Subungual Squamous Cell Carcinoma Associated with Long Standing Onychomycosis: Aggressive Surgical Approach with a Favourable Outcome.
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ABSTRACT:
SUBMITTER: Grigorov Y
PROVIDER: S-EPMC5535663 | biostudies-other | 2017 Jul
REPOSITORIES: biostudies-other
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Project description:BackgroundSquamous cell carcinoma (SCC) of the skin is a common form of nonmelanoma skin cancer. Monocyte chemotactic protein 1-induced protein 1 (MCPIP1), also called Regnase-1, is an RNase with anti-inflammatory properties. In normal human skin, its expression is predominantly restricted to the suprabasal epidermis. The main aim of this study was to investigate whether MCPIP1 is involved in the pathogenesis of SCC.MethodsWe analyzed the distribution of MCPIP1 in skin biopsies of patients with actinic keratoses (AKs) and SCCs. To explore the mechanisms by which MCPIP1 may modulate tumorigenesis in vivo, we established a mouse model of chemically induced carcinogenesis.ResultsSkin expression of MCPIP1 changed during the transformation of precancerous lesions into cutaneous SCC. MCPIP1 immunoreactivity was high in the thickened area of the AK epidermis but was predominantly restricted to keratin pearls in fully developed SCC lesions. Accelerated development of chemically induced skin tumors was observed in mice with loss of epidermal MCPIP1 (Mcpip1eKO). Papillomas that developed in Mcpip1eKO mouse skin were larger and characterized by elevated expression of markers typical of keratinocyte proliferation and tumor angiogenesis. This phenotype was correlated with enhanced expression of IL-6, IL-33 and transforming growth factor-beta (TGF-β). Moreover, our results demonstrated that in keratinocytes, the RNase MCPIP1 is essential for the negative regulation of genes encoding SCC antigens and matrix metallopeptidase 9.ConclusionsOverall, our results provide a mechanistic understanding of how MCPIP1 contributes to the development of epidermoid carcinoma.
| S-EPMC8667402 | biostudies-literature
Project description:The unc-13 homolog B (UNC13B) gene encodes a presynaptic protein, mammalian uncoordinated 13-2 (Munc13-2), which is highly expressed in the brain-predominantly in the cerebral cortex-and plays an essential role in synaptic vesicle priming and fusion, potentially affecting neuronal excitability. However, the functional significance of the UNC13B mutation in human disease is not known. In this study, we screened for novel genetic variants in a cohort of 446 unrelated cases (families) with partial epilepsy without acquired causes by trio-based whole-exome sequencing. UNC13B variants were identified in 12 individuals affected by partial epilepsy and/or febrile seizures from eight unrelated families. The eight probands all had focal seizures and focal discharges in EEG recordings, including two patients who experienced frequent daily seizures and one who showed abnormalities in the hippocampus by brain MRI; however, all of the patients showed a favourable outcome without intellectual or developmental abnormalities. The identified UNC13B variants included one nonsense variant, two variants at or around a splice site, one compound heterozygous missense variant and four missense variants that cosegregated in the families. The frequency of UNC13B variants identified in the present study was significantly higher than that in a control cohort of Han Chinese and controls of the East Asian and all populations in the Genome Aggregation Database (gnomAD). Computational modelling, including hydrogen bond and docking analyses, suggested that the variants lead to functional impairment. In Drosophila, seizure rate and duration were increased by Unc13b knockdown compared to wild-type flies, but these effects were less pronounced than in sodium voltage-gated channel alpha subunit 1 (Scn1a) knockdown Drosophila. Electrophysiological recordings showed that excitatory neurons in Unc13b-deficient flies exhibited increased excitability. These results indicate that UNC13B is potentially associated with epilepsy. The frequent daily seizures and hippocampal abnormalities but ultimately favourable outcome under anti-epileptic therapy in our patients indicate that partial epilepsy caused by UNC13B variant is a clinically manageable condition.
