Age-dependent and sex-dependent disparity in mortality in patients with adrenal incidentalomas and autonomous cortisol secretion: an international, retrospective, cohort study

Background: The association between cortisol secretion and mortality in patients with adrenal incidentalomas is controversial. We aimed to assess all-cause mortality, prevalence of comorbidities, and occurrence of cardiovascular events in uniformly stratified patients with adrenal incidentalomas and cortisol autonomy (defined as non-suppressible serum cortisol on dexamethasone suppression testing). Methods: We conducted an international, retrospective, cohort study (NAPACA Outcome) at 30 centres in 16 countries. Eligible patients were aged 18 years or older with an adrenal incidentaloma (diameter ≥1 cm) detected between Jan 1, 1996, and Dec 31, 2015, and availability of a 1 mg dexamethasone suppression test result from the time of the initial diagnosis. Patients with clinically apparent hormone excess, active malignancy, or follow-up of less than 36 months were excluded. Patients were stratified according to the 0800–0900 h serum cortisol values after an overnight 1 mg dexamethasone suppression test; less than 50 nmol/L was classed as non-functioning adenoma, 50–138 nmol/L as possible autonomous cortisol secretion, and greater than 138 nmol/L as autonomous cortisol secretion. The primary endpoint was all-cause mortality. Secondary endpoints were the prevalence of cardiometabolic comorbidities, cardiovascular events, and cause-specific mortality. The primary and secondary endpoints were assessed in all study participants. Findings: Of 4374 potentially eligible patients, 3656 (2089 [57·1%] with non-functioning adenoma, 1320 [36·1%] with possible autonomous cortisol secretion, and 247 [6·8%] with autonomous cortisol secretion) were included in the study cohort for mortality analysis (2350 [64·3%] women and 1306 [35·7%] men; median age 61 years [IQR 53–68]; median follow-up 7·0 years [IQR 4·7–10·2]). During follow-up, 352 (9·6%) patients died. All-cause mortality (adjusted for age, sex, comorbidities, and previous cardiovascular events) was significantly increased in patients with possible autonomous cortisol secretion (HR 1·52, 95% CI 1·19–1·94) and autonomous cortisol secretion (1·77, 1·20–2·62) compared with patients with non-functioning adenoma. In women younger than 65 years, autonomous cortisol secretion was associated with higher all-cause mortality than non-functioning adenoma (HR 4·39, 95% CI 1·93–9·96), although this was not observed in men. Cardiometabolic comorbidities were significantly less frequent with non-functioning adenoma than with possible autonomous cortisol secretion and autonomous cortisol secretion (hypertension occurred in 1186 [58·6%] of 2024 patients with non-functioning adenoma, 944 [74·0%] of 1275 with possible autonomous cortisol secretion, and 179 [75·2%] of 238 with autonomous cortisol secretion; dyslipidaemia occurred in 724 [36·2%] of 1999 patients, 547 [43·8%] of 1250, and 123 [51·9%] of 237; and any diabetes occurred in 365 [18·2%] of 2002, 288 [23·0%] of 1250, and 62 [26·7%] of 232; all p values <0·001). Interpretation: Cortisol autonomy is associated with increased all-cause mortality, particularly in women younger than 65 years. However, until results from randomised interventional trials are available, a conservative therapeutic approach seems to be justified in most patients with adrenal incidentaloma. Funding: Deutsche Forschungsgemeinschaft, Associazione Italiana per la Ricerca sul Cancro, Università di Torino

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

“The past is a different country, they do things differently there”: using the SEER data-base to assess prognosis in neuroendocrine tumours

Neuroendocrine neoplasms (NENs) are still considered to be rare neoplasms, and their epidemiology has been classically studied in large population-based cancer registries. Besides the benefits and the limitations that a cancer registry may have for all the registered cancers, the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Programme, has a number of drawbacks for the study of NENs. The change in management of NENs, either from diagnostic or from therapeutic points of view, the role of the Ki-67 labelling index and introduction of sensitive functional imaging, along with the misclassification of the more benign types of NENs, are the main limitations of the prognostic ability of the SEER data-base, particularly when including older data

