Pituitary adenomas are currently classified by histological, immunocytochemical and numerous ultrastructural characteristics lacking unequivocal prognostic correlations. We investigated the ...prognostic value of a new clinicopathological classification with grades based on invasion and proliferation. This retrospective multicentric case–control study comprised 410 patients who had surgery for a pituitary tumour with long-term follow-up. Using pituitary magnetic resonance imaging for diagnosis of cavernous or sphenoid sinus invasion, immunocytochemistry, markers of the cell cycle (Ki-67, mitoses) and p53, tumours were classified according to size (micro, macro and giant), type (PRL, GH, FSH/LH, ACTH and TSH) and grade (grade 1a: non-invasive, 1b: non-invasive and proliferative, 2a: invasive, 2b: invasive and proliferative, and 3: metastatic). The association between patient status at 8-year follow-up and age, sex, and classification was evaluated by two multivariate analyses assessing disease- or recurrence/progression-free status. At 8 years after surgery, 195 patients were disease-free (controls) and 215 patients were not (cases). In 125 of the cases the tumours had recurred or progressed. Analyses of disease-free and recurrence/progression-free status revealed the significant prognostic value (
p
< 0.001;
p
< 0.05) of age, tumour type, and grade across all tumour types and for each tumour type. Invasive and proliferative tumours (grade 2b) had a poor prognosis with an increased probability of tumour persistence or progression of 25- or 12-fold, respectively, as compared to non-invasive tumours (grade 1a). This new, easy to use clinicopathological classification of pituitary endocrine tumours has demonstrated its prognostic worth by strongly predicting the probability of post-operative complete remission or tumour progression and so could help clinicians choose the best post-operative therapy.
Post-transplant diabetes mellitus (PTDM) has emerged as a major adverse effect of immunosuppressive drugs (ISD). As recipients of organ transplants survive longer, the complications of diabetes ...mellitus have assumed greater importance. The predominant factor for causing PTDM by corticosteroids seems to be the aggravation of insulin resistance, however several studies have displayed deleterious effects on insulin secretion and β-cells. Calcineurin inhibitors induce PTDM by a number of mechanisms, including decreased insulin secretion and a direct toxic effect on the pancreatic β-cells. Recent
in vitro studies stress on the increased apoptosis of β-cells when exposed to these drugs. Studies involving other immunosuppressive agents (mycophenolate mofetil MMF, sirolimus) are scarcer and lead to conflicting results, while daclizumab seems to have a neutral effect. Clinical studies have consistently shown a greater potential of tacrolimus to induce PTDM compared with cyclosporine. Reducing PTDM incidence is a feasible goal while using corticosteroid-sparing regimens and/or lower tacrolimus trough levels. In patients developing PTDM, conversion from tacrolimus to cyclosporine could improve or reverse glucose tolerance abnormalities. In the absence of well-designed studies in this specific indication, treatment of PTDM is based on the same principles as type 2 diabetes mellitus. Thiazolidinediones do not display any pharmacological interaction with calcineurin inhibitors, but their safety and efficacy in PTDM need to be confirmed in large-scale randomized trials. Use of sulfonylureas has to be cautious regarding the suspected interaction of some of them with calcineurin inhibitors. If needed, insulin regimens have to be adapted in patients who display the particular glycaemic profile of corticosteroid-induced diabetes. Incretin-based therapies, due to their specific action on β-cell apoptosis and proliferation, raise promises that have to be confirmed in clinical studies.
Until methods for inducing specific graft tolerance become available, immunosuppressive regimens should be tailored to the individual patient on the basis of predictive criteria for the development of PTDM.
Le diabète post-transplantation (DPT) est un des principaux effets secondaires des immunosuppresseurs. Avec l’augmentation de la survie des receveurs d’organes, les complications du diabète sont devenues un problème majeur. L’action diabétogène principale des corticoïdes passe par l’aggravation de l’insulinorésistance, mais plusieurs études ont rapporté des effets délétères sur la sécrétion d’insuline et sur la cellule β pancréatique. Les inhibiteurs de la calcineurine peuvent induire un DPT par plusieurs mécanismes, principalement en diminuant la sécrétion d’insuline et par un effet toxique direct sur la cellule β. Des études
in vitro récentes ont montré une augmentation de l’apoptose des cellules, soumises aux inhibiteurs de la calcineurine. Dans de rares études qui impliquent d’autres immunosuppresseurs mycophénolate mofétil (MMF), sirolimus les résultats apparaissent contradictoires, le daclizumab semble, quant à lui, ne présenter aucun effet délétère.
