Sentinel lymph node biopsy versus observation in high-risk cutaneous squamous cell carcinoma in immunosuppressed and immunocompetent patients: An inverse probability of treatment weighting study.

BACKGROUND: The survival benefit of sentinel lymph node biopsy (SLNB) in immunocompetent and immunosuppressed patients with high-risk cutaneous squamous cell carcinoma (cSCC) has not been established. OBJECTIVE: To determine whether SLNB improves disease-specific survival (DSS) in high-risk cSCC. Secondary objectives were to analyse disease-free survival, nodal recurrence-free survival and overall survival (OS). METHODS: Multicentre, retrospective, observational cohort study comparing survival outcomes in immunosuppressed and immunocompetent patients treated with SLNB or watchful waiting. Inverse probability of treatment weighting was used to adjust for possible confounding effects. RESULTS: We studied 638 tumours in immunocompetent patients (SLNB n = 42, observation n = 596) and 173 tumours in immunosuppressed patients (SLNB n = 28, observation n = 145). Overall, SLNB was positive in 15.7% of tumours. SLNB was associated with a reduced risk of nodal recurrence (NR) (hazard ratio [HR], 0.05 [95% CI, 0.01-0.43]; p = 0.006), disease specific mortality (HR, 0.17 [95% CI, 0.04-0.72]; p = 0.016) and all-cause mortality (HR, 0.33 [95% CI, 0.15-0.71]; p = 0.004) only in immunocompetent patients. CONCLUSIONS: SLNB was associated with improvements in NR, DSS and OS in immunocompetent but not in immunosuppressed patients with high-risk cSCC.

Low-Level Expression of p-S6 Is Associated with Nodal Metastasis in Patients with Head and Neck Cutaneous Squamous Cell Carcinoma.

Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer. The incidence of metastasis for cSCC is estimated to be around 1.2-5%. Ribosomal protein S6 (p-S6) and the p21 protein (p21) are two proteins that play central roles in other cancers. These proteins may be equally important in cSCC, and together, these could constitute a good candidate for metastasis risk assessment of these patients. We investigate the relationship of p-S6 and p21 expression with the impact on the prognosis of head and neck cSCC (cSCCHN). p-S6 and p21 expression was analyzed by immunohistochemistry on paraffin-embedded tissue samples from 116 patients with cSCCHN and associations sought with clinical characteristics. Kaplan-Meier estimators and Cox proportional hazard regression models were also used. The expression of p-S6 was significantly inversely associated with tumor thickness, tumor size, desmoplastic growth, pathological stage, perineural invasion and tumor buds. p21 expression was significantly inversely correlated with >6 mm tumor thickness, desmoplastic growth, and perineural invasion. p-S6-negative expression significantly predicted an increased risk of nodal metastasis (HR = 2.63, 95% CI 1.51-4.54; p < 0.001). p21 expression was not found to be a significant risk factor for nodal metastasis. These findings demonstrate that p-S6-negative expression is an independent predictor of nodal metastasis. The immunohistochemical expression of p-S6 might aid in better risk stratification and management of patients with cSCCHN.

PINK1 Immunoexpression Predicts Survival in Patients Undergoing Hepatic Resection for Colorectal Liver Metastases.

PTEN-induced kinase-1 (PINK1) is the initiator of the canonical mitophagy pathway. Our aim was to study the immunoexpression of PINK1 in surgical specimens from ninety patients with metastatic colorectal adenocarcinoma (CRC) to the liver (CRLM). Tissue arrays were produced, and immunohistochemical studies were analyzed by the H-Score method. The mean immunoexpression of PINK1 in normal tissues was between 40 to 100 points. In tumoral tissues, positive PINK1 immunoexpression was observed in all samples, and no differences were noted between CRCs. In CRLMs, a significant under-expression was noted for PINK1 from the rectum (71.3 ± 30.8; p < 0.042) compared to other sites. Altered PINK1 immunoexpression in CRCs, either higher than 100 points or lower than 40 points, was associated with worse overall survival (OS) (p < 0.012) due to a shorter post-metastatic survival (PMS) (p < 0.023), and it was found to be a significant independent predictor of prognosis in a multivariate model for OS and PMS (HR = 1.972, 95% CI 0.971-4.005; p = 0.022. HR = 2.023, 95% CI 1.003-4.091; p = 0.037, respectively). In conclusion, altered PINK1 immunoexpression determined in CRCs with resected CRLM predicts a worse prognosis, possibly due to the abnormal function of mitophagy.