Effect of long-term orlistat treatment on serum levels of advanced glycation end-products in women with polycystic ovary syndrome

Background: Women with polycystic ovary syndrome (PCOS) exhibit elevated serum advanced glycation end-products (AGE) compared with healthy subjects. Short-term administration of orlistat has been shown to reduce the postmeal increase in serum AGE levels in women with PCOS and in controls. Objective: To evaluate the long-term effect of orlistat and a low-calorie diet on serum AGE levels, and on the hormonal and metabolic profile of obese PCOS and normal women. Design: A clinical trial of 6 months of orlistat administration with an energy-restricted diet [basic metabolic rate (BMR) 600 kcal/day] in all subjects. Subjects: Twenty-nine women with PCOS [aged 27.52 ± 5.77 years; body mass index (BMI) 35.43 ± 5.31 kg/m2] and 18 controls (aged 32.06 ± 5.64 years; BMI 36.39 ± 6.47 kg/m2). Measurements: Serum AGE levels (U/ml), hormonal and metabolic profile. Results: PCOS and controls did not differ in BMI (P = 0.58), waist-to-hip ratio (WHR) (P = 0.44), fasting insulin concentration (P = 0.45) and glucose-to-insulin ratio (GIR) (P = 0.34). PCOS women exhibited statistically higher AGE (P < 0.001) and testosterone levels (P < 0.001) compared with controls. After 6 months of orlistat treatment, AGE levels showed a statistically significant decrease in both groups (PCOS: baseline 9.08 ± 1.84, post-orlistat 8.56 ± 1.95, P = 0.001; controls: baseline 5.02 ± 0.62, post-orlistat 4.91 ± 0.69, P = 0.03), independently of the BMI reduction in the PCOS group. A significant reduction was observed in BMI (PCOS: P < 0.001; controls: P < 0.001), WHR (PCOS: P = 0.002; controls: P = 0.04), fasting insulin (PCOS: P < 0.001; controls: P = 0.008), and testosterone concentrations in PCOS (P < 0.001). SHBG concentration (PCOS: P = 0.004; controls: P = 0.008) and GIR (PCOS: P < 0.001; controls: P = 0.03) were significantly increased. A significant improvement was also observed in insulin resistance indices post-treatment in both groups. Conclusions: Our data suggest that orlistat has a beneficial effect in reducing elevated AGE levels and improving the hormonal and metabolic profile in women with PCOS after 6 months of treatment, independently of BMI changes. © 2006 The Authors

Clinical value of right hemicolectomy for appendiceal carcinoids using pathologic criteria

Background: Appendiceal carcinoids (AC) are usually adequately treated by appendectomy. The European Neuroendocrine Tumours Society (ENETS) has recently reconsidered the previous pathologic criteria to identify patients at high risk of extra-appendiceal disease, who are thought to require right hemicolectomy (RHC). Aim: The aim of this retrospective, observational study was to evaluate previous and currently introduced criteria, in identifying patients with AC in whom RHC is justified. Subjects and methods: Twelve patients who underwent RHC for AC were retrospectively identified. Demographic and follow-up data were collected and appendectomy specimens were reviewed for the presence of indications leading to RHC defined as: tumor diameter >= 2 cm, tumor location at the base, mesoappendiceal extension, mitotic index Ki-67 >= 2%. RHC specimens were examined to identify evidence of extra-appendiceal disease, remaining and/or metastatic disease. Results: Four patients fulfilled two criteria and 8 one criterion for RHC. Two patients had tumors >= 2.0 cm, 5 located at the base, 8 invading the mesoappendix and periappendiceal fat; Ki-67 PI was 1% in all cases measured except one, in which it was 3%. Post-RHC, 3 patients (25%) had extra-appendiceal disease (no residual disease was identified in surgical margins); 1 had tumor at the colon specimen and 2 had lymph node metastasis. All 3 patients fulfilled only one pathologic criterion; 1 had tumor mesoappendiceal extension and 2 tumor location at the base of the appendix. Conclusions: Applying previous and currently introduced pathologic criteria, 25% of high-risk patients with AC had identifiable extra-appendiceal disease following RHC that might be not detected following the recently introduced ENETS criteria. (J. Endocrinol. Invest. 34: 255-259, 2011) (C) 2011, Editrice Kurti

