Clinical and biochemical outcomes after adrenalectomy for primary aldosteronism in tertiary and quaternary referral centers: data from SOPRANO study.

Hypertension cure following adrenalectomy in unilateral primary aldosteronism (PA) remains uncertain. Previous meta-analyses have shown highly variable surgical outcomes. Our study aimed to determine the unknown proportion of complete clinical and biochemical success in tertiary and quaternary referral centers. We conducted a systematic review and meta-analysis of studies reporting surgical outcomes of unilateral PA patients within the Surgical Outcome of PRimary Aldosteronism progNostic mOdels (SOPRANO) study. From 27 publications we identified 32 eligible studies, of which 22 were judged to be at low risk of bias. Eighteen were single-center studies, while fourteen were multi-center studies, with patients recruited from 132 referral centers worldwide. Adrenalectomy was performed on 5887 patients, with 4861 (83%) included in the final analysis. The pooled estimates of complete clinical and biochemical success for all studies were 39% (95% CI: 34-44%) and 99% (95% CI: 96-99%), respectively, similar to that found for studies at low risk of bias. Multivariate meta-regression analyses for all studies and low-bias risk studies revealed that BMI (P < 0.01), recruitment time period (P < 0.01), and hypertension duration (P < 0.05) inversely correlated with complete clinical success, while BMI (P < 0.05) and the number of enrolled centers (P < 0.05) inversely correlated with complete biochemical success. In summary, our findings offer robust estimates of complete clinical and biochemical success rates following adrenalectomy for unilateral PA in tertiary and quaternary referral centers and identify new potential effect modifiers that can help clinicians to inform and counsel patients about post-surgery expectations, guaranteeing effective treatment and ultimately enhancing outcomes.

Treatment of a Severe Form of Euglycemic Ketoacidosis in a Patient Treated with SGLT-2 Inhibitors with the Aid of Somatostatin.

Currently, the use of SGLT2 inhibitors is becoming more widespread, both for their role in controlling diabetes, and for their pleiotropic effects on glomerular hyperfiltration and heart failure. Along with their positive effects, these drugs can lead to various complications, the most severe being euglycemic ketoacidosis. The clinical case we have reported precisely describes this potentially serious complication which occurred in a 47-year-old patient who had been on SGLT2 inhibitor therapy for 5 years. In the resolution of this case we used, in addition to standard therapy, the continuous infusion of somatostatin, resulting in a rapid resolution of ketoacidosis and an improvement in the clinical condition.

Prognostic models to predict complete resolution of hypertension after adrenalectomy in primary aldosteronism: A systematic review and meta-analysis.

Complete resolution of hypertension (CRH) after adrenalectomy for primary aldosteronism is far from a certainty. Although several prognostic models have been proposed to predict outcome after adrenalectomy, studies have not clarified which of the available models can be used reliably in clinical practice. To identify, describe and appraise all prognostic models developed to predict CRH, and meta-analyse their predictive performances. We searched MEDLINE, Embase and Web of Science for development and validation studies of prognostic models. After selection, we extracted descriptive statistics and aggregated area under the receiver operator curve (AUC) using meta-analysis. From 25 eligible studies, we identified 12 prognostic models used for predicting CRH after total adrenalectomy in primary aldosteronism. We report the results for 3 models that had available data from at least 3 external validation studies: the primary aldosteronism surgical outcome (PASO) score (AUC: 0.81; 95% confidence interval [CI]: 0.74-0.86; 95% predictive interval [PI]: 0.04-1.00), Utsumi nomogram (AUC: 0.79; 95% CI: 0.72-0.85; 95% PI: 0.03-1.00) and the aldosteronoma resolution score (ARS) model (AUC: 0.77; 95% CI: 0.74-0.80; 95% PI: 0.59-0.86 for all studies and AUC: 0.80; 95% CI: 0.75-0.85; 95% PI: 0.57-0.93 for the studies with the same adrenal vein sampling-guided adrenalectomy rate compared to the models meta-analysed). The PASO score, Utsumi nomogram and ARS model showed comparable discrimination performance to predict CRH in primary aldosteronism. Unlike the ARS model, the number of external validation studies for the PASO score and the Utsumi nomogram was relatively low to draw definite conclusions.

Assessment of performance of stratum-specific likelihood ratios of the aldosteronoma resolution score for predicting hypertension cure after adrenalectomy for primary aldosteronism: a systematic review and meta-analysis.