The TINCR ubiquitin-like microprotein is a tumor suppressor in squamous cell carcinoma.

The TINCR (Terminal differentiation-Induced Non-Coding RNA) gene is selectively expressed in epithelium tissues and is involved in the control of human epidermal differentiation and wound healing. Despite its initial report as a long non-coding RNA, the TINCR locus codes for a highly conserved ubiquitin-like microprotein associated with keratinocyte differentiation. Here we report the identification of TINCR as a tumor suppressor in squamous cell carcinoma (SCC). TINCR is upregulated by UV-induced DNA damage in a TP53-dependent manner in human keratinocytes. Decreased TINCR protein expression is prevalently found in skin and head and neck squamous cell tumors and TINCR expression suppresses the growth of SCC cells in vitro and in vivo. Consistently, Tincr knockout mice show accelerated tumor development following UVB skin carcinogenesis and increased penetrance of invasive SCCs. Finally, genetic analyses identify loss-of-function mutations and deletions encompassing the TINCR gene in SCC clinical samples supporting a tumor suppressor role in human cancer. Altogether, these results demonstrate a role for TINCR as protein coding tumor suppressor gene recurrently lost in squamous cell carcinomas.

Therapeutic success of sodium thiosulfate in treating cutaneous calciphylaxis in a patient with hyperphosphataemic familial tumoral calcinosis.

Calciphylaxis is a potencially disorder in patients with hyperphosphatemic familial tumoral calcinosis (HFTC). Patients commonly present livedo racemosa and retiform purpura, which may progress to necrosis and very painful ulcers. Treatment with sodium thiosulfate provides good results; however, intralesional and intravenous treatment can be limited by its adverse effects. Topical sodium thiosulfate has been successfully reported for cutaneous calcification associated with connective tissue diseases and calciphylaxis in patients with chronic kidney disease. We provide a case report of a patient with HFTC and calciphylaxis who was treated with topical sodium thiosulfate with a rapid and complete response with no side effects.

Effects of COVID-19 Lockdown on Tumour Burden of Melanoma and Cutaneous Squamous Cell Carcinoma.

The aim of this study was to compare tumour burden in patients who underwent surgery for melanoma and cutaneous squamous cell carcinoma during nationwide lockdown in Spain due to COVID-19 (for the period 14 March to 13 June 2020) and during the same dates in 2019 before the COVID-19 pandemic. In addition, associations between median tumour burden (Breslow thickness for melanoma and maximum clinical diameter for cutaneous squamous cell carcinoma) and demographic, clinical, and medical factors were analysed, building a multivariate linear regression model. During the 3 months of lockdown, there was a significant decrease in skin tumours operated on (41% decrease for melanoma (n = 352 vs n = 207) and 44% decrease for cutaneous squamous cell carcinoma (n = 770 vs n = 429)) compared with the previous year. The proportion of large skin tumours operated on increased. Fear of SARS-CoV-2 infection, with respect to family member/close contact, and detection of the lesion by the patient or doctor, were related to thicker melanomas; and fear of being diagnosed with cancer, and detection of the lesion by the patient or relatives, were related to larger size cutaneous squamous cell carcinoma. In conclusion, lockdown due to COVID-19 has resulted in a reduction in treatment of skin cancer.

Immunohistochemical expression analysis of MMP-1, TIMP-2 and p53 in Barrett's esophagus, dysplasia and esophageal adenocarcinoma.

Barrett's esophagus (BE) is the most important risk factor for the development of esophageal adenocarcinoma. It develops through a progressive sequence of histologic and molecular events that begin with metaplasia and then progresses through various stages of dysplasia. Matrix metalloproteinases are involved in the degradation of the extracellular matrix and play an important role in tumor progression. The immunohistochemical expression of MMP-1, TIMP-2 and p53 in 111 samples from 45 patients diagnosed with BE with and without dysplasia and adenocarcinoma of the esophagus was retrospectively studied, and statistical analysis was conducted to measure the association between their expression and the degree of dysplasia present. MMP-1 was expressed in 33.3% of the samples studied, mainly in the adenocarcinoma subgroup with up to 40% positive cases (p = 0.494). In contrast, TIMP-2 was expressed in 25.2% of the samples, and no positive cases were identified in the adenocarcinoma subgroup (p = 0.037). Aberrant p53 expression was observed in 81.4% of the samples diagnosed with some degree of dysplasia (p < 0.001). MMP-1 showed no statistically significant differences between diagnostic entities. A statistically significant loss of TIMP-2 expression was observed in distal esophageal adenocarcinoma samples, which contrasts with the aberrant expression of p53 in dysplastic cases.

