Clinical and oncological outcomes in single-stage versus staged surgery for pediatric craniopharyngiomas: a multicenter retrospective study.

PURPOSE: Craniopharyngiomas (CPGs) are aggressive brain tumors responsible of severe morbidity in children. The best treatment strategies are under debate. Our study evaluates surgical, pituitary, and hypothalamic outcomes of a tailored staged-surgical approach compared to a single-stage radical approach in children with CPGs. METHODS: Multicenter retrospective study enrolling 96 children treated for CPGs in the period 2010-2022. The surgical management was selected after a multidisciplinary evaluation. Primary endpoint includes the inter-group comparison of preservation/improvement of hypothalamic-pituitary function, the extent of resection, and progression-free survival (PFS). Secondary endpoints include overall survival (OS), morbidity, and quality of life (QoL). RESULTS: Gross Total Resection (GTR) was reached in 46.1% of cases in the single-stage surgery group (82 patients, age at surgery 9 ± 4.7 years) and 33.3% after the last operation in the staged surgery group (14 patients age 7.64 ± 4.57 years at first surgery and 9.36 ± 4.7 years at the last surgery). The PFS was significantly higher in patients addressed to staged- compared to single-stage surgery (93.75% vs 70.7% at 5 years, respectively, p = 0.03). The recurrence rate was slightly higher in the single-stage surgery group. No significant differences emerged in the endocrinological, visual, hypothalamic outcome, OS, and QoL comparing the two groups. CONCLUSIONS: In pediatric CPGs' surgical radicality and timing of intervention should be tailored considering both anatomical extension and hypothalamic-pituitary function. In selected patients, a staged approach offers a safer and more effective disease control, preserving psychophysical development.

A novel allelic donkey ß-lactoglobulin I protein isoform generated by a non-AUG translation initiation codon is associated with a nonsynonymous SNP.

ß-lactoglobulin I (ß-LG I) is one of the most important whey proteins in donkey milk. However, to our knowledge, there has been no study focusing on the full nucleotide sequences of this gene (BLG I). Current investigation of donkey BLG I gene is very limited with only 2 variants (A and B) characterized so far at the protein level. Recently, a new ß-LG I variant, with a significantly higher mass (+1,915 Da) than known variants has been detected. In this study, we report the whole nucleotide sequence of the BLG I gene from 2 donkeys, whose milk samples are characterized by the ß-LG I SDS-PAGE band with a normal electrophoretic mobility (18,514.25 Da, ß-LG I B1 form) the first, and by the presence of a unique ß-LG I band with a higher electrophoretic mobility (20,428.5 Da, ß-LG I D form) the latter. A high genetic variability was found all over the 2 sequenced BLG I alleles. In particular, 16 polymorphic sites were found in introns, one in the 5' flanking region, 3 SNPs in the 5' untranslated region and one SNP in the coding region (g.1871G > A) located at the 40th nucleotide of exon 2 and responsible for the AA substitutions p.Asp28 > Asn in the mature protein. Two SNPs (g.920-922CAC > TGT and g.1871G/A) were genotyped in 93 donkeys of 2 Italian breeds (60 Ragusana and 33 Amiatina, respectively) and the overall frequencies of g.920-922CAC and g.1871A were 0.3065 and 0.043, respectively. Only the rare allele g.1871A was observed to be associated with the slower migrating ß-LG I. Considering this genetic diversity and those found in the database, it was possible to deduce at least 5 different alleles (BLG I A, B, B1, C, D) responsible for 4 potential ß-LG I translations. Among these alleles, B1 and D are those characterized in the present research, with the D allele of real novel identification. Haplotype data analysis suggests an evolutionary pathway of donkey BLG I gene and a possible phylogenetic map is proposed. Analyses of mRNA secondary structure showed relevant changes in the structures, as consequence of the g.1871G > A polymorphism, that might be responsible for the recognition of an alternative initiation site providing an additional signal peptide. The extension of 19 AA sequence to the mature protein, corresponding to the canonical signal peptide with an additional alanine residue, is sufficient to provide the observed molecular weight of the slower migrating ß-LG I encoded by the BLG I D allele.