| S-EPMC8634081 | biostudies-literature
Project description:ImportanceSquamous cell carcinoma (SCC) is the most frequent malignant neoplasm found in solid organ transplant recipients and is associated with a more aggressive disease course and higher risk of metastasis and death than in the general population.ObjectivesTo report the clinicopathologic features of and identify factors associated with aggressive SCC in solid organ transplant recipients.MethodsThis retrospective multicentric case series included 51 patients who underwent solid organ transplantation and were found to have aggressive SCC, defined by nodal or distant metastasis or death by local progression of primary SCC. Standard questionnaires were completed by the researchers between July 18, 2005, and January 1, 2015. Data were analyzed between February 22, 2016, and July 12, 2016.ResultsOf the 51 participants, 43 were men and 8 were women, with a median age of 51 years (range, 19-71 years) at time of transplantation and 62 years (range, 36-77 years) at time of diagnosis of aggressive SCC. The distribution of aggressive SCC was preferentially on the face (34 [67%]) and scalp (6 [12%]), followed by the upper extremities (6 [12%]). A total of 21 tumors (41%) were poorly differentiated, with a median tumor diameter of 18.0 mm (range, 4.0-64.0 mm) and median tumor depth of 6.2 mm (range, 1.0-20.0 mm). Perineural invasion was present in 20 patients (39%), while 23 (45%) showed a local recurrence. The 5-year overall survival rate was 23%, while 5-year disease-specific survival was 30.5%.Conclusions and relevanceResults of this case series suggest that anatomical site, differentiation, tumor diameter, tumor depth, and perineural invasion are important risk factors in aggressive SCC in solid organ transplant recipients.
| S-EPMC6439577 | biostudies-literature
Project description:PurposeAggressive cutaneous squamous cell carcinoma (cSCC) is often a disfiguring and lethal disease. Very little is currently known about the mutations that drive aggressive cSCC.Experimental designWhole-exome sequencing was performed on 39 cases of aggressive cSCC to identify driver genes and novel therapeutic targets. Significantly, mutated genes were identified with MutSig or complementary methods developed to specifically identify candidate tumor suppressors based upon their inactivating mutation bias.ResultsDespite the very high-mutational background caused by UV exposure, 23 candidate drivers were identified, including the well-known cancer-associated genes TP53, CDKN2A, NOTCH1, AJUBA, HRAS, CASP8, FAT1, and KMT2C (MLL3). Three novel candidate tumor suppressors with putative links to cancer or differentiation, NOTCH2, PARD3, and RASA1, were also identified as possible drivers in cSCC. KMT2C mutations were associated with poor outcome and increased bone invasion.ConclusionsThe mutational spectrum of cSCC is similar to that of head and neck squamous cell carcinoma and dominated by tumor-suppressor genes. These results improve the foundation for understanding this disease and should aid in identifying and treating aggressive cSCC.
| S-EPMC4367811 | biostudies-literature
Project description:The aim of the present study was to investigate the association between cluster of differentiation (CD) 164 expression with clinicopathological parameters and prognosis among patients with oral cavity squamous cell carcinoma (OSCC). The present study retrospectively reviewed 70 patients with OSCC who underwent curative primary surgery. A number of patients subsequently received postoperative chemoradiotherapy although the specimens were not exposed to radiation or chemotherapy prior to anti-CD164 antibody immunohistochemical staining. CD164 overexpression was arbitrarily defined as exhibiting an H-score of ≥120. Univariate and multivariate analyses were performed for sex, age, American Joint Committee on Cancer stage, tumour location, histological grade, surgical margin and H-score. The 5-year overall survival rate was 54.4% and the median follow-up time was 46 months for surviving patients. Univariate analyses revealed that a low overall survival rate was associated with advanced-stage disease (P<0.001), buccogingival tumour location (P=0.038) and a CD164 H-score of <120 (P=0.016). Multivariate Cox's regression analyses revealed that poor overall survival rate was associated with advanced-stage disease (P=0.001) and a CD164 H-score of <120 (P=0.04). CD164 overexpression in OSCC was associated with favourable survival rate. Thus, CD164 expression may be a clinically useful predictor of prognosis in patients with OSCC.