The Aldosteronoma Resolution Score (ARS) is the most studied scoring system for predicting the high likelihood of hypertension cure after adrenalectomy for unilateral primary aldosteronism (PA). However, the ARS's accuracy in PA patients worldwide is uncertain. We aimed to perform a meta-analysis of the accuracy, discrimination, and calibration of the ARS using stratum-specific likelihood ratios (SSLR) by organizing available data from cohort studies. We searched PubMed, Embase (Ovid), the Cochrane CENTRAL, Web of Science to November 2021 according to PRISMA statement. The quality assessment used adapted TRIPOD and PROBAST criteria. Thirteen studies comprising 2158 PA patients from North America (43%), Europe (32%), Asia (22%), and other continents, were included. The pooled estimate of the area under the receiver operating characteristic curve for all studies was 0.77 (95% CI: 0.73-0.81), and the ratio of the observed to expected complete resolution of hypertension (CRH) for all studies was 0.9 (95% CI: 0.8-1.0). The summary estimates of the SSLR for all studies were 0.31, 0.89, and 3.1, for the low (ARS 0-1), medium (ARS 2-3), and high-likelihood group (ARS 4-5) of CRH, respectively. However, substantial heterogeneity existed among studies. Follow-up period, and adrenalectomy AVS (adrenal vein sampling)-guided served as potential sources of heterogeneity for quantitative studies, which were measurement and reference standard for qualitative studies selection. In conclusion, in patients with unilateral PA, the ARS is currently an accurate prediction tool, the easiest and cheapest, for identifying long-term high likelihood of CRH after adrenalectomy, particularly when the adrenalectomy is AVS-guided.

Adrenalectomy is comparable with medical treatment for reduction of left ventricular mass in primary aldosteronism: meta-analysis of long-term studies.

BACKGROUND: Primary aldosteronism (PA) is associated with an increase in left ventricular (LV) mass beyond the amount needed to compensate the hypertension-related workload. Available evidence suggests effectiveness of surgical treatment of PA in decreasing LV mass, whereas data on medical treatment are controversial. We have conducted a meta-analysis of long-term follow-up studies on surgical and medical treatment of PA to compare the effects of treatments on LV mass. METHODS: Medline and Cochrane searches were performed including the following words: hyperaldosteronism, left ventricular mass, mineralocorticoid receptor antagonists, surgery, adrenalectomy, and follow-up studies. Studies published within 2013 focusing on cardiac effects of treatment and follow-up longer than 6 months were selected. Data extraction was performed independently by 2 authors. RESULTS: Of 61 retrieved articles, 4 were included in the analysis. These studies enrolled 355 patients with PA who had an average follow-up of 4.0 years after unilateral adrenalectomy (n = 178) or treatment with mineralocorticoid receptor antagonists (n = 177). Despite greater effect of surgery over medical treatment in reducing blood pressure, meta-analysis of the selected studies demonstrated no significant difference in LV mass change between patients with PA who were treated with mineralocorticoid receptor antagonists or adrenalectomy (standard mean difference = 0.130; 95% confidence interval = -0.085 to 0.345; P = 0.24; I2 = 0%). CONCLUSIONS: Available evidence indicates that reduction of LV mass is not different in PA patients treated with adrenalectomy or mineralocorticoid receptor antagonists.

Relationships of plasma lipoprotein(a) levels with insulin resistance in hypertensive patients.

BACKGROUND: Lipoprotein(a) [Lp(a)] is an emergent cardiovascular risk factor that is related to the presence and severity of cardiovascular damage in hypertensive patients. In these patients, insulin resistance is frequently detected but its relationship with plasma Lp(a) is not clear. The aim of this study was to examine the relationships between Lp(a) and variables of glucose metabolism in hypertension. METHODS: In 527 consecutive, non-diabetic, middle-aged hypertensive patients we measured anthropometric indexes, 24-hour creatinine clearance, lipid profile including Lp(a) levels, fasting glucose, insulin and C-peptide, and calculated the Homeostatic Model Assessment (HOMA) index. RESULTS: Lp(a) levels were significantly and progressively lower with increasing HOMA-index values. Lp(a) was inversely related to fasting glucose, insulin, and C-peptide, HOMA-index, and creatinine clearance and directly related to LDL-cholesterol. Multiple regression analysis adjusted for age, sex, body mass index, blood pressure, smoking habit, alcohol intake, renal function, lipid profile, history of cardiovascular events, and drug use showed that HOMA-index and creatinine clearance were inversely and independently associated to Lp(a) levels. CONCLUSIONS: Insulin resistance and higher fasting insulin levels are associated with lower plasma Lp(a) in hypertensive patients. This association might be relevant in the assessment of cardiovascular risk in these patients.

