Association between serum TSH concentration and bone mineral density: an umbrella review.

INTRODUCTION: The aim of this study was to summarize the results of previous studies, standardize the data, and present new statistical results in order to provide physicians with clinically significant outcomes regarding the association between serum TSH concentration and bone mineral density (BMD). METHODS: To perform this umbrella review, a systematic search was conducted in which major online medical databases, such as PubMed, Web of Science, Embase, Scopus, Cochrane Library, and Google Scholar, were searched for meta-analyses and systematic reviews regarding the effect of TSH on BMD. Furthermore, all primary studies were screened for statistical analysis. RESULTS: The statistical outcomes of the present study were based on the data of 75,898 patients. The pooled risk ratio of any kind of fracture in patients with subclinical hyperthyroidism was estimated to be 1.36 (95% CI: 1.18-1.56; p < 0.001). The SMD for BMD in the distal radius in male patients receiving L-thyroxine suppression therapy was estimated to be -0.61 (95% CI: -1.10-(-0.11); p = 0.02). Furthermore, the pooled risk ratio of any fracture in patients receiving L-thyroxine suppression therapy was estimated to be 1.98 (95% CI: 0.98 - 3.98; p = 0.06). In these patients, the BMD may significantly differ from that in non-treated patients. However, the difference depends on the type of bone. CONCLUSIONS: Our data confirmed that subclinical hyperthyroidism has a detrimental effect on bones, causing decreased BMD. Based on the obtained results, the authors suggest that a reduced TSH serum level itself may be an individual factor associated with decreased BMD and, thus, with a greater risk of bone fracture. Nevertheless, it should be noted that the effects of TSH suppression therapy differ between areas of interest for assessing BMD. Furthermore, the results have shown that this issue may, in specific areas, concern not only postmenopausal women but also male patients. These conclusions should contribute to a careful consideration of the application of TSH suppressive therapy in all patients. Particular attention should be given to patients after DTC, while all the advantages and disadvantages of implementing L-thyroxine therapy should be individually considered.

A challenging case of ectopic ACTH-dependent Cushing's syndrome due to medullary thyroid carcinoma.

Not required for Clinical Vignette.

The thrombotic risk in Cushing's syndrome-questions, answers, and the algorithm to consider in its assessment: part I-thrombotic risk not related to surgery.

Introduction: Recently, 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. Methods: The 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. Results: To 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. Summary: Our 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.

Prediction of disease recurrence in patients after complete pancreatic NET (PanNET) G2 resection.

INTRODUCTION: The number of detected pancreatic neuroendocrine tumours (PanNETs) has been increasing over the last decades. Surgical resection remains the only potentially curative treatment, but the management is still controversial. This study aimed to compare patients after radical PanNET G2 resection to determine the most important predictive factors for relapse. MATERIAL AND METHODS: All patients with histologically confirmed PanNET G2 who underwent successful surgery between 2006 and 2020 with the intention of radical treatment were enrolled. RESULTS: In total, 44 patients were eligible for the analysis. The average follow-up was 8.39 ± 4.5 years. Disease recurrence was observed in 16 (36.36%) patients. The dominant location of the primary tumour was the tail of the pancreas (43.18%), especially in the subgroup with disease recurrence (56.25%). The smallest tumour diameter associated with the PanNET G2 recurrence was 22 mm. The relationship between the largest dimension of the tumour with a division of < 4 cm vs. > 4 cm and the relapse was close to statistical significance. Recurrence was associated with a larger tumour size (p = 0.018). There was a statistically significant relationship and a weak correlation between Ki-67 (p = 0.036, V Cramer = 0.371) and disease relapse. CONCLUSION: For the group of PanNET G2 patients after radical surgery, the overall risk of recurrence was 36.36%, with the highest rate in the first 5 years after surgery, but in individual cases it occurred significantly later, even 10 years after surgery. The most important predictive factors of the PanNET G2 recurrence was Ki-67 over 5.75% and size of tumour > 4 cm.

24-hour urine metanephrine excretion in patients diagnosed with adrenal incidentaloma: impact of commonly used drugs on a clinical decision.

