Evaluation of selected circulating cytokines from the IL-6 family - interleukin 6, oncostatin M, and cardiotrophin-1 - in gastro-entero-pancreatic and bronchial neuroendocrine tumours.

Introduction: The incidence of neuroendocrine tumours (NETs) increased over the last years. Most of them are non-functioning, and the course of the disease is asymptomatic for a long time. This results in late diagnosis at an advanced stage. The aim of our study was the evaluation of selected circulating cytokines of interleukin-6 family - interleukin 6 (IL-6), oncostatin M (OSM), and cardiotrophin-1 (CT1) - in NETs. Material and methods: The study group comprised 80 patients (56%) in several subgroups, including gastroenteropancreatic (GEPNETs, n = 64, 80%) and bronchopulmonary neuroendocrine tumours (BPNETs, n = 16; 20%). Serum IL-6, OSM, and CT1 concentrations were tested using ELISA. Results: The median concentration of IL-6 was 41.5 pg/ml in the study group and 32.6 pg/ml in the control group, and the difference was statistically significant (p < 0.001). The concentration of OSM was significantly lower in the study group than in the control group (p < 0.001), at 105.6 pg/ml and 115.5 pg/ml, respectively. There was a significant difference (p < 0.01) in concentration of CT1 in the study group (222.0 pg/ml) and controls (267.2 pg/ml). Our investigation into selected IL-6 family cytokines revealed differential modulation of signal transduction pathways. Conclusions: These findings suggest that despite utilising a common signalling transducer, individual IL-6 family cytokines exert distinct biological effects on neuroendocrine tumour development. Notably, IL-6 appears to promote tumourigenesis, while OSM and CT1 exhibit inhibitory effects on gastro-entero-pancreatic and bronchial neuroendocrine tumour development. Further studies are necessary to validate the diagnostic utility of IL-6 family cytokines in NETs.

Adverse Events of Radioligand Therapy in Patients with Progressive Neuroendocrine Neoplasms: The Biggest Eastern European Prospective Study.

BACKGROUND: Neuroendocrine neoplasms (NENs) are neoplastic tumors developing in every part of the body, mainly in the gastrointestinal tract and pancreas. Their treatment involves the surgical removal of the tumor and its metastasis, long-acting somatostatin analogs, chemotherapy, targeted therapy, and radioligand therapy (RLT). MATERIALS AND METHODS: A total of 127 patients with progressive neuroendocrine neoplasms underwent RLT-4 courses, administered every 10 weeks-with the use of 7.4 GBq [177Lu]Lu-DOTA-TATE or tandem therapy with 1.85 GBq [177Lu]Lu-DOTA-TATE and 1.85 GBq [90Y]Y-DOTA-TATE. Assessment of short- and long-term complications, as well as the calculation of progression-free survival (PFS) and overall survival (OS) were performed. RESULTS: RLT caused a statistically but not clinically significant decrease in blood morphology parameters during both short- and long-term observations. Glomerular filtration rate (GFR) significantly decreased only in a long-term observation after RLT; however, it was clinically acceptable. Computed predictions of progression-free survival (PFS) and overall survival (OS) indicated that five years post-RLT, there is a 74% chance of patients surviving, with only a 58.5% likelihood of disease progression. CONCLUSIONS: Computed predictions of PFS and OS confirmed treatment efficiency and good patient survival. RLT should be considered a safe and reliable line of treatment for patients with progressive NENs as it causes only a low number of low-grade adverse events.

Significant improvement of ganglion cell complex in optical coherence tomography and photopic negative response in electroretinography after transsphenoidal resection of pituitary macroadenoma.

Not required for Clinical Vignette.

Polish diagnostic and therapeutic recommendations for adrenocortical carcinoma.

Advances in the diagnosis and treatment of adrenocortical carcinoma (ACC), along with the development of new therapeutic and diagnostic methods, have prompted a team of experts to formulate the first Polish guidelines for managing ACC. This article presents the diagnostic and therapeutic recommendations resulting from the discussion of specialists from various medical specialities, who participated in a series of online meetings aimed at developing consistent and effective recommendations under the National Oncology Strategy. These guidelines aim to optimise ACC treatment in Poland through coordinated efforts of multidisciplinary specialist teams, ensuring an effective and modern approach.

