FOXD2-AS1 expression in OSCC cells were determined via reverse transcription and quantitative polymerase chain reaction. Short hairpin RNA targeting FOXD2-AS1 was transfected into OSCC cells to silence FOXD2-AS1 expression. Then, loss-of-function experiments (n = 3 each assay) were performed to measure cell proliferation, apoptosis, migration, and invasion using colony formation, TdT-mediated dUTP Nick-End Labeling, wound healing and Transwell assays, respectively. RNA binding relation was verified by RNA immunoprecipitation and luciferase reporter assays. Rescue experiments were designed to validate whether FOXD2-AS1 affects cell behavior via the gene cellular retinoic acid binding protein 2 (CRABP2). Statistics were processed by GraphPad Prism 6.0 Software and SPSS software. RESULTS: FOXD2-AS1 was significantly upregulated in Cal27 and SCC9 cells (6.8 and 6.4 folds). In response to FOXD2-AS1 knockout, OSCC cell proliferation, migration and invasion were suppressed (approximately 50% decrease) while OSCC cell apoptosis was enhanced (more than two-fold increase). FOXD2-AS1 interacted with miR-378 g to alter CRABP2 expression. CRABP2 upregulation partly rescued (*p < 0.05, **p < 0.01, ***p < 0.001) the inhibitory impact of FOXD2-AS1 depletion on malignant characteristics of OSCC cells. CONCLUSION: FOXD2-AS1 enhances OSCC malignant cell behaviors by interacting with miR-378 g to regulate CRABP2 expression.

Functional Role of DUSP6 in the EGFR-mediated Progression of Head and Neck Squamous Cell Carcinoma.

BACKGROUND/AIM: Epidermal growth factor receptor (EGFR) over-expression is commonly observed in advanced head and neck squamous cell carcinoma (HNSCC) and is correlated with poor patient outcomes. However, the role of dual-specificity phosphatase 6 (DUSP6) in EGFR-associated HNSCC progression remains poorly understood. This study aimed to investigate the correlation between DUSP6 expression and EGFR signaling in malignant HNSCC tissues. MATERIALS AND METHODS: Data mining and in vitro assays were employed to assess DUSP6 expression levels in HNSCC tissues compared to normal tissues. Additionally, the correlation between DUSP6 and EGFR expression was examined. Functional assays were conducted to investigate the modulation of DUSP6 expression by EGFR signaling and its involvement in EGF-induced cell migration and anoikis resistance. RESULTS: Our analysis revealed a significant elevation in DUSP6 expression in HNSCC tissues compared to normal tissues and a strong correlation between DUSP6 and EGFR expression. EGFR signaling modulated DUSP6 expression in a dose- and time-dependent manner, primarily through the extracellular signal-regulated kinase (ERK) pathway. Knockdown experiments demonstrated the functional role of DUSP6 in EGF-induced cell migration and anoikis resistance. CONCLUSION: The findings of this study elucidate the intricate signaling networks governing DUSP6 expression and its interplay with EGFR signaling in HNSCC. Moreover, the results provide insights into the potential role of DUSP6 as a therapeutic target and highlight the importance of personalized treatment strategies in HNSCC management.

Clinical Impact of Pelvic Sentinel Lymph Node Biopsy for Vulvar Squamous Cell Carcinoma.