Miki (Mitotic Kinetics Regulator) Immunoexpression in Normal Liver, Cirrhotic Areas and Hepatocellular Carcinomas: a Preliminary Study with Clinical Relevance.

Hepatocellular carcinoma (HCC) is the most common type of primary malignant tumor in the liver. One of the main features of cancer survival is the generalized loss of growth control exhibited by cancer cells, and Miki is a protein related to the immunoglobulin superfamily that plays an important role in mitosis. We aim to study protein expression levels of Miki in non-tumoral liver and 20 HCCs recruited from a Pathology Department. Clinical information was also obtained. A tissue microarray was performed, and immunohistochemical techniques applied to study protein expression levels of Miki. In normal liver, Miki was weakly expressed, showing nuclear staining in the hepatocytes. Cirrhotic areas and HCCs showed a variety of staining patterns. Most HCC samples showed positive expression, with three different staining patterns being discernible: nuclear, cytoplasmic and mixed. Statistical analysis showed a significant association between grade of differentiation, Ki-67 proliferative index, survival rates and staining patterns. This study has revealed the positive expression of Miki in normal liver, cirrhotic areas and HCCs. Three different staining patterns of Miki expression with clinical relevance were noted in HCCs.

Correlation of focal adhesion kinase expression with nodal metastasis in patients with head and neck cutaneous squamous cell carcinoma.

BACKGROUND: Focal adhesion kinase (FAK) and cortactin overexpression is frequently detected in a variety of cancers, and has been associated with poor clinical outcome. However, there are no data in cutaneous squamous cell carcinoma (cSCC). OBJECTIVE: To investigate the relationship of FAK and cortactin expression with the clinicopathologic features and the impact on the prognosis of cSCC patients. METHODS: FAK and cortactin expression was analyzed by immunohistochemistry on paraffin-embedded tissue samples from 100 patients with cSCC, and correlated with the clinical data. RESULTS: FAK overexpression was a significant risk factor for nodal metastasis with crude and adjusted ratios (HRs) of 2.04, (95% CI [1.08-3.86], [P = 0.029]) and 2.23 (95% CI [1.01-4.91], [P = 0.047]), respectively. Cortactin expression was not a significant risk factor for nodal metastasis. CONCLUSION: These findings demonstrate that FAK overexpression is an independent predictor of nodal metastasis that might be helpful for risk stratification and management of patients with cSCC.

Cutaneous and Mucosal Manifestations Associated with Celiac Disease.

Celiac disease (CD) is an immune-mediated, gluten-induced enteropathy that affects predisposed individuals of all ages. Many patients with CD do not report gastrointestinal symptoms making it difficult to reach an early diagnosis. On the other hand, CD is related to a wide spectrum of extra-intestinal manifestations, with dermatitis herpetiformis (DH) being the best characterized. These associated conditions may be the clue to reaching the diagnosis of CD. Over the last few years, there have been multiple reports of the association between CD and several cutaneous manifestations that may improve with a gluten-free diet (GFD). The presence of some of these skin diseases, even in the absence of gastrointestinal symptoms, should give rise to an appropriate screening method for CD. The aim of this paper is to describe the different cutaneous manifestations that have been associated with CD and the possible mechanisms involved.

Establishing cut-off points with clinical relevance for bcl-2, cyclin D1, p16, p21, p27, p53, Sox11 and WT1 expression in glioblastoma - a short report.