Adipokines in Neuroendocrine Tumors: An Evaluation of the Serum Levels of Ghrelin and Leptin.

Neuroendocrine tumors (NETs) are a heterogeneous group of tumors that are characteristically different from other malignancies. The difference is not only in the prognosis, which is usually more favorable in such patients, but also in the high clinical progression of the disease, where NET patients do not experience the cachexia typical of other malignancies. The purposes of this study were to evaluate the ghrelin and leptin levels in a group of patients diagnosed with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and bronchopulmonary neuroendocrine tumors (BP-NETs) and to analyze the relationship between the body mass index (BMI), cachexia and selected NET markers. The study group comprised 52 patients with GEP-NETs and BP-NETs, while the controls comprised 67 healthy volunteers. The ghrelin and leptin concentrations were determined in both groups. The concentrations of chromogranin A, serotonin, 5-hydroxyindoleacetic acid (5-HIAA), total cholesterol, triglycerides and glucose were determined in the study group. Characteristics of the study group and of the controls were defined by age, sex and BMI, and the effects of these factors on the ghrelin and leptin concentrations were assessed. The data obtained were subject to statistical analysis. The study cohort showed higher levels of ghrelin as compared to the controls (142.31 ± 26.00 vs. 121.49 ± 35.45, p = 0.016), and no statistical difference in the levels of leptin (11.15 ± 9.6 vs. 12.94 ± 20.30, p = 0.439) were observed. Significantly lower levels of leptin were found in patients with the small intestine primary location, as compared to individuals with primary locations in the lungs and the pancreas (4.9 ± 6.49 vs. 16.97 ± 15.76, p = 0.045, and 4.9 ± 6.49 vs. 12.89 ± 8.56, p = 0.016, respectively). A positive correlation was observed between the leptin levels and the BMIs in both the study group (rS = 0.33, p = 0.016) and the controls (rS = 0.41, p = 0.001). The study group showed a negative correlation between the leptin levels and 5-HIAA (rS = -0.32, p = 0.026) and a negative correlation between the leptin levels and Ki-67 (rS = -0.33, p = 0.018). The control group showed negative correlations between the ghrelin and the volunteer age (rS = -0.41, p = 0.008), the leptin and the volunteer age (rS = -0.44, p < 0.001), the leptin and total cholesterol (rS = -0.24, p < 0.049) as well as the leptin and triglycerides (rS = -0.33, p < 0.006). The current study emphasized the importance of the markers' determination, where ghrelin appears as a valuable diagnostic biomarker in NETs, probably responsible for maintaining a normal BMI, despite the progression of the disease.

Angiogenic biomarkers of response to treatment with peptide receptor radionuclide therapy in neuroendocrine tumours.

BACKGROUND: Neuroendocrine tumours (NETs) are a heterogeneous group of tumours, which is characterized by rich vascularization. The role of angiogenesis in NETs has been widely researched. Peptide receptor radionuclide therapy (PRRT) is an effective treatment method for patients with disease progression in NETs. Due to the heterogeneousness of NETs, the response to treatment varies. Currently, the finding of efficient markers helpful in assessing the response to treatment in NETs is crucial. The aim of this study was to assess chromogranin A (CgA) and angiogenic factors in gastro-entero-pancreatic (GEP) and broncho-pulmonary (BP) NET patients treated with PRRT. MATERIAL AND METHODS: The study group included 40 patients with GEP NETs and BP NETs who completed four cycles of PRRT. Serum levels of CgA and angiogenic factors such as vascular endothelial growth factor (VEGF), its receptors (VEGF-R1, VEGF-R2, VEGF-R3), were assessed before and after four cycles of PRRT. All tests were determined using ELISA. RESULTS: The concentration of CgA, VEGF-R1 and VEGF-R2 decreased significantly, whereas VEGF-R3 increased significantly after PRRT. PRRT did not affect VEGF, it was similar before and after the radioisotope treatment. Based on AUROC, only for VEGF-R1 AUC was a consequence of 0.7 which can be considered as a good response to PRRT treatment. CONCLUSIONS: VEGF-R1 may be a potential biomarker useful in assessing the effectiveness of PRRT in NET patients.

