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.

Effectiveness and safety of tildrakizumab for the treatment of psoriasis in real-world settings at 24 weeks: A retrospective, observational, multicentre study by the Spanish Psoriasis Group.

BACKGROUND: Tildrakizumab is a humanized, IgG1/κ antibody that interacts with the p19 subunit of interleukin 23. It is approved for the treatment of moderate-to-severe plaque psoriasis. Real-world evidence on the effectiveness and safety of tildrakizumab is limited. OBJECTIVES: To assess the effectiveness and safety of tildrakizumab at 24 weeks in patients with moderate-to-severe plaque psoriasis in routine clinical practice. METHODS: Retrospective, observational, multicentre study including adult patients with moderate-to-severe plaque psoriasis treated with tildrakizumab under real-life conditions. Patient data were extracted from anonymized electronic medical records. Statistical analysis was performed using SPSS22. RESULTS: A total of 190 patients were included. About 53.9% were men with a mean age of 51.45 (SD 3.9) and a mean BMI of 29.13 (SD 6.21). About 79.8% (132 out of 190) of patients had previously received biological therapy (BT) and 17.3% (33 out of 191) had psoriatic arthritis. Baseline PASI was 10.7 (SD 6.53). Up to 109 patients reached Week 24 and at this point mean baseline PASI decreased to 1.7 (SD 4.8), representing an 88.79% mean PASI reduction. At 6 months, 87.1% and 40.3% of the treated patients achieved PASI ≤3 and ≤1, respectively. At Week 24 mean BSA decreased from 13.2 (SD 10.07) to 1.6 (SD 4.40) and mean DLQI went from 12.5 (SD 7.12) to 1.2 (SD 3.27). Multivariate analysis showed no differences when effectiveness was correlated with gender, obesity, psoriatic arthritis or prior exposure to BT. The rate of adverse events (AE) was 5.9% (11 out of 190), where infections were the most frequent AE (4 out of 11). One patient suffered a haemorrhagic ictus and one patient died due to causes unrelated to the study. CONCLUSION: Tildrakizumab was effective and safe in a large cohort of patients with moderate-to-severe plaque psoriasis treated in a routine clinical setting.

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.

Retrospective study of apremilast drug survival in psoriasis patients in a daily practice setting: A long-term experience.

There is limited evidence about the real-world survival of apremilast in patients with psoriasis, especially over the long term. To evaluate the long-term survival of apremilast and its predictive factors when used to treat psoriasis. A retrospective hospital-based study, including data collected from 104 patients. Survival curves were estimated using the Kaplan-Meier estimator. Proportional hazard Cox regression models were used for multivariate analysis. The average duration of the treatment before discontinuation was 28.82 months (95% CI, 22.08-35.57 months) and the median was 12 months (95% CI, 2.68-21.31 months). The retention rates were 51% (1 year), and 33% (5 years). The survival study revealed statistically significant differences between patients with PASI<10 and those in the PASI≥10 group (log-rank test, p < 0.001). The 5-year prevalences were 64% for patients with a PASI of <10 and 5% for those with an index ≥10. In the PASI < 10-patient group, the retention rates were 77% (1 year) and 64% (5 years). Furthermore, 66% of patients who continued apremilast treatment for more than 2 years were receiving off-label doses (30 mg/day). Apremilast may be a suitable and efficient alternative for the treatment of psoriasis patients in the PASI<10 group.

Psoriasis of the external auditory canal: prevalence, clinical features and impact on quality of life.

Psoriasis of the external auditory canal (PsEAC) is often under-recognized. The aims of this study were to assess the prevalence of PsEAC, its association with a particular psoriasis subtype and its impact on quality of life (QoL). A prospective study was carried out in two Spanish university hospitals, enrolling consecutive patients who attended a consultation for psoriasis. The clinical features of psoriasis and PsEAC were recorded and the Dermatology Life Quality Index (DLQI) and Itch Numerical Rating Scale (Itch-NRS) were distributed to patients. Overall, 188 of 1000 patients (18.8%) included in the study had PsEAC, which was associated with severity of psoriasis, presence of inverse psoriasis and involvement of the scalp, nails and genitals, but not with obesity or psoriatic arthritis. PsEAC was the main reason for consultation in 27 patients, with itching being the main symptom. In this study, PsEAC had a prevalence of 18.8%. The occurrence of PsEAC was associated with poorer QoL, as measured by DLQI and Itch-NRS.

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.

Ustekinumab Drug Survival in Patients with Psoriasis: A retrospective Study of Real Clinical Practice.

Background and objectives: The efficacy and safety of ustekinumab have been proved in clinical trials. In daily clinical practice, knowing the factors that determine survival differences of biological drugs allows psoriasis treatment to be optimized as a function of patient characteristics. The main objectives of this work are to understand ustekinumab drug survival in patients diagnosed with plaque psoriasis in the Hospital Universitario Central de Asturias (HUCA Dermatology Department, and to identify the predictors of drug discontinuation. Materials and Methods: A retrospective hospital-based study, including data from 148 patients who were receiving ustekinumab (Stelara®) between 1 February 2009 and 30 November 2019, were collected. Survival curves were approximated through the Kaplan-Meier estimator and compared using the log-rank test. Proportional hazard Cox regression models were used for multivariate analyses while both unadjusted and adjusted hazard ratios (HR) were used for summarizing the studied differences. Results: The average duration of the treatment before discontinuation was 47.57 months (SD 32.63 months; median 41 months). The retention rates were 82% (2 years), 66% (5 years), and 58% (8 years). Median survival was 80 months (95% confidence interval. CI 36.9 to 123.01 months). The survival study revealed statistically significant differences between patients with arthritis (log-rank test, p < 0.001) and those who had previously received biological treatment (log-rank test, p = 0.026). The five-year prevalence in patients still under treatment was 80% (those without arthritis) and 54% (arthritis patients). In the multivariate analysis, only the patients with arthritis had a lower rate of drug survival. No statistically significant differences were observed for any of the other comorbidities studied. The first and second most frequent causes of discontinuation were secondary failure and arthritis inefficacy, respectively. Conclusion: Ustekinumab is a biological drug conferring high survival in plaque psoriasis patients. Ustekinumab survival is lower in patients with arthritis.