| S-EPMC5661421 | biostudies-literature
Project description:IntroductionGalectin-9, a β-galactoside-binding protein, might be a potential target in cancer personalized therapy, but contradicting data exist regarding its prognostic significance in malignancy. Previous studies showed low or absent expression of galectin-9 on tumour cells of oral squamous cell carcinoma (OSCC); thus, we aimed to assess the prognostic impact of its expression on tumour-associated immune cells (TAICs).Material and methodsA retrospective analysis was conducted on 62 patients with OSCC. Tissue microarrays were constructed with chemo- and radiotherapy-naïve tissue samples and stained with anti-galectin-9 antibody. Cytoplasmic reactions in TAICs were counted as positive, and the percentage of galectin-9-positive cells was calculated.ResultsThe expression of galectin-9 was not associated with any demographic factors, other than diabetes mellitus type 2, for which there were lower levels of expression (p = 0.029). Higher levels of galectin-9 were associated with less locally advanced tumours (p = 0.023) and lack of nodal metastases (p = 0.014). Galectin-9 expression positively correlated with PD-L1 expression on TAICs (p = 0.009). Patients with > 50% galectin-9-positive cells were determined to have a superior 5-year overall survival (p = 0.029).ConclusionsFuture studies are necessary to investigate the effects of galectin-9 on the tumour micro-environment, and galectin-9-targeted treatment may be considered, especially with its correlation to PD-L1 in OSCC.
| S-EPMC10230243 | biostudies-literature
Project description:PurposeNon-squamous cell carcinoma (non-SCC) accounts for about 5% of laryngeal malignancies. Survival data are limited, and consensus on management principles is lacking. The present study reviews our experience in the surgical treatment of non-metastatic non-SCC of the larynx and compares oncological and functional outcomes in a cohort of patients affected by traditional SCC.MethodsWe collected data on 592 patients affected by laryngeal neoplasms. Univariate and multivariable survival analyses were performed using Cox proportional-hazards models; survival estimates were reported by hazard ratios (HR) with 95% confidence intervals (CI), and survival curves were established with the Kaplan-Meier method.ResultsWe identified 326 patients affected by untreated SCC, while 21 had non-SCC histotypes. The non-SCC cohort was composed of 5 soft tissue sarcomas, 8 chondrosarcomas, 2 adenoid cystic carcinomas, 2 neuroendocrine carcinomas, 2 solitary fibrous tumors, 1 Kaposi's sarcoma, and 1 malignant peripheral nerve sheath tumor. Overall survival and disease-specific survival were not significantly different according to histology (p = 0.6 and p = 0.349, respectively). The non-SCC group showed an increased risk of recurrence (HR 5.87; CI95 2.15-16.06; p < 0.001). Nonetheless, no significant difference (p = 0.31) was found at multivariable analysis between the two groups in total laryngectomy-free survival with an organ preservation rate over 5 years of 81% for the non-SCC histologies.ConclusionNon-SCC is a broad spectrum pathology, but generalized laryngeal surgical management principles are still feasible and it is possible to identify patients amenable to conservative surgical treatment without affecting survival.