Longitudinal Changes in Ki-67 Indices in Small-Intestinal Neuroendocrine Tumours and Their Impact on Survival.

INTRODUCTION: The purpose of this study was to evaluate longitudinal changes in Ki-67 indices of SI-NETs and assess the impact of these in overall survival (OS). METHODS: We screened 551 patients with SI-NETs diagnosed from 1993, through 2021, identified using the SI-NET databases from five European referral centres. Only patients with well-differentiated tumours and available baseline tumour samples and follow-up re-biopsies were included. For tumour grading, apart from 2017 WHO classification system, we applied a recently proposed SI-NET site-specific modified histopathological grading system with Ki-67 cut-offs of 5 and 10%. Uni- and multivariable regression analyses were used to determine whether there was a difference between OS in SI-NET patients stratified by increment of Ki-67 indices over time and/or progression to a higher grade. RESULTS: We included 45 patients. Median Ki-67 index at SI-NET diagnosis was 2% (range: 0.5-15%). Thirty-three patients had Ki-67 indices <5% (70.2%), 6 had Ki-67: 5-10% (12.8%), and 8 had Ki-67 ≥10% (17%). Mean time to re-biopsy was 48.8 months (SD: ±162.5). At re-biopsy, the median change in Ki-67 index (absolute value; follow-up minus time of diagnosis) was 1% (range: -10 to +38%). An increase in Ki-67 occurred in 20 patients (42.6%); in 14 patients, the change in Ki-67 resulted in progression to higher tumour grade following the modified grading system. Patients with an increment in Ki-67 ≥1% had a median OS of 32.9 months versus 80.5 months in patients without (HR = 5.6, 95% CI: 1.42-22.02; p = 0.014). When applying the novel modified histopathological grading system for SI-NETs, patients with grade progression had a median OS of 32.9 months versus 53.7 months in those without (HR = 4.61, 95% CI: 1.22-13.54; p = 0.022). At multivariable analysis, grade progression was confirmed as an independent predictor for death (HR = 7.2, 95% CI: 1.58-32.82; p = 0.011). CONCLUSIONS: Metachronous increment in Ki-67 indices and related grade progression over time following a site-specific modified histopathological grading system with Ki-67 cut-offs of 5 and 10% is observed in approximately 1/3 of SI-NETs subjected to re-biopsy and it is associated with worse survival outcomes.

European Neuroendocrine Tumor Society (ENETS) 2024 guidance paper for the management of well-differentiated small intestine neuroendocrine tumours.

Both the incidence and prevalence of well-differentiated neuroendocrine tumours from the small intestine (Si-NET) are gradually increasing. Most patients have non-functioning tumours with subtle GI symptoms and tumours are often discovered incidentally by endoscopy or at advanced disease stages by imaging depicting mesenteric lymph node and /or liver metastases while around 30% of the patients present with symptoms of the carcinoid syndrome. Adequate biochemical assessment and staging including functional imaging is crucial for treatment-related decision-making that should take place in an expert multidisciplinary team setting. Preferably, patients should be referred to specialised ENETS Centres of Excellence or centres of high expertise in the field. This guidance paper provides the current evidence and best knowledge for the management of Si-NET grade (G) 1-3 following 10 key questions of practical relevance for the diagnostic and therapeutic decision making.

Clinical management of typical and atypical carcinoids/neuroendocrine tumors in ENETS centres of excellence (CoE): Survey from the ENETS lung NET task force.

