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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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Nienke van Welie, Maite Portela, Kim Dreyer, Linda J Schoonmade, Madelon van Wely, Ben Willem J Mol, A. S. van Trotsenburg, Cornelis B Lambalk, Velja Mijatovic, and Martijn J. Finken

Objective: Thyroid dysfunction is a known side effect of iodinated contrast media. There is some evidence to suggest that iodinated contrast media administered to pregnant women may cause thyroid dysfunction not only in themselves but also in their offspring. Here, we systematically evaluated literature on the use of iodinated contrast media prior to or during pregnancy on the offspring’s thyroid function.

Design: Systematic review of published literature.

Materials and Methods: Relevant studies were identified by PubMed, EMBASE and The Cochrane Library up to June 5, 2020. All study designs, reporting on the fetal or neonatal thyroid function after exposure to iodinated contrast media prior to or during pregnancy, were included. We undertook random effects meta-analysis and pooled the estimates as proportions with 95% confidence intervals (CIs).

Results: We identified 402 articles, of which 26 were included. Six studies reported (N=369) on exposure to iodinated contrast media prior to pregnancy by hysterosalpingography and 20 studies (N=670) on exposure to these media during pregnancy by amniofetography, urography or computed tomography. There was low to high risk of bias. The proportion of (transient) neonatal thyroid dysfunction was 0.0% (95%CI, 0.0-2.9%) for hysterosalpingography, 2.25% (95%CI, 0.03-6.55%) for amniofetography and 0.0% (95%CI, 0.0-0.02%) for computed tomography. There was a tendency towards an increased risk of thyroid dysfunction with higher amounts of contrast used.

Conclusions: Exposure to iodinated contrast media prior to or during pregnancy may increase the risk of thyroid dysfunction in offspring. We recommend keeping the amount of contrast used as low as possible.

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Camille Sollier, Emilie Capel, Caroline Aguilhon, Vasily Smirnov, Martine Auclair, Claire Douillard, Myriam Ladsous, Sabine Defoort-Dhellemmes, Jennifer Gorwood, Laura Braud, Roberto Motterlini, Camille Vatier, Olivier Lascols, Eric Renard, Corinne Vigouroux, and Isabelle Jéru

Objective

The term Multiple Symmetric Lipomatosis (MSL) describes a heterogeneous group of rare monogenic disorders and multifactorial conditions, characterized by upper-body adipose masses. Biallelic variants in LIPE encoding hormone sensitive lipase (HSL), a key lipolytic enzyme, were implicated in three families worldwide. We aimed to further delineate LIPE-related clinical features and pathophysiological determinants.

Methods

A gene panel was used to identify pathogenic variants. The disease features were reviewed at the French lipodystrophy reference center. The immunohistological, ultrastructural, and protein expression characteristics of lipomatous tissue were determined in surgical samples from one patient. The functional impact of variants was investigated by developing a model of adipose stem cells (ASCs) isolated from lipomatous tissue.

Results

We identified new biallelic LIPE null variants in three unrelated patients referred for MSL and/or partial lipodystrophy. The hallmarks of the disease, appearing in adulthood, included lower-limb lipoatrophy, upper-body and abdominal pseudolipomatous masses, diabetes and/or insulin resistance, hypertriglyceridemia, liver steatosis, high blood pressure, and neuromuscular manifestations. Ophthalmological investigations revealed numerous auto-fluorescent drusen-like retinal deposits in all patients. Lipomatous tissue and patient ASCs showed loss of HSL and decreased expression of adipogenic and mature adipocyte markers. LIPE-mutated ASCs displayed impaired adipocyte differentiation, decreased insulin response, defective lipolysis, and mitochondrial dysfunction.

Conclusions

Biallelic LIPE null variants result in a multisystemic disease requiring multidisciplinary care. Loss of HSL expression impairs adipocyte differentiation, consistent with the lipodystrophy/MSL phenotype and associated metabolic complications. Detailed ophthalmological examination could reveal retinal damage, further pointing to the nervous tissue as an important disease target.