PURPOSE: Glioblastoma (GBM) ranks among the most challenging cancers to treat and there is an urgent need for clinically relevant prognostic and diagnostic biomarkers. Here, we set out to investigate the expression of eight proteins (bcl-2, cyclin D1, p16, p21, p27, p53, Sox11 and WT1) in GBM with the specific aim to establish immunohistochemistry cut-off points with clinical relevance. METHODS: Immunohistochemistry (IHC) was used to examine protein expression in 55 surgical GBM specimens using H-scores, and IHC cut-off points were established using the Cutoff Finder web platform. Protein co-expression and its correlation with histopathological features were assessed, and cases were classified according to IDH1 mutation status. Survival curves were determined using Kaplan-Meier analyses. RESULTS: Clinical and molecular parameters found to be correlated with overall survival (OS) were tumor size (r = -0.278; p = 0.048), p53 (r = -0.452; p = 0.001), p16 (r = 0.351; p = 0.012) and Sox11 (r = 0.324; p = 0.020). In addition, we found that tumor size correlated with cyclin D1 (r = -0.282; p = 0.037), p53 (r = 0.269; p = 0.041), Sox11 (r = -0.309; p = 0.022) and WT1 (r = -0.372; p = 0.003). Variables found to be significantly associated with IDH1 mutation status were OS (p < 0.01), age (p < 0.01), cyclin D1 (p = 0.046), p16 (p = 0.019) and Sox11 (p = 0.012). Variables found to be significantly associated with a poor survival were tumor size >5 cm (p < 0.001), bcl-2 score > 40 (p = 0.034), cyclin D1 score ≤ 70 (p = 0.004), p16 score ≤ 130 (p = 0.005), p53 score > 20 (p = 0.003), Sox11 score ≤ 40 (p < 0.001) and WT1 score ≤ 270 (p = 0.02). CONCLUSIONS: Correlations between protein biomarkers and main clinical GBM variables were identified. The establishment of distinct biomarker cut-off points may enable clinicians and pathologists to better weigh their prognostic value.

Brains with sporadic Creutzfeldt-Jakob disease and copathology showed a prolonged end-stage of disease.

AIMS: To investigate the expression of major proteins related to primary neurodegenerative diseases and their prognostic significance in brains with Creutzfeldt-Jakob disease (CJD). MATERIALS AND METHODS: Thirty consecutive cases of confirmed CJD during the period 2010-2015 at Basque Brain bank were retrospectively reviewed. Moreover, major neurodegenerative-associated proteins (phosphorylated Tau, 4R tau, 3R tau, alpha-synuclein, TDP43, amyloid beta) were tested. Clinical data were reviewed. Cases were divided according to the presence or absence of copathology. Survival curves were also determined. RESULTS: Copathology was significantly associated with survival in brains with CJD (4.2±1.2 vs 9.2±1.9; P=0.019) and in brains with MM1/MV1 CJD (2.1±1.0 vs 6.7±2.8; P=0.012). Besides, the presence of more than one major neurodegenerative-associated protein was significantly associated with survival (4.2±1.2 vs 10.7±2.6; P=0.017). Thus, univariate analyses further pointed out variables significantly associated with better survival: copathology in CJD (HR=0.430; P=0.033); more than one neurodegenerative-associated protein in CJD (HR=0.369; P=0.036) and copathology in MM1/MV1 CJD (HR=0.525; P=0.032). CONCLUSION: The existence of copathology significantly prolongs survival in patients with rapidly progressive dementia due to CJD. The study of major neurodegenerative-associated proteins in brains with CJD could allow us to further understand the molecular mechanisms behind prion diseases.

Tumor programmed cell death ligand 1 expression correlates with nodal metastasis in patients with cutaneous squamous cell carcinoma of the head and neck.

BACKGROUND: Binding of tumor-expressed programmed cell death ligand 1 (PD-L1) to the programmed cell death 1 (PD-1) surface receptor blocks T-cell activation thereby leading to immune evasion. Tumor PD-L1 expression has been associated with poor outcome in a wide variety of cancers; however, data in cutaneous squamous cell carcinoma (cSCC) are scarce and conflicting. OBJECTIVE: To investigate the relationship of tumor PD-L1 expression with the clinicopathologic features and prognosis of cSCC. METHODS: PD-L1 expression was analyzed by immunohistochemistry on paraffin-embedded tissue samples from 100 patients with cSCC. Cumulative/dynamic receiver operating characteristic curve was used to determine the optimal PD-L1 threshold. Kaplan-Meier estimators and Cox proportional hazards regression models were also used. RESULTS: On the basis of cumulative/dynamic receiver operating characteristic curves, we defined the cut-off score for PD-L1 expression as ≥25% of tumor cells positively stained. PD-L1 expression was a significant risk factor for nodal metastasis with crude and adjusted hazard ratios of 3.39 (1.71-6.65) and 6.54 (2.28-18.78), respectively. LIMITATIONS: This is a retrospective study limited to cSCC of the head and neck. CONCLUSION: These findings indicate that tumor PD-L1 expression predicts increased risk for nodal metastasis in patients with cSCC.

