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Abstract Background Over the past decade, numerous treatment options have emerged for patients with locally advanced and metastatic neuroendocrine tumours (NETs). Nevertheless, the optimal timing of treatment interventions remains uncertain, given the highly variable disease course observed in these patients, even when patients have the same tumour stage and grade. The aim of the study was to evaluate the predictive role of standardized uptake values (SUVs) and volumetric parameters obtained from pretreatment [68Ga]Ga-DOTA-TATE for response to SSA therapy in patients with NET. In this retrospective study, we included 42 patients (21 women, 21 men; age range: 46–84 years) with histologically confirmed, metastatic, NET (G1 13, G2 28 cases); median Ki-67 index 5%, range 1–16) who received long acting SSA as a first line treatment and underwent [68Ga]Ga-DOTA-TATE PET/CT before SSA treatment. For all [68Ga]Ga-DOTA-TATE avid lesion SUVmax, SUVmean, somatostatin receptor expression tumour volume (STV), total lesion somatostatin receptor expression (TLD, STV multiplied by SUV mean) and Tmean/Smean (SUVmean of tumours/metastases divided by SUVmean of normal spleen) were measured. Finally, the sum of STV (total STV, TSTV) and TLD (total TLD, TTLD) was calculated for each patient and used in the analysis. Results During the study period, 14 patients had stable disease (33.3%) and 28 patients experienced progression (66.7%), among whom 12 patients died. The median progression-free survival (PFS) and overall survival (OS) were 26.5 and 46.5 months, respectively. In the univariate and multivariate analysis, in the whole population study, Tmean/Smean ratio (HR 1.88, 95% CI 1.06–3.35, p = 0.03), Ki-67 index (HR 1.14, CI 1.03–1.26, p = 0.01) and pre-treatment chromogranin A serum concentration (HR 1.01, CI 1.0–1.03, p = 0.01) were significantly associated with PFS. Among patients with small intestinal NETs, TSTV (

Objective: Cushing’s syndrome (CS) is associated with an 18-fold greater risk of venous thromboembolism (VTE). We aimed to identify factors which provoke VTE among patients with CS and VTE and to describe the anticoagulant regimen used in these cases. Methods: In this retrospective observational study, patients included in the European Registry on CS (ERCUSYN) in Krakow center, Poland, were followed for the occurrence of VTE and anticoagulant treatment. We identified factors provoking VTE according to the International Society of Thrombosis and Hemostasis (ISTH), along with factors included in the Padua score and CS-VTE score. Results: Of the 128 patients followed for a median of 4.3 years, there were nine patients who experienced ten VTE episodes (prevalence of 7.8% and incidence of 13.4 per 1000 patient-years). All VTEs were classified as provoked according to the ISTH guidance, predominantly due to the transient major and minor (50% and 20%, respectively) factors, while they were less commonly due to persistent (30%) factors. In 2/9 patients, we could not identify any risk factor for VTE according to the Padua score, while in 2/6 patients according to the CS-VTE score. Patients were mostly anticoagulated with vitamin K antagonists (4/8 patients), followed by direct oral anticoagulants (3/8) and low-molecular-weight heparin (1/8). The median duration of anticoagulation was 2.75 years and exceeded beyond the primary treatment in 28% of episodes provoked by transient factors. Conclusion: Further, multicenter studies are required to create a validated thrombotic risk score and guidelines regarding VTE treatment in CS patients.

IntroductionThe T2-signal intensity (SI) of somatotroph pituitary neuroendocrine tumors (sPitNET) is associated with treatment response and granulation pattern. Our aim was to evaluate SI assessment methods and their clinical implications, including responsiveness to preoperative first-generation somatostatin analogs (SSA).MethodsThis single-center, observational study included unselected, consecutive patients with newly diagnosed acromegaly. Out of 109 treatment-naïve patients, 69 were eligible. The qualitative Visual Method involved a visual comparison of the sPitNET with the temporal gray matter. The Three Tissue Method compared the quantified SI of the sPitNET, temporal white matter, and gray matter. The signal intensity ratio of the sPitNET vs. gray matter (GM-SIR) was calculated. Tumors were divided into three groups: hyperintense (HYPER), isointense (ISO), and hypointense (HYPO) according to the Visual Method, Three Tissue Method, and GM-SIR. These groups were compared in terms of demographic, radiological, and biochemical features. The SI assessment methods were investigated for their ability to predict preoperative SSA responsiveness.ResultsSI assessment methods classified SI type correspondingly in 58-75.4% of cases. ISO constituted 39-49% of the analyzed sPitNETs. All methods identified significant differences in tumor volume between the SI groups, with HYPO being more biochemically active per tumor volume unit. According to the Three Tissue Method, patients with ISO had the youngest age at diagnosis and onset. According to the Visual Method, ISO had a lower chance of achieving insulin-like growth factor 1 (IGF1) normalization compared to HYPO (odds ratio (OR) 0.089, confidence interval (CI) 0.015-0.538, p= 0.008)), with no differences between HYPER and HYPO. Only the Visual Method predicted the IGF1 normalization after SSA. HYPER and ISO sPitNETs were classified in electron microscopy as both densely and sparsely granulated. Bihormonal tumors presented only as HYPO and ISO. According to the Three Tissue Method, no HYPO was diagnosed with sparse granulation.DiscussionWe demonstrated discrepancies between the SI assessment methods. The Visual Method predicted the outcome of preoperative treatment with SSA. Clinically, ISO behaved similarly to HYPER. Further studies are needed to unify SI assessment and improve its clinical applicability in acromegaly.