Sporadic Creutzfeldt-Jakob disease with glial PrPRes nuclear and perinuclear immunoreactivity.

Proteinase K-resistant prion protein (PrPRes ) nuclear and perinuclear immunoreactivity in oligodendrocytes of the frontal cortex is found in one case of otherwise typical sporadic Creutzfeldt-Jakob disease (sCJD) type VV2a. The PrP nature of the inclusions is validated with several anti-PrP antibodies directed to amino acids 130-160 (12F10), 109-112 (3F4), 97-102 (8G8) and the octarepeat region (amino acids 59-89: SAF32). Cellular identification and subcellular localization were evaluated with double- and triple-labeling immunofluorescence and confocal microscopy using antibodies against PrP, glial markers, and histone H3. Based on review of the literature and our own experience, this is a very odd situation that deserves further validation in other cases.

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.

The Cw6 and late-cornified envelope genotype plays a significant role in anti-tumor necrosis factor response among psoriatic patients.

Our aim was to determine whether the HLA-Cw6 and late-cornified envelope (LCE) deletion polymorphisms were related to disease improvement among psoriasis patients treated with anti-tumor necrosis factor (TNF) antibodies. The study included a total of 116 patients. Positive response (68%) was defined as a reduction of at least 75% of the Psoriasis Area and Severity Index (PASI) after 24 weeks of starting the anti-TNF therapy. We found a trend toward a better response among Cw6-positive patients. The frequency of patients who did not reach the PASI75 was higher among the LCE-DD patients (P=0.028; odds ratio=2.45, 95% confidence interval=1.09-5.52). Patients who were Cw6-positive and LCE-I carriers (ID/II) were significantly more likely to reach PASI75 than those who were Cw6-negative and LCE-DD (P=0.034; odds ratio=3.14, 95% confidence interval=1.07-9.24). In conclusion, we found an interaction between the HLA-Cw6 and LCE genotypes on disease improvement among psoriatic patients treated with anti-TNFs.

Psoriasis vulgaris with or without arthritis and independent of disease severity or duration is a risk factor for hypercholesterolemia.

BACKGROUND: Psoriasis (Ps) has been associated with an increased incidence of cardiovascular disease. Interesting epidemiological evidence suggests associations between Ps and dyslipidemia (DL), a well-established risk factor for cardiovascular disease. OBJECTIVE: This study aimed to investigate the association between Ps and multiple measurements of DL, which include levels of triglycerides (TGs), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and total cholesterol (TCh). We also studied the relationship between DL and disease duration. METHODS: A prospective hospital-based study was conducted. A total of 661 Caucasian patients with chronic plaque Ps and 661 sex- and age-matched controls were enrolled. RESULTS: Multivariate analysis showed that in psoriatic patients the odds ratio (OR) of TCh >200 mg/dl was 1.406 (95% confidence interval 1.115-1.173), the OR of LDL cholesterol >130 mg/dl was 1.375 (95% confidence interval 1.088-1.738), the OR of HDL cholesterol <40 mg/dl was 0.881 (95% confidence interval 0.599-1.297), and the OR of TGs >150 mg/dl was 1.041 (95% confidence interval 0.783-1.385). We did not find a relationship between lipid levels and disease duration. CONCLUSION: Based on our population Ps is associated with alterations in TCh and LDL cholesterol, but not in TGs and HDL cholesterol, when ATP III panel levels are used. These alterations are not related to disease duration.

Do patients with inflammatory bowel disease really know what other immune-mediated inflammatory diseases they are diagnosed with?

BACKGROUND AND AIMS: The association of inflammatory bowel disease (IBD) with other immune-mediated inflammatory diseases (IMIDs) in the same patient is well known. We aimed to evaluate the degree of knowledge that patients with IBD have regarding the coexistence of other IMIDs and to analyze the factors associated with the concordance between self-reported and confirmed medical information. METHODS: Patients with IBD at a tertiary hospital answered a questionnaire on the presence of 54 IMIDs (self-reported diagnosis), and their IMID diagnosis was confirmed in their medical records (reference diagnosis). Agreement between the self-reported IMID and the IMID according to medical records was evaluated. The association between concordance and different predictors was evaluated using logistic regression models. RESULTS: A total of 1,620 patients were included. Six hundred and twenty-six (39%) patients were diagnosed with at least one IMID, and 177 (11%) with two or more. Overall agreement between patients´ self-report and medical records was k:0.61. When we grouped IMIDs according to affected organs or systems, agreement on rheumatic IMIDs was moderate (k:0.58), whereas agreement on cutaneous (k:0.66), endocrine (k: 0.74) and ocular (k:0.73) IMIDs was substantial. Among patients who had IMIDs, the factor associated with greater concordance was female gender, while lower concordance was associated with a lower educational level and the fact that the IMID had been diagnosed at the same time or later than IBD. CONCLUSION: The knowledge that patients with IBD have regarding the coexistence of other IMIDs is poor, especially in rheumatic IMIDs.