The adverse prognostic effect of tumor budding on the evolution of cutaneous head and neck squamous cell carcinoma.

BACKGROUND: Tumor budding is a readily detectable histopathologic feature that has been recognized as an adverse prognostic factor in several human cancers. OBJECTIVE: We sought to assess the correlation of tumor budding with the clinicopathologic features and the prognostic value of tumor budding in cutaneous squamous cell carcinoma (cSCC). METHODS: Forty-nine primary nonmetastatic and 49 primary metastatic cSCCs to regional lymph nodes were retrospectively studied. Statistical analyses were carried out to assess the relationship between tumor budding, clinicopathologic parameters, and patient survival. RESULTS: Tumor budding was observed in 45 cases of 98 (46%). High-intensity budding (≥5 tumor buds) was observed in 20 tumors. Presence of tumor buds was a significant risk factor for nodal metastasis with crude and adjusted hazard ratios (HRs) of 8.92 (95% CI, 4.39-18.1) and 6.93 (95% CI, 3.30-14.5), respectively, and for reduced overall survival time (crude and adjusted HRs of 2.03 [95% CI, 1.26-3.28] and 1.72 [95% CI, 1.05-2.83], respectively). LIMITATIONS: This was a retrospective study limited to cSCCs of the head and neck. Examined tumors were >2 mm thick, and all were from a primary excision. CONCLUSION: These results indicate an increased frequency of nodal metastasis and risk of death in patients with tumor buds.

Sporadic adult-onset leucodystrophy with axonal spheroids and pigmented glia with no mutations in the known targeted genes.

AIMS: Adult-onset orthochromatic leucodystrophy, associated with pigmented macrophages and hereditary diffuse leucoencephalopathy with spheroids, are two disorders with similar clinical manifestations, radiological characteristics and neuropathological findings. Mutations in the colony-stimulating factor 1 receptor (CSF1R) gene are the hallmark of this spectrum of disease. Furthermore, polycystic membranous lipomembranous osteodysplasia with sclerosing leucoencephalopathy is caused by mutations in two genes, DAP12 and TREM2, which encode proteins involved in the same pathways as CSF1R. We describe a case of sporadic adult-onset orthochromatic leucodystrophy associated with pigmented macrophages diagnosed by biopsy without harbouring mutations in the known targeted genes. METHODS AND RESULTS: A 51-year-old woman, with no familial history of neurological diseases, developed a progressive neurological deterioration showing inappropriate behaviour, ataxia, spasticity, axial dystonia and agitation. Radiological images and a stereotaxic biopsy were conclusive with adult-onset orthochromatic leucodystrophy associated with pigmented macrophages. Genetic analysis did not show mutations in either CSF1R, DAP12 or TREM2. CONCLUSIONS: We add support to the idea that all these entities are closely related diseases linked to a convergent metabolic pathway, but caused by different genes or perhaps by the combination of individually non-pathogenic variations of selected genes. Genetic defects are still barely known in a substantial number of adult leucodystrophies.

CDKAL1 gene variants affect the anti-TNF response among Psoriasis patients.

The heterogeneous response to anti-TNF biological drugs among Psoriasis (Psor) patients might be explained by gene variants linked to the risk for Psor. Common variants in the CDKAL1 gene have been associated with the risk of developing Psor. Our hypothesis was that these variants could also influence the response to anti-TNFs among Psor-patients. A reduction of at least 75% in the Psoriasis area and severity index (PASI 75) at week 24 was considered a positive response to treatment. A total of 116 patients (78 responders and 38 non-responders) were genotyped for the CDKAL1 rs6908425, rs4712523, rs111739077, and rs77152992 (p.P409L) single nucleotide polymorphisms. Allele and genotype frequencies differed between the two response groups, with the highest difference for the rs6908425: CC homozygotes were significantly more common among responders (72% vs. 45%; p=0.005; OR=3.14, 95%CI=1.40-7.05). In conclusion, our data suggested that CDKAL1 gene variants have a significant effect on the response to anti-TNF therapies among Psor patients. If confirmed on other large cohorts of patients, the genotyping of these variants might help to predict the biological response.