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Dorte Glintborg, Katrine Hass Rubin, Tanja Gram Petersen, Øjvind Lidegaard, Guy T’Sjoen, Malene Hilden, and Marianne Skovsager Andersen

Background

Cardiovascular risk could be increased in transgender persons, but the mechanism is undetermined.

Aim

The aim of this study was to assess the risk of cardiovascular outcomes in Danish transgender persons compared to controls.

Methods

The study design was a historical register-based cohort study in Danish transgenders and age-matched controls. The main outcome measure was cardiovascular diagnosis (any CVD) including medicine prescriptions for CVD during 2000–2018. The transgender cohort (n = 2671) included persons with International Classification of Diseases-10 diagnosis code of ‘gender identity disorder’ (n = 1583) and persons with legal sex change (n = 1088), 1270 were assigned female at birth (AFAB) and 1401 were assigned male at birth (AMAB). Controls (n = 26 710) were matched by age (n = 5 controls of same and n  = 5 controls of other birth sex) of the respective transgender.

Results

The median (interquartile range) age at study inclusion was 22 (18; 29) years for AFAB and 26 (21; 39) years for AMAB. The mean (s.d.) follow-up time was 4.5 (4.2) years for AFAB and 5.7 (4.8) years for AMAB. The hazard ratio (HR) for any CVD was significantly higher in transgenders vs controls of same and other birth sex, with highest adjusted HR in transgenders AFAB vs control men: 2.20 (95% CI: 1.64;2.95), P < 0.001. Gender-affirming hormone treatment (GAHT) explained part of elevated risk of CVD in transgenders AFAB, whereas GAHT did not contribute to the elevated risk of CVD in transgenders AMAB.

Conclusions

The risk of cardiovascular diagnosis was increased in transgenders. The mechanism should be further investigated.

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Sandra Rodríguez-Rodero, Paula Morales-Sánchez, Juan Ramón Tejedor, Andrés Coca-Pelaz, Cristina Mangas, Alfonso Peñarroya, Iván Fernández-Vega, Luís Fernández-Fernández, Carmen M Álvarez-López, Agustín F Fernández, Marina Arranz Álvarez, Aurora Astudillo, Pedro Pujante Alarcón, Cecilia Ragnarssön, Alberto Colina Alonso, Héctor Enrique Torres Rivas, Juan Pablo Rodrigo Tapia, Sandra Nieto Torrero, Yaiza Pedroche-Just, Rita María Regojo Zapata, Ana M Rodríguez-García, Anabel Abó, Milagros Balbín, Edelmiro Menéndez, Elías Delgado, and Mario F Fraga

Objective

The minimally invasive fine-needle aspiration cytology (FNAC) is the current gold standard for the diagnosis of thyroid nodule malignancy. However, the correct discrimination of follicular neoplasia often requires more invasive diagnostic techniques. The lack of suitable immunohistochemical markers to distinguish between follicular thyroid carcinoma and other types of follicular-derived lesions complicates diagnosis, and despite most of these tumours being surgically resected, only a small number will test positive for malignancy. As such, the development of new orthogonal diagnostic approaches may improve the accuracy of diagnosing thyroid nodules.

Design

This study includes a retrospective, multi-centre training cohort including 54 fresh-frozen follicular-patterned thyroid samples and two independent, multi-centre validation cohorts of 103 snap-frozen biopsies and 33 FNAC samples, respectively.

Methods

We performed a genome-wide genetic and epigenetic profiling of 54 fresh-frozen follicular-patterned thyroid samples using exome sequencing and the Illumina Human DNA Methylation EPIC platform. An extensive validation was performed using the bisulfite pyrosequencing technique.

Results

Using a random forest approach, we developed a three-CpG marker-based diagnostic model that was subsequently validated using bisulfite pyrosequencing experiments. According to the validation cohort, this cost-effective method discriminates between benign and malignant nodules with a sensitivity and specificity of 97 and 88%, respectively (positive predictive value (PPV): 0.85, negative predictive value (NPV): 0.98).

Conclusions

Our classification system based on a minimal set of epigenetic biomarkers can complement the potential of the diagnostic techniques currently available and would prioritize a considerable number of surgical interventions that are often performed due to uncertain cytology.

Significance statement

In recent years, there has been a significant increase in the number of people diagnosed with thyroid nodules. The current challenge is their etiological diagnosis to discount malignancy without resorting to thyroidectomy. The method proposed here, based on DNA pyrosequencing assays, has high sensitivity (0.97) and specificity (0.88) for the identification of malignant thyroid nodules. This simple and cost-effective approach can complement expert pathologist evaluation to prioritize the classification of difficult-to-diagnose follicular-patterned thyroid lesions and track tumor evolution, including real-time monitoring of treatment efficacy, thereby stimulating adherence to health promotion programs.

