Plasma Biomarker Profile and Clinical Correlations in Adult Patients With Tuberous Sclerosis Complex.

OBJECTIVES: Different pathophysiologic mechanisms, especially involving astrocytes, could contribute to tuberous sclerosis complex (TSC). We assessed neurodegeneration and astrocytopathy plasma biomarkers in adult patients with TSC to define TSC biomarker profile and investigate clinical-radiologic correlations. METHODS: Patients with TSC aged 15 years or older followed at Policlinico "Umberto I" of Rome were consecutively enrolled (July 2021-June 2022). The plasma levels of the following biomarkers were compared between patients and age/sex-matched healthy controls (HCs): tTau, pTau181, Abeta40, Abeta42, neurofilament light chain, and glial fibrillary acid protein (GFAP). RESULTS: Thirty-one patients (20 females/11 males; median age 30 years, interquartile range 24-47) and 38 HCs were enrolled. Only GFAP was significantly higher in the whole TSC population than in HCs (132.71 [86.14-231.06] vs 44.80 [32.87-66.76] pg/mL, p < 0.001), regardless of genotype. GFAP correlated with the disease clinical (ρ = 0.498, p = 0.005) and radiologic severity (ρ = 0.417, p = 0.001). It was significantly higher in patients with epileptic spasms (254.50 [137.54-432.96] vs 86.92 [47.09-112.76] pg/mL, p < 0.0001), moderate-severe intellectual disability (200.80 [78.40-427.6] vs 105.08 [46.80-152.58] pg/mL, p = 0.040), and autism spectrum disorder (306.26 [159.07-584.47] vs 109.34 [72.56-152.08] pg/mL, p = 0.021). DISCUSSION: Our exploratory study documented a significant increase of GFAP plasma concentration in adult patients with TSC, correlated with their neurologic severity, supporting the central role of astrocytopathy in TSC pathophysiology.

Syphilis: a mini review of the history, epidemiology and focus on microbiota.

Syphilis is a chronic systemic infectious disease caused by the spirochaete bacterium Treponema pallidum(syphilis treponeme). In recent decades there has been a drastic increase in cases of syphilis,with a relative increase in scientific interest in this regard. However, the data concerning the studyof microbiota in syphilis are few and very scattered.This brief review provides a quick update on the disease, with particular attention to the role of themicrobiota, an aspect not always adequately considered in the evaluation of the pathology. The usualcoexistence of different sexually transmitted diseases in the same patients led us to delve also intothe possible role of the microbiota in the pathogenesis of syphilis; indeed, not all sexual contactslead to infections, suggesting that host immunity and local microbiota could modulate the historyof sexually transmitted disease. In both males and females, alteration of the microbiota may be involvedin syphilis as well as in the other sexually transmitted diseases. Finally, since 9% of the totalproteome of T. pallidum is spent for transportome, the latter may provide essential nutrients, makingT. pallidum able to adapt to a diverse range of microenvironments and stresses in the human host.

The Fatty Acid and Protein Profiles of Circulating CD81-Positive Small Extracellular Vesicles Are Associated with Disease Stage in Melanoma Patients.

The early detection of cutaneous melanoma, a potentially lethal cancer with rising incidence, is fundamental to increasing survival and therapeutic adjustment. In stages II-IV especially, additional indications for adjuvant therapy purposes after resection and for treatment of metastatic patients are urgently needed. We investigated whether the fatty acid (FA) and protein compositions of small extracellular vesicles (sEV) derived from the plasma of stage 0-I, II and III-IV melanoma patients (n = 38) could reflect disease stage. The subpopulation of sEV expressing CD81 EV marker (CD81sEV) was captured by an ad hoc immune affinity technique from plasma depleted of large EV. Biological macromolecules were investigated by gas chromatography and mass spectrometry in CD81sEV. A higher content of FA was detectable in patients with respect to healthy donors (HD). Moreover, a higher C18:0/C18:1 ratio, as a marker of cell membrane fluidity, distinguished early (stage 0-I) from late (III-IV) stages' CD81sEV. Proteomics detected increases in CD14, PON1, PON3 and APOA5 exclusively in stage II CD81sEV, and RAP1B was decreased in stage III-IV CD81sEV, in comparison to HD. Our results suggest that stage dependent alterations in CD81sEV' FA and protein composition may occur early after disease onset, strengthening the potential of circulating sEV as a source of discriminatory information for early diagnosis, prediction of metastatic behavior and following up of melanoma patients.