Open versus endoscopic adrenalectomy in the treatment of localized (stage I/II) adrenocortical carcinoma: results of a multiinstitutional Italian survey.

BACKGROUND: We compared the oncologic effectiveness of open adrenalectomy and endoscopic adrenalectomy in the treatment of patients with localized adrenocortical carcinoma. METHODS: One hundred fifty-six patients with localized adrenocortical carcinoma (stage I/II) who underwent R0 resection were included in an Italian multiinstitutional surgical survey. They were divided into 2 groups based on the operative approach (either conventional or endoscopic). RESULTS: One hundred twenty-six patients underwent open adrenalectomy and 30 patients underwent endoscopic adrenalectomy. The 2 groups were well matched for age, sex, lesion size, and stage (P = NS). The mean follow-up time was similar for the 2 groups (P = NS). The local recurrence rate was 19% for open adrenalectomy and 21% for endoscopic adrenalectomy, whereas distant metastases were recorded in 31% of patients in the conventional adrenalectomy group and 17% in the endoscopic adrenalectomy group (P = NS). The mean time to recurrence was 27 ± 27 months in the conventional open adrenalectomy group and 29 ± 33 months in the endoscopic adrenalectomy group (P = NS). No significant differences were found between the 2 groups in terms of 5-year disease-free survival (38.3% vs 58.2%) and 5-year overall survival rates (48% vs 67%; P = NS). CONCLUSION: The operative approach does not affect the oncologic outcome of patients with localized adrenocortical carcinoma, if the principles of surgical oncology are respected.

Adrenocortical carcinoma: effect of hospital volume on patient outcome.

PURPOSE: Optimal management of adrenocortical carcinoma (ACC) involves a detailed diagnostic workup, radical surgery, and appropriate adjuvant therapy. However, due to the rarity of this disease, adequate expertise is necessary to ensure optimal patient care. We evaluated if the experience of a treating center influences the outcome of ACC. METHODS: Two hundred sixty-three patients who underwent adrenalectomy for ACC were included in a multi-institutional surgical survey and divided into 2 groups: "high-volume center" (HVC) (≥10 adrenalectomies for ACC) and "low-volume center" (LVC) (<10 adrenalectomies for ACC). A comparative analysis was performed. RESULTS: One hundred seventy-two patients underwent adrenalectomy at HVC and 91 at LVC. The two groups were homogeneous for age, sex, clinical presentation, and stage. The mean lesions size of ACC was higher in HVC than in LVC (104.1 ± 54.6 vs 82.8 ± 41.3 mm; P < 0.001). A significantly higher rate of lymph node dissection (P < 0.01) and of multiorgan resection (P < 0.01) was accomplished in HVC. The number of patients who underwent adjuvant therapy was significantly higher in HVC (P < 0.001). Local recurrence rate was lower in patients treated at HVC (6% vs 18.5%; P = NS). Mean time to recurrence was significantly longer in HVC than in LVC (25.2 ± 28.1 vs 10.1 ± 7.5; P < 0.01). CONCLUSION: The expertise of dedicated centers had a positive impact on the outcome of patients with ACC, resulting in a lower recurrence rate and improved mean time to recurrence. The improved patient outcome could be related not only to the appropriateness of the surgical procedure, but also to a more adequate multidisciplinary approach.

Adrenal incidentalomas in the laparoscopic era and the role of correct surgical indications: observations from 255 consecutive adrenalectomies in an Italian series.

BACKGROUND: The purpose of our study was to evaluate the impact of laparoscopic adrenalectomy on patients with incidentalomas. We analyzed the results of a multi-centre trial that was performed to evaluate the effectiveness of imaging (computed tomography and magnetic resonance imaging) to obtain a correct preoperative diagnosis. METHODS: We obtained our data from the results of a questionnaire that was distributed by mail or email in May 2005 to several surgical units operating in the Campania Region, Italy. Lap Club, a collaborative laparoscopic surgery study group founded in Naples in 1995, distributed the questionnaire. Thirteen centres participated in the audit. In all, we analyzed 255 adrenalectomies performed on 250 patients. We performed statistical analysis using SPSS software. RESULTS: The distribution of pathologic findings demonstrates that the number of lesions caused by cancer discovered from a preoperative indication of incidentaloma has been even smaller (1/114, 0.8%) than the previous numbers reported in the literature. Moreover, whereas most patients with adrenal cancer had lesions larger than 6 cm (7/8, 87.5%), the majority of patients with adrenal metastases had lesions 6 cm or smaller (10/12, 83.3%). Different indications for adrenalectomy emerged on comparison of endocrine surgery units with general surgery units. This difference appears to be significant (p < 0.001), especially on evaluation of the number of nonfunctioning adenomas and the number of endocrine lesions that were observed and treated. CONCLUSION: Laparoscopy remains the gold standard method for adrenalectomy, but its availability must not obligate physicians to treat with surgery when an incidentaloma is detected through imaging. Adrenal malignancies when metastatic are often 6 cm or smaller. If they are single and they originated from a non-small lung cancer, they must be removed. The endocrine surgery unit remains the best setting to evaluate and treat adrenal gland surgical pathology.