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Prerna Dogra, Michael Rivera, Travis J McKenzie, Trenton R Foster, Benzon M Dy, Melanie L Lyden, William F Young, and Irina Bancos

Objective

Benign adrenal cysts are rare lesions of the adrenal glands. Limited data are available to guide management. We aimed to describe the presentation and outcomes of patients with benign adrenal cysts.

Design

Retrospective longitudinal cohort study.

Methods

Consecutive patients with histologically or radiologically confirmed adrenal cysts between 1995 and 2021 were identified. Pheochromocytomas and malignancy were excluded.

Results

Benign adrenal cysts were diagnosed in 92 patients (53, 57% women) at a median age of 45 years. Mode of discovery was incidental on imaging in 81 (88%), symptoms of mass effect in 9 (9.8%), and others in 2 (2.2%). Majority (89, 97%) of patients had unilateral cysts (45 right, 44 left) with a median size of 48 mm (range 4–200) at diagnosis. On imaging, most cysts were round/oval (85.4%), homogenous (83.2%) lesions with calcifications (64.0%) and no vascular enhancement (97.7%). During a median follow-up of 65 months (range 7–288), adrenal cysts demonstrated minimal enlargement (median size change 6 mm, median growth rate 2 mm/year). On hormonal evaluation, 10% (5/50 tested) had an abnormal overnight dexamethasone suppression test, and 9.5% (4/42 tested) had an abnormal case detection testing for primary aldosteronism. Patients treated with adrenalectomy (46, 50%) were younger (36.9 years vs 50.8 years, P = 0.0009) and had more rapidly enlarging cysts (median growth rate 5.5 mm/year vs 0.4 mm/year, P = 0.0002).

Conclusion

Benign adrenal cysts are usually incidentally discovered, non-functional, homogenous lesions without vascular enhancement that demonstrate minimal growth. Adrenalectomy should be reserved for patients with heterogeneous lesions, abnormal hormonal evaluation, or those with mass effect symptoms.

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Camille Buffet, Lucie Allard, Erell Guillerm, Cécile Ghander, Elise Mathy, Charlotte Lussey-Lepoutre, Nicolas Julien, Eliane Touma, Pauline Quilhot, Gaelle Godiris-Petit, Jean-Marc Lacorte, Laurence Leenhardt, and Jérôme Alexandre Denis

Introduction

Recently, targeted therapies using BRAF V600E and MEK inhibitors (dabrafenib and trametinib, respectively) have been recommended in BRAF-mutated anaplastic thyroid carcinoma (ATC). Considering the fast development of ATC, droplet digital PCR (ddPCR) performed on fine-needle aspirate (FNA), which is a rapid, reliable, and low-cost method, appears interesting for the detection of BRAF V600E mutation in these patients and allows early initiation of targeted therapies.

Results

In our two patients, both presenting extensive cervical masses inaccessible to surgery, ddPCR results were available in less than 24 h. Therefore, dabrafenib and trametinib were started only a few days after first contact.

Conclusions

We suggest that ddPCR on FNA be used in non-resectable cervical masses for rapid BRAF V600E mutation detection in the hope that starting targeted therapies early might improve outcomes.

Free access

Paul Stewardson, Markus Eszlinger, and Ralf Paschke

Objective

Genetic testing is increasingly used to diagnose or rule out thyroid cancer in indeterminate fine-needle aspirations. This review evaluates the usefulness of these methods with considerations of advantages and limitations.

Design

Given the diagnostic problem associated with the increasing incidental detection of indeterminate thyroid nodules in the context of thyroid cancer overtreatment, we consider the conditions and respective necessary settings for the role of genetic testing to improve presurgical malignancy risk stratification.

Methods

We review diagnostic pathway requirements and commercially available molecular tests with their respective advantages and disadvantages and discuss the prerequisites required for local application and implementation including quality assurance for local ultrasound and cytopathology practices.

Results

Recent improvements in available molecular diagnostic tests have brought high sensitivity and specificity in initial validation studies, but whether these promising results translate to other clinical settings depends on the quality of the local thyroid nodule diagnostic pathway.

Conclusions

Genetic testing can meaningfully improve presurgical malignancy risk assessment, but more work is needed to implement and use genetic testing effectively in local settings.