Lung carcinoid tumours are neuroendocrine neoplasms originating from the bronchopulmonary tract's neuroendocrine cells, accounting for only 1%-3% of all lung cancers but 30% of all neuroendocrine tumours. The incidence of lung carcinoids, both typical and atypical, has been increasing over the years due to improved diagnostic methods and increased awareness among clinicians and pathologists. The most recent WHO classification includes a subgroup of lung carcinoids with atypical morphology and higher mitotic count and/or Ki67 labelling index. Despite appropriate surgery, the 5-year survival rate for atypical carcinoids barely exceeds 50%-70%. The role of adjuvant therapy in lung carcinoids is not well-defined, and clinical decisions are generally based on the presence of high-risk features. Long-term follow-up is essential to monitor for recurrence, although the optimal follow-up protocol remains unclear. To address the lack of consensus in clinical management decisions, the European Neuroendocrine Tumor Society (ENETS) initiated a survey among 20 expert centres. The survey identified varied opinions on approaches to imaging, surgery, use of adjuvant therapy, and follow-up protocols. Notably, the absence of dedicated multidisciplinary lung neuroendocrine tumour boards in some centres was evident. Experts agreed on the need for a prospective adjuvant trial in high-risk patients, emphasizing the feasibility of such a study. In conclusion, the study highlights the need for a more uniform adoption of existing guidelines in the management of lung carcinoid tumours and emphasizes the importance of international collaboration to advance research and patient care. Close collaboration between healthcare providers and patients is vital for effective long-term surveillance and management of these rare tumours.

Differential diagnosis of thyroid orbitopathy - diseases mimicking the presentation or activity of thyroid orbitopathy.

Thyroid orbitopathy (TO) is the most common cause of orbital tissue inflammation, accounting for about 60% of all orbital inflammations. The inflammatory activity and severity of TO should be diagnosed based on personal experience and according to standard diagnostic criteria. Magnetic resonance imaging (MRI) of the orbit is used not only to identify swelling and to differentiate inflammatory active from non-active TO, but also to exclude other pathologies, such as orbital tumours or vascular lesions. However, a group of diseases can mimic the clinical manifestations of TO, leading to serious diagnostic difficulties, especially when the patient has previously been diagnosed with a thyroid disorder. Diagnostic problems can be presented by cases of unilateral TO, unilateral or bilateral TO in patients with no previous or concomitant symptoms of thyroid disorders, lack of symptoms of eyelid retraction, divergent strabismus, diplopia as the only symptom of the disease, and history of increasing diplopia at the end of the day. The lack of visible efficacy of ongoing immunosuppressive treatment should also raise caution and lead to a differential diagnosis of TO. Differential diagnosis of TO and evaluation of its activity includes conditions leading to redness and/or swelling of the conjunctiva and/or eyelids, and other causes of ocular motility disorders and eye-setting disorders. In this paper, the authors review the most common diseases that can mimic TO or falsify the assessment of inflammatory activity of TO.

Modified Histopathological Grading Optimizes Prediction of Survival Outcomes in Small Intestinal Neuroendocrine Tumours.