Practical Guide to New Treatments for SARS-CoV-2 Infection in Dermatology Patients Being Treated With Common Immunomodulators. / Guía práctica de las nuevas alternativas terapéuticas frente a SARS-CoV-2 en pacientes con inmunomoduladores de uso frecuente en dermatología.

Immunosuppressants and immunomodulators are widely used in dermatology. Some of these drugs, however, can increase the risk of severe COVID-19. New antivirals against SARS-CoV-2 have been shown to reduce progression to COVID-19 pneumonia in susceptible patients, but their availability is limited. On May 23, 2022, the Spanish Agency for Medicines and Medical Devices (AEMPS) updated its priority eligibility criteria for SARS-CoV-2 antiviral therapy. In this practical guide, we review the indications for these new drugs and provide guidance on which patients with mild to moderate COVID might benefit from their use in dermatology.

SARS-CoV-2 vaccine-associated subacute thyroiditis: insights from a systematic review.

PURPOSE: To perform a systematic review on published cases of subacute thyroiditis (SAT) secondary to SARS-CoV-2 vaccination, to highlight main features and increase the awareness of this condition. METHODS: Original reports of SAT developed after SARS-CoV-2 vaccination (mRNA, viral vector, or inactivated virus vaccines) were retrieved from a search of electronic databases. Individual patient data on demographics, medical history, type of vaccine, workup and therapies were collected. Wilcoxon rank-sum, Kruskal-Wallis and chi-squared tests were employed for comparisons. RESULTS: 30 articles including 48 reports were retrieved, 3 additional cases evaluated by the Authors were described and included for analysis. Of the 51 patients, 38 (74.5%) were women, median age was 39.5 years (IQR 34-47). Patients developed SAT after a median of 10 days (IQR 4-14) after the vaccine shot. Baseline thyroid exams revealed thyrotoxicosis in 88.2% of patients, decreasing at 31.6% at follow-up. Corticosteroids were used in 56.4% of treated patients. Patients undergoing non-mRNA vaccines were most frequently Asian (p = 0.019) and reported more frequently weight loss (p = 0.021). All patients with a previous diagnosis of thyroid disease belonged to the mRNA vaccine group. CONCLUSION: SARS-CoV-2 vaccine-associated SAT is a novel entity that should be acknowledged by physicians. Previous history of thyroid disease may predispose to develop SAT after mRNA vaccines, but further studies and larger cohorts are needed to verify this suggestion. SARS-CoV-2 vaccine-associated SAT is usually of mild/moderate severity and could be easily treated in most cases, thus it should not raise any concern regarding the need to be vaccinated.

SARS-CoV-2 detection in primary thyroid sarcoma: coincidence or interaction?

INTRODUCTION: Thyroid dysfunctions associated with SARS-CoV-2 are emerging in scientific literature. During the second COVID-19 epidemic spread, we evaluated a patient with the suspect of subacute thyroiditis. METHODS AND RESULTS: Specimen from fine-needle aspiration of a hypoechoic undefined area was analyzed for cytology and for SARS-CoV-2 detection. SARS-CoV-2 was retrieved by real-time polymerase chain reaction on the cytologic sample, which was then cultured on Vero E6 cells and demonstrated to be cytopathic. Whole-genome sequence was deposited. Histological exam diagnosed a rare case of primary thyroid sarcoma with diffuse and strong expression of mouse double minute 2 homolog (MDM2) oncoprotein. Ultrastructural examination confirmed, in several neoplastic cells, the presence of viral particles in cytoplasmic vacuoles. CONCLUSIONS: In our hypothesis, SARS-CoV-2 and sarcoma coexistence could represent a synergistic interplay, ultimately favoring both viral persistence and tumor proliferation: the overexpression of MDM2 in tumor cells might have generated a favorable immunological niche for SARS-CoV-2 localization and, in turn, SARS-CoV-2 could have favored tumor growth by inducing MDM2-mediated p53 downregulation. Functional studies are needed to confirm this suggestive pathway.

Change in newly diagnosed Graves' disease phenotype between the twentieth and the twenty-first centuries: meta-analysis and meta-regression.