Lichen sclerosus and hidradenitis suppurativa: Two case reports of a new possible association.

We report the cases of two women affected by lichen sclerosus also having clinical signs of hidradenitis suppurativa. Lichen sclerosus is a chronic autoimmune disease, in which activated fibroblasts produce significantly altered collagen leading to fibrosis Hidradenitis suppurativa is a chronic relapsing inflammatory disease affecting folliculopilosebaceous unit and apocrine gland, which lesions are nodules and abscesses. The association between lichen sclerosus and autoimmune disorders is well known, but not the one with hidradenitis suppurativa. We present two case reports of these unusual comorbidities.

IFN-γ/IL-6 and related cytokines in chronic spontaneous urticaria: evaluation of their pathogenetic role and changes during omalizumab therapy.

BACKGROUND: Recent studies highlight that high levels of cytokines may precede the onset of many systemic autoimmune disorders and may also be related to chronic spontaneous urticaria (CSU) activity. METHODS: Eight patients with CSU candidate to omalizumab therapy were enrolled. Four healthy controls were included with the purpose of comparing baseline cytokine levels. We evaluated serum levels of IFN-γ, IL-2, 4, 6, 8, and 10, TNF-α, and GM-CSF. For the patient group, venous blood samples were drawn at T0, T1 (1 week after first drug administration), T2 (after 3 months), T3 (after 6 months), and in case of relapse. Cytokine levels were measured using the human cytokines 8-plex kit. Disease activity and effect of therapy were calculated by means of Urticaria Activity Score 7. RESULTS: Higher levels of IL-6 and IFN-γ were found in patients with CSU compared to those observed in the control group. Moreover, a common trend between these cytokines and the clinical history of disease could be hypothesized, with a decrease in levels of IFN-γ and IL-6 following remission of CSU with omalizumab treatment. Levels of other tested cytokines were similar between patients and healthy subjects. CONCLUSION: IFN-γ and IL-6 are proinflammatory cytokines that are strongly related to autoimmunity. Despite being limited by the small sample size, our data offer new insight into a better understanding of the pathogenesis of CSU and support the need for further investigations.

Prognostic factors in head and neck melanoma according to facial aesthetic units.

BACKGROUND: Head and neck melanoma is a clinical challenge. Indeed, cutaneous head and neck melanoma shows a worse prognosis in comparison to melanomas of other body sites. Although the emphasis on facial cosmetic preservation plays a pivotal role in comparison to other body areas, specific Facial Aesthetic Units (FAU) could also play a key role in the prognostic evaluation of the malignancy. METHODS: The aim of the current study was to evaluate the general outcome and clinicopathological features of head and neck melanoma and to detect prognostic differences according to each FAU. The Kaplan-Meier product was used to calculate survival curves, while Cox proportional-hazard regression was performed to evaluate the predictive value of each FAU. RESULTS: A total of 221 head and neck melanoma patients was included in our analysis. In the nasal FAU, we found a high rate of local recurrence, which affected significantly disease-free survival. The worse prognosis was observed in melanoma of the scalp, which showed a greater tendency to skip metastases in internal organs. Moreover, we found that scalp showed a low incidence of non-melanoma skin cancers, if compared to other FAU, highlighting that the scalp local milieu might play a more prominent role in melanoma biology than chronic UV exposition. CONCLUSIONS: Although FAUs have an aesthetic function, they could also play a role in the evaluation and follow-up of melanoma.

Mast cells and cancer.

Mast cells (MCs) are a potent proangiogenic factor in tumors, they product several pro-angiogenic factors such as fibroblast growth factor 2 (FGF-2), vascular epithelial growth factor (VEGF), tryptase and chymase. Tryptase is a serine protease classified as α-tryptase and ß-tryptase, both produced by MCs. Tryptase degrades the tissues, playing an important role in angiogenesis and in the development of metastases. Serum tryptase increases with age, with increased damage to cells and risk of developing a malignancy and it could be considered the expression of a fundamental role of MCs in tumor growth or, on the contrary, in the antitumor response. Many biomarkers have been developed in clinical practice for improving diagnosis and prognosis of some neoplasms. Elevated tryptase levels are found in subgroups of patients with haematologic and solid cancers. In the current review, we want to update the perspectives of tryptase as a potential biomarker in daily practice in different neoplasms.