Objective: Amiodarone is an iodine-rich molecule and an effective antiarrhythmic drug. It is a first-line treatment for patients with life-threatening ventricular arrhythmias and for prevention in patients at high risk. The use of amiodarone may cause serious adverse effects such as pharmacotherapy-resistant, life-threatening amiodarone-induced thyrotoxicosis (AIT)leading to rapid deterioration of the patient's condition.According to the European Thyroid Association (ETA) guidelines, emergency thyroidectomy is the first-line treatment option in these cases. ; however, is not always feasible in the clinical setting due to the high anesthetic risk.We aimed to assess the clinical course and results of urgent thyroidectomy and 131-I therapy in patients with severe AIT with worsening of cardiac status. Methods: Retrospective analysis of the clinical course and outcomes of life-threatening AIT refractory to pharmacotherapy in patients hospitalized at a tertiary endocrinology center between 2014 and 2022. Results: An electronic database search identified 75 patients hospitalized for severe AIT. At the time of AIT diagnosis, median Thyroid-stimulating hormone (TSH) concentration was 0.001 mIU/L (range 0.001–0.35), fT4 63.2 pmol/L (range 9.0 - >100), and fT3 10.2 pmol/L (range 3.8–49.3). All patients received optimal conservative treatment. Among them, 20 required urgent radical therapy due to worsening arrhythmias and/or AIT-related heart failure. In this group, 6 patients died before any radical treatment was applied, 6 underwent total thyroidectomy, while 8 patients were successfully treated with 131-I (in 6 cases after rhTSH stimulation). The median dose of 131-I used for the therapy was 784MBq (range 627–860). The decision to treat with 131-I despite low but detectable 131-I uptake (median value 6 %) was made in cases of significant contraindications to anesthesia due to refractory ventricular arrhythmias, exacerbation of severe heart failure unresponsive to cardiac treatment, myocardial infarction during AIT course, massive pulmonary embolism. Conclusion: The decision regarding the optimal time and type of radical treatment of AIT refractory to pharmacotherapy is critical for patients management and should not be delayed. Urgent therapy with 131-I may be an effective therapeutic option in patients who are unsuitable for thyroidectomy due to the high risk of anesthesia.

IntroductionNormosmic isolated hypogonadotropic hypogonadism (nIHH) is a clinically and genetically heterogeneous disorder. Deleterious variants in over 50 genes have been implicated in the etiology of IHH, which also indicates a possible role of digenicity and oligogenicity. Both classes of genes controlling GnRH neuron migration/development and hypothalamic/pituitary signaling and development are strongly implicated in nIHH pathogenesis. The study aimed to investigate the genetic background of nIHH and further expand the genotype–phenotype correlation.MethodsA total of 67 patients with nIHH were enrolled in the study. NGS technology and a 38-gene panel were applied.ResultsCausative defects regarded as at least one pathogenic/likely pathogenic (P/LP) variant were found in 23 patients (34%). For another 30 individuals, variants of unknown significance (VUS) or benign (B) were evidenced (45%). The most frequently mutated genes presenting P/LP alterations were GNRHR (n = 5), TACR3 (n = 3), and CHD7, FGFR1, NSMF, BMP4, and NROB1 (n = 2 each). Monogenic variants with solid clinical significance (P/LP) were observed in 15% of subjects, whereas oligogenic defects were detected in 19% of patients. Regarding recurrence, 17 novel pathogenic variants affecting 10 genes were identified for 17 patients. The most recurrent pathogenic change was GNRHR:p.Arg139His, detected in four unrelated subjects. Another interesting observation is that P/LP defects were found more often in genes related to hypothalamic–pituitary pathways than those related to GnRH.ConclusionsThe growing importance of the neuroendocrine pathway and related genes is drawing increasing attention to nIHH. However, the underestimated potential of VUS variants in IHH etiology, particularly those presenting recurrence, should be further elucidated.

IntroductionRecently, it has been reported that there is a great diversity in strategies used for thromboprophylaxis in patients with Cushing’s syndrome (CS). An aim of this review was to discuss these practices in light of the existing data on the thrombotic risk in patients with CS and guidelines for medically ill patients.MethodsThe four relevant topics and questions on thrombotic risk in CS were identified. The current guidelines on prevention and diagnosis of venous thromboembolism (VTE) were reviewed for the answers. An algorithm to consider in the assessment of the thrombotic risk in patients with CS was proposed.ResultsTo address both generic and CS-specific risk factors for VTE, the algorithm includes the stepwise approach consisting of Padua Score, urine free cortisol, and CS-VTE score, with no indication for routine thrombophilia testing in the prediction of an index VTE episode. Having confirmed VTE, selected patients require thrombophilia testing to aid the duration of anticoagulant treatment. The separate part of the algorithm is devoted to patients with ectopic adrenocorticotropic hormone syndrome in whom exclusion of VTE precedes introducing routine thromboprophylaxis to prevent VTE. The cancer-related VTE also prompts thromboprophylaxis, with the possible vessel invasion. The algorithm presents a unifactorial and multifactorial approach to exclude high-bleeding risks and safely introduce thromboprophylaxis with low-molecular-weight heparin.SummaryOur article is the first to present an algorithm to consider in the thrombotic risk assessment among patients with Cushing’s syndrome as a starting point for a broader discussion in the environment. A plethora of factors affect the VTE risk in patients with CS, but no studies have conclusively evaluated the best thromboprophylaxis strategy so far. Future studies are needed to set standards of care.

