An international simulated-use study to assess nurses' preferences between two lanreotide syringes for patients with neuroendocrine tumours or acromegaly (PRESTO 3).

PURPOSE: PRESTO 3 evaluated nurses' preference for the Somatuline® Autogel® syringe versus the Lanreotide Pharmathen syringe after injection-pad testing. METHODS: This international simulated-use study included oncology/endocrinology nurses with ≥ 1 years' experience in managing neuroendocrine tumours (NETs) and/or acromegaly. Each nurse tested both syringes twice in a randomised order before completing an electronic survey. The primary objective was to assess overall preference (%, 95% confidence interval [CI]) for the Somatuline Autogel syringe versus the Lanreotide Pharmathen syringe. Secondary objectives included rating syringe performance and ranking the importance of syringe attributes. RESULTS: Ninety-four nurses were enrolled: mean age, 41.0 (SD, 11.5) years. The percentage of nurses stating a preference ("strong" or "slight") for the Somatuline Autogel syringe (86.2% [95% CI 77.5-92.4%]) was significantly higher than 50% (p < 0.0001). Performance rating was significantly higher for the Somatuline Autogel syringe versus Lanreotide Pharmathen syringe for 10 of the 11 attributes tested (p < 0.05). The syringe attributes considered most important when injecting patients in routine clinical practice were "easy to use from preparation to injection" (30.9%) and "comfortable to handle during use from preparation to injection" (16.0%). The attribute most commonly rated as least important was "fast administration from preparation to injection" (26.6%). CONCLUSION: Nurses strongly preferred the user experience of the Somatuline Autogel syringe over the Lanreotide Pharmathen syringe. "Ease of use" and "comfortable to handle" were the most important syringe attributes, and performance rating was significantly higher with Somatuline Autogel versus Lanreotide Pharmathen syringe for all but one attribute.

Drugs called somatostatin analogues (SSAs) can be used to treat patients with neuroendocrine tumours or acromegaly over a prolonged period of time. SSAs are given as injections and act by slowing the production of hormones by the body and in some cases reducing the growth of the tumour. To help to provide the best care possible, it is important that the syringe used for the injection is easy to use and delivers the SSA effectively. Somatuline Autogel is a syringe that can be used to inject an SSA called lanreotide. Previous studies showed that patients and nurses preferred the injection experience when using the Somatuline Autogel syringe compared with a syringe used to inject another SSA called octreotide long-acting release. A new syringe used for lanreotide injections has been developed recently by a company called Pharmathen. In the PRESTO 3 study, we compared the user experience of the Somatuline Autogel syringe and the Lanreotide Pharmathen syringe. We asked 94 nurses from Europe and the US to test both syringes, in a randomised order, using injection pads, and then to answer questions about their overall preference between the two syringes and how well the syringe performed for a set of syringe features. Overall, 86% of nurses preferred the Somatuline Autogel syringe over the Lanreotide Pharmathen syringe. Of the 11 features of the syringe that we assessed, 10 were rated higher for the Somatuline Autogel syringe than the Lanreotide Pharmathen syringe. The syringe features "ease of use" and "comfortable to handle" were considered the most important. The results of the PRESTO 3 study indicated that there is a difference in the user experience between the syringes, particularly for confidence and ease of use, and that it is important to offer syringe choices to nurses who are using SSA injections to treat patients.

Pasireotide effects on biochemical control and glycometabolic profile in acromegaly patients switched from combination therapies or unconventional dosages of somatostatin analogs.