INTRODUCTION: Incidentaloma is an adrenal tumor detected during diagnostic imaging performed for extra­adrenal causes. Evaluation of metanephrine concentrations in a 24­hour urine collection can be a significant challenge in patients with multiple medications and comorbidities. OBJECTIVES: The aim of this study was to evaluate the effect of commonly used groups of drugs on metanephrine levels in the 24­hour urine collection. PATIENTS AND METHODS: A total of 1051 patients with adrenal mass below 10 Hounsfield units on unenhanced computed tomography were included in the study. Patients diagnosed with Cushing or Conn syndrome, adrenal carcinoma, pheochromocytoma, active extra­adrenal malignant neoplasms, and exacerbation of severe illnesses were excluded. Metanephrine, normetanephrine, and 3­methoxytyramine in the 24­hour urine collection were measured by high­performance liquid chromatography with electrochemical detection. Information on concomitant medication (ß­blockers, calcium channel blockers [CCBs], loop diuretics, thiazide diuretics, potassium­sparing diuretics, α­blockers, angiotensin­converting enzyme inhibitors / angiotensin II receptor blockers, metformin, nonmetformin antidiabetic drugs [NMADs], lipid­lowering drugs, proton pump inhibitors, levothyroxine, thyreostatics, antidepressants, neuroleptics, benzodiazepines, glucocorticosteroids, inhaled B­receptor agonists, and ipratropium) was collected from each patient. RESULTS: The urinary excretion of normetanephrine was significantly higher in the patients on ß­blockers, CCBs, loop diuretics, α­blockers, NMADs, and neuroleptics. α­Blockers increased urine metanephrine concentration, and NMADs, antidepressants, and glucocorticosteroids lowered it. There was no association between the analyzed drugs and urinary 3­methoxytyramine level. CONCLUSIONS: Many drug groups interfere with the measurement of urinary fractionated metanephrines. These interactions should be taken into account during interpretation of a hormonal evaluation, as they can be crucial for further management, especially for making a decision on surgical treatment.

Whole-Exome Screening and Analysis of Signaling Pathways in Multiple Endocrine Neoplasia Type 1 Patients with Different Outcomes: Insights into Cellular Mechanisms and Possible Functional Implications.

Multiple endocrine neoplasia type 1 (MEN1) is a syndrome characterized by tumors in multiple organs. Although being a dominantly inherited monogenic disease, disease phenotypes are unpredictable and differ even among members of the same family. There is growing evidence for the role of modifier genes in the alteration of the course of this disease. However, genome-wide screening data are still lacking. In our study, we addressed the different outcomes of the disease, focusing on pituitary and adrenocortical tumors. By means of exome sequencing we identified the affected signaling pathways that segregated with those symptoms. Most significantly, we identified damaging alterations in numerous structural genes responsible for cell adhesion and migration. Additionally, in the case of pituitary tumors, genes related to neuronal function, survival, and morphogenesis were repeatedly identified, while in patients with adrenocortical tumors, TLR10, which is involved in the regulation of the innate immunity, was commonly modified. Our data show that using exome screening, it is possible to find signatures which correlate with the given clinical MEN1 outcomes, providing evidence that studies addressing modifier effects in MEN1 are reasonable.

Differences in clinical characteristics, treatment, and outcomes of sporadic and MEN-1-related insulinomas.