Open access

Claudia Campana, Peter M van Koetsveld, Richard A Feelders, Wouter W de Herder, Anand M Iyer, Marie-Louise F van Velthuysen, Marije J Veenstra, Elisabeth S R van den Dungen, Sanne E Franck, Diego Ferone, Federico Gatto, and Leo J Hofland

Objective

The aim of this study was to develop an open-source and reproducible digital quantitative analysis (DIA) of somatostatin receptor subtype 2a (SST2) staining in formalin-fixed paraffin-embedded tissues of pancreatic neuroendocrine tumors (panNETs) and growth hormone (GH)-secreting pituitary adenomas (GHomas).

Design

SST2 immunostaining of 18 panNETs and 39 GHomas was assessed using a novel DIA protocol and compared with a widely used semi-quantitative immunoreactivity score (IRS).

Methods

The DIA software calculates the staining intensity/area and the percentage of positive cells (%PC). Four representative images were selected for each sample by two independent selectors (S1 and S2), with the analysis performed by two independent analyzers (A1 and A2). Agreement between observers was calculated using the concordance correlation coefficient (CCC).

Results

In panNETs, the CCC ranged 0.935–0.977 for intensity/area and 0.942–0.983 for %PC. In GHomas, the CCC ranged 0.963–0.997 for intensity/area and 0.979–0.990 for %PC. In both panNETs and GHomas, the DIA staining intensity was strongly correlated with the IRS (Spearman rho: 0.916–0.969, P < 0.001), as well as the DIA %PC with the IRS %PC (Spearman rh: 0.826–0.881, P < 0.001). In GHomas, the biochemical response to somatostatin receptor ligands correlated with SST2 expression, evaluated both as DIA intensity/area (Spearman rho: −0.448 to −0.527, P = 0.007–0.004) and DIA %PC (Spearman rho: −0.558 to −0.644, P ≤ 0.001).

Conclusions

The DIA has an excellent inter-observer agreement and showed a strong correlation with the widely used semi-quantitative IRS. The DIA protocol is an open-source, highly reproducible tool and provides a reliable quantitative evaluation of SST2 immunohistochemistry.

Free access

Massimo Terzolo and Martin Fassnacht

Adrenocortical carcinoma (ACC) accounts for a minority of all malignant tumors in adults. Surgery remains the most important therapeutic option for non-metastatic ACC. Whether a subset of patients with small ACC may benefit from minimally invasive surgery remains a debated issue, but we believe that surgeon’s expertise is more important than surgical technique to determine outcome. However, even a state-of-the-art surgery cannot prevent disease recurrence that is determined mainly by specific tumor characteristics. We consider that the concomitant presence of the following features characterizes a cohort of patients at low risk of recurrence, (i) R0 resection (microscopically free margin), (ii) localized disease (stage I-II ACC), and (iii) low-grade tumor (ki-67 <10%). After the ADIUVO study, we do not recommend adjuvant mitotane as a routine measure for such patients, who can be managed with active surveillance thus sparing a toxic treatment. Patients at average risk of recurrence should be treated with adjuvant mitotane. For patients at very high risk of recurrence, defined as the presence of at least one of the following: Ki67 >30%, large venous tumor thrombus, R1 resection or stage IV ACC, we increasingly recommend to combine mitotane with four cycles of platinum-based chemotherapy. However, patients at moderate-to-high risk of recurrence should be ideally enrolled in the ongoing ADIUVO2 trial. We do not use adjuvant radiotherapy of the tumor bed frequently at our institutions, and we select patients with incomplete resection, either microscopically or macroscopically, for this treatment. In the long-term, prospective multicenter trials are required to improve patient care.

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Mariana Costanzo, María Sol Touzon, Roxana Marino, Gabriela Guercio, Pablo Ramirez, María Celeste Mattone, Natalia Pérez Garrido, María Marcela Bailez, Elisa Vaiani, Marta Ciaccio, María Laura Galluzzo Mutti, Alicia Belgorosky, and Esperanza Berensztein

Background

Differences/disorders of sex development (DSD) are congenital conditions in which the development of chromosomal, gonadal, or anatomical sex is atypical.

Objective

The aim of this study is to report the histological characteristics and immunoexpression patterns of gonadal parenchyma in patients with 46,XX testicular and ovotesticular DSD, with a focus on the detection of germ cell malignancies.

Design

Inclusion criteria were SRY-negative 46,XX testicular and ovotesticular DSD with available samples from gonadal biopsy or gonadectomy for the review of histological findings. Gonadal histology was assessed on hematoxylin and eosin-stained sections and immunohistochemical analysis. Histopathological criteria from the last World Health Organization classification of urogenital tumors were used to identify undifferentiated gonadal tissue, gonadoblastoma, and dysgerminoma.