Objective: Registers of diagnoses and treatments exist in different forms in the European countries and are potential sources to answer important research questions. Prevalence and incidence of thyroid diseases are highly dependent on iodine intake and, thus, iodine deficiency disease prevention programs. We aimed to collect European register data on thyroid outcomes to compare the rates between countries /regions with different iodine status and prevention programs. Design: Register-based cross-sectional study. Methods: National register data on thyroid diagnoses and treatments were requested from 23 European countries/regions. The provided data were critically assessed for suitability for comparison between countries/regions. Sex-and age-standardized rates were calculated. Results: Register data on ≥1 thyroid diagnoses or treatments were available from 22 countries/regions. After critical assessment, data on medica tion, surgery, and cancer were found suitable for comparison between 9, 10, and 13 countries/regions, respectively. Higher rates of antithyroid medication and thyroi d surgery for benign disease and lower rates of thyroid hormone therapy were found f or countries with iodine insufficiency before approx. 2001, and no relationship was observed with recent iodine intake or prevention programs. Conclusions: The collation of register data on thyroid outcomes from European countries is impeded by a high degree of heterogeneity in the availabilit y and quality of data between countries. Nevertheless, a relationship between historic iodine intake and rates of treatments for hyper- and hypothyroid disorders is indicated . This study illustrates both the challenges and the potential for the application of register data of thyroid outcomes across Europe.

IntroductionUp to 5% of all pituitary tumors are hereditary e.g. due to MEN1 or aryl hydrocarbon receptor-interacting protein (AIP) genes mutations.ObjectivesThe study was aimed at the assessment of the frequency and characteristics of AIP-mutation related tumors in patients with apparently sporadic pituitary macroadenomas in the Polish population.Materials and methodsThe study included 131 patients (57 males, 74 females; median age 42 years) diagnosed with pituitary macroadenomas, and with a negative family history of familial isolated pituitary adenoma (FIPA) or multiple endocrine neoplasia type 1 (MEN1) syndromes. Sanger sequencing was used for the assessment of AIP gene variants. The study was approved by the Ethics Board of JUMC.ResultsAIP variants were identified in five of the 131 included subjects (3.8%): one diagnosed with Cushing’s disease, two with acromegaly, and two with non-secreting adenomas. Patients harboring hereditary AIP gene alterations did not differ from the rest of the study group in median age at diagnosis (41.0 vs. 42.5 years, P=0.8), median largest tumor diameter (25 vs. 24 mm, P=0.6), gender distribution (60.0% vs. 56.3% females, P=0.8), secreting tumor frequency (60.0% vs. 67.5%, P=0.7), or acromegaly diagnosis frequency (40.0% vs.37.3%, P=0.9).ConclusionsIn our series of apparently sporadic pituitary macroadenomas, AIP gene variant carriers did not differ substantially from patients with negative genetic testing. A risk factor-centred approach to AIP genetic screening may result in missing germline variants. Considering the clinical impact of such genetic variants and their relatively low penetrance, it is, however, doubtful if general genetic screening benefits the whole cohort of pituitary macroadenoma patients and their families.

Cushing disease (CD) is caused by a pituitary tumor which oversecretes adrenocorticotropic hormone (ACTH). It is a serious endocrine disease associated with increased mortality and impaired quality of life. The management of CD remains challenging. Although transsphenoidal surgery is the treatment of choice in most cases, in approximately half of CD patients, second or third-line treatment options are needed. Currently, new medical therapies are available which target adrenal steroidogenesis, pituitary somatostatin and dopamine receptors, and glucocorticoid receptors. Selection of which medication to use should be individualized and is determined by many factors including severity of the disease, possible side effects, patients preferences and local availability. The aim of this article is to describe currently available medical therapy to help clinicians individualize the treatment options in the context of recently updated Pituitary Society recommendations.

BackgroundAdrenal hemorrhage is a rare, usually life-threating complication. The most common neoplasm resulting in spontaneous adrenal bleeding is pheochromocytoma and it accounts for nearly 50% of cases. Currently, the recommendations for the diagnosis and management of patients with adrenal bleeding due to pheochromocytoma are unavailable.Materials and methodsWe performed a database search for all pheochromocytoma patients, diagnosed and treated from 2005 to 2021 in tertiary endocrinology center. 206 patients were identified, 183 with complete data were included in the analysis. We investigated clinicopathological characteristics, treatment and outcomes of hemorrhagic pheochromocytoma cases and characterize our approach to perioperative diagnosis and medical management. Finally our experiences and data from previously published articles concerning adrenal hemorrhage were analyzed to propose a diagnostic and therapeutic algorithm for hemorrhagic pheochromocytomas.ResultsIn the whole group, seven patients (4 men and 3 women) with adrenal bleeding were found, (3.8%). Median patient’s age was 49 years (range: 36-78 years). The most common manifestation of adrenal bleeding was acute abdominal pain (5/7). Two patients developed shock. Hormonal assessment was performed in five patients, based on 24-hour urinary fractionated metanephrines with urinary 3-methoxytyramine. Normetanephrine was elevated in all patients, metanephrine and 3-methoxytyramine - in four cases (4/5). Most patients (6/7) had symptoms suggesting pheochromocytoma before hemorrhage – most commonly paroxysmal hypertension (4/7). One patient died, before the diagnosis of adrenal bleeding was made. Diagnostic imaging performed in six out of seven patients revealed adrenal tumor, with median largest diameter equal to 7.4 cm (range: 5-11 cm). Five patients had elective surgery, in one case an urgent surgery was performed. In all cases the diagnosis of pheochromocytoma was confirmed in postoperative histopathology or in autopsy. The perioperative survival rate was 85.7%.ConclusionsDiagnosis of pheochromocytoma should be always considered in patients with adrenal bleeding, especially with accompanying abdominal pain, hemodynamic shock and previous history of pheochromocytoma-associated symptoms. Lack of proper diagnosis of pheochromocytoma before surgery is associated with an additional perioperative risk. To improve the decision making in this life-threatening clinical situation, based on our results and literature data, we proposed a diagnostic and treatment algorithm.