Les études cliniques s’accordent, cependant, à démontrer le fort potentiel du tacrolimus à induire un DPT en comparaison à la ciclosporine. La réduction de l’incidence du DPT est possible et repose sur l’utilisation de schémas d’immunosuppression sans glucocorticoïdes et/ou avec de faibles doses de tacrolimus. Chez les patients développant un DPT, la substitution du tacrolimus par la ciclosporine est susceptible d’améliorer ou de corriger les anomalies du métabolisme glucidique. En l’absence d’études spécifiques réalisées dans ce domaine, la prise en charge du DPT est semblable à celle du diabète de type 2. Les thiazolidinediones ne présentent aucune interaction pharmacologique avec les inhibiteurs de la calcineurine, mais leur efficacité et leur tolérance nécessitent d’être confirmées dans des études randomisées à grande échelle. Le recours aux sulfamides hypoglycémiants doit rester prudent en raison, pour certains d’entre eux, d’interactions avec les inhibiteurs de la calcineurine. Si nécessaire, les schémas d’insulinothérapie doivent être adaptés chez les patients présentant le profil glycémique particulier du diabète corticoinduit. Les incrétino-mimétiques, de par leur action spécifique sur l’apoptose et sur la prolifération des cellules β, représentent une thérapeutique d’avenir dans cette indication du DPT, mais ces promesses doivent être confrontées aux résultats d’études cliniques. Dans l’attente de méthodes susceptibles d’induire une tolérance spécifique en greffe d’organe, le recours aux immunosuppresseurs doit être adapté à chaque patient en fonction de son risque potentiel de développer un DPT.
Objectives
The aim of this study was to investigate whether the quadrivalent human papillomavirus (HPV) vaccine Gardasil is associated with a change in the risk of autoimmune disorders (ADs) in young ...female subjects.
Design
Systematic case–control study of incident ADs associated with quadrivalent HPV vaccination in young women across France.
Participants and setting
A total of 113 specialised centres recruited (from December 2007 to April 2011) females aged 14–26 years with incident cases of six types of ADs: idiopathic thrombocytopenic purpura (ITP), central demyelination/multiple sclerosis (MS), Guillain–Barré syndrome, connective tissue disorders (systemic lupus erythematosus, rheumatoid arthritis/juvenile arthritis), type 1 diabetes mellitus and autoimmune thyroiditis. Control subjects matched to cases were recruited from general practice.
Analysis
Multivariate conditional logistic regression analysis; factors included age, geographical origin, smoking, alcohol consumption, use of oral contraceptive(s) or vaccine(s) other than Gardasil received within 24 months before the index date and personal/family history of ADs.
Results
Overall, 211 definite cases of ADs were matched to 875 controls. The adjusted odds ratio (OR) for any quadrivalent HPV vaccine use was 0.9 95% confidence interval (CI) 0.5–1.5. The individual ORs were 1.0 (95% CI 0.4–2.6) for ITP, 0.3 (95% CI 0.1–0.9) for MS, 0.8 (95% CI 0.3–2.4) for connective disorders and 1.2 (95% CI 0.4–3.6) for type 1 diabetes. No exposure to HPV vaccine was observed in cases with either Guillain–Barré syndrome or thyroiditis.
Conclusions
No evidence of an increase in the risk of the studied ADs was observable following vaccination with Gardasil within the time periods studied. There was insufficient statistical power to allow conclusions to be drawn regarding individual ADs.
Aims
To validate strategies to prevent exercise‐induced hypoglycaemia via insulin‐dose adjustment in adult patients with type 1 diabetes (T1D) on pump therapy.
Methods
A total of 20 patients randomly ...performed four 30‐min late post‐lunch (3 h after lunch) exercise sessions and a rest session: two moderate sessions 50% maximum oxygen consumption (VO2max) with 50 or 80% basal rate (BR) reduction during exercise + 2 h and two intense sessions (75% VO2max) with 80% BR reduction or with their pump stopped. Two additional early post‐lunch sessions (90 min after lunch) were analysed to compare hypoglycaemia incidence for BR reduction versus bolus reduction.
