Molecular characterization of epithelial-mesenchymal transition and medical treatment related-genes in non-functioning pituitary neuroendocrine tumors.

Introduction: Different medical therapies have been developed for pituitary adenomas. However, Non-Functioning Pituitary Neuroendocrine Tumors (NF-PitNET) have shown little response to them. Furthermore, epithelial-mesenchymal transition (EMT) has been linked to resistance to medical treatment in a significant number of tumors, including pituitary adenomas. Methods: We aimed to evaluate the expression of EMT-related markers in 72 NF-PitNET and 16 non-tumoral pituitaries. To further explore the potential usefulness of medical treatment for NF-PitNET we assessed the expression of somatostatin receptors and dopamine-associated genes. Results: We found that SNAI1, SNAI2, Vimentin, KLK10, PEBP1, Ki-67 and SSTR2 were associated with invasive NF-PitNET. Furthermore, we found that the EMT phenomenon was more common in NF-PitNET than in GH-secreting pituitary tumors. Interestingly, PEBP1 was overexpressed in recurrent NF-PitNET, and could predict growth recurrence with 100% sensitivity but only 43% specificity. In parallel with previously reported studies, SSTR3 is highly expressed in our NF-PitNET cohort. However, SSTR3 expression is highly heterogeneous among the different histological variants of NF-PitNET with very low levels in silent corticotroph adenomas. Conclusion: NF-PitNET showed an enhanced EMT phenomenon. SSTR3 targeting could be a good therapeutic candidate in NF-PitNET except for silent corticotroph adenomas, which express very low levels of this receptor. In addition, PEBP1 could be an informative biomarker of tumor regrowth, useful for predictive medicine in NF-PitNET.

Endocrine Late Effects in Childhood Cancer Survivors.

Childhood cancer management has improved considerably over the years, leading to a significant improvement in survival of up to 80%. However, childhood cancer survivors are at the highest risk of developing sequelae resulting from treatment, with endocrine complications being frequently observed among survivors. Multiple predisposing factors for endocrine sequelae have been identified, including age at diagnosis, treatment received, radiation, tumor type, and genetic polymorphisms, which could explain the individual predisposition to develop drug toxicity. Novel agents targeting tumor growth and immune checkpoint inhibitors have recently become the cornerstone for the treatment of different cancers, triggering a myriad of immune-related endocrinopathies. Endocrine sequelae of cancer therapy will have an impact on not only childhood but also on the survival and quality of life of these highly complex patients. Therefore, lifelong monitoring of childhood cancer survivors at risk of endocrine diseases is paramount. Encouraging oncologists and endocrinologists to develop new follow-up and early detection guidelines that minimize sequelae among these patients has become a priority, promoting integration between pediatric and adult units since many sequelae may manifest only after years to decades of follow-up.

Molecular determinants of enhanced response to somatostatin receptor ligands after debulking in large GH-producing adenomas.

OBJECTIVE: Large somatotrophic adenomas depict poor response to somatostatin receptor ligands (SRLs). Debulking has shown to enhance SRLs effect in some but not all cases and tumour volume reduction has been proposed as the main predictor of response. No biological studies have been performed so far in this matter. We aimed to identify molecular markers of response to SRLs after surgical debulking in GH-secreting adenomas. DESIGN: We performed a multicenter retrospective study. PATIENTS: 24 patients bearing large GH-producing tumours. MEASUREMENTS: Clinical data and SRLs response both before and after surgical debulking were collected, and 21 molecular biomarkers of SRLs response were studied in tumour samples by gene expression. RESULTS: From the 21 molecular markers studied, only two of them predicted enhanced SRLs response after surgery. Tumours with improved response to SRLs after surgical debulking showed lower levels of Ki-67 (MKI67, FC = 0.17 and P = .008) and higher levels of RAR-related orphan receptor C (RORC) (FC = 3.1 and P Ë‚ .001). When a cut-off of no detectable expression was used for Ki-67, the model provided a sensitivity of 100% and a specificity of 52.6% with an area under the curve of 65.8%. Using a cut-off of 2 units of relative expression of RORC, the prediction model showed 100% of sensitivity and specificity. CONCLUSIONS: High levels of RORC and low levels of Ki-67 identify improved SRLs response after surgical debulking in large somatotropic adenomas. To determine their expression would facilitate medical treatment decision-making after surgery.

Endocrine sequelae in childhood cancer survivors. / Secuelas endocrinológicas en supervivientes de cáncer infantil.

Thanks to the advances in cancer treatment, the five-year survival rate after childhood cancer has increased up to 80%. Therefore 1/500 young adults will be a survivor. Endocrine sequelae are most common, affecting 40-60% of survivors. The most frequent sequelae include growth failure and gonadal and thyroid diseases. Sequelae occur more frequently in survivors from central nervous system tumors, leukemia, and lymphoma. Their development will depend on the type of cancer, its location, age at diagnosis, and treatment administered. Treatments associated to more endocrine sequels are cranial radiotherapy and hematopoietic cell transplantation. Because of the high prevalence of endocrine sequelae, international guidelines recommend endocrinologists to prospectively evaluate the survivors. As some of these endocrine changes will not develop until adult life, transition programs should be implemented, and active investigation should be made to decrease the endocrine consequences of cancer treatment.