Serum tryptase levels in melanoma patients: case-control study and review of the literature.

BACKGROUND: Serum tryptase results from the constant release of the enzyme from mast cells and serum tryptase levels are commonly considered to be related to the total number of mast cells. They are increased in several malignancies, as pancreatic carcinoma, angiosarcoma, hepatic carcinoma and proliferative and/or non-proliferative hematological disorders. Contrariwise, it has been reported that the number of tryptase- and chymase-positive mast cells was lower in deeply invasive melanoma compared to in-situ melanoma and dysplastic nevi. Considering the underlying pathophysiological linkages between mast cells and melanocytes and that serum tryptase is related to angiogenesis, tissue-degrading proprieties and metastatization, we have decided to evaluate serum tryptase levels in melanoma patients and in a healthy control. METHODS: We performed a case-control study evaluating serum tryptase in melanoma and in healthy group. Starting from an initial general analysis, we have performed a sub-analysis for each sample. RESULTS: In general population serum tryptase was statistically higher in elderly patients. Generally, in melanoma patients, median serum tryptase was in lower normal range. We found a decreasing of serum tryptase levels from the healthy control to thin (≤1.00 mm Breslow thickness), reaching the lowest levels in thicker melanoma (≥1.01 mm Breslow thickness), in ulcerated and metastatic melanoma. CONCLUSIONS: Tryptase may have a protective role in melanoma or in the early stage of the tumorigenesis. Serum tryptase is an easy and useful biomarker to better investigate melanoma biology.

Vitamin D and melanoma: state of the art and possible therapeutic uses.

Despite the presence of several studies in literature, the real connection between vitamin D serological levels, vitamin D receptor and melanoma remains unclear, probably because of the complex correlation between vitamin D and melanoma. Indeed, UV radiations are not reported as the main risk factor for melanoma in non-sun-exposed, while systemic immunosuppression, anatomical and physiological features may contribute to malignancy. Therefore, the correlation between melanoma cells in sun-exposed areas and vitamin D, as well as vitamin D receptor could be different from the one in melanoma of sun-shielded sites. These differences may also explain the controversial results reported in the literature regarding the correlation between melanoma and vitamin D, as well as the different outcomes in melanoma patients treated with vitamin D as adjuvant therapy. The aim of this review is to highlight the most recent findings about vitamin D and melanoma, focusing on the anatomic site of the primary tumor as well as on the possible therapeutic uses of vitamin D in melanoma patients.

Correlation of serum tryptase levels with total number of nevi, Breslow thickness, ulceration, and mitotic index in melanoma patients: evaluation of a promising prognostic marker.

Current evidences suggest that mast cells contribute to the proliferation and differentiation of skin melanocytes. According to these findings, we carried out an observational cross-sectional study to investigate the correlation between the total number of nevi (TN), Breslow thickness (BT), and serum tryptase (ST) levels in a cohort of 35 melanoma (MM) patients. A Mann-Whitney test was performed to compare ST values within each variable. Subsequently, the independent predictive factors were assessed by multiple logistic regression. Pearson's χ-test was chosen to detect statistically significant findings on the TN and the histopatological variables (Breslow, ulceration, and mitotic index). The TN was assessed using a dichotomous scale (≤ 10 or > 10). Patients with TN of 10 or less (3.48 vs. 6.05 ng/ml; P = 0.045), patients with a Breslow thickness of at least 1.01 mm (2.99 vs. 5.67 ng/ml; P = 0.1), and ulcerated MM (2.37 vs. 6.05 ng/ml; P < 0.001) showed lower median ST levels. Similarly, MM with mitotic index of at least 1/mm had median ST levels lower than MM with mitotic index less than 1/mm (P = 0.005). Multiple logistic regression confirmed the statistical significance for the variables ulceration, TN, and mitotic index. Pearson's χ-test showed a statistically significantly (P = 0.003) increased prevalence of MMs with a BT of at least 1.01 mm in patients with a TN of 10 or less. Patients with a TN of 10 or less also showed a higher prevalence of ulceration and mitotic index of at least 1/mm in comparison with the rest of the cohort. Our study highlights lower median ST levels in patients whose MM thickness is at least 1.01 mm; this may encourage new studies on the role of ST in MM also according to the number of nevi.