PURPOSE: To evaluate the impact of pasireotide (PAS) therapy on hormonal and glycometabolic outcome in patients with acromegaly previously treated with combination medical therapies or unconventional dosages of first-generation somatostatin receptor ligands (fg-SRLs). METHODS: Retrospective study carried out in two referral centers for pituitary diseases. Twenty-one acromegalic patients were switched to PAS (12 had biochemical control, 9 were uncontrolled). Data were collected after 3- and 6-months PAS treatment, and at the last available visit (median 35 months). RESULTS: After switching to PAS therapy, a significant reduction in IGF-1 values was observed [median 39%; 0.79 xULN (IQR 0.5-1.01) vs 1.29 xULN (IQR 1.06-1.83); p = 0.009]. IGF-1 reduction was statistically significant in the 9 patients previously uncontrolled (61%, p = 0.016), and in the 12 controlled subjects (33%, p = 0.037). At last follow-up, the number of patients reaching an acceptable biochemical control (IGF-1 < 1.3 xULN) raised from 57 to 90% (p = 0.032). Mean HbA1c levels increased from 5.7% (5.5-5.9) to 6.0% (5.9-7) (p = 0.002), and the percentage of diabetic patients raised from 14% (3/21) to 67% (14/21) (p = 0.004). At the last evaluation HbA1c was ≥ 7.0% in 5 patients (24%). Antidiabetic drugs were initiated in 9 new patients, and in 7 out of 9 metformin alone was effective. Younger age and male sex were predictors for the maintenance of glucose homeostasis. CONCLUSION: PAS monotherapy can be effective in acromegalic patients previously treated with combination medical therapies or unconventional dosages of fg-SRLs. Glucose imbalance can be managed in the vast majority of cases by use of lifestyle interventions and metformin.

Improved overall survival in patients developing endocrine toxicity during treatment with nivolumab for advanced non-small cell lung cancer in a prospective study.

PURPOSE: Immune checkpoint inhibitors (ICPIs) disrupting PD-1/PD-L1 axis have revolutionized the management of advanced non-small cell lung cancer (NSCLC). Some studies identified the development of endocrine toxicity as predictor of better survival in cancer patients treated with ICPIs. The aim of study was to evaluate survival and new onset of immune-related endocrine adverse events (irAEs) in patients treated with nivolumab for advanced NSCLC. METHODS: In a prospective study, 73 patients with previously treated advanced NSCLC received nivolumab in monotherapy. Blood samples were collected at each cycle to monitor thyroid autoimmunity, thyroid, adrenal and somatotroph axes, while thyroid morphology was evaluated by ultrasonography. RESULTS: An impaired thyroid function was recorded in 23.4% of patients (n = 15). Eight patients developed asymptomatic transient thyrotoxicosis (ATT) evolving to hypothyroidism in 50% of cases. In addition, seven patients developed overt hypothyroidism without ATT and with negative autoantibodies. Patients who developed hypothyroidism proved to have better overall survival (OS) as compared with non-developers at both univariate (p = 0.021) and multivariate analyses (p = 0.023). The survival curve of patients with reduced IGF-I at baseline, or displaying its reduction during the follow-up, showed significantly reduced median survival compared to patients with normal/high IGF-I levels (p = 0.031). CONCLUSIONS: Thyroid function abnormalities are the major irAEs in patients treated with nivolumab, and hypothyroidism onset is associated with prolonged survival. Our findings indicate that the development of hypothyroidism is a positive predictive biomarker of nivolumab antitumor efficacy in patients with NSCLC. Low IGF-I levels could represent a negative prognostic factor during nivolumab therapy.

Disease control of acromegaly does not prevent excess mortality in the long term: results of a nationwide survey in Italy.

OBJECTIVE: This study aimed to assess the long-term outcome of patients with acromegaly. DESIGN: This is a multicenter, retrospective, observational study which extends the mean observation period of a previously reported cohort of Italian patients with acromegaly to 15 years of follow-up. METHODS: Only patients from the centers that provided information on the life status of at least 95% of their original cohorts were included. Life status information was collected either from clinical records or from the municipal registry offices. Standardized mortality ratios (SMRs) were computed comparing data with those of the general Italian population. RESULTS: A total of 811 patients were included. There were 153 deaths, with 90 expected and an SMR of 1.7 (95% CI 1.4-2.0, p < 0.001). Death occurred after a median of 15 (women) or 16 (men) years from the diagnosis, without gender differences. Mortality remained elevated in the patients with control of disease (SMR 1.3, 95% CI 1.1-1.6). In the multivariable analysis, only older age and high IGF1 concentrations at last available follow-up visit were predictors of mortality. The oncological causes of death outweighed the cardiovascular ones, bordering on statistical significance with respect to the general population. CONCLUSIONS: Mortality remains significantly high in patients with acromegaly, irrespectively of disease status, as long as the follow-up is sufficiently long with a low rate of patients lost to follow-up. Therapy strategy including radiotherapy does not have an impact on mortality. Oncological causes of death currently outweigh the cardiovascular causes.

Impact of microscopic extrathyroidal extension on differentiated thyroid cancer post-surgical risk of recurrence: a retrospective analysis.