BackgroundPeptide receptor radionuclide therapy (PRRT) is one of the most effective therapeutic options for the treatment of metastatic, well-differentiated neuroendocrine tumors (NETs). It improves progressive disease-free survival and enables the control of hormone secretion in functioning tumors.Currently, there are no clearly established predictors of response to PRRT. The main factors hindering such a prediction are the heterogeneity of somatostatin receptor expression within and between lesions, lack of standardized parameters for functional imaging, and the use of different PRRT protocols.The main goal of our study was to quantify SUVmax changes in [68Ga]Ga-DOTA-TATE PET/CT scans as a potential predictor of long-term response to PRRT.Material and methodsOut of 20 patients treated with PRRT using [177Lu]Lu and/or [177Lu]Lu/[90Y]Y-DOTA-TATE in 2017–2019 due to dissemination of neuroendocrine neoplasm, 12 patients underwent [68Ga]Ga-DOTA-TATE PET/CT on average 3.1 months before and 4.5 months after PRRT and were eligible for the analysis.In total, 76 NET lesions were evaluated. We measured SUVmax for every lesion in both PET/CT scans (before and after PRRT). Those values were corrected by liver SUVmax and liver SUVmean measured in volumetric analysis and specified as SUVlmax and SUVlmean. As a next step, changes in SUVlmax and SUVlmean were assessed based on both PET/CT scans. Finally, results were correlated with the clinical outcome assessed as progressive disease, disease stabilization, or partial response.ResultsThe mean follow-up period was 19.9 months. Progressive disease, partial response, and disease stabilization were found in five, two, and five patients, respectively. Among patients with a partial response, the decrease in mean SUVlmax was 66.3% when compared to baseline. In patients with stable disease, the decrease in SUVlmax was 30.3% when compared to baseline. In patients with progressive disease, the mean increase in SUVlmax was 9.1% when compared to baseline. The changes in SUVlmean were -69,8%, -30.8%, and -3.7%, respectively.ConclusionsA decrease in the SUVmax value in NET lesions, corrected by normal liver tissue uptake assessed in [68Ga]Ga-DOTA-TATE PET/CT scans, indicates a lower risk for NET progressive disease within 20 months after PRRT and may constitute an additional and independent parameter for the estimation of overall risk for disease progression.

Broad availability and cost-effectiveness of 99Mo/99mTc generators worldwide support the use, and thus the development, of novel 99mTc-labelled radiopharmaceuticals. In recent years, preclinical and clinical developments for neuroendocrine neoplasms patient management focused on somatostatin receptor subtype 2 (SST2) antagonists, mainly due to their superiority in SST2-tumour targeting and improved diagnostic sensitivity over agonists. The goal of this work was to provide a reliable method for facile preparation of a 99mTc-labelled SST2 antagonist, [99mTc]Tc-TECANT-1, in a hospital radiopharmacy setting, suitable for a multi-centre clinical trial. To ensure successful and reproducible on-site preparation of the radiopharmaceutical for human use shortly before administration, a freeze-dried three-vial kit was developed. The final composition of the kit was established based on the radiolabelling results obtained during the optimisation process, in which variables such as precursor content, pH and buffer, as well as kit formulations, were tested. Finally, the prepared GMP-grade batches met all predefined specification parameters together with long-term kit stability and stability of the product [99mTc]Tc-TECANT-1. Furthermore, the selected precursor content complies with micro-dosing, based on an extended single-dose toxicity study, where histopathology NOEL was established at 0.5 mg/kg BW, being more than 1000 times higher than the planned human dose of 20 µg. In conclusion, [99mTc]Tc-TECANT-1 is suitable to be advanced into a first-in-human clinical trial.

IntroductionNeuroendocrine neoplasms including neuroendocrine tumors (NETs) are often diagnosed as primary disseminated or inoperable. In those cases, systemic extensive therapy is necessary, but radical treatment is unlikely. As described in the literature, in some selected cases, peptide receptor radionuclide therapy (PRRT) may be used as a first-line/neoadjuvant therapy that allows further successful surgery. Such treatment may enable a reduction of total tumor burden or allow a radical treatment which improves the final outcomes.AimThis study aims to assess whether neoadjuvant PRRT could be a treatment option for patients with initially unresectable NETs.MethodsAmong the group of 114 patients treated with PRRT between the years 2005 and 2020, in 32 cases, it was the first-line therapy, mainly due to massive disease burden at the time of diagnosis. Among them, nine patients received PRRT as the first-line treatment due to the primary inoperable tumors with the intention of preoperative reduction of the tumor size in order to allow for a surgical treatment.ResultsNeoadjuvant PRRT enabled surgery in four out of nine (45%) patients. Finally, in two out of four cases, the goal (radical surgery) has been achieved.ConclusionPRRT may be considered not only as a palliative but also as a neoadjuvant therapy in advanced, somatostatin-positive NETs that were initially inoperable.