PURPOSE: According to a few recent studies, the clinical phenotype of Graves' disease (GD) at onset is becoming milder in recent years, in terms of prevalence and severity of hyperthyroidism, goiter and overt eye disease. The aim of this study was to assess the change in GD phenotype across the late twentieth and the early twenty-first centuries. MATERIALS AND METHODS: We carried out a systematic search of studies published between 1/1/1980 and 12/31/2017 describing naïve GD patients at diagnosis. We collected epidemiological, clinical, biochemical and serological data reported in the selected studies, and (1) conducted a single-arm meta-analysis to compare clinical and biochemical characteristics of naïve GD patients before and after year 2000 and (2) performed a meta-regression to identify the trend of the observed clinical presentations. RESULTS: Eighty selected articles were related to the period before the year 2000, 30 to the years 2000-2017. According to demographics, the two defined populations were homogeneous at meta-analysis: overall estimated female prevalence was 81% [95% CI 79-82], mean estimated age of the entire population was 39.8 years [95% CI 38.4-41.1], with no significant differences between pre- and post-2000 groups (p > 0.05). The overall estimated prevalence of smokers was 40% [95% CI 33-46], with no significant difference between the two groups (p > 0.05). Mean estimated free thyroxine (FT4) and free triiodothyronine (FT3) levels at diagnosis were higher in the pre-2000 group: 4.7 ng/dl [95% CI 4.5-4.9] for FT4 and 14.2 pg/ml [95% CI 13.3-15.1] for FT3, as compared to the post-2000 group: 3.9 ng/dl [95% CI 3.6-4.2] for FT4 and 12.1 pg/ml [95% CI 11.0-13.3] for FT3 (all p < 0.01). Goiter estimated prevalence was higher in the pre-2000 group, 87% [95% CI 84-90], than in the post-2000 group, 56% [95% CI 45-67]. Estimated prevalence for Graves' Orbitopathy (GO) was 34% [95% CI 27-41] in the pre-2000 group and 25% [95% CI 19-30] in the post-2000 group (p = 0.03). Accordingly, meta-regression adjusted for covariates showed an average annual reduction of FT4 (- 0.040 ± 0.008 ng/dl, p < 0.0001), FT3 (- 0.316 ± 0.019 pg/ml, p < 0.0001), goiter prevalence (- 0.023 ± 0.008%, p = 0.006), and goiter size (- 0.560 ± 0.031 ml, p < 0.0001). CONCLUSIONS: Our meta-analysis and meta-regression confirmed that GD phenotype at diagnosis is nowadays milder than in the past; we hypothesize that conceivable factors involved in this change are iodoprophylaxis, worldwide decrease in smoking habits, larger use of contraceptive pill and micronutrient supplementation, as well as earlier diagnosis and management.

The interplay between thyroid and liver: implications for clinical practice.

A complex relationship exists between thyroid and liver in health and disease. Liver plays an essential physiological role in thyroid hormone activation and inactivation, transport, and metabolism. Conversely, thyroid hormones affect activities of hepatocytes and hepatic metabolism. Serum liver enzyme abnormalities observed in hypothyroidism may be related to impaired lipid metabolism, hepatic steatosis or hypothyroidism-induced myopathy. Severe hypothyroidism may have biochemical and clinical features, such as hyperammonemia and ascites, mimicking those of liver failure. Liver function tests are frequently abnormal also in hyperthyroidism, due to oxidative stress, cholestasis, or enhanced osteoblastic activity. Antithyroid drug-associated hepatotoxicity is a rare event, likely related mainly to an idiosyncratic mechanism, ranging from a mild hepatocellular damage to liver failure. Propylthiouracil-induced liver damage is usually more severe than that caused by methimazole. On the other hand, thyroid abnormalities can be found in liver diseases, such as chronic hepatitis C, liver cirrhosis, hepatocellular carcinoma, and cholangiocarcinoma. In particular, autoimmune thyroid diseases are frequently found in patients with hepatitis C virus infection. These patients, especially if thyroid autoimmunity preexists, are at risk of hypothyroidism or, less frequently, thyrotoxicosis, during and after treatment with interpheron-alpha alone or in combination with ribavirin, commonly used before the introduction of new antiviral drugs. The present review summarizes both liver abnormalities related to thyroid disorders and their treatment, and thyroid abnormalities related to liver diseases and their treatment.

Immunomodulatory effect of vitamin D and its potential role in the prevention and treatment of thyroid autoimmunity: a narrative review.