PURPOSE: In the last edition of the American Joint Committee on Cancer (AJCC) staging system, differentiated thyroid cancers (DTC) showing microscopic extrathyroidal extension (mETE) are considered comparable to intrathyroidal cancers for their clinical behavior and prognosis. The aim of the study is to evaluate the impact of this updated assessment of T, when applied to the postoperative recurrence risk stratification, according to the American Thyroid Association Guidelines (ATA-RR). METHODS: One-hundred DTC patients who underwent total thyroidectomy were retrospectively evaluated. The downstaging of mETE was introduced in the definition of T, and the updated classification defined as modified ATA-RR (ATAm-RR). For each patient, post-surgical basal and stimulated thyroglobulin (Tg) levels, neck ultrasound (US) and post-ablative 131-I whole body scan (WBS) reports were considered. The predictive performance (PP) of disease recurrence was calculated both for each single parameter, as well as for all of them. RESULTS: According to ATAm-RR classification, 19/100 patients (19%) were downstaged. ATA-RR proved a significant PP for disease recurrence (DR) (sensitivity 75.0%, specificity 63.0%, p = 0.023). However, ATAm-RR performed slightly better due to an increased specificity (sensitivity 75.0%, specificity 83.7%, p < 0.001). For both classifications, the PP was optimal when all the above-mentioned predictive parameters were considered. CONCLUSION: Our results suggest that the new assessment of T considering mETE resulted in a downgrading of ATA-RR class in a significant number of patients. This provides a better PP for disease recurrence, and the best PP was obtained when considering the whole predictive variables together.

The effect of sodium restriction on iodine prophylaxis: a review.

PURPOSE: Sodium is essential to life. However, its dietary excess is detrimental to the cardiovascular system, and sodium restriction is a crucial step in cardiovascular prevention. Iodine deficiency has been fought worldwide for decades, and substantial success has been achieved introducing the use of iodine-enriched salt. Nevertheless, areas of iodine deficiency persist around the world, both in developing and industrialized countries, and a major concern affecting dietary sodium reduction programs is represented by a possible iodine intake deficiency. There are substantial differences in the source of alimentary iodine among countries, such as iodized salt added, household tap water, seafood, or salt employed in packaged food. It is clear that a sodium-restricted diet can induce differences in terms of iodine intake, depending on the country considered. Moreover, iodine status has undergone relevant changes in many countries in the last years. METHODS: Systematic review of literature evidence about the possible effects of sodium restriction on population iodine status. RESULTS: To date, the available results are conflicting, depending on country, salt iodization policy, as well as time frame of data collection. However, to ensure an optimal iodine supply by salt fortification, without exceeding the current recommendation by World Health Organization for salt intake, seems to be an achievable goal. CONCLUSION: A balanced approach may be obtained by an adequate iodine concentration in fortified salt and by promoting the availability of iodized salt for household consumption and food industry use. In this scenario, updated prospective studies are strongly needed.

Clinical and radiological presentation of parasellar ectopic pituitary adenomas: case series and systematic review of the literature.

PURPOSE: Parasellar ectopic pituitary adenomas (pEPAs) are extremely rare tumors located out of the sella turcica. PEPAs are heterogeneous entities in terms of anatomical localization and secretion of anterior pituitary hormones. METHODS: Multicenter retrospective study. Clinical charts' consultation of patients diagnosed with parasellar lesions, to identify all subjects fulfilling the diagnostic criteria of parasellar EPAs. Systematic review of the literature focused on the medical management of prolactin-secreting pEPAs and on the prevalence of radiological bone invasion in pEPAs. RESULTS: We identified four cases of pEPAs: (1) 54-year-old female with a prolactin-secreting suprasellar EPA successfully treated with cabergoline; (2) 74-year-old male with a non-functioning EPA of the sphenoidal sinus treated with endoscopic transsphenoidal surgery; (3) 75-year-old female with a giant lesion of the skull base (maximum diameter 7.2 cm) diagnosed as a non-functioning EPA after biopsy; (4) 49-year-old male with a silent corticotroph EPA of the sphenoidal sinus and clivus. Three out of four cases had radiological evidence of invasion of the surrounding bone structures. A systematic review of the literature highlighted that medical therapy can be effective in prolactin-secreting pEPAs. Overall, we found mention of local invasiveness in 65/147 cases (44.2%), confirmed by radiological signs of bone invasion/erosion. CONCLUSION: Our experience confirms the heterogeneity of pEPAs in terms of clinical and radiological presentation, as well as hormone secretion. PEPAs show a high frequency of radiological bone invasion, though similar to that of sellar pituitary adenomas. Although extremely rare, pEPAs need to be considered in the differential diagnosis of parasellar lesions.