Recurrence and metastatic potential in Type 1 gastric neuroendocrine neoplasms

Background: The aim of our study was to assess clinico-pathological and biochemical parameters of Type 1 Gastric Neuroendocrine Neoplasms (GNEN1) with respect to tumours propensity for recurrence and metastasis. Methods: Hospital charts of GNEN1 patients were reviewed at a single tertiary referral centre. Results: We included 114 consecutive patients (74 women; age at baseline 54.5 ± 12.7 years [mean ± SD]) with GNEN1. All tumours (n = 114) were well differentiated; Grade 1 (G1) accounted for 56 patients (49%), whereas 46 (40%) were Grade 2 (G2) and 12 (11%) of unknown Grade. Overall follow-up encompassed 45.3 ± 46 (mean ± SD) months in 84 patients who were subjected to annual surveillance; 44 (52%) developed recurrence in the stomach during follow-up with 22 experiencing multiple recurrences; three (2.6%) presented with metastases in locoregional lymph nodes (n = 3) and/or the liver (n = 2); No metastasis or death was reported during follow-up. Median recurrence-free survival (RFS) was 31 months (95% CI: 7.6-54.4). Among clinico-pathological and biochemical parameters investigated, endoscopic intervention compared with surgery (P-value =.009) and higher serum-gastrin levels (s-gastrin) at baseline and first-year follow-up were associated with recurrence (P-value =.022 and.003 respectively) and also shorter RFS (log-rank P =.009 for type of intervention and.014 for s-gastrin, respectively). Receiver Operator Curve analysis of s-gastrin levels at first-year follow-up for recurrence demonstrated an area under the curve of 0.702. Conclusion: Despite the relatively high prevalence of G2 tumours, endoscopically and/or surgically treated GNEN1 remains an indolent disease with a low metastatic propensity and no disease-specific mortality reported in our series. Many patients though will experience local recurrence, warranting long-term endoscopic surveillance with s-gastrin biomarker being a complementary tool in recurrence prediction. © 2019 John Wiley & Sons Lt

Increased autophagy/mitophagy levels in primary tumours of patients with pancreatic neuroendocrine neoplasms

Background/aims: We assessed the levels of autophagy and mitophagy, that are linked to cancer development and drug resistance, in well differentiated pancreatic neuroendocrine neoplasms (PanNENs) and correlated them with clinico-pathological parameters. Methods: Fluorescent immunostaining for the autophagy markers LC3Β and p62/or LAMP1 was performed on 22 PanNENs and 11 controls of normal pancreatic tissues and validated through Western blotting. Autophagy quantitative scoring was generated for LC3B-positive puncta and analysed in relation to clinico-pathological parameters. TOMM20/LC3B qualitative assessment of mitophagy levels was undertaken by fluorescent immunostaining. The presence of autophagy/mitophagy was validated by transmission electron microscopy. Results: Autophagy levels (LC3B-positive puncta/cell) were discriminative for normal vs. NEN pancreatic tissue (p = 0.007). A significant association was observed between autophagy levels and tumour grade (Ki67 < 3% vs. Ki67 ≥ 3%; p = 0.021), but not functionality (p = 0.266) size (cut-off of 20 mm; p = 0.808), local invasion (p = 0.481), lymph node- (p = 0.849) and distant metastases (p = 0.699). Qualitative assessment of TOMM20/LC3B demonstrated strong mitophagy levels in PanNENs by fluorescent immunostaining as compared with normal tissue. Transmission electron microscopy revealed enhanced autophagy and mitophagy in PanNEN tissue. Response to molecular targeted therapies in metastatic cases (n = 4) did not reveal any patterns of association to autophagy levels. Conclusions: Increased autophagy levels are present in primary tumours of patients with PanNENs and are partially attributed to upregulated mitophagy. Grade was the only clinico-pathological parameter associated with autophagy scores. © 2020, The Author(s)