BackgroundNeuroendocrine neoplasms are a heterogeneous group of cancers that develop from enterochromaffin cells of the diffuse endocrine system, with an increase in incidents over the last years. Ovarian neuroendocrine tumors (NET) are rare neoplasms, comprising 0.1% of all ovarian neoplasms and less than 5% of all neuroendocrine tumors. They may arise alone (as monodermal, specialized teratoma – ovarian carcinoid) or as a part of other ovarian lesion: cystic mature or immature teratomas. Due to the rarity and limited amount of such cases reported in the literature, there is no consensus on diagnostic and therapeutic procedures in this group of patients.Materials and MethodsThe group of 10 patients at the age of 19 to 77 years (mean 42.8 ± 17.9), diagnosed with unilateral NET within ovarian teratoma were analyzed. The histopathological type of tumor, progression free survival after surgical treatment and presence of hormonally active syndrome were assessed.Results70% (n=7) of patients was diagnosed with mature cystic teratomas containing NET component and 30% (n=3) with monodermal teratoma (strumal carcinoid). All cases of monodermal teratomas were found in women at premenopausal age. Determined Ki67 ranged from 2% to 9%. Ninety percent of lesions (n=9) stained positive for synaptophysin and chromogranin, while markers: CK20, CK7, TTF-1 and CDX2 were negative in all cases, which ruled out their metastatic nature. None of the patients presented with carcinoid syndrome. All followed-up patients remain progression-free, which confirms surgical intervention being a crucial and sufficient method of treatment.ConclusionsThe prognosis and clinical behavior of NETs associated with ovarian teratomas are good with long progression-free survival.

Abstract Purpose To evaluate the optimal tracer uptake time, the minimal amount of radioactivity and the inter-observer agreement for 11C-choline positron emission tomography/computed tomography (PET/CT) in patients with primary hyperparathyroidism (pHPT). Methods Twenty-one patients with biochemically proven pHPT were retrospectively studied after injection of 6.3 ± 1.2 MBq/kg 11C-choline. PET data of the first nine patients, scanned for up to 60 min, were reconstructed in 10-min frames from 10- to 60-min postinjection (p.i.), mimicking varying 11C-choline uptake times. Parathyroid adenoma to background contrast ratios were calculated and compared, using standardized uptake values (SUVs). Data was reconstructed with varying scan durations (1, 2.5, 5, and 10 min) at 20–30-min p.i. (established optimal uptake time), mimicking less administered radioactivity. To establish the minimal required radioactivity, the SUVs in the shorter scan durations (1, 2.5, and 5 min) were compared to the 10-min scan duration to determine whether increased variability and/or statistical differences were observed. Four observers analyzed the 11C-choline PET/CT in four randomized rounds for all patients. Results SUVpeak of the adenoma decreased from 30 to 40 p.i. onwards. All adenoma/background contrast ratios did not differ from 20- to 30-min p.i. onwards. The SUVs of adenoma in the scan duration of 1, 2.5, and 5 min all differed significantly from the same SUV in the 10-min scan duration (all p = 0.012). However, the difference in absolute SUV adenoma values was well below 10% and therefore not considered clinically significant. The inter-observer analysis showed that the Fleiss’ kappa of the 1-min scan were classified as “moderate,” while these values were classified as “good” in the 2.5-, 5-, and 10-min scan duration. Observers scored lower certainty scores in the 1- and 2.5-min scans compared to the 5- and 10-min scan durations. Conclusion The optimal time to start PET/CT scanning in patients with pHPT is 20 min after mean injection of 6.3 MBq/kg 11C-choline, with a recommended scan duration of at least 5 min. Alternatively, the radioactivity dose can be lowered by 50% while keeping a 10-min scan duration without losing the accuracy of 11C-choline PET/CT interpretation.

Traumatic brain injury affects many people each year, resulting in a serious burden of devastating health consequences. Motor-vehicle and work-related accidents, falls, assaults, as well as sport activities are the most common cause s of traumatic brain injuries. Consequently, they may lead to permanent or transient pituitary insufficiency that causes adverse changes in body composition, worrisome meta bolic function, reduced bone density, and a significant decrease in one’s quality of lif e. The prevalence of post-traumatic hypopituitarism is difficult to determine, and the exac t mechanisms lying behind it remain unclear. Several probable hypotheses have been sugges ted. The diagnosis of pituitary dysfunction is very challenging both due to the commo n occurrence of brain injuries, the subtle character of clinical manifestations, the variable course of the disease, as well as the lack of proper diagnostic algorithms. Insufficienc y of somatotropic axis is the most common abnormality, followed by presence of hypogonadi sm, hypothyroidism, hypocortisolism, and diabetes insipidus. The purpose of this re view is to summarize the current state of knowledge about post-traumatic hypopituita rism. Moreover, based on available data and on our own clinical experience, we sugges t an algorithm for the evaluation of post-traumatic hypopituitarism. In addition, well-designed studies are needed to further investigate the pathophysiology, epidemiology, and timing of pituitary dysfunction after a traumatic brain injury with the purpose of establishing appropriate standards of care.

