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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 (< 125.85 cm 3 vs. ≥ 125.85 cm 3 , p = 0.023) and TTLD (< 4168.95 vs. ≥ 4168.95, p = 0.026) were significantly associated with PFS in the univariate analyses. No significant correlation was found between measured volumetric parameters and OS., Conclusion: Volumetric parameters of pretreatment 68[Ga]Ga-DOTA-TATE PET/CT may be useful in prediction of the response to SSA (used in monotherapy as a first-line therapy) in patients with NET., Competing Interests: Declarations Ethics approval and consent to participate The study protocol was approved by the Commission for Ethics in Scientific Research at the Jagiellonian University Medical College in Krakow (approval no 118.0043.1.1.2024). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements. Consent for publication. Not applicable. Competing interests The authors declare that they have no competing interests., (© 2024. The Author(s).)

Introduction: As transcatheter aortic valve implantation (TAVI) indications expand, understanding the valve degeneration process and potential influencing biomarkers becomes increasingly important., Aim: To investigate temporal changes in biomarker levels and their potential association with 18 F-fluorodeoxyglucose ( 18 F-FDG) and 18 F-sodium fluoride ( 18 F-NaF) uptake, assessed using positron emission tomography/computed tomography (PET/CT) studies as markers for native aortic annulus calcifications and early-stage TAVI valve degeneration., Material and Methods: A total of 71 TAVI patients underwent blood sampling and transthoracic echocardiography at baseline (pre-TAVI) and 6, 12, 18, and 24 months after the procedure. PET/CT using 18 F-NaF and 18 F-FDG was performed at 6 and 24 months. Serum levels of matrix metalloproteinase-3 (MMP-3), matrix metalloproteinase-9 (MMP-9), and osteopontin (OPN) were measured. In addition, plasma levels of osteoprotegerin (OPG), lipoprotein a (Lp(a)), and oxidized LDL (ox-LDL) were assessed., Results: Finally, 31 patients (median age: 84.0 years) completed the study. Valve function improved after TAVI and remained stable during follow-up. Over 24 months, OPN levels decreased ( p = 0.010), while MMP-3 and MMP-9 levels increased ( p = 0.046 and p = 0.041). MMP-3 and MMP-9 showed multiple positive correlations across time points. OPN, ox-LDL, and OPG demonstrated significant negative correlations with follow-up effective orifice area index and effective orifice area (EOA). No significant correlations were found between biomarkers and PET/CT uptake., Conclusions: Significant biomarker changes over 24 months and negative correlations with EOA suggest potential roles in aortic valve function. However, no correlations between biomarkers and PET/CT results were observed., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2024 Termedia Sp. z o. o.)

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., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Jagiellonian Univerity Medical College.)

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.

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&#95;001344 intronic T/C substitution), rs2069762 (T/G substitution in the promoter region of the IL2 NM&#95;000586), rs3731198 ( CDKN2A , NM&#95;000077 intronic A/G substitution), and rs1800872 (C/A substitution in the promoter region of the IL10 NM&#95;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.

Background: Peptide 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 Methods: Out 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., Results: The 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., Conclusions: A 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Opalińska, Morawiec-Sławek, Kania-Kuc, Al Maraih, Sowa-Staszczak and Hubalewska-Dydejczyk.)

Background: Adrenal 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 Methods: We 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., Results: In 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%., Conclusions: Diagnosis 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Rzepka, Kokoszka, Grochowska, Ulatowska-Białas, Lech, Opalińska, Przybylik-Mazurek, Gilis-Januszewska and Hubalewska-Dydejczyk.)