INTRODUCTION: Although in most cases insulinomas are small, benign, sporadic tumours, they can also be associated with hereditary syndromes, most commonly multiple endocrine neoplasia type 1 (MEN-1). Such a diagnosis significantly affects patient management. The objective was to elucidate the clinical differences between sporadic and MEN-1-linked insulinoma. MATERIAL AND METHODS: Comparison of clinical and histopathological characteristics, types of surgery, and outcomes of patients with sporadic and MEN-1-related insulinoma diagnosed between 2015 and 2022. RESULTS: There were 17 cases of insulinomas that underwent MEN-1 genetic testing (10 women and 7 men). In 7 cases, the mutation in the menin gene was confirmed. The median age at the time of diagnosis of sporadic insulinoma related to MEN-1 was 69 years (range 29-87) and 31.5 years (16-47), respectively. Primary hyperparathyroidism (PHP) was found in 6 of 7 patients with MEN-1-related insulinoma, while in none of the patients without MEN-1 mutations. Multifocal pancreatic NETs were found in 3 patients with MEN-1 syndrome, while in all sporadic cases there was a single pancreatic tumour. Two patients with insulinoma related to MEN-1 had a positive familial history of MEN-1-related diseases, while none with sporadic form. Dissemination at diagnosis was found in 4 cases, including 3 patients with insulinoma related to MEN-1-related insulinoma. Patients with sporadic and MEN-1-related insulinoma did not differ in tumour size, Ki-67 proliferation index, and outcome. CONCLUSIONS: Of all the features evaluated, only the multifocal nature of pancreatic neuroendocrine tumour (PanNET) lesions and a positive family history differentiated between patients with sporadic and MEN-1-related insulinomas. An age of insulinoma diagnosis of less than 30 years may be a strong indicator of an increased risk of MEN-1 syndrome.

Difficulties in the diagnosis and treatment of ruptured pheochromocytoma.

Not required fo Clinical Vignette.

Development of the 99mTc-Labelled SST2 Antagonist TECANT-1 for a First-in-Man Multicentre Clinical Study.

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.

AIP gene germline variants in adult Polish patients with apparently sporadic pituitary macroadenomas.

Introduction: Up to 5% of all pituitary tumors are hereditary e.g. due to MEN1 or aryl hydrocarbon receptor-interacting protein (AIP) genes mutations. Objectives: The 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 methods: The 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. Results: AIP 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). Conclusions: In 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.

Whole-exome sequencing as a tool for searching for genetic background modifiers in MEN1 patients with neuroendocrine pancreatic tumours, including insulinomas.

INTRODUCTION: Multiple endocrine neoplasia type 1 (MEN1) is a monogenic disease caused by inactivating variants in the MEN1 gene. Although the reason for its development is well-known, disease phenotypes are unpredictable and differ even among carriers of the same pathogenic driver mutation. Genetic, epigenetic, and environmental factors may play a role in driving the individual phenotype. Those factors, however, still mostly remain unidentified. In our work, we focused on the inherited genetic background in pancreatic neuroendocrine neoplasms (pNENs) in MEN1 patients, and the pancreatic tumour subgroup with insulinoma. MATERIAL AND METHODS: Whole exome sequencing was performed in MEN1 patients. The symptoms of interest were pancreatic neuroendocrine tumours in one analysis and insulinoma in the second. The study included families as well as unrelated cases. Genes with variants that are not neutral to the encoded gene product were defined in symptom-positive patients as compared to symptom-negative controls. The interpretation of the results was based on functional annotations and pathways shared between all patients with the given symptom in the course of MEN1. RESULTS: Whole-exome screening of family members and unrelated patients with and without pNENs revealed a number of pathways that are common for all the analysed cases with pNENs. Those included pathways crucial for morphogenesis and development, proper insulin signalling, and structural cellular organization. An additional analysis of insulinoma pNEN patients revealed additional pathways engaged in glucose and lipid homeostasis, and several non-canonical insulin-regulating mechanisms. CONCLUSIONS: Our results show the existence of pathways that are identified in a non-literature-predefined manner, which might have a modifying function in MEN1, differentiating the specific clinical outcomes. Those results, although preliminary, provide evidence of the reasonableness of performing large-scale studies addressing the genetic background of MEN1 patients in determining their individual outcomes.

A patient with advanced breast cancer and hyperthyroidism associated with struma ovarii.

Not required for Clical Vignettes.

[111In]In-CP04 as a novel cholecystokinin-2 receptor ligand with theranostic potential in patients with progressive or metastatic medullary thyroid cancer: final results of a GRAN-T-MTC Phase I clinical trial.