PRRT: identikit of the perfect patient.

Peptide receptor radionuclide therapy (PRRT) has been strengthened since the publication of NETTER-1. Nevertheless, the correct positioning in the therapeutic algorithm is debated, and no optimal sequence has yet been standardized. Possible criteria to predict the response to PRRT in neuroendocrine tumors (NET) have been proposed. The aim of this review is to define the perfect identity of the eligible patient who can mostly benefit from this therapy. Possible predictive criteria which have been analysed were: primary tumor site, grading, tumor burden, FDG PET and 68Ga-PET uptake. Primary tumor site and 68Ga-PET uptake do not play a pivotal role in predicting the response, while tumor burden, FDG PET uptake and grading seem to represent predictive/prognostic factors for response to PRRT. The heterogeneity in trial designs, patient populations, type of radionuclides, previous therapies and measurement of outcomes, inevitably limits the strength of our conclusions, therefore care must be taken in applying these results to clinical practice. In conclusion, the perfect patient, selected by 68Ga-PET uptake, will likely have a relatively limited liver tumor burden, a ki67 index <20% and will respond to PRRT irrespective to primary tumor. Nevertheless, we have mostly prognostic than predictive factors to predict the efficacy of PRRT in individual patients, while a promising tool could be the NETest. However, to date, the identikit of the perfect patient for PRRT is a puzzle without some pieces and still we cannot disregard a multidisciplinary discussion of the individual case to select the patients who will mostly benefit from PRRT.

Safety and effectiveness of Omnitrope® in patients with growth hormone deficiency: snapshot analysis of PATRO Adults study in the Italian population.

PURPOSE: PATRO adults is an ongoing, multicenter, observational, post-marketing surveillance study aimed at investigating the long-term safety (primary endpoint) and effectiveness (secondary endpoint) of the recombinant human growth hormone (rhGH) Omnitrope® during routine clinical practice. This report describes data from Italian participants in PATRO Adults with growth hormone deficiency (GHD), up to August 2017. METHODS: Participants were adults (aged > 18 years) with GHD requiring rhGH therapy and were prescribed Omnitrope®, including those who had previously received another rhGH product. Adverse events (AEs) were evaluated in all study participants. Data were collected on insulin-like growth factor (IGF)-I levels and cardiovascular risk factors, including blood pressure, lipids, and anthropometric parameters. RESULTS: From September 2007 to August 2017, 88 patients (mean age 48.9 years, 58.0% male) were enrolled at 8 sites in Italy. The mean treatment duration with Omnitrope® was 51.5 ± 37 months. AEs occurred in 54 patients; the most common were asthenia (20.5%), headache (14.8%), and arthralgia (13.6%). Serious AEs occurred in 22 patients (25%), including pneumonia (n = 2) and renal failure (n = 2). Neoplasms (2 benign and 1 malignant) developed in three patients, but none were considered to be drug-related. There were no significant changes in fasting glucose or glycosylated hemoglobin (HbA1c) during the study period. Long-term Omnitrope® therapy showed slight positive effects on lipid profile, while no significant changes were observed in body weight and BMI during the study. CONCLUSION: This snapshot analysis of Italian participants in PATRO Adults confirmed the long-term safety and effectiveness of Omnitrope® in adults with GHD.

Impact of the SARS-CoV2 pandemic dissemination on the management of neuroendocrine neoplasia in Italy: a report from the Italian Association for Neuroendocrine Tumors (Itanet).