Background: Paraneoplastic neurological syndromes (PNS) affecting the CNS (central nervous system) are rare, presenting in less than 1% of all those with cancer. The pathogenesis of paraneoplastic neurological syndromes is not fully understood, but it is presumed to result from an immune attack on the underlying malignancy. The presence of different types of onconeural antibodies may occur in different tumors and can lead to different clinical manifestations, making the early detection of cancers challenging., Aim: An evaluation of [18F]FDG PET/CT in neoplastic tumor detection in patients with paraneoplastic neurological syndromes having negative or unremarkable results of conventional radiological imaging., Methods: Among all patients diagnosed with paraneoplastic neurological syndromes in the Neurology Department in 2016-2020, 15 patients with unremarkable conventional radiological findings who underwent [18F]FDG PET/CT were included in the study., Results: [18F]FDG PET/CT enabled localization of suspected malignancy in 53% (8 of 15) of PNS cases with previous unremarkable conventional radiological findings., Conclusion: [18F]FDG PET/CT may be considered as a useful tool for neoplastic tumor detection in patients with paraneoplastic neurological syndromes, accelerating the diagnostic process and enabling faster initiation of appropriate treatment.

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Background: Neuroendocrine 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 Methods: The 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., Results: 70% (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., Conclusions: The prognosis and clinical behavior of NETs associated with ovarian teratomas are good with long progression-free survival., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest, (Copyright © 2021 Opalińska, Sowa-Staszczak, Olearska, Ulatowska-Bialas, Gilis-Januszewska and Hubalewska-Dydejczyk.)

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.

Introduction: Neuroendocrine 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., Aim: This study aims to assess whether neoadjuvant PRRT could be a treatment option for patients with initially unresectable NETs., Methods: Among 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., Results: Neoadjuvant PRRT enabled surgery in four out of nine (45%) patients. Finally, in two out of four cases, the goal (radical surgery) has been achieved., Conclusion: PRRT may be considered not only as a palliative but also as a neoadjuvant therapy in advanced, somatostatin-positive NETs that were initially inoperable., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Opalińska, Sowa-Staszczak, Grochowska, Olearska and Hubalewska-Dydejczyk.)

Multiple neuroendocrine neoplasia type 1 (MEN1) is a rare genetic disorder with an autosomal dominant inheritance, predisposing carriers to benign and malignant tumors. The phenotype of MEN1 syndrome varies between patients in terms of tumor localization, age of onset, and clinical aggressiveness, even between affected members within the same family. We describe a heterogenic phenotype of the MEN1 variant c.781C>T (LRG&#95;509t1), which was previously reported only once in a family with isolated hyperparathyroidism. A heterozygous missense variant in exon 4 of the gene was identified in the sequence of the MEN1 gene, i.e., c.781C>T, leading to the amino acid change p.Leu261Phe in a three-generation family. In the screened family, 5/6 affected members had already developed hyperparathyroidism. In the index patient and two other family members, an aggressive course of pancreatic neuroendocrine tumor (insulinoma and non-functioning neuroendocrine tumors) with dissemination was diagnosed. In the index patient, late diagnosis and slow progression of the disseminated neuroendocrine tumor have been observed (24 years of follow-up). The very rare variant of MEN1 , LRG&#95;509t1 c.781C>T /p.Leu261Phe (LRG&#95;509p1), diagnosed within a three-generation family has a heterogenic clinical presentation. Further follow-up of the family members should be carried out to confirm the spectrum and exact time of clinical presentation.