Results

Median age at first histological evaluation of gonadal samples was 1.46 years (range: 0.16–16 years). Totally 15 patients were classified as ovotesticular and only 1 as testicular DSD. Most individuals had bilateral ovotestes (12/15). No histological alterations were found in the ovarian parenchyma, while signs of dysgenesis were seen in all cases of testicular parenchyma. In 4/15 ovotesticular DSD, a prepubertal biopsy failed to identify ovarian parenchyma. We detected early prepubertal preinvasive and invasive malignancies in this cohort (five patients had undifferentiated gonadal tissue, five gonadoblastoma, and one dysgerminoma).

Conclusion

46,XX disorders of gonadal development are historically considered at a low risk for germ cell cancer, and the need for assessment of gonadal histology has been questioned. The finding of early germ cell malignancies in our cohort brings awareness and needs further research.

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Isabella Nasi-Kordhishti, Florian Grimm, Sabrina Giese, Katalin Nóra Lörincz, Benjamin Bender, and Jürgen Honegger

Objective

In Cushing’s disease (CD), detection of an adenoma by MRI is challenging. The aim of this study is to compare real-life MRI in the initial diagnostic workup of CD with high-quality MRI performed in a tertiary center for pituitary diseases.

Design and methods

We retrospectively analyzed 139 patients with CD who underwent primary transsphenoidal surgery (TSS) in our department and had both an MRI conducted at a different institution (external MRI; extMRI) and an MRI conducted at our institution (internal MRI; intMRI). Preoperative interpretation of MRI was performed independently by an external radiologist (extRAD), an internal neuroradiologist (intRAD) and a pituitary surgeon (SURG). Intraoperative detection of an adenoma and endocrinological remission provided proof of the true adenoma localization in 105 patients.

Results

Interpretation of extMRI by extRAD and SURG was concordant in only 64% (89/139) of cases, while 74.1% (103/139) concordance was observed for interpretation of intMRI by intRAD and SURG. Based on extMRI, the true localization of the adenoma was correctly predicted in only 46.7% of the patients by extRAD and in 65.7% by SURG. In contrast, the sensitivity to correctly identify the adenoma on intMRI was 80.0% for intRAD and 94.3% for SURG.

Conclusion

Both the quality of MRI and the reader’s experience are paramount for detection of microadenomas in CD. Every effort should be made to perform high-quality initial MRI according to current standards and to ensure rating by an expert in pituitary imaging.

Open access

Peter Daley-Yates, Brian Keppler, Noushin Brealey, Shaila Shabbir, Dave Singh, and Neil Barnes

Objective

The aim of this study was toidentify dose-related systemic effects of inhaled glucocorticoids (GCs) on the global metabolome.

Design and methods

Metabolomics/lipidomic analysis from plasma was obtained from 54 subjects receiving weekly escalating doses (µg/day) of fluticasone furoate (FF; 25, 100, 200, 400 and 800), fluticasone propionate (FP; 50, 200, 500, 1000 and 2000), budesonide (BUD; 100, 400, 800, 1600 and 3200) or placebo. Samples (pre- and post-dose) were analysed using ultrahigh-performance liquid chromatography-tandem mass spectroscopy and liquid chromatography-mass spectrometry. Ions were matched to library standards for identification and quantification. Statistical analysis involved repeated measures ANOVA, cross-over model, random forest and principal component analysis using log-transformed data.

Results

Quantifiable metabolites (1971) had few significant changes (% increases/decreases; P < 0.05) vs placebo: FF 1.34 (0.42/0.92), FP 1.95 (0.41/1.54) and BUD 2.05 (0.60/1.45). Therapeutic doses had fewer changes: FF 0.96 (0.36/0.61), FP 1.66 (0.44/1.22) and BUD 1.45 (0.56/0.90). At highest/supratherapeutic doses, changes were qualitatively similar: reduced adrenal steroids, particularly glucuronide metabolites of cortisol and cortisone and pregnenolone metabolite DHEA-S; increased amino acids and glycolytic intermediates; decreased fatty acid β-oxidation and branched-chain amino acids. Notable qualitative differences were lowered dopamine metabolites (BUD) and secondary bile acid profiles (BUD/FF), suggesting CNS and gut microbiome effects.

Conclusions

Dose-dependent metabolomic changes occurred with inhaled GCs but were seen predominately at highest/supratherapeutic doses, supporting the safety of low and mid therapeutic doses. At comparable therapeutic doses (FF 100, FP 500 and BUD 800 µg/day), FF had the least effect on the most sensitive markers (adrenal steroids) vs BUD and FP.