Abstract Background Real life implementation studies performed in different settings have proved that lifestyle interventions in the prevention of type 2 diabetes (DM2) can be effective, although the weight reduction results are typically modest compared to randomized control trials. Our objective was to identify the factors that predict successful weight loss in a less intensive, lower budget, real life setting lifestyle diabetes prevention intervention. Methods Study participants (n = 175) with increased DM2 risk (Finnish Diabetes Risk Score (FINDRISC) > 14) but no diabetes at baseline received ten group lifestyle counselling sessions, physical activity and motivation sessions during a ten-month intervention. Stepwise regression analysis was used to determine demographic, clinical, and lifestyle predictors of successful weight reduction defined as a reduction of ≥5% of the initial body weight. Results At 12 months following the initiation of the intervention, 23.4% of study participants lost ≥5% weight (mean loss of 7.9 kg, SD = 5.8). Increased physical activity (44% vs 25%, p = 0.03), decreased total fat consumption (88% vs 65%, p = 0.006) and adherence to four-five lifestyle goals (71% vs 46%, p = 0.007) were more often reported among those who managed to lose ≥5% weight versus those who did not. In a multivariate analysis, meeting the ≥5% weight loss goal was most effective in individuals with a higher baseline BMI (OR 1.1, 95%CI 1.0–1.2), baseline and medium versus higher education (OR 5.4, 95% CI 1.2–24.7) and a history of increased glucose (OR 2.6, 95%CI 1.1–1.3). A reduction of total fat in the diet was an independent lifestyle predictor, increasing the probability of successful weight loss by 3.8 times (OR 3.8, 95% CI 1.2–11.4). Conclusion Baseline higher BMI, lower education and a history of increased glucose predicted the successful weight loss among individuals with a high risk for the DM2 following lifestyle intervention in a real life primary health care setting. People who manage to lose weight more often adhere to lifestyle changes, while the reduction of total fat in diet independently predicts successful weight loss. Further studies exploring the predictors of success in implementation studies in DM2 prevention should help health care providers redesign interventions to improve their effectiveness and outcomes. Trial registration ISRCTN, ID ISRCTN96692060 , registered 03.08.2016 retrospectively.

Background and Objectives: Long-acting somatostatin analogues (SSA) (octreotide LAR and lanreotide Autogel) are recommended as first line treatment of locally advanced or metastatic well-differentiated neuroendocrine tumors (NETs) with a good expression of somatostatin receptor (SSTR). Both of these SSAs are usually administered via injections repeated every 4 weeks. The purpose of the study was to compare the route of SSA administration (injection performed by professional medical staff and self-administration of the drug) with progression-free survival. Materials and methods: 88 patients in 2019 and 96 patients in 2020 with locally advanced or metastatic well-differentiated NETs were included in the study. All patients had a good expression of SSTR type 2 and had been treated for at least 3 months with a stable dose of long-acting somatostatin analogue every 4 weeks. All of them had received training on drug self-injections from professional NET nurses at the beginning of the COVID-19 epidemic. Results: The rate of NET progression in the study group in 2020 was higher than in 2019 29.1% vs. 18.1% (28 vs. 16 cases), p = 0.081. Conclusions: The method of administration of long-acting SSA injection performed by professional medical staff vs. self-injection of the drug may significantly affect the risk of NET progression. The unequivocal confirmation of such a relationship requires further observation.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a large and very diverse group of neoplasms. Clinical presentation of NETs depends on the site of the primary tumor and whether the tumor is functioning (i.e., secreting peptides or neuroamines that produce symptoms). The diagnosis of GEP-NET is further complicated by symptomatic differences that occur depending on the type of secreted peptide or neuroamine. Due to their heterogeneity and unique characteristics, early diagnosis of GEP-NETs is difficult, which increases the likelihood of metastatic disease and reduces the scope of therapeutic possibilities. Thus, a multidisciplinary approach for the treatment of GEP-NETs is necessary. This review is the result of presentations that were delivered during an expert meeting on the treatment of GEP-NETs supported by Ipsen. We summarize the current knowledge on the epidemiology, incidence, diagnosis, and treatment of GEP-NETs. We examined the role of the somatostatin analog (SSA) lanreotide and the impact of the data from the recently published, randomized, double-blind, placebo -controlled CLARINET study (Controlled study of Lanreotide Antiproliferative Response In Neuroendocrine Tumors) on disease management. We also review the recent treatment options and recommendations for GEP-NETs.

Abstract Background Real life implementation studies performed in different settings and populations proved that lifestyle interventions in prevention of type 2 diabetes can be effective. However, little is known about long term results of these translational studies. Therefore, the purpose of this study was to examine the maintenance of diabetes type 2 risk factor reduction achieved 1 year after intervention and during 3 year follow-up in primary health care setting in Poland. Methods Study participants (n = 262), middle aged, slightly obese, with increased type 2 diabetes risk ((age 55.5 (SD = 11.3), BMI 32 (SD = 4.8), Finnish Diabetes Risk Score FINDRISC 18.4 (SD = 2.9)) but no diabetes at baseline, were invited for 1 individual and 10 group lifestyle counselling sessions as well as received 6 motivational phone calls and 2 letters followed by organized physical activity sessions combined with counselling to increase physical activity. Measurements were performed at baseline and then repeated 1 and 3 years after the initiation of the intervention. Results One hundred five participants completed all 3 examinations (baseline age 56.6 (SD = 10.7)), BMI 31.1 (SD = 4.9)), FINDRISC 18.57 (SD = 3.09)). Males comprised 13% of the group, 10% of the patients presented impaired fasting glucose (IFG) and 14% impaired glucose tolerance (IGT). Mean weight of participants decreased by 2.27 kg (SD = 5.25) after 1 year (p = 5% was achieved after 1 and 3 years by 27 and 19% of the participants, respectively. Repeated measures analysis revealed significant changes observed from baseline to year 1 and year 3 in: weight (p = 0.048), BMI (p = 0.001), total cholesterol (p = 0.013), TG (p = 0.061), fasting glucose level (p = 0.037) and FINDRISC (p = 0.001) parameters. The conversion rate to diabetes was 2% after 1 year and 7% after 3 years. Conclusions Type 2 diabetes prevention in real life primary health care setting through lifestyle intervention delivered by trained nurses leads to modest weight reduction, favorable cardiovascular risk factors changes and decrease of diabetes risk. These beneficial outcomes can be maintained at a 3-year follow-up. Trial registration ISRCTN, ID ISRCTN96692060 , registered 03.08.2016 retrospectively