Transcatheter aortic valve implantation (TAVI) is now a well-established treatment for severe aortic stenosis. As the number of procedures and indications increase, the age of patients decreases. However, their durability and factors accelerating the process of degeneration are not well-known. The aim of the study was to verify the possibility of using [ 18 F]F-sodium fluoride ([ 18 F]F-NaF) and [ 18 F]F-fluorodeoxyglucose ([ 18 F]F-FDG) positron emission tomography/computed tomography (PET/CT) in assessing the intensity of TAVI valve degenerative processes. In 73 TAVI patients, transthoracic echocardiography (TTE) at initial (before TAVI), baseline (after TAVI), and during follow-up, as well as transesophageal echocardiography (TEE) and PET/CT, were performed using [ 18 F]F-NaF and [ 18 F]F-FDG at the six-month follow-up (FU) visit as a part of a two-year FU period. The morphology of TAVI valve leaflets were assessed in TEE, transvalvular gradients and effective orifice area (EOA) in TTE. Calcium scores and PET tracer activity were counted. We assessed the relationship between [ 18 F]F-NaF and [ 18 F]F-FDG PET/CT uptake at the 6 = month FU with selected indices e.g.,: transvalvular gradient, valve type, EOA and insufficiency grade at following time points after the TAVI procedure. We present the preliminary PET/CT ([ 18 F]F-NaF, [ 18 F]F-FDG) results at the six-month follow-up period as are part of an ongoing study, which will last two years FU. We enrolled 73 TAVI patients with the mean age of 82.49 ± 7.11 years. A significant decrease in transvalvular gradient and increase of effective orifice area and left ventricle ejection fraction were observed. At six months, FU valve thrombosis was diagnosed in four patients, while 7.6% of patients refused planned controls due to the COVID-19 pandemic. We noticed significant correlations between valve types, EOA and transaortic valve gradients, as well as [ 18 F]F-NaF and [ 18 F]F-FDG uptake in PET/CT. PET/CT imaging with the use of [ 18 F]F-FDG and [ 18 F]F-NaF is intended to be feasible, and it practically allows the standardized uptake value (SUV) to differentiate the area containing the TAVI leaflets from the SUV directly adjacent to the ring calcifications and the calcified native leaflets. This could become the seed for future detection and evaluation capabilities regarding the progression of even early degenerative lesions to the TAVI valve, expressed as local leaflet inflammation and microcalcifications.

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Purpose: To evaluate the optimal tracer uptake time, the minimal amount of radioactivity and the inter-observer agreement for 11 C-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 11 C-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 11 C-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 11 C-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 11 C-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 11 C-choline PET/CT interpretation.

Mitochondria are dynamic, semi-autonomous organelles that execute numerous life-sustaining tasks in eukaryotic cells. Functioning of mitochondria depends on the adequate action of versatile proteinaceous machineries. Fine-tuning of mitochondrial activity in response to cellular needs involves continuous remodeling of organellar proteome. This process not only includes modulation of various biogenetic pathways, but also the removal of superfluous proteins by adenosine triphosphate (ATP)-driven proteolytic machineries. Accordingly, all mitochondrial sub-compartments are under persistent surveillance of ATP-dependent proteases. Particularly important are highly conserved two inner mitochondrial membrane-bound metalloproteases known as m -AAA and i -AAA (ATPases associated with diverse cellular activities), whose mis-functioning may lead to impaired organellar function and consequently to development of severe diseases. Herein, we discuss the current knowledge of yeast, mammalian, and plant AAA proteases and their implications in mitochondrial function and homeostasis maintenance.

Mitochondria are multifunctional organelles that play a central role in energy metabolism. Owing to the life-essential functions of these organelles, mitochondrial content, quality and dynamics are tightly controlled. Across the species, highly conserved ATP-dependent proteases prevent malfunction of mitochondria through versatile activities. This study focuses on a molecular function of the plant mitochondrial inner membrane-embedded AAA protease (denoted i -AAA) FTSH4, providing its first bona fide substrate. Here, we report that the abundance of the Tim17-2 protein, an essential component of the TIM17:23 translocase (Tim17-2 together with Tim50 and Tim23), is directly controlled by the proteolytic activity of FTSH4. Plants that are lacking functional FTSH4 protease are characterized by significantly enhanced capacity of preprotein import through the TIM17:23-dependent pathway. Taken together, with the observation that FTSH4 prevents accumulation of Tim17-2, our data point towards the role of this i -AAA protease in the regulation of mitochondrial biogenesis in plants., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2018. Published by The Company of Biologists Ltd.)