Stricter criteria increase the validity of a quick intraoperative parathyroid hormone assay in primary hyperparathyroidism.

BACKGROUND: A "quick" intraoperative parathyroid hormone (PTH) (QPTH) assay evaluates parathyroid hypersecretion during parathyroidectomy. We investigated the likelihood of increasing surgical success rates by introducing stricter parameters in intraoperative PTH monitoring. MATERIAL/METHODS: One hundred one patients with sporadic primary hyperparathyroidism were studied. Intraoperative plasma intact PTH (iPTH) levels were measured with a modified 2-site antibody immunochemiluminometric assay. iPTH values were determined before the manipulation of parathyroid tissue (t-10') and then 3 (t+3') and 10 (t+10') minutes after resection of the suspected pathologic parathyroid gland(s). RESULTS: The median (interquartile range) baseline iPTH level was 259.6 (536) ng/L at t-10' and 64.1 (139.5) ng/L at t+10'. At t+3' and t+10', the median percentage decrease of iPTH from baseline was 56.1% and 77.3%, respectively. In 7 patients, the iPTH level decreased very slowly, and in patients with a double adenoma, an initial increase in the iPTH level occurred because of considerable manipulation during surgery. Despite a decrease of about 50% in iPTH level, persistent hyperparathyroidism was identified after a few months in 2 patients with a multiglandular pathologic condition in which a relatively larger parathyroid "masked" the hyperactivity of other parathyroid glands. CONCLUSIONS: A QPTH is useful during parathyroidectomy. A decrease in the iPTH level of > or =70% from baseline indicates a successful operation and reduces the likelihood of false-positive results. The evaluation of more than 1 PTH level is required if multiglandular disease is suspected or excessive intraoperative manipulation occurs.

Italian audit on therapy of hypertension in chronic kidney disease: the TABLE-CKD study.

A large body of evidence supports the validity of decreasing blood pressure to target levels in patients with essential hypertension to prevent cardiovascular disease. This issue becomes even more critical in chronic kidney disease because of the remarkably greater risk for cardiovascular fatal and nonfatal events. Indeed, renal patients should maintain blood pressure levels less than those suggested for the general population. Paradoxically, management of hypertension in this high-risk patient population is far from optimal and certainly worse with respect to essential hypertension. The Target Blood Pressure Levels in Chronic Kidney Disease (TABLE-CKD) study, performed in Italian patients with mild to advanced chronic kidney disease regularly followed-up by nephrologists, has shown that the prevalence of patients at target blood pressure is less than 20%. The assessment of antihypertensive strategy in these patients, however, suggests that there is room for improvement; in particular, a more aggressive treatment of volume expansion may ameliorate hypertension control in this population characterized by a high salt sensitivity of blood pressure.

Fibronectin-induced proliferation in thyroid cells is mediated by alphavbeta3 integrin through Ras/Raf-1/MEK/ERK and calcium/CaMKII signals.

We recently demonstrated in an immortalized thyroid cell line that integrin stimulation by fibronectin (FN) simultaneously activates two signaling pathways: Ras/Raf/MAPK kinase (Mek)/Erk and calcium Ca2+/calcium calmodulin-dependent kinase II (CaMKII). Both signals are necessary to stimulate Erk phosphorylation because CaMKII modulates Ras-induced Raf-1 activity. In this study we present evidence that extends these findings to normal human thyroid cells in primary culture, demonstrating its biological significance in a more physiological cell model. In normal thyroid cells, immobilized FN-induced activation of p21Ras and Erk phosphorylation. This pathway was responsible for FN-induced cell proliferation. Concurrent increase of intracellular Ca2+ concentration and CaMKII activation was observed. Both induction of p21Ras activity and increase of intracellular Ca2+ concentration were mediated by FN binding to alphavbeta3 integrin. Inhibition of the Ca2+/CaMKII signal pathway by calmodulin or CaMKII inhibitors completely abolished the FN-induced Erk phosphorylation. Binding to FN induced Raf-1 and CaMKII to form a protein complex, indicating that intersection between Ras/Raf/Mek/Erk and Ca2+/CaMKII signaling pathways occurred at Raf-1 level. Interruption of the Ca2+/CaMKII signal pathway arrested cell proliferation induced by FN. We also analyzed thyroid tumor cell lines that displayed concomitant aberrant integrin expression and signal transduction. These data confirm that integrin activation by FN in normal thyroid cells generates Ras/Raf/Mek/Erk and Ca2+/CaMKII signaling pathways and that both are necessary to stimulate cell proliferation, whereas in thyroid tumors integrin signaling is altered.