Background and aimsThe DE-PLAN was a European multicenter study, with the primary objective of testing whether a community-based lifestyle modification programme could serve as a means of primary prevention for type 2 diabetes (T2D) in high-risk individuals (based on the FINDRISC questionnaire). The aim of this study was to examine the impact of a 1-year community-based lifestyle intervention on health-related quality of life (HRQOL) in individuals from four participating European centers (Athens, Barcelona, Krakow, Kaunas), through a post-hoc analysis.Materials and methodsEach center was allowed to implement different intervention strategies specifically tailored to the needs of their corresponding population sample. Before and after the intervention, participants underwent clinical evaluation, anthropometric measurements, an oral glucose tolerance test and lipid profile measurements. Health-related quality of life was assessed using the validated HRQOL-15D questionnaire. A difference of ±0.015 in the 15D questionnaire score was set as the threshold of clinically meaningful change.ResultsData from 786 participants (67% females, mean age 59.7±9.4 years, BMI 31.5±4.5 kg/m2) with complete data regarding the HRQOL were analyzed (Athens: 104, Barcelona: 434, Krakow: 175, Kaunas: 70). After 1 year, a significant overall improvement in HRQOL was shown, as depicted by a change of 15D score from baseline value (0.88±0.9) to post-intervention (0.90±0.87, PConclusionA community-based lifestyle intervention programme aiming at T2D prevention, applied on a heterogeneous population and with varied methods, was shown to improve overall health-related quality of life to a clinically meaningful degree.

The application of Fourier transform infrared (FTIR) microspectroscopy for the analysis of biomolecular composition of adrenal gland tumors is described. Samples were taken intraoperatively from three types of adrenal lesions: adrenal adenoma (ACA), adrenal cortical hyperplasia (ACH), both derived from adrenal cortical cells, and pheochromocytoma (Ph) derived from chromaffin cells of the adrenal medulla. The specimens were cryo-sectioned and freeze-dried. Since the investigated lesions originated from different cell types, it was predictable that they might differ in biomolecular composition. The experimental results were used to determine which absorption bands differentiate the analyzed samples the most. The main difference was observed in the lipid functional groups. The experimental results indicated that the level of lipids was higher in both the adenoma and the hyperplasia samples compared to pheochromocytomas. In contrast, the level of proteins was higher in the pheochromocytomas. Furthermore, differences within the range of nucleic acids and carbohydrates were observed in the studied adrenal gland tumor types.

Recently, radiolabelled antagonists targeting somatostatin receptors subtype 2 (SST2) in neuroendocrine neoplasms demonstrated certain superior properties over agonists. Within the ERA-PerMED project “TECANT” two 99mTc-Tetramine (N4)-derivatized SST2 antagonists (TECANT-1 and TECANT-2) were studied for the selection of the best candidate for clinical translation. Receptor-affinity, internalization and dissociation studies were performed in human embryonic kidney-293 (HEK293) cells transfected with the human SST2 (HEK-SST2). Log D, protein binding and stability in human serum were assessed. Biodistribution and SPECT/CT studies were carried out in nude mice bearing HEK-SST2 xenografts, together with dosimetric estimations from mouse-to-man. [99mTc]Tc-TECANT-1 showed higher hydrophilicity and lower protein binding than [99mTc]-TECANT-2, while stability was comparable. Both radiotracers revealed similar binding affinity, while [99mTc]Tc-TECANT-1 had higher cellular uptake (>50%, at 2 h/37 °C) and lower dissociation rate (99mTc]Tc-TECANT-1 showed lower blood values, kidney and muscles uptake, whereas tumour uptake was comparable to [99mTc]Tc-TECANT-2. SPECT/CT imaging confirmed the biodistribution results, providing the best tumour-to-background image contrast for [99mTc]Tc-TECANT-1 at 4 h post-injection (p.i.). The estimated radiation dose amounted to approximately 6 µSv/MBq for both radiotracers. This preclinical study provided the basis of selection of [99mTc]Tc-TECANT-1 for clinical translation of the first 99mTc-based SST2 antagonist.