CONTEXT: One of the major prognostic indices in neuroendocrine tumours (NETs) is Ki67 proliferation index. OBJECTIVE: To identify optimal grading Ki-67 cut-offs to delineate differences in prognosis of patients with small intestinal NETs (SI-NETs). DESIGN, SETTING, PARTICIPANTS: Multicentre retrospective cohort analysis of 551 SI-NET patients diagnosed from 1993 through 2021 at five European referral centres with a mean(±SD) follow-up time of 51.5(±52.9) months. MAIN OUTCOME MEASURES: Overall- and event-free survival (OS and EFS) rates. RESULTS: Median age at baseline was 62.3(range:17-90) years; 252(45.7%) patients were female. All SI-NETs were well-differentiated with 326 being grade 1(G1; 59.2%), 169G2(30.7%), and only 8G3(1.5), while 48 tumours were of unspecified grade (8.7%). The median Ki67 was 2%(range:1-70%). Two-hundred forty-seven patients (44.8%) had distant metastases at baseline (stage IV), 217 locoregional disease (41.1%; stage III), whereas 29(7.1%) and 25(4.5%) presented at stages II and I, respectively. The median OS was 214.7(95%CI:152.7-276.6) months and the median EFS was 79.8(95%CI:68.2-91.5) months, respectively. In multivariable Cox-regression OS analysis, the proposed modified histopathological Ki67 grading system (K67:5-10% group: HR=2.2, 95%CI:1.15-4.31; p=0.018 and K67≥10% group: HR=5.11, 95%CI:2.87-9.09; p<0.001), age (HR=1.07, 95%CI:1.04-1.09; p<0.001), Charlson Comorbidity Index (HR=1.08, 95%CI:1-1.16; p=0.028) and TNM stage (HR=1.79, 95%CI:1.05-3.06; p=0.034) were independent predictors for death. Pertinent EFS analysis, confirmed the proposed modified histopathological Ki67 grading system (K67≥10% group: HR=4.01, 95%CI:2.6-6.37; p<0.001) and age (HR=1.04, 95%CI:1.02-1.05; p<0.001) as independent predictors for recurrence, progression and/or death. CONCLUSIONS: Ki-67 proliferation index was a strong and independent predictor of OS and EFS. A modified histopathological grading system applying Ki-67 cut-offs of 5 and 10% could be superior to predict differences in SI-NET patient survival outcomes.

Transforming growth factors ß and their signaling pathway in renal cell carcinoma and peritumoral space-transcriptome analysis.

PURPOSE: The aim of the study was to verify hypotheses: Are transforming growth factors TGFß1-3, their receptors TGFßI-III, and intracellular messenger proteins Smad1-7 involved in the pathogenesis of kidney cancer? What is the expression of genes of the TGFß/Smads pathway in renal cell carcinoma (RCC) tissues, peritumoral tissues (TME; tumor microenvironment), and in normal kidney (NK) tissue?. METHODS: Twenty patients with RCC who underwent total nephrectomy were included into the molecular analysis. The mRNA expression of the genes was quantified by RT-qPCR. RESULTS: The study showed that the expression of the genes of TGFß/Smads pathway is dysregulated in both RCC and the TME: TGFß1, TGFß3 expression is increased in the TME in comparison to the NK tissues; TGFß2, TGFß3, TGFßRI, TGFßRIII, Smad1, Smad2, Smad3, and Smad6 are underexpressed in RCC comparing to the TME tissues; TGFßRI, TGFßRIII, and Smad2 are underexpressed in RCC in comparison to the NK tissues. CONCLUSION: On the one hand, the underexpression of the TGFß signaling pathway genes within the malignant tumor may result in the loss of the antiproliferative and pro-apoptotic activity of this cytokine. On the other hand, the overexpression of the TGFß/Smads pathway genes in the TME than in tumor or NK tissues most probably results in an immunosuppressive effect in the space surrounding the tumor and may have an antiproliferative and pro-apoptotic effect on non-neoplastic cells present in the TME. The functional and morphological consistency of this area may determine the aggressiveness of the tumor and the time in which the neoplastic process will spread.

Use and perceived utility of [18 F]FDG PET/CT in neuroendocrine neoplasms: A consensus report from the European Neuroendocrine Tumor Society (ENETS) Advisory Board Meeting 2022.