INTRODUCTION: The organization of the healthcare system has significantly changed after the recent COVID-19 outbreak, with a negative impact on the management of oncological patients. The present survey reports data collected by the Italian Association for Neuroendocrine Tumors on the management of patients with neuroendocrine neoplasia (NEN) during the pandemic dissemination. METHODS: A survey with 57 questions was sent to NEN-dedicated Italian centers regarding the management of patients in the period March 9, 2020, to May 9, 2020 RESULTS: The main modification in the centers' activity consisted of decreases in newly diagnosed NEN patients (- 76.8%), decreases in performed surgical procedures (- 58%), delays to starting peptide receptor radionuclide therapy (45.5%), postponed/canceled follow-up examinations (26%), and canceled multidisciplinary teams' activity (20.8%). A low proportion of centers (< 10%) reported having to withdraw systemic anti-tumor medical treatment due to concerns about the pandemic situation, whereas PRRT was withdrawn from no patients. CONCLUSION: Although the COVID-19 outbreak induced the centers to reduce some important activities in the management of NEN patients, the Italian network was able to provide continuity in care without withdrawing anti-tumor treatment for the majority of patients.

Somatostatin receptor expression and patients' response to targeted medical treatment in pituitary tumors: evidences and controversies.

BACKGROUND: Somatostatin receptors (SSTs) are widely co-expressed in pituitary tumors. SST2 and SST5 are the most represented SST subtypes. First-generation somatostatin receptor ligands (SRLs) mainly target SST2, while pasireotide, a multi-receptor ligand, shows high binding affinity for both SST5 and SST2. Therefore, SRLs are routinely used as medical treatment for GH-, TSH-, and ACTH-secreting pituitary tumors. METHODS: Critical revision of literature data correlating SST expression with patients' response to SRLs. RESULTS: SST2 expression in somatroph tumors directly correlates with GH and IGF-1 decrease after first-generation SRL treatment. SST2 immunohistochemistry represents a valuable tool to predict biochemical response to first-generation SRLs in acromegalic patients. Pasireotide seems to exert its biological effects via SST2 in unselected patients. However, in those subjects resistant to first-generation SRLs, harbouring tumors with negligible SST2 expression, pasireotide can act throughout SST5. More than somatotroph tumors, TSH-omas represent the paradigm of tumors showing a satisfactory response to SRLs. This is probably due to the high SST2 expression observed in nearly 100% of cases, as well as to the balanced amount of SST5. In corticotroph tumors, pasireotide mainly act via SST5, although there is a need for translational studies correlating its efficacy with SST expression in this peculiar tumor histotype. CONCLUSIONS: The assumption "more target receptor, more drug efficacy" is not straightforward for SRLs. The complex pathophysiology of SSTs, and the technical challenges faced to translate research findings into clinical practice, still need our full commitment to make receptor evaluation a worthwhile procedure for individualizing treatment decisions.

Arthropathy in acromegaly: a questionnaire-based estimation of motor disability and its relation with quality of life and work productivity.

PURPOSE: Arthropathy is a common and disabling complication of acromegaly. Since in this condition radiological findings rarely correspond to functional impairment, we elected to quantify in a large cohort of acromegalic patients: the degree of motor disability compared with data from general population, the impact of joint involvement on quality of life and work productivity, and to look for associated factors. METHODS: In 211 acromegalic patients, 131 with controlled disease and 80 with active disease, eight validated scales were used to evaluate the (i) prevalence and distribution of arthropathy, (ii) degree of motor disability and joint symptoms (VAS, AIMS symptoms and WOMAC), (iii) quality of life (AcroQoL and PASQ) and work capability (WPAI:GH) as consequences of joint complications. RESULTS: Using the WOMAC questionnaire, for which population based normative values are available, a significantly higher prevalence and severity of motor disability was detected in acromegalics compared to the general population from literature. The results provided by the different questionnaires turned out to be highly concordant. All measures of motor disability correlated both with impaired quality of life and motor disability and were worse in females and in patients with higher BMI. CONCLUSIONS: The questionnaires VAS, AIMS symptoms, and WOMAC (this latter both as a whole and with its functionality subscale), with their scores, proved to be the most adequate tools to evaluate motor disability and its consequences on both quality of life and work productivity in acromegaly. Female gender and higher BMI are associated with worse articular symptoms.

Analysis of characteristics and outcomes by growth hormone treatment duration in adult patients in the Italian cohort of the Hypopituitary Control and Complications Study (HypoCCS).