Results
In all, 100 late post‐lunch sessions were analysed. Regardless of exercise type and BR reduction, no more hypoglycaemic events occurred in the period until the next morning than occurred after the rest sessions. In the afternoon, no more hypoglycaemic events occurred with 80% BR reduction/moderate exercise or with pump discontinuation/intense exercise than for the rest session, whereas more hypoglycaemic events occurred with 50% BR reduction/moderate exercise and 80% BR reduction/intense exercise. After early post‐lunch exercise (n = 37), a trend towards fewer hypoglycaemic episodes was observed with bolus reduction versus BR reduction (p = 0.07). Mean blood glucose fell by ∼3.3 mmol/l after 30 min of exercise, irrespective of dose reduction, remaining stable until the next morning with no rebound hyperglycaemia.
Conclusion
In adults with T1D, to limit the hypoglycaemic risk associated with 30 min of exercise 3 h after lunch, without carbohydrate supplements, the best options seem to be to reduce BR by 80% or to stop the pump for moderate or intense exercise, or for moderate exercise 90 min after lunch, to reduce the prandial bolus rather than the BR.
Automated closed-loop (CL) insulin therapy has come of age. This major technological advance is expected to significantly improve the quality of care for adults, adolescents and children with type 1 ...diabetes. To improve access to this innovation for both patients and healthcare professionals (HCPs), and to promote adherence to its requirements in terms of safety, regulations, ethics and practice, the French Diabetes Society (SFD) brought together a French Working Group of experts to discuss the current practical consensus. The result is the present statement describing the indications for CL therapy with emphasis on the idea that treatment expectations must be clearly defined in advance. Specifications for expert care centres in charge of initiating the treatment were also proposed. Great importance was also attached to the crucial place of high-quality training for patients and healthcare professionals. Long-term follow-up should collect not only metabolic and clinical results, but also indicators related to psychosocial and human factors. Overall, this national consensus statement aims to promote the introduction of marketed CL devices into standard clinical practice.
Recently discovered mutations of
gene, encoding for the GR, in patients with glucocorticoid resistance and bilateral adrenal incidentalomas prompted us to investigate whether GR mutations might be ...associated with adrenal hyperplasia.
The multicenter French Clinical Research Program (Muta-GR) was set up to determine the prevalence of GR mutations and polymorphisms in patients harboring bilateral adrenal incidentalomas associated with hypertension and/or biological hypercortisolism without clinical Cushing's signs.
One hundred patients were included in whom
sequencing revealed five original heterozygous GR mutations that impaired GR signaling
. Mutated patients presented with mild glucocorticoid resistance defined as elevated urinary free cortisol (1.7 ± 0.7 vs 0.9 ± 0.8 upper limit of normal range,
= 0.006), incomplete 1 mg dexamethasone suppression test without suppressed 8-AM adrenocorticotrophin levels (30.9 ± 31.2 vs 16.2 ± 17.5 pg/mL) compared to the non-mutated patients. Potassium and aldosterone levels were lower in mutated patients (3.6 ± 0.2 vs 4.1 ± 0.5 mmol/L,
= 0.01, and 17.3 ± 9.9 vs 98.6 ± 115.4 pg/mL,
= 0.0011, respectively) without elevated renin levels, consistent with pseudohypermineralocorticism.
characterization of mutated patients' fibroblasts demonstrated GR haploinsufficiency as revealed by below-normal glucocorticoid induction of
gene expression. There was no association between GR polymorphisms and adrenal hyperplasia in this cohort, except an over-representation of
polymorphism.
The 5% prevalence of heterozygous
mutations discovered in our series is higher than initially thought and encourages GR mutation screening in patients with adrenal incidentalomas to unambiguously differentiate from Cushing's states and to optimize personalized follow-up.
The use by diabetes patients of real-time continuous interstitial glucose monitoring (CGM) or the FreeStyle Libre® (FSL) flash glucose monitoring (FGM) system is becoming widespread and has changed ...diabetic practice. The working group bringing together a number of French experts has proposed the present practical consensus. Training of professionals and patient education are crucial for the success of CGM. Also, institutional recommendations must pay particular attention to the indications for and reimbursement of CGM devices in populations at risk of hypoglycaemia. The rules of good practice for CGM are the precursors of those that need to be enacted, given the oncoming emergence of artificial pancreas devices. It is necessary to have software combining user-friendliness, multiplatform usage and average glucose profile (AGP) presentation, while integrating glucose and insulin data as well as events. Expression of CGM data must strive for standardization that facilitates patient phenotyping and their follow-up, while integrating indicators of variability. The introduction of CGM involves a transformation of treatment support, rendering it longer and more complex as it also includes specific educational and technical dimensions. This complexity must be taken into account in discussions of organization of diabetes care.