Somatostatin receptor (SST) PET/CT is the gold standard for well-differentiated neuroendocrine tumours (NET) imaging. Higher grades of neuroendocrine neoplasms (NEN) show preferential [18F]FDG (FDG) uptake, and even low-grade NET may de-differentiate over time. FDG PET/CT's prognostic role is widely accepted; however, its impact on clinical decision-making remains controversial and its use varies widely. A questionnaire-based survey on FDG PET/CT use and perceived decision-making utility in NEN was submitted to the ENETS Advisory Board Meeting attendees (November 2022, response rate = 70%). In 3/15 statements, agreement was higher than 75%: (i) FDG was considered useful in NET, irrespective of grade, in case of mis-matched lesions (detectable on diagnostic CT but negative/faintly positive on SST PET/CT), especially if PRRT is contemplated (80%); (ii) in NET G3 if curative surgery is considered (82%); and (iii) in NEC prior to surgery with curative intent (98%). FDG use in NET G3, even in the presence of matched lesions, as a baseline for response assessment was favoured by 74%. Four statements obtained more than 60% consensus: (i) FDG use in NET G3 if locoregional therapy is considered (65%); (ii) in neuroendocrine carcinoma before initiating active therapy as a baseline for response assessment (61%); (iii) biopsy to re-assess tumour grade prior to a change in therapeutic management (68%) upon detection of FDG-positivity on the background of a prior G1-2 NET; (iv) 67% were in favour to reconsider PRRT to treat residual SST-positive lesions after achieving complete remission on FDG of the SST-negative disease component. Multidisciplinary opinion broadly supports the use of FDG PET/CT for characterisation of disease biology and to guide treatment selection across a range of indications, despite the lack of full consensus in many situations. This may reflect existing clinical access due to lack of reimbursement or experience with this investigation, which should be addressed by further research.

A new antiviral hypothesis and radioactive iodine therapy to other cancers, such as breast cancer, lung cancer, and glioblastoma multiforme (GBM)?

Radioactive iodine therapy (RIT) is an effective, safe, and cheap method in benign and malignant thyroid diseases. There is still an unresolved question of whether RIT treatment also plays a role in the treatment of, for example, breast cancer, lung cancer, or glioblastoma multiforme (GBM). These studies are currently being carried out in rats in combination with genes, but it may be an interesting challenge to assess "pure" RIT alone, thanks to the expression of sodium iodide symporter (NIS), is effective in other organ nodules, both benign and malignant. Cloning of the NIS in 1996 provided an opportunity to use NIS as a powerful theranostic transgene. In addition, NIS is a sensitive reporter gene that can be monitored by high-resolution PET imaging using the radiolabels [¹²4I]sodium iodide ([¹²4I]NaI) or [18F] tetrafluoroborate ([¹8F]TFB). Based on published positron emission tomography (PET) results, [¹²4I]sodium iodide and internally synthesized [18F]TFB were compared in an orthotopic animal model of NIS-expressing glioblastoma. The results showed improved image quality using [¹8F]TFB. Based on these results, we will be able to extend the NIS gene therapy approach using non-viral gene delivery vehicles to target orthotopic tumour models with low-volume disease such as GBM. Is it possible to treat RIT alone without using the NIS gene in GBM? After all, the NIS symporter was detected not only in the thyroid gland, but also in different tumours. The administration of RIT is completely harmless; the only complication is hypothyroidism. Indeed, recently it has been shown that, for example, in the case of thyroid cancer, the maximum RIT is 37000 MBq (1000 mCi). When beneficial effects of therapy in GBM are not possible (e.g. neurosurgery, modulated electro-hyperthermia, chemotherapy, immunotherapy, cancer vaccines, or oncolytic viruses), could RIT provide a "revolution" using NIS?

Epidemiology of Neuroendocrine Neoplasms and Results of Their Treatment with [177Lu]Lu-DOTA-TATE or [177Lu]Lu-DOTA-TATE and [90Y]Y-DOTA-TATE-A Six-Year Experience in High-Reference Polish Neuroendocrine Neoplasm Center.