BACKGROUND/AIM: This study investigated the clinical impact of resection of pelvic sentinel lymph nodes (PSLNs) in squamous cell vulvar cancer (SCVC). PATIENTS AND METHODS: Sixty-two groins of 33 patients with SCVC who underwent sentinel lymph node (SLN) resection between 2010 and 2021 at the University Hospital of Cologne, Germany, were analyzed in this retrospective cohort study. The frequency of additionally resectable PSLNs, histological findings, and count rates were analyzed and compared to the findings for inguinal sentinel lymph nodes (ISLNs). RESULTS: In all patients and in 61 (98%) of the 62 radiolabeled groins, at least one SLN could be resected. Five (8%) of the 62 groins had histologically confirmed lymph node metastases (4/33 patients, 12%). Twenty (33%) of the 62 groins underwent additional PSLN resection. Resection of these PSLNs was feasible without causing an additional burden for the patients. None of the PSLNs showed signs of tumor infiltration. Information on the extent of radioactivity for ISLNs and simultaneously for PSLNs, expressed as count rate of intraoperative measurement with the gamma probe, was available for 20 (32%) groins. In three (15%) of these cases, the highest count rate in a SLN was found in a PSLN and not in an ISLN. CONCLUSION: Resection of PSLNs is feasible and can be performed without short-term complications. In patients with early SCVC, resection of PSLNs is not necessary, even in those with early infiltration of inguinal lymph nodes. The intraoperative count rate of SLN is not relevant for the decision to perform resection.

MRI Texture Analysis of Inguinal Lymph Node Metastasis in Vulvar Cancer - Associations With Histopathology.

BACKGROUND/AIM: Texture analysis is a quantitative imaging technique that provides novel biomarkers beyond conventional image reading. This study aimed to investigate the correlation between texture parameters and histopathological features of lymph nodes in patients with vulvar cancer. PATIENTS AND METHODS: Overall, nine female patients (mean age 70.1±13.4 years, range=39-87 years) were included in the analysis. All patients had squamous cell carcinomas and underwent upfront surgery with inguinal lymph node resection. Immunohistochemical assessment was performed using several markers of the epithelial-mesenchymal transition. The presurgical magnetic resonance imaging (MRI) was analyzed with the MaZda package. RESULTS: In discrimination analysis, several parameters derived from T1-weighted images showed statistically significant differences between non-metastatic and metastatic lymph nodes. The highest statistical significance was reached by the texture feature "S(0,3)InvDfMom" (p=0.016). In correlation analysis, significant associations were found between MRI texture parameters derived from both T1-weighted and T2-weighted images and the investigated histopathological features. Notably, S(0,3)InvDfMom derived from T1-weighted images highly correlated with the Vimentin-score (r=0.908, p=0.001). CONCLUSION: Several associations between MRI texture analysis and immunohistochemical parameters were identified in metastasized lymph nodes of cases with vulvar cancer.

Molecular Pathology of Gastroesophageal Cancer.

Upper gastroesophageal carcinomas consist of cancers arising from the esophagus and stomach. Squamous cell carcinomas and adenocarcinomas are seen in the esophagus and despite arising from the same organ have different biology. Gastric adenocarcinomas are categorized into 4 molecular subtypes: high Epstein-Barr virus load, microsatellite unstable cancers, chromosomal unstable (CIN) cancers, and genomically stable cancers. Genomically stable gastric cancers correlate highly with histologically defined diffuse-type cancers. Esophageal carcinomas and CIN gastric cancers often are driven by high-level amplifications of oncogenes and contain a high degree of intratumoral heterogeneity. Targeted therapeutics is an active area of research for gastroesophageal cancers.

Double-faced CX3CL1 enhances lymphangiogenesis-dependent metastasis in an aggressive subclone of oral squamous cell carcinoma.