INTRODUCTION: Medullary thyroid cancer (MTC) is a rare malignant tumour of the parafollicular C-cells with an unpredictable clinical course and currently suboptimal diagnostic and therapeutic options, in particular in advanced disease. Overexpression of cholecystokinin-2 receptors (CCK2R) represents a promising avenue to diagnostic imaging and targeted therapy, ideally through a theranostic approach. MATERIALS AND METHODS: A translational study (GRAN-T-MTC) conducted through a Phase I multicentre clinical trial of the indium-111 labelled CP04 ([111In]In-CP04), a CCK2R-seeking ligand was initiated with the goal of developing a theranostic compound. Patients with proven advanced/metastatic MTC or short calcitonin doubling time were enrolled. A two-step concept was developed through the use of low- and high-peptide mass (10 and 50 µg, respectively) for safety assessment, with the higher peptide mass considered appropriate for therapeutic application. Gelofusine was co-infused in a randomized fashion in the second step for the evaluation of potential reduction of the absorbed dose to the kidneys. Imaging for the purpose of biodistribution, dosimetry evaluation, and diagnostic assessment were performed as well as pre-, peri-, and postprocedural clinical and biochemical assessment. RESULTS: Sixteen patients were enrolled. No serious adverse events after application of the compound at both peptide amounts were witnessed; transient tachycardia and flushing were observed in two patients. No changes in biochemistry and clinical status were observed on follow-up. Preliminary dosimetry assessment revealed the highest dose to urinary bladder, followed by the kidneys and stomach wall. The effective dose for 200 MBq of [111In]In-CP04 was estimated at 7±3 mSv and 7±1 mSv for 10 µg and 50 µg CP04, respectively. Administration of Gelofusine reduced the dose to the kidneys by 53%, resulting in the organ absorbed dose of 0.044±0.019 mSv/MBq. Projected absorbed dose to the kidneys with the use of [177Lu]Lu-CP04 was estimated at 0.9±0.4 Gy/7.4 GBq. [111In]In-CP04 scintigraphy was positive in 13 patients (detection rate of 81%) with superior diagnostic performance over conventional imaging. CONCLUSION: In the present study, [111In]In-CP04 was shown to be a safe and effective radiopharmaceutical with promising theranostic characteristics for patients with advanced MTC.

Individualized medical treatment options in Cushing disease.

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.

Pituitary stalk metastasis of a neuroendocrine tumour of unknown origin.

Not required for Clinical Vignettes.

Prevalence of Selected Single-Nucleotide Variants in Patients with Neuroendocrine Tumors-Potential Clinical Relevance.

INTRODUCTION: The genetic basis of neuroendocrine tumors (NETs), whose incidence is continuously increasing, is still not fully defined. The majority of NETs are sporadic, and only a small percentage occur as part of hereditary genetic syndromes. However, the associations of multiple genetic variants have been found as clinically relevant in several neoplasms. The aim of this study was to evaluate whether selected, literature-based genetic variants may have a potential role in NET susceptibility and clinical outcome in Polish patients. MATERIALS/METHODS: A total of 185 patients recruited from one clinical center were enrolled. In the first part of the study, the molecular analysis including four single-nucleotide variants (rs8005354 (DAD1, NM_001344 intronic T/C substitution), rs2069762 (T/G substitution in the promoter region of the IL2 NM_000586), rs3731198 (CDKN2A, NM_000077 intronic A/G substitution), and rs1800872 (C/A substitution in the promoter region of the IL10 NM_000572)) was performed in 107 participants (49 patients with NETs with different primary site NETs and a control group of 58 healthy adult volunteers). In the second stage, the same single-nucleotide polymorphisms (SNPs) were assessed in 127 patients with NET and analyzed in terms of clinical data (primary site, serum CgA concentration, and metastatic disease). RESULTS: The analysis of homozygotes revealed a statistically significant higher prevalence of TT homozygotes of variant rs3731198 in the control group (p = 0.0209). In NET patients, there was a statistically significant higher prevalence of GG homozygotes of variant rs1800872 (p = 0.003). There was a statistically significant correlation between the rs3731198 variant and lymph node metastases (p = 0.0038 with Bonferroni correction). CONCLUSIONS: Our study indicates that GG homozygotes of variant rs1800872 are more often observed in NET patients, while TT homozygotes of variant rs3731198 are less frequent in this group. The rs3731198 variant may be related to an increased risk of lymph node metastasis. Further, larger multicenter studies are warranted to evaluate the potential genetic factors of sporadic NETs.