Pituitary dysfunction after traumatic brain injury: are there definitive data in children?

In the past decade, several studies in adults and children have described the risk of pituitary dysfunction after traumatic brain injury (TBI). As a result, an international consensus statement recommended follow-up on the survivors. This paper reviews published studies regarding hypopituitarism after TBI in children and compares their results. The prevalence of hypopituitarism ranges from 5% to 57%. Growth hormone (GH) and ACTH deficiency are the most common, followed by gonadotropins and thyroid-stimulating hormone. Paediatric studies have failed to identify risk factors for developing hypopituitarism, and therefore we have no tools to restrict screening in severe TBI. In addition, the present review highlights the lack of a unified follow-up and the fact that unrecognised pituitary dysfunction is frequent in paediatric population. The effect of hormonal replacement in patient recovery is important enough to consider baseline screening and reassessment between 6 and 12 months after TBI. Medical community should be aware of the risk of pituitary dysfunction in these patients, given the high prevalence of endocrine dysfunction already reported in the studies. Longer prospective studies are needed to uncover the natural course of pituitary dysfunction, and new studies should be designed to test the benefit of hormonal replacement in metabolic, cognitive and functional outcome in these patients.

Pituitary dysfunction after traumatic brain injury in children: is there a need for ongoing endocrine assessment?

BACKGROUND: Hypopituitarism has been widely described in adults after traumatic brain injury (TBI); however, the available data in paediatric populations are scarce. Here, we report the results of a prospective, long-term study in children, adolescents and young adults. STUDY GROUP: Thirty-seven children (age, 2 months to 19·9 years) of 51 eligible patients were followed for 1 year. Clinical and baseline endocrine variables were assessed in all 3 and 12 months after TBI; children ≥ 6 years underwent two stimulation tests (glucagon stimulation and megatest). RESULTS: In the group ≥6 years, 11 of 23 patients (47·8%) had a subnormal GH peak 3 months after TBI that persisted in 8 of 23 patients (34%) after 1 year. The GH response showed no correlation with injury severity (GCS, Marshall classification). Growth velocity was normal in all patients, except for one. Body mass index (BMI) SDS increased significantly in the group with low GH response. A suboptimal cortisol was observed in 10 of 23 subjects, which normalized in all but three, 1 year thereafter. All patients but one showed a pubertal response to GnRH testing. No clinical or hormonal abnormalities were detectable in children <6 years. CONCLUSION: Our results recommend to prospectively follow children after TBI: firstly, because the impairment of pituitary function cannot be predicted, and secondly, to avoid the potential consequences of pituitary dysfunction. Prospective clinical trials are needed before recommending a systematic screening after TBI and/or GH therapy either in postpubertal children or in prepubertal children who grow normally.

The tumour necrosis factor (TNF)-alpha-308GA promoter polymorphism is related to prenatal growth and postnatal insulin resistance.

OBJECTIVE: Variation in the tumour necrosis factor gene, (TNF) has been associated with insulin resistance traits. We questioned whether the TNF-308G/A polymorphism is associated with birthweight and insulin resistance in children born small for gestational age (SGA), a patient population known to be at risk for insulin resistance. DESIGN: A cross-sectional, hospital-based study assessing insulin sensitivity in SGA children. PATIENTS: One hundred and ninety-eight school-age children born either SGA (n=90, age 7.4+/- 4.5 years) or appropriate for gestational age (AGA, n=108, age 8.7+/- 4.0 years). MEASUREMENTS: All children were genotyped for the TNF-308G/A polymorphism; a biochemical profile was also performed in prepubertal SGA (n=58) and AGA (n=57) subjects. RESULTS: Genotype frequencies for the TNF-308G/A single nucleotide polymorphisms (SNPs) (GG and GA/AA) differed between SGA and AGA children (86%vs. 72% and 14%vs. 28%, respectively; P=0.025). The GG genotype was associated with lower birthweight and birth length (2747.0+/- 23.3 g vs. 2851.0+/- 45.7 g, P=0.045, and 47.0+/- 0.2 cm vs. 48.2+/- 0.4 cm, P=0.011, respectively) and, in AGA but not in SGA children, with higher systolic blood pressure [103.3 (95% confidence interval (CI) 96.4-110.2) mmHg vs. 92.8 (84.9-100.7) mmHg; P=0.028], higher blood glucose [4.8 (4.7-5.0) mmol/l vs. 4.5 (4.3-4.8) mmol/l; P=0.042] and higher homeostasis model assessment for insulin resistance (HOMA-IR) index [1.4 (1.1-1.7) vs. 0.9 (0.4-1.3); P=0.005]. In multivariate analysis, the TNF-308GG genotype was an independent predictor of HOMA-IR during childhood, explaining 8% of its variance. CONCLUSION: SGA children show increased frequency of the TNF-308G allele, an allele that is associated with prenatal growth and with postnatal insulin resistance. The TNF-308G/A polymorphism may have implications in the growth and metabolic abnormalities that characterise SGA children.