Because cancer cells have a genetically unstable nature, they give rise to genetically different variant subclones inside a single tumor. Understanding cancer heterogeneity and subclone characteristics is crucial for developing more efficacious therapies. Oral squamous cell carcinoma (OSCC) is characterized by high heterogeneity and plasticity. On the other hand, CX3C motif ligand 1 (CX3CL1) is a double-faced chemokine with anti- and pro-tumor functions. Our study reported that CX3CL1 functioned differently in tumors with different cancer phenotypes, both in vivo and in vitro. Mouse OSCC 1 (MOC1) and MOC2 cells responded similarly to CX3CL1 in vitro. However, in vivo, CX3CL1 increased keratinization in indolent MOC1 cancer, while CX3CL1 promoted cervical lymphatic metastasis in aggressive MOC2 cancer. These outcomes were due to double-faced CX3CL1 effects on different immune microenvironments indolent and aggressive cancer created. Furthermore, we established that CX3CL1 promoted cancer metastasis via the lymphatic pathway by stimulating lymphangiogenesis and transendothelial migration of lymph-circulating tumor cells. CX3CL1 enrichment in lymphatic metastasis tissues was observed in aggressive murine and human cell lines. OSCC patient samples with CX3CL1 enrichment exhibited a strong correlation with lower overall survival rates and higher recurrence and distant metastasis rates. In conclusion, CX3CL1 is a pivotal factor that stimulates the metastasis of aggressive cancer subclones within the heterogeneous tumors to metastasize, and our study demonstrates the prognostic value of CX3CL1 enrichment in long-term monitoring in OSCC.

NCAPD2 promotes the malignant progression of oral squamous cell carcinoma via the Wnt/ß-catenin pathway.

Oral squamous cell carcinoma (OSCC) is the most common type of oral cancer, with a poor prognosis, yet the underlying mechanism needs further exploration. Non-SMC condensin I complex subunit D2 (NCAPD2) is a widely expressed protein in OSCC, but its role in tumor development is unclear. This study aimed to explore NCAPD2 expression and its biological function in OSCC. NCAPD2 expression in OSCC cell lines and tissue specimens was analyzed using quantitative polymerase chain reaction, western blotting, and immunohistochemistry. Cancer cell growth was evaluated using cell proliferation, 5-Ethynyl-2'-deoxyuridine (EdU) staining, and colony formation assays. Cell migration was evaluated using wound healing and Transwell assays. Apoptosis was detected using flow cytometry. The influence of NCAPD2 on tumor growth in vivo was evaluated in a mouse xenograft model. NCAPD2 expression was significantly higher in OSCC than that in normal oral tissue. In vitro, the knockdown of NCAPD2 inhibited OSCC cell proliferation and promoted apoptosis. NCAPD2 depletion also significantly inhibited the migration of OSCC cells. Moreover, NCAPD2 overexpression induced inverse effects on OSCC cell phenotypes. In vivo, we demonstrated that downregulating NCAPD2 could inhibit the tumorigenicity of OSCC cells. Mechanically, OSCC regulation by NCAPD2 involved the Wnt/ß-catenin signaling pathway. These results suggest NCAPD2 as a novel oncogene with an important role in OSCC development and a candidate therapeutic target for OSCC.

Ex Vivo Evaluation of Antiangiogenic Drugs in Oral Cancer: Potential Implications for Targeting Vasculogenic Mimicry.

BACKGROUND/AIM: Oral squamous cell carcinoma (OSCC) is characterized by early metastasis, clinical resistance and poor prognosis. Recently, we showed that aggressive OSCC cells co-express endothelial cell markers and can form tube-like structures, known as vasculogenic mimicry (VM), a process associated with poor prognosis in head and neck cancers. Given the limited success of current antiangiogenic therapy in treating OSCC, this study sought to explore the efficiency of these drugs in targeting an ex vivo model of VM. MATERIALS AND METHODS: OSCC cell lines from the tongue and floor of the mouth in addition to human endothelial cells were used. The treatments comprised a set of clinically relevant antiangiogenic drugs: sorafenib, sunitinib, and axitinib, which were administered in different doses. Multiple ex vivo approaches including cell tubulogenesis, proliferation, apoptosis, and migration assays were used. RESULTS: Although these drugs inhibited the formation of endothelial cell capillaries, they showed clear differential effects on OSCC cell-derived VM and cell morphology. Sorafenib inhibited the tubulogenesis of aggressive OSCC cells compared with the limited effect of sunitinib and axitinib. Furthermore, our data consistently demonstrated a preferential efficacy of certain drugs over others. Sorafenib and sunitinib exhibited anti-cancer effects on tumor cell proliferation, apoptosis, and cell migration, compared with the limited effect of axitinib. CONCLUSION: The antiangiogenic drugs, except sorafenib, had limited effect on VM formation in vitro and exhibited varying anti-cancer effects on OSCC cells. These data support the notion that VM formation may in part explain the development of drug resistance in OSCC cells.