The main role of vitamin D is to control mineral homeostasis. However, recent studies suggested the existence of a number of extraskeletal effects. Among the latter, preclinical studies provided consistent data on the involvement of vitamin D in innate and adaptive immunity and autoimmunity. Molecular biology studies showed that both vitamin D receptor and vitamin D enzymatic complexes are expressed in a large number of cells and tissues unrelated to mineral homeostasis. In contrast, only a few randomized clinical trials in humans investigated the possible role of vitamin D in the prevention or treatment of immunological disorders. In this regard, low serum vitamin D levels have been reported in observational trials in human autoimmune disorders. The aim of the present paper was to review the potential implications of vitamin D in immune modulation, with special focus on thyroid autoimmune disorders.

Features and outcome of differentiated thyroid carcinoma associated with Graves' disease: results of a large, retrospective, multicenter study.

BACKGROUND: Whether differentiated thyroid cancer (DTC) occurring concomitantly with Graves' disease (GD) is more aggressive and bound to a less favorable outcome is controversial. OBJECTIVE: Aim of this multicenter retrospective study was to compare baseline features and outcome of DTC patients with GD (DTC/GD+) or without GD (DTC/GD-). PATIENTS: Enrolled in this study were 579 patients referred to five endocrine units (Cagliari, Pavia, Pisa, Siena, and Varese) between 2005 and 2014: 193 patients had DTC/GD+ , 386 DTC/GD-. Patients were matched for age, gender and tumor size. They underwent surgery because of malignancy, large goiter size, or relapse of hyperthyroidism in GD. RESULTS: Baseline DTC features (histology, lymph node metastases, extrathyroidal extension) did not differ in the two groups, except for multifocality which was significantly more frequent in DTC/GD+ (27.5% vs. 7.5%, p < 0.0001). At the end of follow-up (median 7.5 years), 86% of DTC/GD+ and 89.6% DTC/GD- patients were free of disease. Patients with persistent or recurrent disease (PRD) had "biochemical disease" in the majority of cases. Microcarcinomas were more frequent in the DTC/GD+ group (60% vs. 37%, p < 0.0001) and had an excellent outcome, with no difference in PRD between groups. However, in carcinomas ≥ 1 cm, PRD was significantly more common in DTC/GD+ (24.4% vs. 11.5%; p = 0.005). In the whole group, univariate and multivariate analyses showed that GD+ , lymph node involvement, extrathyroidal invasion, multifocality and tall cell histotype were associated with a worse outcome. Female gender and microcarcinomas were favorable features. No association was found between baseline TSH-receptor antibody levels and outcome. Graves' orbitopathy (GO) seemed to be associated with a better outcome of DTC, possibly because patients with GO may early undergo surgery for hyperthyroidism. CONCLUSIONS: GD may be associated with a worse outcome of coexisting DTC only if cancer is ≥ 1 cm, whereas clinical outcome of microcarcinomas is not related to the presence/absence of GD.

Effects of adalimumab on T-helper-17 lymphocyte- and neutrophil-related inflammatory serum markers in patients with moderate-to-severe hidradenitis suppurativa.

BACKGROUND: T-helper (Th)-17 lymphocytes and neutrophils are the main sources of the proinflammatory cytokines involved in the pathogenesis of hidradenitis suppurativa (HS). OBJECTIVES: This study aims to evaluate the improvement of the inflammatory serum markers (ISM) levels in patients with moderate-to-severe HS who receive adalimumab. METHODS: Nineteen moderate-to-severe HS patients were prospectively recruited. Each of the patients received 40 mg of adalimumab weekly. The ISM levels and modified Hidradenitis Suppurativa Score (mHSS) scores were assessed at baseline and at week 36. Nineteen healthy volunteers (HC) constituted the control group. RESULTS: Before adalimumab treatment, the HS patients showed significantly increased levels of interleukin (IL)-6, IL-8, IL-10, IL-17A, soluble TNF receptor II (sTNF-RII), and C-reactive protein (CRP) as well as an increased erythrocyte sedimentation rate (ESR) (all P < .01). At week 36, the circulating levels of IL-1ß, IL-6, IL-8, IL-10, IL-17A, soluble TNF receptor I (sTNF-RI), sTNF-RII, and CRP, as well as the ESR (all P < .05), decreased significantly in the HS patients who received adalimumab. The decrease in levels of IL-6 (r = 0.65, P = .003), IL-8 (r = 0.52, P = .024), sTNF-RI (r = 0.55, P = .015), and CRP (r = 0.47, P < .040) and the ESR (r = 0.60, P < .006) were significantly well correlated with clinical improvements according to the mHSS. CONCLUSIONS: Adalimumab improves the ISM-based systemic inflammatory burden in patients with moderate-to-severe HS. IL-6, IL-8, sTNF-RI and CRP and the ESR may serve as novel biomarkers for a therapeutic response.