Andrenocortical carcinomas: twelve-year prospective experience.

Adrenocortical carcinoma (AC) is a rare tumor with poor prognosis. Twenty-two patients (14 F, 8 M; age 22 to 59 years; median, 43 years) with AC were evaluated prospectively in a single center: tumor stage was I-II in 12 cases and III-IV in 10. The overall survival in our cohort was 41.6 +/- 42 months; 16 subjects are still alive. Curative surgery was followed by longer survival than debulking or no surgery (p < 0.0001). The first relapse was highly predictive for further recurrences. Recurrent ACs were progressively more aggressive, and they occurred with variable but ever shorter intervals. At diagnosis, 14 patients (63.5%) presented with features of clear adrenocortical hyperactivity. Despite the absence of clinical signs of hormonal excess, all other patients presented some abnormalities of steroid secretion. The most common clinical finding was a recent diagnosis of moderate-to-severe hypertension (68%), poorly controlled by pharmacological treatment, often associated with multiple cardiovascular risk factors. High mitotic rate and undifferentiated polymorph cellular pattern were associated with worse prognosis. Response to treatments other than surgery (mitotane chemotherapy) was better in patients treated early after the first surgery. In conclusion, curative surgery was the most effective treatment. Monitoring arterial pressure, endocrine parameters, and metabolic parameters can be helpful for the early detection of AC recurrences.

Changes of serum albumin and C-reactive protein are related to changes of interleukin-6 release by peripheral blood mononuclear cells in hemodialysis patients treated with different membranes.

Protein malnutrition, a condition associated with an albumin concentration less than 3.5 g/dL, has been shown to be a major risk factor for increased mortality in hemodialysis patients. The aim of this cross-over study was to evaluate the relationship between the type of membrane adopted and serum albumin changes by measuring peripheral blood mononuclear cells (PBMC) interleukin-6 (IL-6) release, serum albumin, and plasma concentrations of C-reactive protein (CRP) in 18 patients dialyzed with different membranes. During the study, all patients were dialyzed with cuprophan (CU), synthetically modified cellulosic (SMC) membrane (a new cellulosic membrane with lesser complement activation), and cellulose diacetate (CD) membrane, and have served as their own controls. IL-6 spontaneous release by PBMC resulted after 3 months of SMC (436.2 +/- 47.4 pg/mL) significantly (P < 0.05) reduced as compared with CU (569.3 +/- 24.5 pg/mL). This effect was more evident after 6 months of dialysis with SMC (220 +/- 35.3 pg/mL, P < 0.01 versus CU and versus 3 months of SMC). The passage to CD membrane was followed by a progressive new increase in the IL-6 PBMC release (332.3 +/- 30.7 after 3 months, and 351.2 +/- 35.8 pg/mL after 6 months, respectively) that, however, remained significantly (P < 0.05) lower than CU. The behavior of CRP plasma levels resembled that of IL-6 PBMC release (23.3 +/- 4.7 in CU, 11.0 +/- 2.1 after 3 months in SMC, and 7.9 +/- 1.5 after 6 months in SMC, respectively). IL-6 release values were positively correlated with circulating levels of CRP (r = 0.3264, P < 0.002). Serum albumin increased after 6 months of dialysis with SMC membranes (3.25 +/- 0.09 g/dL in CU and 3.64 +/- 0.07 g/dL in SMC, P < 0.05). When the patients were switched to CD, serum albumin showed a slight, though not statistically significant, decrease. Serum albumin concentrations negatively correlated with both IL-6 release values (r = -0.247, P < 0.05) and CRP plasma levels (r = -0.433, P < 0.001). In conclusion, our data clearly show that a significant relationship exists between biocompatibility of the membranes and serum albumin changes; serum albumin levels, in fact, are negatively correlated with the PBMC spontaneous IL-6 release values and CRP circulating levels.