PURPOSE: To examine differences in effects according to growth hormone (GH) treatment duration in adult GH-deficient patients. METHODS: In the Italian cohort of the observational Hypopituitary Control and Complications Study, GH-treated adults with GH deficiency (GHD) were grouped by duration of treatment; ≤ 2 years (n = 451), > 2 to ≤ 6 years (n = 387) and > 6 years (n = 395). Between-group differences in demographics, medical history, physical characteristics, insulin-like growth factor-I standard deviation score (IGF-I SDS) and lipid profile at baseline, last study visit and changes from baseline to last study visit were assessed overall, for adult- and childhood-onset GHD and by gender using ANOVA for continuous variables and Chi-squared test for categorical variables. RESULTS: At baseline, treatment duration groups did not differ significantly for age, gender, body mass index, GHD onset, IGF-I SDS, lipid profile, and quality of life. Mean initial GH dose did not differ significantly according to treatment duration group in any subgroup, except female patients, with highest mean dose seen in the longest duration group. In the longest duration group for patients overall, adult-onset patients and male patients, there were significant decreases in GH dose from baseline to last visit, and in total and low-density lipoprotein (LDL)-cholesterol concentrations. IGF-I SDS increased, to a greater extent, in the longest duration group for patients overall and female patients. CONCLUSIONS: The results show that long-term GH treatment is associated with decreasing GH dose, increased IGF-I, decreased LDL-cholesterol and the presence of surrogate markers that help to give confidence in a diagnosis of GHD.

Long-term safety and efficacy of Omnitrope® in adults with growth hormone deficiency: Italian interim analysis of the PATRO Adults study.

PURPOSE: To report the long-term effectiveness and safety of the recombinant human growth hormone Omnitrope®, a somatropin biosimilar to Genotropin®, in Italian patients with growth hormone deficiency (GHD) enrolled in the PATRO Adults study. METHODS: The PATRO Adults study is an ongoing observational, longitudinal, non-interventional global post-marketing surveillance study, conducted in several European countries. The primary endpoint is long-term safety; secondary endpoints include the effectiveness of Omnitrope®, which was assessed using serum insulin-like growth factor-1 levels, body composition, bone mineral density and lipid levels. Here we report the data from the Italian patients enrolled in the study. RESULTS: Sixty-seven patients (mean age 50.4 years, 61.2% male) have been enrolled and have received a mean 45.4 ± 24.3 months of Omnitrope®. A total of 55.2% of patients were reported to have experienced adverse events (AEs), including arthralgia, myalgia, abdominal distension and hypoaesthesia, and 4.5% had adverse drug reactions. Fourteen serious AEs have been recorded; none of these are considered related to the study drug. The effectiveness of Omnitrope® was similar to other available somatropin preparations. CONCLUSIONS: This study confirms the effectiveness and safety of Omnitrope® in adult patients with GHD in Italy. However, due to the limited size of the study population, these results need to be further confirmed by the global PATRO Adults study.

Anti-tumoral effects of somatostatin analogs: a lesson from the CLARINET study.

Octreotide and lanreotide, the first-generation somatostatin analogs, successfully control hormone hyperproduction, and related syndromes, in patients with acromegaly and neuroendocrine tumors. However, their anti-tumor effect, rather evident in large number of pituitary adenomas in acromegalic patients, has been hypothesized for a long time in patients with neuroendocrine tumors as well, although a significant tumor shrinkage has rarely been observed. However, the recent publication of the CLARINET study has strengthened the evidence, already emerged with the PROMID trial, that the long-term treatment with the first-generation long-acting somatostatin analogs may exert an anti-tumor activity on G1 and G2 enteropancreatic neuroendocrine tumors, as well. After the publication, majority of international guidelines have updated their algorithms in line with these results and this class of drugs obtained the indication as anti-tumor agents in the majority of patients with neuroendocrine tumors.

Rare diseases in clinical endocrinology: a taxonomic classification system.

PURPOSE: Rare endocrine-metabolic diseases (REMD) represent an important area in the field of medicine and pharmacology. The rare diseases of interest to endocrinologists involve all fields of endocrinology, including rare diseases of the pituitary, thyroid and adrenal glands, paraganglia, ovary and testis, disorders of bone and mineral metabolism, energy and lipid metabolism, water metabolism, and syndromes with possible involvement of multiple endocrine glands, and neuroendocrine tumors. Taking advantage of the constitution of a study group on REMD within the Italian Society of Endocrinology, consisting of basic and clinical scientists, a document on the taxonomy of REMD has been produced. METHODS AND RESULTS: This document has been designed to include mainly REMD manifesting or persisting into adulthood. The taxonomy of REMD of the adult comprises a total of 166 main disorders, 338 including all variants and subtypes, described into 11 tables. CONCLUSIONS: This report provides a complete taxonomy to classify REMD of the adult. In the future, the creation of registries of rare endocrine diseases to collect data on cohorts of patients and the development of common and standardized diagnostic and therapeutic pathways for each rare endocrine disease is advisable. This will help planning and performing intervention studies in larger groups of patients to prove the efficacy, effectiveness, and safety of a specific treatment.