Elucidating the Role of Let-7d-5p and OLR1 in the Progression and Prognosis of Oral Squamous Cell Carcinoma via FAK/P53 Signaling Axis.

BACKGROUND/AIM: Despite advances in oral squamous cell carcinoma (OSCC) diagnosis and treatment, the five-year survival rate remains low, underscoring the need for improved biomarkers and therapeutic strategies. This study investigated the role of let-7d-5p microRNA (miRNA) and its target gene OLR1 in OSCC, focusing on their implications in tumor progression, metastasis and potential as therapeutic targets. MATERIALS AND METHODS: Employing next-generation sequencing and bioinformatic tools, we profiled differentially expressed miRNAs in metastatic OSCC cell lines, identifying let-7d-5p as a key down-regulated miRNA and OLR1 as a novel target of let-7d-5p. We validated this interaction using luciferase reporter assays and studied the biological effects of modulating let-7d-5p and OLR1 expression on OSCC cell proliferation, migration, invasion, and stemness. Additionally, we analyzed clinical data to establish the relevance of OLR1 expression in OSCC prognosis. RESULTS: Our findings revealed let-7d-5p as a potent suppressor of OSCC metastasis, primarily by targeting and down-regulating OLR1. OLR1-silencing reduced OSCC cell invasiveness, migration, and stemness, indicating its prominent role in tumor progression. Mechanistically, let-7d-5p modulates a signaling cascade involving FAK, SRC, PAXILLIN, and p53, influencing cellular apoptosis and chemoresistance. Clinically, elevated OLR1 expression significantly correlates with advanced OSCC stages and poorer survival rates, highlighting its potential as a prognostic marker and therapeutic target. CONCLUSION: Our study uncovers the significance of the let-7d-5p-OLR1 axis in OSCC pathogenesis, offering novel insights for future therapeutic interventions.

PI3K/AKT Signaling Pathway Mediated Autophagy in Oral Carcinoma - A Comprehensive Review.

Oral cancer is the most heterogeneous cancer at clinical and histological levels. PI3K/AKT/mTOR pathway was identified as one of the most commonly modulated signals in oral cancer, which regulates major cellular and metabolic activity of the cell. Thus, various proteins of PI3K/AKT/mTOR pathway were used as therapeutic targets for oral cancer, to design more specific drugs with less off-target toxicity. This review sheds light on the regulation of PI3K/AKT/mTOR, and its role in controlling autophagy and associated apoptosis during the progression and metastasis of oral squamous type of malignancy (OSCC). In addition, we reviewed in detail the upstream activators and the downstream effectors of PI3K/AKT/mTOR signaling as potential therapeutic targets for oral cancer treatment.

Therapies for cutaneous squamous cell carcinoma in recessive dystrophic epidermolysis bullosa: a systematic review of 157 cases.

