Context Epigenetic alterations may play a role in the development and behaviour of Pituitary Neuroendocrine Tumours (PitNETs). Objective To evaluate the effect of methylation of Tumour Suppressor Genes (TSGs) in their gene expression and in the behaviour of PitNETs. Material and Methods We use MS-MLPA and q-RT-PCR techniques to analyse the DNA-promoter hypermethylation and the gene expression of 35 TSGs in 105 PitNETs. We define functionality, size and invasiveness of tumours according to their clinical manifestations, Hardy’s classification and MRI invasion of the cavernous sinus, respectively. Results We observed different methylation patterns among PitNET subtypes. CASP8 was the most hypermethylated gene in all PitNET subtypes. The methylation status of TP73 correlated negatively with their gene expression in the overall series (p=0.013) and in some subtypes. MSH6 and CADM1 showed higher methylation frequency in macro than in microadenomas in the overall series and in corticotroph PitNETs (all p≤0.053). ESR1 and RASSF1 were higher methylated in non-invasive than in invasive tumours in the overall series (p=0.054 and p=0.031, respectively) and in the gonadotroph subtype (sGT) (p=0.055 and p=0.050, respectively). ESR1 and CASP8 appeared more hypermethylated in functioning than in sCT (p=0.034 and p=0.034, respectively). Conclusions DNA-methylation of TSGs has a selective effect on their gene expression and on the growth and invasiveness of PitNETs. Its involvement in their functionality is biased because all silent operated tumours are macroadenomas while all operated microadenomas are functioning ones. Therefore, the subtypes of PitNETs should be considered as different entities.

Bariatric surgery is effective in remission of obesity comorbidities. This study was aimed at comparing CVD risk between morbidly obese patients with type 2 diabetes and pre-diabetes before and after bariatric surgery as well as assessing comorbidities. This is a retrospective observational study with 105 patients with type 2 diabetes (DMbaseline) and prediabetes (preDMbaseline) who underwent Roux-en-Y gastric bypass. Data were collected preoperative and then at 3,6,12,18,24,36,48, and 60 months after surgery. Anthropometric, cardiovascular and glycemic parameters were assessed. CVD risk was calculated using the Framingham Risk Score. Prior to surgery, 48 patients had type 2 diabetes, while 57 had pre-diabetes. Mean age was 48 (9.2) and mean BMI was 52 (7.4). 26.1% of patients had a high CVD risk. CVD risk decreased in patients with type 2 diabetes and prediabetes at month 12 after surgery compared to the baseline risk (p < 0.001). BMI, body fat percentage, fasting plasma glucose, HbA1c, c-peptide, HOMA-IR, LDL-c, systolic blood pressure, and diastolic blood pressure decreased during the first year after surgery. From the 12th month until the 60th, they showed a flat trend, or a very mild increase in some cases. 3.2% of patients maintained high CVD risk at 60 months. Type 2 diabetes remission was 92%. No patient of the preDMbaseline group developed type 2 diabetes. Bariatric surgery reduces CVD risk in type 2 diabetes and pre-diabetes. Given that patients with type 2 diabetes benefit the most, more studies are necessary to consider pre-diabetes as a criterion for metabolic surgery in patients with BMI ≥ 35 kg/m2.

The classification of pituitary neuroendocrine tumors (PitNETs) subtypes continues generating interest. In 2017, the World Health Organization (WHO) proposed considering the immunohistochemical (IHC) analysis of pituitary-specific transcription factors (TF) for their typification. The present study targeted the quantification of pituitary-specific TF (TPIT, PIT-1, SF-1, GATA2, ESR1) gene expression by RT-qPCR to overcome the shortcomings of IHC and to complement it. We analyzed 251 tumors from our collection of PitNETs and performed additional IHC studies in a subset of 56 samples to analyze the concordance between gene and protein expression of the TF. The molecular and IHC studies allowed us to significantly reduce the percentage of null cell tumors in our series, most of which were reclassified as gonadotroph tumors. The concordance between the molecular and the immunohistochemical studies was good for tumors coming from the corticotroph and Pit-1 lineages but worsened for the rest of the tumors. Indeed, the RT-qPCR helped to improve the typification of plurihormonal Pit-1 and unusual tumors. Overall, our results suggest that the RT-qPCR of pituitary-specific TF and hormone genes could help pathologists, endocrinologists, and neurosurgeons to improve the management of patients with pituitary tumors.

MiR-17-5p and E2F1 have been described as deregulated in cancer, but they have scarcely been studied in pituitary neuroendocrine tumours (PitNETs). This study evaluates the relationship of E2F1 and miR-17-5p with the invasiveness and proliferation of PitNETs. In this cross-sectional descriptive study, we evaluated the expression of E2F1, MYC, and miR-17-5p by quantitative real time PCR analysis in 60 PitNETs: 29 gonadotroph (GT), 15 functioning somatotroph (ST), and 16 corticotroph (CT) tumours, of which 8 were silent (sCT). The clinical data were collected from the Spanish Molecular Register of Pituitary Adenomas (REMAH) database. We defined invasiveness according to the Knosp classification and proliferation according to a molecular expression of Ki-67 ≥ 2.59. E2F1 was more expressed in invasive than in non-invasive tumours in the whole series (p = 0.004) and in STs (p = 0.01). In addition, it was overexpressed in the silent subtypes (GTs and sCTs; all macroadenomas) and normoexpressed in the functioning ones (fCTs and STs; some microadenomas). miR-17-5p was more expressed in proliferative than in non-proliferative tumours (p = 0.041) in the whole series but not by subtypes. Conclusions: Our study suggests that in PitNETs, E2F1 could be a good biomarker of invasiveness, and miR-17-5p of proliferation, helping the clinical management of these tumours.

Almost one third of patients do not achieve type 2 diabetes remission after bariatric surgery or are unable to sustain this effect long term. Our objective was to delve further into the dynamic responses of diabetes after bariatric surgery and to evaluate the “time-within-remission range” as a variable of metabolic control. A descriptive cohort study was done using a computerised multicentre and multidisciplinary registry. All data were adjusted by propensity score. A total of 1186 subjects with a follow-up of 4.5 ± 2.5 years were included. Type of surgery, diabetes remission, recurrence of diabetes, “time-within-remission range” and key predictors of diabetes outcomes were assessed. All patients (70% women, 51.4 ± 9.2 years old, body mass index (BMI) 46.3 ± 6.9 kg/m²) underwent primary bariatric procedures. “Time-within-remission range” were 83.3% (33.3–91.6) after gastric bypass, 68.7% (7.1–87.5) after sleeve gastrectomy and 90% (83.3–92.8) after malabsorptive techniques (p < 0.001 for all). Duration of diabetes, baseline HbA1c and insulin treatment were significantly negatively correlated with the “time-within-remission range”. The association of bariatric techniques with “time-within-remission range”, using gastric bypass as a reference, were: odds ratio (OR) 3.70 (2.34–5.84), p < 0.001 for malabsorptive techniques and OR 0.55 (0.40–0.75), p < 0.001 for sleeve gastrectomy. Characteristics of type 2 diabetes powerfully influence the outcomes of bariatric surgery. The “time-within-remission range” unveils a superiority of gastric bypass compared to sleeve gastrectomy.