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Alexander A Leung, Janice L Pasieka, Martin D Hyrcza, Danièle Pacaud, Yuan Dong, Jessica M Boyd, Hossein Sadrzadeh, and Gregory A Kline

Objective: Despite the significant morbidity and mortality associated with pheochromocytoma and paraganglioma, little is known about their epidemiology. The primary objective was to determine the incidence of pheochromocytoma and paraganglioma in an ethnically diverse population. A secondary objective was to develop and validate algorithms for case detection using laboratory and administrative data.

Design: Population-based cohort study in Alberta, Canada from 2012 to 2019.

Methods: Patients with pheochromocytoma or paraganglioma were identified using linked administrative databases and clinical records. Annual incidence rates per 100,000 people were calculated and stratified according to age and sex. Algorithms to identify pheochromocytoma and paraganglioma, based on laboratory and administrative data, were evaluated.

Results: A total of 239 patients with pheochromocytoma or paraganglioma (collectively with 251 tumors) were identified from a population of 5,196,368 people over a period of 7 years. The overall incidence of pheochromocytoma or paraganglioma was 0.66 cases per 100,000 people per year. The frequency of pheochromocytoma and paraganglioma increased with age and was highest in individuals aged 60 to 79 years (8.85 and 14.68 cases per 100,000 people per year for males and females, respectively). An algorithm based on laboratory data (metanephrine >2-fold or normetanephrine >3-fold higher than the upper limit of normal) closely approximated the true frequency of pheochromocytoma and paraganglioma with an estimated incidence of 0.54 cases per 100,000 people per year.

Conclusion: The incidence of pheochromocytoma and paraganglioma in an unselected population of western Canada was unexpectedly higher than rates reported from other areas of the world.

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Stephanie A Roberts and Ursula B Kaiser

Pubertal timing is regulated by the complex interplay of genetic, environmental, nutritional and epigenetic factors. Criteria for determining normal pubertal timing, and thus the definition of precocious puberty, have evolved based on published population studies. The significance of the genetic influence on pubertal timing is supported by familial pubertal timing and twin studies. In contrast to the many monogenic causes associated with hypogonadotropic hypogonadism, only four monogenic causes of central precocious puberty (CPP) have been described. Loss-of-function mutations in Makorin Ring Finger Protein 3(MKRN3), a maternally imprinted gene on chromosome 15 within the Prader–Willi syndrome locus, are the most common identified genetic cause of CPP. More recently, several mutations in a second maternally imprinted gene, Delta-like noncanonical Notch ligand 1 (DLK1), have also been associated with CPP. Polymorphisms in both genes have also been associated with the age of menarche in genome-wide association studies. Mutations in the genes encoding kisspeptin (KISS1) and its receptor (KISS1R), potent activators of GnRH secretion, have also been described in association with CPP, but remain rare monogenic causes. CPP has both short- and long-term health implications for children, highlighting the importance of understanding the mechanisms contributing to early puberty. Additionally, given the role of mutations in the imprinted genes MKRN3 and DLK1 in pubertal timing, other imprinted candidate genes should be considered for a role in puberty initiation.

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Grégory Mougel, Arnaud Lagarde, Frédérique Albarel, Wassim Essamet, Perrine Luigi, Céline Mouly, Magaly Vialon, Thomas Cuny, Frédéric Castinetti, Alexandru Saveanu, Thierry Brue, Anne Barlier, and Pauline Romanet

Background:

The ‘3PAs’ syndrome, associating pituitary adenoma (PA) and pheochromocytoma/paraganglioma (PPGL), is sometimes associated with mutations in PPGL-predisposing genes, such as SDHx or MAX. In ’3PAs’ syndrome, PAs can occur before PPGL, suggesting a new gateway into SDHx/MAX-related diseases.

Objective:

To determine the SDHx/MAX mutation prevalence in patients with isolated PAs and characterize PAs of patients with SDHx/MAX mutations.

Design:

Genes involved in PAs (AIP/MEN1/CDKN1B) or PPGLs (SDHx/MAX) were sequenced in patients with isolated PAs. We then conducted a review of cases of PA in the setting of ’3PAs’ syndrome.

Results:

A total of 263 patients were recruited. Seven (likely) pathogenic variants were found in AIP, two in MEN1, two in SDHA, and one in SDHC. The prevalence of SDHx mutations reached 1.1% (3/263). Of 31 reported patients with PAs harboring SDHx/MAX mutations (28 published cases and 3 cases reported here), 6/31 (19%) developed PA before PPGL and 8/31 (26%) had isolated PA. The age of onset was later than in patients with AIP/MEN1 mutations. PAs were mainly macroprolactinomas and showed intracytoplasmic vacuoles seen on histopathology.