Antithyroid drug treatment for Graves' disease: baseline predictive models of relapse after treatment for a patient-tailored management.

BACKGROUND: Antithyroid drugs (ATDs) are first-line treatment for Graves' hyperthyroidism worldwide, but relapses are frequent. The reliability of individual risk factors to predict at baseline subsequent relapse is poor. Predictive scores grouping single risk factors might help to select the best treatment (pharmacological vs. ablative). OBJECTIVE: To assess the predictivity of a recently developed score (Clinical Severity Score, CSS) and to compare it with another score (GREAT score). PATIENTS: A retrospective observational, single-center study was conducted of 387 consecutive, newly diagnosed Graves' patients, who completed an 18-24 months ATD course and were followed for at least 2 years. RESULTS: Hyperthyroidism relapsed in 185 patients (48%). At diagnosis and before treatment, the relapse group had higher serum TSH-receptor antibody and free thyroxine levels and larger goiters than the remission group, with no differences in Graves' orbitopathy prevalence and severity. In the multivariate analyses, only large goiter size was significantly associated with an increased recurrence hazard ratio. Using CSS, the risk of relapse increased from 36% in the mild category and 49% in the moderate category to 59% in the severe category, with quite a good area under the curve (AUC) (0.60; 95% CI: 0.55; 0.66). GREAT score showed an increase in relapse from 34% for class I (mild) and 49% for class II (moderate) to 64% for class III (severe) (AUC, 0.63; CI: 0.58; 0.68). CONCLUSIONS: Both CSS and GREAT score are useful, although imperfect, tools to predict at baseline relapse of hyperthyroidism after treatment. In real life they may help the clinician to tailor a treatment for newly diagnosed Graves' hyperthyroidism.

Physical performance in newly diagnosed hypothyroidism: a pilot study.

OBJECTIVE: Hypothyroidism is complicated by neuromuscular symptoms (myalgias, slowness of movements, and tiredness) and signs (easy fatigability and cramps), which may have a negative impact on general well-being and quality of life. In a pilot, prospective, controlled study, we investigated the features of muscle dysfunction in hypothyroidism by disease questionnaire, biochemical measures, and physical performance tests. MATERIALS AND METHODS: Fifty-seven consecutive patients with newly diagnosed hypothyroidism were enrolled, 27 subclinical (S-Hypo) and 30 overt (O-Hypo). A series of 30 euthyroid subjects, with similar demographic characteristics, served as controls. Patients were administered a short disease questionnaire and underwent laboratory exams and standardized physical tests, both at baseline and after restoration of biochemical euthyroidism. RESULTS: Compared to euthyroid controls, the O-Hypo group showed significantly higher prevalence of neuromuscular symptoms and significantly higher serum creatine phosphokinase (CPK) levels (p value < 0.0001). S-Hypo had slightly higher CPK levels and prevalence of neuromuscular symptoms than controls. Both S-Hypo and O-Hypo patients performed worse than controls in the six-minute walking test. Differences between patients and controls in handgrip strength test and timed chair standing test failed to reach statistical significance (although a trend was noticeable), possibly due to the small sample size. In O-Hypo, an inverse correlation was found between CPK levels and the handgrip strength test (p value < 0.001). Restoration of euthyroidism was associated with normalization of questionnaire responses, six-minute walking test, as well as serum CPK levels. CONCLUSION: In addition to neuromuscular symptoms, hypothyroidism is associated with abnormalities of physical performance. The six-minute walking test is the most valuable test to assess this aspect. In the pilot study, levothyroxine therapy could reverse muscle functional abnormalities.