Neuroendocrine neoplasms (NENs) are a group of neoplasms arising from neuroendocrine cells. The worldwide incidence and prevalence of the NENs are estimated to be 6/100,000 and 35/100,000, respectively. Those numbers are increasing every decade, requiring higher and higher diagnosis and treatment costs. Radioligand therapy (RLT) using beta-emitting radioisotopes is an efficient and relatively safe method of treatment, typically used as a second-line treatment. RLT tolerability is higher than other available pharmacotherapies (chemotherapy or tyrosine kinase inhibitors). Recent studies show an increase in overall survival among patients treated with RLT. The present study aimed to learn the epidemiology of NENs in Poland and assess the effectiveness of RLT in a high-reference center. A prospective analysis of 167 patients treated with RLT in one of Poland's highest-reference NEN centers was performed. The analysis covered 66 months of observation (1 December 2017-30 May 2023), during which 479 RLT single administrations of radioisotope were given. The standard procedure was to give four courses of [177Lu]Lu-DOTA-TATE alone, or tandem therapy-[177Lu]Lu-DOTA-TATE and [90Y]Y-DOTA-TATE. Grading analysis showed that most patients had non-functioning G2 NEN with a mean Ki-67 of 6.05% (SD ± 6.41). The most common primary tumor location was the pancreas. Over two-thirds of patients did undergo surgery due to primary tumors or distant metastases. The majority of patients were using lanreotide as a chronically injected somatostatin analog. Median progression-free survival (PFS) on somatostatin analogs was 21.0 (IQR = 29.0) months. Directly after the last course of RLT, disease stabilization was noted in 69.46% of patients, partial regression was noted in 20.36% of patients, complete regression was noted in 0.60% of patients, and progression was noted in 9.58% of patients. In long-term follow-up, the median observation time among patients who underwent four treatment cycles (n = 108) was 29.8 (IQR = 23.9) months. Stabilization of the disease was observed in 55.56% of the patients and progression was observed in 26.85% of the patients, while 17.59% of patients died. Median PFS was 29.3 (IQR 23.9), and the median OS was 34.0 months (IQR 16.0). The mean age of NEN diagnosis is the sixth decade of life. It takes almost three years from NEN diagnosis to the start of RLT. In long-term observation, RLT leads to disease stabilization in over half of the patients with progressive disease. No differences in PFS or OS depend on the radioisotope used for RLT. In Poland, organized coordination of NEN treatment in high-reference centers ensures the continuity of patient care.

The Risk of Venous Thromboembolism in Neuroendocrine Neoplasms.

Neuroendocrine neoplasms (NENs) differ from other malignancies in their ability to produce hormones and biogenic amines, as well as offer a better prognosis in well-differentiated tumors. There are no definite data on the occurrence of thromboembolic events in NENs and no recommendations regarding the use of antithrombotic prophylaxis in this group. Accurate assessment of the thromboembolic risk in NENs represents an important issue, in order to reduce morbidity and mortality due to complications of VTE. The aim of this work was to review the occurrence of thromboembolic events in NENs and the use of antithrombotic prophylaxis in this group. A total of 28 studies identified on PubMed were analyzed. NENs, especially of pancreatic primary, exhibit an increased thrombotic risk. Atypical VTE locations are quite common in NENs. Hormonally active NENs are associated with a significantly increased thromboembolic risk. Further studies in NENs are needed to evaluate the parameters of coagulation and fibrinolysis as predictive biomarkers for VTE complications.

European Neuroendocrine Tumour Society (ENETS) 2023 guidance paper for nonfunctioning pancreatic neuroendocrine tumours.

This ENETS guidance paper for well-differentiated nonfunctioning pancreatic neuroendocrine tumours (NF-Pan-NET) has been developed by a multidisciplinary working group, and provides up-to-date and practical advice on the management of these tumours. Using the extensive experience of centres treating patients with NF-Pan-NEN, the authors of this guidance paper discuss 10 troublesome questions in everyday clinical practice. Our many years of experience in this field are still being verified in the light of the results of new clinical, which set new ways of proceeding in NEN. The treatment of NF-Pan-NEN still requires a decision of a multidisciplinary team of specialists in the field of neuroendocrine neoplasms.

Management of hypoparathyroidism: a Position Statement of the Expert Group of the Polish Society of Endocrinology.