Conclusions:

We discovered SDHx mutations in patients bearing PA who had no familial or personal history of PPGL. However, the question of incidental association remains unresolved and data to determine the benefit of SDHx/MAX screening in these patients are lacking. We recommend that patients with isolated PA should be carefully examined for a family history of PPGLs. A family history of PPGL, as well as the presence of intracytoplasmic vacuoles in PA, requires SDHx/MAX genetic testing of patients.

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Claudia Giavoli, Eriselda Profka, Noemi Giancola, Giulia Rodari, Federico Giacchetti, Emanuele Ferrante, Maura Arosio, and Giovanna Mantovani

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Matteo Rottoli, Paolo Bernante, Angela Belvedere, Francesca Balsamo, Silvia Garelli, Maddalena Giannella, Alessandra Cascavilla, Sara Tedeschi, Stefano Ianniruberto, Elena Rosselli Del Turco, Tommaso Tonetti, Vito Marco Ranieri, Gilberto Poggioli, Lamberto Manzoli, Uberto Pagotto, Pierluigi Viale, and Michele Bartoletti

Objective:

Specific comorbidities and old age create a greater vulnerability to severe Coronavirus Disease 19 (COVID-19). While obesity seems to aggravate the course of disease, the actual impact of the BMI and the cutoff which increases illness severity are still under investigation. The aim of the study was to analyze whether the BMI represented a risk factor for respiratory failure, admission to the intensive care unit (ICU) and death.

Research design and methods:

A retrospective cohort study of 482 consecutive COVID-19 patients hospitalised between March 1 and April 20, 2020. Logistic regression analysis and Cox proportion Hazard models including demographic characteristics and comorbidities were carried out to predict the endpoints within 30 days from the onset of symptoms.

Results:

Of 482 patients, 104 (21.6%) had a BMI ≥ 30 kg/m2. At logistic regression analysis, a BMI between 30 and 34.9 kg/m2 significantly increased the risk of respiratory failure (OR: 2.32; 95% CI: 1.31–4.09, P = 0.004) and admission to the ICU (OR: 4.96; 95% CI: 2.53–9.74, P < 0.001). A significantly higher risk of death was observed in patients with a BMI ≥ 35 kg/m2 (OR: 12.1; 95% CI: 3.25–45.1, P < 0.001).

Conclusions:

Obesity is a strong, independent risk factor for respiratory failure, admission to the ICU and death among COVID-19 patients. A BMI ≥ 30 kg/m2 identifies a population of patients at high risk for severe illness, whereas a BMI ≥ 35 kg/m2 dramatically increases the risk of death.

Open access

Bastiaan Sol, Jeroen M.k. de Filette, Gil Awada, Steven Raeymaeckers, Sandrine Aspeslagh, C.e. Andreescu, Bart Neyns, and Brigitte Velkeniers

BACKGROUND.

Pituitary carcinomas are rare but aggressive and require maximally coordinated multimodal therapies. For refractory tumors, unresponsive to temozolomide (TMZ), therapeutic options are limited. Immune checkpoint inhibitors (ICI) may be considered for treatment as illustrated in the present case report.

CASE.

We report a patient with ACTH-secreting pituitary carcinoma, progressive after multiple lines of therapy including chemotherapy with TMZ, who demonstrated disease stabilization by a combination of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) ICI therapy.

DISCUSSION.

Management of pituitary carcinoma beyond TMZ remains ill-defined and relies on case reports. TMZ creates, due to hypermutation, more immunogenic tumors and subsequently potential candidates for ICI therapy. This case report adds support to the possible role of ICI in the treatment of pituitary carcinoma.

CONCLUSION.

ICI therapy could be a promising treatment option for pituitary carcinoma, considering the mechanisms of TMZ-induced hypermutation with increased immunogenicity, pituitary expression of CTLA-4 and PD-L1, and the frequent occurrence of hypophysitis as a side effect of ICI therapy.

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Cécile Thomas-Teinturier, Isabelle Oliver-Petit, Helene Pacquement, Brice Fresneau, Rodrigue Sétchéou Allodji, Cristina Veres, Stephanie Bolle, Delphine Berchery, Charlotte Demoor-Goldschmidt, Nadia Haddy, Ibrahima Diallo, and Florent de Vathaire

Context:

Growth hormone (GH) deficiency is a common late effect of cranial irradiation. However, concerns have been raised that GH treatment might lead to an increased risk of a second neoplasm (SN).

Objective:

To study the impact of GH treatment on the risk of SN in a French cohort of survivors of childhood cancer (CCS) treated before 1986.

Design and setting:

Cohort study and nested case–control study.