Summary
Aim
Real‐life studies are needed to confirm the clinical relevance of findings from randomised controlled trials (RCTs). This study aimed to assess the effectiveness and tolerability of ...vildagliptin add‐on vs. other oral antihyperglycaemic drugs (OADs) added to OAD monotherapy in a real‐life setting, and to explore the advantages and limitations of large‐scale ‘pragmatic’ trials.
Methods
EDGE was a prospective, 1‐year, worldwide, real‐life observational study in which 2957 physicians reported on the effects of second‐line OADs in 45,868 patients with T2DM not reaching glycaemic targets with monotherapy. Physicians could add any OAD, and patients entered either vildagliptin or (pooled) comparator cohort. The primary effectiveness and tolerability end‐point (PEP) evaluated proportions of patients decreasing HbA1c > 0.3%, without hypoglycaemia, weight gain, peripheral oedema or gastrointestinal side effects. The most clinically relevant secondary end‐point (SEP 3) was attainment of end‐point HbA1c < 7% without hypoglycaemia or ≥ 3% increase in body weight.
Results
In this large group of T2DM patients, a second OAD was added at mean HbA1c of 8.2 ± 1.3%, with no baseline HbA1c difference between cohorts. Second‐line OAD therapy attained the PEP in the majority of patients, with higher attainment in those prescribed a vildagliptin‐based regimen. The adjusted odds ratio was 1.49 (95% CI: 1.42, 1.55; p < 0.001). In patients with baseline HbA1c ≥ 7%, SEP 3 was achieved by 35% of patients on a vildagliptin‐based combination and by 23% of those receiving comparator combinations. The adjusted odds ratio was 1.96 (95% CI: 1.85, 2.07; p < 0.001). Safety events were reported infrequently and safety profiles of vildagliptin and other OADs were consistent with previous data.
Conclusion
EDGE demonstrates that in a ‘real‐life’ setting, vildagliptin as second OAD can lower HbA1c to target without well‐recognised OAD side effects, more frequently than comparator OADs. In addition, EDGE illustrates that conducting large‐scale, prospective, real‐life studies poses challenges but yields valuable clinical information complementary to RCTs.
Abstract Aim Despite half of all type 2 diabetes mellitus (T2DM) patients being over 65 and treatment being complicated by an elevated risk of iatrogenic hypoglycaemia, information about antidiabetic ...treatment is scarce in this age group. This prospective observational study compares DPP4-inhibitors (DPP4-i) with conventional oral antidiabetic drugs (COAD) in the real-life treatment of elderly patients with T2DM uncontrolled on metformin alone. Methods Two treatment cohorts (DPP4-i and COAD, constituted on the basis of the GP decision of add-on therapy at the 1st visit) were compared after 6 months. The primary objective was to assess the incidence of hypoglycaemic episodes in relationship with glycaemic control assessed by HbA1c level. Results Demographics and disease history were comparable between the two cohorts (DPP4-i, n = 931 and COAD, n = 257) at baseline. The incidence of hypoglycaemia/severe hypoglycaemia was significantly higher over 6 months in the COAD cohort (20.1%/2.4% vs. 6.4%/0.1%; P < 0.001) whereas similar improvements were observed in glycaemic control with HbA1c down from 7.9% to 7.0% (COAD) and 6.9% (DPP4-i). The 7% target was reached without hypoglycaemia in more patients in the DPP4-i than in COAD cohort (59.7% vs. 45.5%; P < 0.001). Patients in both cohorts who experienced hypoglycaemia more frequently had a pre-existing diabetic complication. The COAD was more likely to be discontinued (6.6% vs. 1.6%; P < 0.001). Conclusion This large cohort study of elderly T2DM patients in France shows that the incidence of hypoglycaemia was three times higher in patients prescribed a COAD versus a DPP4-i after 6 months while both treatments induced satisfactory glycaemic control.
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