Maintenance of functional mitochondria is vital for optimal cell performance and survival. This is accomplished by distinct mechanisms, of which preservation of mitochondrial protein homeostasis fulfills a pivotal role. In plants, inner membrane-embedded i -AAA protease, FTSH4, contributes to the mitochondrial proteome surveillance. Owing to the limited knowledge of FTSH4's in vivo substrates, very little is known about the pathways and mechanisms directly controlled by this protease. Here, we applied substrate trapping coupled with mass spectrometry-based peptide identification in order to extend the list of FTSH4's physiological substrates and interaction partners. Our analyses revealed, among several putative targets of FTSH4, novel (mitochondrial pyruvate carrier 4 (MPC4) and Pam18-2) and known (Tim17-2) substrates of this protease. Furthermore, we demonstrate that FTSH4 degrades oxidatively damaged proteins in mitochondria. Our report provides new insights into the function of FTSH4 in the maintenance of plant mitochondrial proteome., Competing Interests: The authors declare no competing financial interests.

Mitochondria play the fundamental role in energy production and integration of many important metabolic and signalling pathways, which makes them essential for the function of a cell. The optimal operation of mitochondria depends on the qualitative and quantitative composition of the organellar proteins - the proteome. To maintain the homeostasis of the mitochondrial proteome, mitochondria developed a protein quality control system, which acts on the molecular, cellular and organellar levels. ATP-dependent proteases constitute a key element of this system. It consists of Lon/PIM1 and ClpXP proteases located in the mitochondrial matrix as well as AAA proteases anchored in the inner mitochondrial membrane. The ATP-dependent proteases degrade misfolded, damaged or not assembled proteins. These enzymes are also involved in complex regulatory mechanisms such as mitochondrial translation, fusion and response to stress. Lack of any of ATP-dependent proteases leads to mitochondrial dysfunction and the development of many major diseases in humans. This work summarizes the current knowledge of the ATP-dependent proteolytic system in mitochondria in different organisms.

Detection of neuroendocrine neoplasms (NENs) and monitoring of their response to therapy is still challenging due to huge heterogeneity of that group of tumors. Actually, NENs visualization is mainly based on molecular imaging while in the past it was relied on less effective structural imaging including CT and MRI. Molecular imaging techniques in combination with structural imaging (hybrid imaging), especially in patients with well-differentiated NENs, in addition to morphological provide the functional information about tumor which benefits in a more accurate patient management, including more sensitive visualization of primary tumors, more precise staging and better therapy follow-up. Overexpression of somatostatin receptors (SSTR) on NENs' cell membrane was a basis for development of somatostatin receptor scintigraphy (SRS) using single photon emission tomography SPECT, which is today a well-established standard in molecular imaging of NENs, and further imaging improvement in the field of positron emission tomography (PET). Use of hybrid imaging (SPECT/CT, PET/CT) increased sensitivity of examination, mainly resulting in better detection of small lesions. Generally, somatostatin receptor imaging with PET/CT is an emerging technique, although still with limited access, but due to several advantages over SSTR SPECT/CT, should be used if available. It is worth mentioning, that both SSTR PET/CT and SSTR SPECT/CT have some limitations, such as relatively low detection rate of benign insulinomas, poorly differentiated GEP-NETs and liver metastases. For that reason further improvement of NETs imaging is necessary. The most promising new tracers' families are based on SSTR antagonists, 64Cu-radiolabeled ligands and glucagon-like peptide-1 receptor (GLP-1R) imaging. Finally, in case of poor-differentiated neuroendocrine cancers 18F-FDG PET/CT may be beneficial in comparison with molecular imaging based on somatostatin receptor modalities.