Treatment of advanced BP-NETS with lanreotide autogel/depot vs placebo: the phase III SPINET study.

Prospective data are lacking on early somatostatin analog (SSA) therapy in bronchopulmonary neuroendocrine tumors (BP-NETs; typical carcinoids and atypical carcinoids (TCs and ACs)). SPINET (EudraCT: 2015-004992-62; NCT02683941) was a phase III, double-blind study of lanreotide autogel/depot (LAN; 120 mg every 28 days) plus best supportive care (BSC) vs placebo plus BSC, with an optional open-label treatment phase (LAN plus BSC). Patients had metastatic/unresectable, somatostatin receptor (SSTR)-positive TCs or ACs. Recruitment was stopped early owing to slow accrual; eligible patients from the double-blind phase transitioned to open-label LAN. The adapted primary endpoint was progression-free survival (PFS) during either phase for patients receiving LAN. Seventy-seven patients were randomized (LAN, n = 51 (TCs, n = 29; ACs, n = 22); placebo, n = 26 (TCs, n = 16; ACs, n = 10)). Median (95% CI) PFS during double-blind and open-label phases in patients receiving LAN was 16.6 (11.3; 21.9) months overall (primary endpoint), 21.9 (12.8, not calculable (NC)) months in TCs, and 13.8 (5.4; 16.6) months in ACs. During double-blind treatment, median (95% CI) PFS was 16.6 (11.3; 21.9) months for LAN vs 13.6 (8.3; NC) months for placebo (not significant); corresponding values were 21.9 (13.8; NC) and 13.9 (13.4; NC) months, respectively, in TCs and 13.8 (5.4; 16.6) and 11.0 (2.8; 16.9) months, respectively, in ACs. Patients' quality of life did not deteriorate and LAN was well tolerated. Although recruitment stopped early and the predefined sample size was not met, SPINET is the largest prospective study to date of SSA therapy in SSTR-positive TCs and ACs and suggests clinical benefit in TCs.

Low somatostatin receptor subtype 2, but not dopamine receptor subtype 2 expression predicts the lack of biochemical response of somatotropinomas to treatment with somatostatin analogs.

OBJECTIVES: To evaluate somatostatin receptor 2A (SSTR2A) and dopamine receptor 2 (DR2) protein expression in somatotropinomas and to relate it to response to somatostatin analogues (SA). DESIGN AND PATIENTS: SSTR2A and DR2 expression was analyzed by immunohistochemistry in 88 somatotropinomas from patients submitted to either pre-surgical or adjuvant SA treatment. Tumors were scored according to percentage of immunostained cells: 0 (< 25%), 1 (25-50%), and 2 (> 50%). Relation between protein expression and response to SA was performed in 66 patients. Response to SA was assessed by percent IGF-I reduction, being considered as an IGF-I per cent reduction higher than 50%. Disease control was also assessed (GH < 1.0 ng/ml and normal IGF-I). RESULTS: SSTR2A and DR2 were expressed in 100% and 98% of tumors, respectively. Biochemical response and disease control rates were 48% and 32%, respectively. Median IGF-I percent reduction after 3 months of SA treatment was lower in the SSTR2A score 0 than in the scores 1 and 2 (p < 0.001, both), and after 6 months in the score 0 than in the score 1 (p = 0.001) and 2 (p < 0.001). Biochemical response and disease control were associated with SSTR2 expression (p < 0.001 and p = 0.004, respectively). A negative predictive value for biochemical response of 100% was found when a SSTR2A expression < 25%of immunostained cells cut-off point was considered. No relation was found between DR2 expression and biochemical response and disease control. CONCLUSION: SSTR2A and DR2 are highly expressed in somatotropinomas. Low SSTR2A, but not DR2, expression is a negative predictive factor to response to SA.