| S-EPMC8738708 | biostudies-literature
Project description:The nuclear orphan receptor NR4A1 functions as tumour suppressor in aggressive lymphomas by pro-apoptotic genomic and non-genomic effects. Here, we immunohistochemically studied the clinico-pathological relevance of NR4A1 protein expression patterns in a cohort of 60 diffuse large B cell lymphoma (DLBCL) patients and non-neoplastic lymph nodes. We observed a significant association between high cytoplasmic NR4A1 and favourable cancer-specific survival and the germinal centre B cell-like subtype, respectively. Moreover, the percentage of lymphoma cells exhibiting cytoplasmic NR4A1 significantly correlated to those showing cleaved caspase 3. Complementary, functional profiling using gene set enrichment of Reactome pathways based on publicly available microarray data was applied to determine pathways potentially implicated in cytoplasmic localization of NR4A1 and validated by means of semi quantitative real-time PCR. The pathway analysis revealed changes in the ERK1/2 pathway, and this was corroborated by the finding that high cytoplasmic NR4A1 was associated with higher expression of ERK1/2 targets in our cohort. These data indicate that high cytoplasmic NR4A1 is associated with a favourable lymphoma-specific survival and highlights the importance of NR4A1 expression patterns as potential prognostic marker for risk assessment in aggressive lymphomas.
| S-EPMC6162226 | biostudies-literature
Project description:Immune suppressed organ transplant recipients suffer increased morbidity and mortality from primary cutaneous SCC. We studied tumor microenvironment in transplant-associated SCC (TSCC), immune-competent SCC and normal skin by IHC, IF and RT-PCR on surgical discard. We determined T cell polarization in TSCC and SCC by intracellular cytokine staining of T cell crawl outs from human skin explants. We studied the effects of IL-22, an inducer of keratinocyte proliferation, on SCC proliferation in vitro. SCC and TSCC are both associated with significantly higher numbers of CD3(+) and CD8(+) T cells compared to normal skin. TSCC showed a higher proportion of Foxp3(+) T regs to CD8(+) T cells compared to SCC and a lower percentage of IFN-γ producing CD4(+) T cells. TSCC, however, had a higher percentage of IL-22 producing CD8(+) T cells compared to SCC. TSCC showed more diffuse Ki67 and IL-22 receptor (IL-22R) expression by IHC. IL-22 induced SCC proliferation in vitro despite serum starvation. Diminished cytotoxic T cell function in TSCC due to decreased CD8/T-reg ratio may permit tumor progression. Increased IL-22 and IL-22R expression could accelerate tumor growth in transplant patients. IL-22 may be an attractive candidate for targeted therapy of SCC without endangering allograft survival.
| S-EPMC3646982 | biostudies-literature
Project description:BackgroundBSN gene encodes Bassoon, an essential protein to assemble the cytomatrix at the active zone of neurotransmitter release. This study aims to explore the relationship between BSN variants and epilepsy.MethodsWhole-exome sequencing was performed in a cohort of 313 cases (trios) with epilepsies of unknown causes. Additional cases with BSN variants were collected from China Epilepsy Gene V.1.0 Matching Platform. The Clinical Validity Framework of ClinGen was used to evaluate the relationship between BSN variants and epilepsy.ResultsFour pairs of compound heterozygous variants and one cosegregating heterozygous missense variant in BSN were identified in five unrelated families. These variants presented statistically higher frequency in the case cohort than in controls. Additional two de novo heterozygous nonsense variants and one cosegregating heterozygous missense variant were identified in three unrelated cases from the gene matching platform, which were not present in the Genome Aggregation Database. The missense variants tended to be located in C-terminus, including the two monoallelic missense variants. Protein modelling showed that at least one missense variant in each pair of compound heterozygous variants had hydrogen bond alterations. Clinically, two cases were diagnosed as idiopathic generalised epilepsy, two as focal epilepsy and the remaining four as epilepsy with febrile seizures plus. Seven out of eight probands showed infancy or childhood-onset epilepsy. Eight out of 10 affected individuals had a history of febrile convulsions. All the cases were seizure-free. The cases with monoallelic variants achieved seizure-free without treatment or under monotherapy, while cases with biallelic missense variants mostly required combined therapy. The evidence from ClinGen Framework suggested an association between BSN variants and epilepsy.ConclusionThe BSN gene was potentially a novel candidate gene for epilepsy. The phenotypical severity was associated with the genotypes and the molecular subregional effects of the variants.
| S-EPMC10439262 | biostudies-literature