BACKGROUND: Invasive cutaneous squamous cell carcinomas (cSCC) are a leading cause of death in recessive dystrophic epidermolysis bullosa (RDEB), a rare blistering genodermatosis. Outcomes of RDEB-cSCC therapies have primarily been described in case reports. Systematic studies are scarce. This systematic review aims to assess the pathophysiology, clinical characteristics, and outcomes of RDEB-cSCCs, with a focus on results and mechanisms of recent immunotherapies and anti-EGFR treatments. RESULTS: A systematic literature search of epidermolysis bullosa and cSCC was performed in February 2024, using PubMed, Embase, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and EudraCT databases. Cases with administration of systematic therapies and unpublished outcomes regarding death were tracked with corresponding authors. Data extraction and risk of bias assessment was performed by two independent reviewers. Of 1132 references in the original search, 163 relevant articles were identified, representing 59 case reports, 7 cohort studies, 49 abstracts, 47 in-vitro/in-vivo experiments, and 1 bioinformatic study. From these, 157 cases of RDEB-cSCCs were included. The majority of RDEB-cSCCs were well-differentiated (64.1%), ulcerated (59.6%), and at least 2 cm in size (77.6%), with a median age at diagnosis of 30 years old (range 6-68.4). Surgery was the primary form of treatment (n = 128), followed by chemotherapy and radiotherapy. Anti-EGFR therapy and immunotherapy was also reported beginning in 2009 and 2019, respectively. Survival time from first cSCC diagnosis to death was available in 50 cases. When stratified by their treatment regimen, median survival time was 1.85 years (surgery + chemotherapy, n = 6), 2 years (surgery only, n = 19), 4.0 years (+ anti-EFGR therapy, n = 10), 4 years (surgery + radiotherapy, n = 9), 4.6 years (+ immunotherapy, n = 4), and 9.5 years (surgery + chemotherapy + radiotherapy; n = 2). Treatment-related adverse events were primarily limited to impaired wound healing for immunotherapies and nausea and fatigue for anti-EGFR therapies. CONCLUSIONS: Despite the challenges of a limited sample size in a rare disease, this systematic review provides an overview of treatment options for cSCCs in RDEB. When surgical treatment options have been exhausted, the addition of immunotherapy and/or anti-EGFR therapies may extend patient survival. However, it is difficult to attribute extended survival to any single treatment, as multiple therapeutic modalities are often used to treat RDEB-cSCCs.

Comparing the clinical outcomes of initial surgery and primary definitive radiotherapy with a dosage of 6600 cGy or higher in cT1-2N0M0 oral cavity squamous cell carcinoma: A nationwide cohort study.

BACKGROUND: To compare the clinical outcomes of two treatment modalities, initial surgery and primary definitive radiotherapy (RT), in Taiwanese patients diagnosed with cT1-2N0M0 oral cavity squamous cell carcinoma (OCSCC). METHODS: Between 2011 and 2019, we analyzed data for 13,542 cT1-2N0M0 patients who underwent initial surgery (n = 13,542) or definitive RT with a dosage of at least 6600 cGy (n = 145) for the treatment of OCSCC. To account for baseline differences, we employed propensity score (PS) matching, resulting in two well-balanced study groups (initial surgery, n = 580; definitive RT, n = 145). RESULTS: Before PS matching, the 5-year disease-specific survival (DSS) rates were 88% for the surgery group and 58% for the RT group. After PS matching, the 5-year DSS rates of the two groups were 86% and 58%, respectively. Similarly, the 5-year overall survival (OS) rates before PS matching were 80% for the surgery group and 36% for the RT group, whereas after PS matching, they were 73% and 36%, respectively. All these differences were statistically significant (p < 0.0001). A multivariable analysis identified treatment with RT, older age, stage II tumors, and a higher burden of comorbidities as independent risk factors for both DSS and OS. We also examined the 5-year outcomes for various subgroups (margin ≥5 mm, margin <5 mm, positive margins, RT combined with chemotherapy, and RT alone) as follows: DSS, 89%/88%/79%/63%/51%, respectively, p < 0.0001; OS, 82%/79%/68%/39%/32%, respectively, p < 0.0001. CONCLUSIONS: In Taiwanese patients with cT1-2N0M0 OCSCC, a remarkably low proportion (1.1%) completed definitive RT. A significant survival disparity of 30% was observed between patients who underwent initial surgery and those who received definitive RT. Interestingly, even patients from the surgical group with positive surgical margins exhibited a significantly superior survival compared to those in the definitive RT group.