Import and assembly of mitochondrial proteins depend on a complex interplay of proteinaceous translocation machineries. The role of lipids in this process has been studied only marginally and so far no direct role for a specific lipid in mitochondrial protein biogenesis has been shown. Here we analyzed a potential role of phosphatidic acid (PA) in biogenesis of mitochondrial proteins in Saccharomyces cerevisiae. In vivo remodeling of the mitochondrial lipid composition by lithocholic acid treatment or by ablation of the lipid transport protein Ups1, both leading to an increase of mitochondrial PA levels, specifically stimulated the biogenesis of the outer membrane protein Ugo1, a component of the mitochondrial fusion machinery. We reconstituted the import and assembly pathway of Ugo1 in protein-free liposomes, mimicking the outer membrane phospholipid composition, and found a direct dependency of Ugo1 biogenesis on PA. Thus, PA represents the first lipid that is directly involved in the biogenesis pathway of a mitochondrial membrane protein.

Mitochondria have to import most of their proteins in order to fulfill a multitude of metabolic functions. Sophisticated import machineries mediate targeting and translocation of preproteins from the cytosol and subsequent sorting into their suborganellar destination. The mode of action of these machineries has been considered for long time as a static and constitutively active process. However, recent studies revealed that the mitochondrial protein import machinery is subject to intense regulatory mechanisms that include direct control of protein flux by metabolites and metabolic signalling cascades., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Mitochondria play central roles in cellular energy conversion, metabolism, and apoptosis. Mitochondria import more than 1000 different proteins from the cytosol. It is unknown if the mitochondrial protein import machinery is connected to the cell division cycle. We found that the cyclin-dependent kinase Cdk1 stimulated assembly of the main mitochondrial entry gate, the translocase of the outer membrane (TOM), in mitosis. The molecular mechanism involved phosphorylation of the cytosolic precursor of Tom6 by cyclin Clb3-activated Cdk1, leading to enhanced import of Tom6 into mitochondria. Tom6 phosphorylation promoted assembly of the protein import channel Tom40 and import of fusion proteins, thus stimulating the respiratory activity of mitochondria in mitosis. Tom6 phosphorylation provides a direct means for regulating mitochondrial biogenesis and activity in a cell cycle-specific manner., (Copyright © 2014, American Association for the Advancement of Science.)

Despite the simplicity of the yeast Saccharomyces cerevisiae, its basic cellular machinery tremendously mirrors that of higher eukaryotic counterparts. Thus, this unicellular organism turned out to be an invaluable model system to study the countless mechanisms that govern life of the cell. Recently, it has also enabled the deciphering of signalling pathways that control flux of mitochondrial proteins to the organelle according to metabolic requirements. For decades mitochondria were considered autonomous organelles that are only partially incorporated into cellular signalling networks. Consequently, only little has been known about the role of reversible phosphorylation as a meaningful mechanism that orchestrates mitochondrial biology accordingly to cellular needs. Therefore, research in this direction has been vastly neglected. However, findings over the past few years have changed this view and new exciting fields in mitochondrial biology have emerged. Here, we summarize recent discoveries in the yeast model system that point towards a vital role of reversible phosphorylation in regulation of mitochondrial protein import., Competing Interests: Conflict of interest: The authors declare no conflict of interest.

Most mitochondrial proteins are imported by the translocase of the outer mitochondrial membrane (TOM). Tom22 functions as central receptor and transfers preproteins to the import pore. Casein kinase 2 (CK2) constitutively phosphorylates the cytosolic precursor of Tom22 at Ser44 and Ser46 and, thus, promotes its import. It is unknown whether Tom22 is regulated under different metabolic conditions. We report that CK1, which is involved in glucose-induced signal transduction, is bound to mitochondria. CK1 phosphorylates Tom22 at Thr57 and stimulates the assembly of Tom22 and Tom20. In contrast, protein kinase A (PKA), which is also activated by the addition of glucose, phosphorylates the precursor of Tom22 at Thr76 and impairs its import. Thus, PKA functions in an opposite manner to CK1 and CK2. Our results reveal that three kinases regulate the import and assembly of Tom22, demonstrating that the central receptor is a major target for the posttranslational regulation of mitochondrial protein import., (Copyright © 2013 Elsevier Inc. All rights reserved.)