Lifestyle interventions in type 2 diabetes (DM2) prevention implementation studies can be effective and lasting. Long-term weight loss maintenance enhances the intervention effect through a significant decrease in diabetes incidence over time. Our objective was to identify factors predicting long-term successful weight reduction maintenance achieved during a DM2 prevention program in patients with high DM2 risk in primary health care. Study participants (n = 263), middle-aged, slightly obese with baseline increased DM2 risk (Finnish Diabetes Risk Score (FINDRISC)>14), but no diabetes were invited to receive 11 lifestyle counselling sessions, guided physical activity sessions and motivational support during 10-months. The study participants had three clinical examinations during the study (baseline, one and three years). Stepwise regression analysis was used to determine demographic, clinical, and lifestyle predictors of weight reduction maintenance two years after the discontinuation of the intervention. Out of 105 patients who completed all three examinations (baseline age 56.6 (standard deviation (SD) = 10.7), body mass index 31.1 kg/m2 (SD = 4.9), FINDRISC 18.6 (SD = 3.1)), 73 patients (70%) showed weight loss during the intervention (mean weight loss 4.2 kg, SD = 5.1). The total weight loss achieved in the maintainers (27 of 73 study participants) two years after the intervention had finished was 6.54 kg (4.47 kg+2.0 kg). The non-maintainers, on the other hand, returned to their initial weight at the start of the intervention (+0.21 kg). In multivariable analysis baseline history of increased glucose (odds ratio (OR) = 3.7; 95% confidence interval (CI) 1.0-13.6) and reduction of total fat in diet during follow-up (OR = 4.3; 95% CI 1.5-12.2) were independent predictors of successful weight loss. Further studies exploring predictors of weight loss maintenance in diabetes prevention are needed to help health care providers to redesign interventions and improve long-term outcomes of real life interventions.

The aim of this study was to assess the utility of [Lys40(Ahx-HYNIC-99mTc/EDDA)NH2]-exendin-4 scintigraphy in the management of patients with hypoglycemia, particularly in the detection of occult insulinoma.Forty patients with hypoglycemia and increased/confusing results of serum insulin and C-peptide concentration and negative/inconclusive results of other imaging examinations were enrolled in the study. In all patients GLP-1 receptor imaging was performed to localise potential pancreatic lesions.Positive results of GLP-1 scintigraphy were observed in 28 patients. In 18 patients postsurgical histopathological examination confirmed diagnosis of insulinoma. Two patients had contraindications to the surgery, one patient did not want to be operated. One patient, who presented with postprandial hypoglycemia, with positive result of GLP-1 imaging was not qualified for surgery and is in the observational group. Eight patients were lost for follow up, among them 6 patients with positive GLP-1 scintigraphy result. One patient with negative scintigraphy was diagnosed with malignant insulinoma. In two patients with negative scintigraphy Munchausen syndrome was diagnosed (patients were taking insulin). Other seven patients with negative results of 99mTcGLP-1 scintigraphy and postprandial hypoglycemia with C-peptide and insulin levels within the limits of normal ranges are in the observational group. We would like to mention that 99mTc-GLP1-SPECT/CT was also performed in 3 pts with nesidioblastosis (revealing diffuse tracer uptake in two and a focal lesion in one case) and in two patients with malignant insulinoma (with the a focal uptake in the localization of a removed pancreatic headin one case and negative GLP-1 1 scintigraphy in the other patient).99mTc-GLP1-SPECT/CT could be helpful examination in the management of patients with hypoglycemia enabling proper localization of the pancreatic lesion and effective surgical treatment. This imaging technique may eliminate the need to perform invasive procedures in case of occult insulinoma.

Introduction: The aim of contemporary medicine is not only a successful course of the operation, leading to improvementof the patient’s health status, but also its satisfactory cosmetic effect. Single incision laparoscopic surgery (SILS) is a newadvance wherein laparoscopy is carried out through a small incision hidden in the umbilicus. It therefore combines thesetwo major objectives allowing for a good clinical result after a practically scarless operation. Aim: To present the preliminary experience in using the SILS method for treatment of patients with adrenal glandtumours.Material and methods: In March 2010 we performed 7 SILS adrenalectomies in patients treated in our department.Preoperative examinations confirmed hormonal activity in 6 of them and in 1 patient increase in the size of thetumour (by 12 mm) was the indication for the operation. All procedures were performed using the lateraltransperitoneal approach where after creation of a small incision in the umbilicus the SILS port was placed. Theoperation was then conducted using a technique similar to standard multiport adrenalectomy. In 1 patient it wasnecessary to place 2 additional trocars in order to properly mobilize the spleen. Results: We did not observe any difference in the operative time versus multiport laparoscopy. No postoperativecomplications occurred. Conclusion: SILS adrenalectomy is a safe procedure but requires a lot of experience in laparoscopic adrenalectomy.If any problem occurs during the procedure it is always possible to place additional trocars and convert the operationto multiport laparoscopy. To date the only evidenced advantage of the new procedure is its better cosmetic result.

Angiogenesis (neoangiogenesis), a process of neovascularization, is an essential step for local tumor growth and distant metastasis formation. We have analysed angiogenesis status: vascular architecture, microvessel density, and vascular endothelial growth factors expression in 62 adrenal pheochromocytomas: 57 benign and 5 malignant. Immunohistochemical evaluation revealed that vascular architecture and vessel density are different in the central and subcapsular areas of the tumor. Furthermore, we have observed a strong correlation between number of macrophages and microvessel density in the central and subcapsular areas of the tumor and between the expression of VEGF-A in tumor cells and microvessel density in central and subcapsular areas of the tumor. Secondary changes in these tumors influence the results and both vascular architecture and microvessel density are markedly disturbed by hemorrhagic and cystic changes in pheochromocytomas. These changes are partially caused by laparoscopic operation technique. However, no differences in vascular parameters were found between pheochromocytomas with benign and malignant clinical behavior. Our observation showed that analysis of angiogenesis, as a single feature, does not help in differentiating malignant and benign pheochromocytomas and has no independent prognostic significance. On the other hand, high microvessel density in pheochromocytoma is a promising factor for antiangiogenic therapy in malignant cases.