Over the past few years, there have been significant advances in our understanding of hypoparathyroidism (HypoPT) in terms of its epidemiology, clinical presentation, etiology, and skeletal and renal complications. Moreover, the available treatment options for HypoPT have changed. This position statement of the Expert Group of the Polish Society of Endocrinology summarizes the current state of knowledge and provides recommendations for optimal management to assist clinicians in the diagnosis, treatment, and monitoring of HypoPT in Poland. The specific aspects of HypoPT management in children, pregnant and lactating women, and patients with chronic kidney disease are also discussed. HypoPT is a rare disorder characterized by hypocalcemia and the lack or deficiency of parathyroid hormone (PTH). Hypoparathyroidism can be associated with complications, including nephrocalcinosis, nephrolithiasis, renal insufficiency, cataract, seizures, cardiac arrhythmia, depression, and an increased risk of infection. Minimizing complications of HypoPT requires careful evaluation and close monitoring of laboratory parameters. Conventional management of HypoPT has focused on maintaining serum calcium levels using oral calcium and active vitamin D. However, this approach is limited because it does not restore normal PTH function, is often associated with inadequate biochemical control, and raises concerns as to long-term side effects. HypoPT is the only classic endocrine insufficiency that is not commonly treated with the substitution of the missing hormone. Recently, recombinant human PTH(1-84) has become available, offering hope that the use of the missing hormone in the treatment of HypoPT will help achieve better control and reduce the risk of complications. However, this treatment is currently unavailable in Poland.

Role of Leptin and Adiponectin in Carcinogenesis.

Hormones produced by adipocytes, leptin and adiponectin, are associated with the process of carcinogenesis. Both of these adipokines have well-proven oncologic potential and can affect many aspects of tumorigenesis, from initiation and primary tumor growth to metastatic progression. Involvement in the formation of cancer includes interactions with the tumor microenvironment and its components, such as tumor-associated macrophages, cancer-associated fibroblasts, extracellular matrix and matrix metalloproteinases. Furthermore, these adipokines participate in the epithelial-mesenchymal transition and connect to angiogenesis, which is critical for cancer invasiveness and cancer cell migration. In addition, an enormous amount of evidence has demonstrated that altered concentrations of these adipocyte-derived hormones and the expression of their receptors in tumors are associated with poor prognosis in various types of cancer. Therefore, leptin and adiponectin dysfunction play a prominent role in cancer and impact tumor invasion and metastasis in different ways. This review clearly and comprehensively summarizes the recent findings and presents the role of leptin and adiponectin in cancer initiation, promotion and progression, focusing on associations with the tumor microenvironment and its components as well as roles in the epithelial-mesenchymal transition and angiogenesis.

Interleukin (IL)-23, IL-31, and IL-33 Play a Role in the Course of Autoimmune Endocrine Diseases.

BACKGROUND: Interleukins (IL)-23, 31, and 33 are involved in the regulation of T helper 17 (Th17)/regulatory T (Treg) cells balance. The role of IL-23, 31 and 33 in non-endocrine autoimmune diseases has been confirmed. Data on the involvement of these cytokines in endocrine autoimmune diseases are limited. OBJECTIVE: This study aimed to determine the involvement of cytokines regulating the T helper 17 (Th17)/regulatory T (Treg) cells axis in the course of autoimmune endocrine diseases. METHODS: A total number of 80 participants were divided into 4 groups: the autoimmune polyendocrine syndrome (APS) group consisting of APS type 2 (APS-2) and type 3 (APS-3) subgroups, the Hashimoto's thyroiditis (HT) group, the Graves' disease (GD) group and the control (C) group. Fifteen cytokines related to Th17 and Treg lymphocytes were determined in the serum of all participants. RESULTS: Higher levels of IL-23 and IL-31 were found in the APS, GD, and HT groups compared to the C group. Higher levels of IL-23 and IL-31 were also observed in the APS-2 group, in contrast to the APS-3 group. Correlation analysis of variables in the groups showed a statistically significant correlation between the cytokines IL-23, IL-31, and IL-33 in the APS and APS-2 groups, but no correlation in the APS-3 and C groups. CONCLUSION: IL-23 and IL-31 are independent factors in the course of HT, GD, and APS-2, in contrast to APS-3. The positive correlation between IL-23 and IL-31, IL-23 and IL-33, and between IL-31 and IL-33 in the APS, APS-2 groups, but the lack of correlation in the APS-3 and C groups may further suggest the involvement of these cytokines in the course of Addison's disease.