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Fengzhou Du, Qiao Chen, Xiaojun Wang, Xiaopeng Guo, Zihao Wang, Lu Gao, Xiao Long, and Bing Xing

Background: Facial abnormality is the most significant feature in acromegaly patients. However, it is unclear whether and how patient facial appearance improves after treatment. This study aimed to identify 3D facial changes in acromegaly patients after surgical treatment.

Methods: This study included 30 acromegaly patients who underwent resection of a pituitary GH adenoma. The location and extent of facial changes were identified by comparing baseline and 2-year follow-up 3D images of the face. Relationships between facial changes and GH and IGF-1 were evaluated with simple or multivariable linear regression models.

Results: Significant soft tissue improvements were observed in acromegaly patients with complete remission, especially in the nose and lip region. Significant reductions in nasal width (3.46 mm, p < 0.001), tip protrusion (1.18 mm, p=0.003), face curve length (3.89 mm, p=0.004) and vermilion area (1.42 cm3, p=0.001) were observed at the 2-year follow-up. Further, changes in nasal width were associated with decreases in GH (β=4.440, p=0.017), the GH nadir (β=4.393, p=0.011) and IGF-1 (β=5.263, p=0.002). The associations were maintained after adjusting for confounders.

Conclusions: Acromegaly patients achieved considerable facial improvements after surgical treatment. The change in nose width was associated with GH and IGF-1 decreases. Better control of patient hormone levels after surgery improves patient facial recovery.

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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.

Free access

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.

Free access

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.

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Maria Cristina Campopiano, Debora Podestà, Francesca Bianchi, Carlotta Giani, Laura Agate, Valeria Bottici, Virginia Cappagli, Loredana Lorusso, Antonio Matrone, Luciana Puleo, Laura Valerio, David Viola, Paolo Piaggi, Rossella Elisei, and Eleonora Molinaro

Objective:

At present, recombinant TSH cannot be used for the treatment of metastatic differentiated thyroid cancer patients. The aim of this study was to evaluate if the type of TSH stimulation, recombinant or endogenous, had an impact on the outcome of these patients.

Design and methods:

We compared the outcome of two propensity score-matched groups of metastatic patients, stimulated by either only recombinant TSH (n = 43) or only endogenous TSH (n = 34).

Results:

As expected from the matching procedure, the clinical–pathological features and the cumulative 131-I activities administered to the two groups were very similar. After 4 years of follow-up, 4% of patients were cured, 3% had biochemical disease and 93% had structural disease. However, 91% of patients obtained a clinical benefit from this therapy in terms of stabilization of the disease or complete remission or partial response. When considering the two groups separately, we did not find any difference in their outcome. When considering the response to 131-I therapy of the single type of metastases, 8% of lymph node metastases and 8% of lung metastases disappeared but none of the bone metastases. The response to 131-I therapy of the single type of metastases was similar when we looked at the two groups separately.

Conclusions:

This study shows (i) an overall clinical benefit of the 131-I therapy, since the majority of patients remained affected but with a stable disease, and (ii) that the preparation with either recombinant or endogenous TSH has no impact on the 131-I therapy efficacy and the outcome of our two groups of patients.

Open access

Marian Schini, Richard Jacques, Eleanor Oakes, Nicola Peel, Jennifer S. Walsh, and Richard Eastell

Introduction: The least significant change (LSC) is a term used in individuals in order to evaluate whether one measurement has changed significantly from the previous one. It is widely used when assessing bone mineral density (BMD) scans. To the best of our knowledge, there no such estimate available in the literature for patients with disorders of calcium metabolism. Our aim was to provide an estimate of the least significant change for albumin adjusted calcium in patients with normocalcaemic hyperparathyroidism (NPHPT) and primary hyperparathyroidism (PHPT).

Methods: We used the within subject standard deviation calculated in a population of NPHPT and PHPT patients and multiplied it by 2.77.

Results: The LSC for NPHPT and PHPT were found to be 0.25 and 0.24 mmol/L respectively (1.00 and 0.96 mg/dL). In clinical practice, the value of 0.25 mmol/L could be used.

Discussion: The least significant change given, could be used in two ways in these patients. First, it gives a range to which values are expected. This can provide some reassurance for the patient and the physician in cases of intermittent hypercalcaemia. Moreover, it can be a marker of whether an individual has an actual significant change of his calcium after parathyroid surgery.