Participants:

Of the 2852 survivors, with a median follow-up of 26 years, 196 had received GH therapy (median delay from cancer diagnosis: 5.5 years).

Main outcome measures:

Occurrence of SN

Results:

In total, 374 survivors developed a SN, including 40 who had received GH therapy. In a multivariate analysis, GH treatment did not increase the risk of secondary non-meningioma brain tumors (RR: 0.6, 95% CI: 0.2–1.5, P = 0.3), secondary non-brain cancer (RR: 0.7, 95% CI: 0.4–1.2, P = 0.2), or meningioma (RR: 1.9, 95% CI: 0.9–4, P = 0.09). Nevertheless, we observed a slight non-significant increase in the risk of meningioma with GH duration: 1.6-fold (95% CI: 1.2–3.0) after an exposure of less than 4 years vs 2.3-fold (95% CI: 0.9–5.6) after a longer exposure (P for trend = 0.07) confirmed by the results of a case–control study.

Conclusion:

This study confirms the overall safety of GH use in survivors of childhood cancer, which does not increase the risk of a SN. The slight excess in the risk of meningioma in patients with long-term GH treatment is non-significant and could be due to difficulties in adjustment on cranial radiation volume/dose and/or undiagnosed meningioma predisposing conditions.

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Juliette Harris, Arthur Gouhier, and Jacques Drouin

Pioneer transcription factors have key roles in development as master regulators of cell fate specification. Only a small fraction of all transcription factors have the pioneer ability that confers access to target genomic DNA sites embedded in so-called “closed” heterochromatin. This ability to seek and bind target sites within the silenced portion of the epigenome is the basis for their role in changing cell fate. Upon binding heterochromatin sites, pioneer factors trigger remodelling of chromatin from a repressed into an active organization. This action is typically exerted at enhancer regulatory sequences, thus allowing activation of new gene subsets. During pituitary development, the only pioneer with a well-documented role is Pax7 that specifies the intermediate lobe melanotrope cell fate. In this review, a particular focus is placed on this Pax7 function but its properties are also considered within the general context of pioneer factor action. Given their potent activity to reprogram gene expression, it is not surprising that many pioneers are associated with tumor development. Over-expression or chromosomal translocations leading to production of chimeric pioneers have been implicated in different cancers. We review here the current knowledge on the mechanism of pioneer factor action.

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Rolf H H Groenwold and Olaf M Dekkers

The validity of clinical research is potentially threatened by missing data. Any variable measured in a study can have missing values, including the exposure, the outcome, and confounders. When missing values are ignored in the analysis, only those subjects with complete records will be included in the analysis. This may lead to biased results and loss of power. We explain why missing data may lead to bias and discuss a commonly used classification of missing data.

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C A Lebbink, B L Dekker, G Bocca, A J A T Braat, J P M Derikx, M P Dierselhuis, B de Keizer, S Kruijff, A B G Kwast, F H van Nederveen, E J M Nieveen van Dijkum, R A J Nievelstein, R P Peeters, C E J Terwisscha van Scheltinga, W J E Tissing, K van der Tuin, M R Vriens, J Zsiros, A S P van Trotsenburg, T P Links, and H M van Santen

Background:

Currently, there are no European recommendations for the management of pediatric thyroid cancer. Other current international guidelines are not completely concordant. In addition, medical regulations differ between, for instance, the US and Europe. We aimed to develop new, easily accessible national recommendations for differentiated thyroid carcinoma (DTC) patients <18 years of age in the Netherlands as a first step toward a harmonized European Recommendation.

Methods:

A multidisciplinary working group was formed including pediatric and adult endocrinologists, a pediatric radiologist, a pathologist, endocrine surgeons, pediatric surgeons, pediatric oncologists, nuclear medicine physicians, a clinical geneticist and a patient representative. A systematic literature search was conducted for all existing guidelines and review articles for pediatric DTC from 2000 until February 2019. The Appraisal of Guidelines, Research and Evaluation (AGREE) instrument was used for assessing quality of the articles. All were compared to determine dis- and concordances. The American Thyroid Association (ATA) pediatric guideline 2015 was used as framework to develop specific Dutch recommendations. Discussion points based upon expert opinion and current treatment management of DTC in children in the Netherlands were identified and elaborated.

Results:

Based on the most recent evidence combined with expert opinion, a 2020 Dutch recommendation for pediatric DTC was written and published as an online interactive decision tree (www.oncoguide.nl).

Conclusion:

Pediatric DTC requires a multidisciplinary approach. The 2020 Dutch Pediatric DTC Recommendation can be used as a starting point for the development of a collaborative European recommendation for treatment of pediatric DTC.