Marta Opalińska

Objective: Most neuroendocrine neoplasms (NENs) are sporadic and occur predominantly in older patients. Early-age disease onset has been increasingly observed in NENs. We aimed to assess the clinical features and outcomes of young adults with sporadic NENs. Design: This is a retrospective study which gathered 20 institutions from 12 countries under the auspices of Women in NET (WiN) ENETS group. Methods: Young patients aged 18-40 years diagnosed with sporadic NENs (well- and poorly-differentiated) from 2010-2020 were enrolled. Patients with appendiceal and type 1 gastric NETs, hereditary syndromes, synchronous malignancy, phaeochromocytoma, paraganglioma, and medullary thyroid cancer, were excluded. Descriptive statistics, comparisons between groups, survival and Cox multivariable analysis were performed. Results: Overall, 478 young patients with sporadic NENs were enrolled. Localised (62%, n=249), well-differentiated (92%, n=433), non-functioning tumours (81%, n=384) and women (58%, n=277) were more prevalent. The pancreas was the most common primary site (33%, n=159). Metastatic disease at diagnosis was more often found in men than women (47%, n=78 vs. 33%, n=78, p=0.004). Five-year OS was 82%. OS was significantly longer in women than men (p=0.019), as well as in rectal (p=0.00245) and lung (p=0.0027) primary tumours compared to pancreatic NENs. The multivariable analysis identified stage, Ki-67, morphology and gender as independent predictors of survival. Conclusions: Young patients with NENs often present with well-differentiated and localised tumours, thereby increasing the probability of curative surgical resection. Prospective research into molecular biology is needed to identify distinct NEN features in young adults and determine risk factors to tailor effective treatment strategies.

Objective. This work presents and evaluates a Monte Carlo (MC) -based scatter correction (SC) method developed for the Jagiellonian positron emission tomography (J-PET) scanner, a modular PET system based on plastic scintillators. Approach. The algorithm employs SimSET-based simulations integrated into a time-of-flight ordered-subsets expectation maximization reconstruction framework to estimate scatter contributions. Phantom studies using the NEMA image quality (IQ) phantom and a proof-of-principle human subject scan with the J-PET scanner were analyzed. To accelerate computation, lutetium–yttrium oxyorthosilicate (LYSO) crystals were also assessed in simulations as a surrogate for the native plastic material BC-404. Main results. In phantom experiments, SC improved contrast recovery coefficients by over 20% and reduced background variability by 8.5%, without introducing significant noise. Residual activity in cold regions was also considerably reduced. Substituting LYSO in the simulations decreased runtime by nearly one order of magnitude, while maintaining deviations below 6% in IQ metrics compared to BC-404. Human subject data demonstrated qualitatively reduced residual scatter and improved organ delineation. Quantitative comparison with the commercial PET/CT scanner by General Electric HealthCare (GE) discovery MI Gen 2 showed consistent activity concentration ratios across organs, although higher noise and residual scatter between organs were observed in J-PET, which most likely originates from lower count density. Significance. The proposed MC-based SC method provides robust scatter removal for J-PET, improving quantitative performance and establishing a foundation for advanced correction and reconstruction techniques. These results bring the plastic scintillator-based J-PET scanner closer to enabling clinically relevant quantitative PET imaging.

Background: PRRT with [ ¹⁷⁷ Lu]Lu-DOTA-TATE improves survival in advanced GEP-NETs, but fixed-activity dosing may result in undertreatment or unnecessary toxicity. Individualized dosimetry and tandem-PRRT with ⁹⁰ Y/ ¹⁷⁷ Lu have been proposed, but prospective randomized evidence is lacking. Methods: DUONEN is an ongoing multicenter, randomized phase 3 trial (N = 92 planned; 56 analyzed) comparing standard fixed-activity [ ¹⁷⁷ Lu]Lu-DOTA-TATE (arm A) with three dosimetry-guided regimens: arm B ( ¹⁷⁷ Lu+ ⁹⁰ Y, variable ⁹⁰ Y); arm C ( ¹⁷⁷ Lu+ ⁹⁰ Y, variable ¹⁷⁷ Lu); arm D (variable ¹⁷⁷ Lu). Organ dosimetry was performed after each cycle, with per-cycle activity modifications to respect kidney (23 Gy) and marrow (2 Gy) thresholds. Safety was assessed by laboratory, renal, and hepatic parameters. Results: Activity reductions predominated in arms B and C, while increases were common in arm D. Median cumulative kidney and marrow doses were highest in arm C (29.1 Gy and 0.79 Gy, respectively), driven by ⁹⁰ Y contribution. Hematologic declines were observed across all arms, most prominently in lymphocytes and platelets, and correlated with marrow dose but not with categorical dose modifications. Renal function remained stable, and no clinically relevant hepatotoxicity occurred. Conclusions: This interim analysis demonstrates the feasibility and safety of dosimetry-guided PRRT strategies, including individualized ¹⁷⁷ Lu escalation and tandem ⁹⁰ Y/ ¹⁷⁷ Lu. DUONEN provides the first randomized prospective evidence for isotope- and patient-tailored PRRT dosing. Long-term follow-up will clarify their impact on efficacy. Clinical trial registration: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2020-006068-99 , identifier 2020-006068-99.

Objectives: The current standard of care for endocrine tumors includes a personalized diagnostic and therapeutic approach aimed at the early detection of tumor recurrence after radical surgery. Assessment of tumor-associated biological factors in serum may be useful in patient management. The aim of this study is to determine whether any of the selected growth factors (VEGF, FGF), lectins (Galectin-1, Galectin-3), proteins (Fascin), or TNF-α measured in serum may serve as a potential marker of recurrence. Methods: A total of 68 cases, including 43 patients with disseminated endocrine neoplasm (neuroendocrine tumor (NET) 30 cases, medullary thyroid cancer (MTC) 6 cases, adrenal neoplasm 7 cases) and 25 healthy participants, were included in the analysis. Serum concentrations of TNF-α, Fascin, VEGF, Galectin-1, Galectin-3, and FGF were determined in all cases. The results were compared between groups. Results: A comparison between all patients and controls revealed differences in TNF-α concentrations (2.88 vs. 0.93 (ng/mL), p = 0.008). When comparing the concentrations of the measured factors between the subgroups (classified by tumor type) and the control group, differences were found for TNF-α (p = 0.007) and Fascin (p = 0.035). In the case of Fascin, differences were found for MTC and adrenal neoplasm patients (0.52 vs. 5.28 (ng/mL), p = 0.048), as well as MTC and NET patients (0.52 vs. 5.59 (ng/mL), p = 0.007), while the differences between NET patients and controls were close to significance (5.59 vs. 3.67 (ng/mL), p = 0.076). For TNF-α, significant differences were found between NET patients and controls (2.88 vs. 0.03 (ng/mL), p = 0.005) as well as between MTC patients and controls (2.77 vs. 0.93 (ng/mL), p = 0.004). Conclusions: Serum concentrations of selected proteins and growth factors (Fascin, TNF-α) are significantly higher in those with disseminated endocrine tumors compared to healthy controls. More studies are needed to determine the role of these selected proteins and growth factors in the early detection of NET/MTC recurrence.

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. 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.

Introduction The number of detected pancreatic neuroendocrine tumors (PanNETs) is increasing over the last decades. Surgical resection remains the only potentially curative treatment, yet 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 the successful surgery between 2006-2020 with intention of radical treatment were enrolled. Results There was forty-four patients eligible for the analysis. The average follow-up was 8.39±4.5 years. The disease recurrence was observed in 16 (36.36%) patients. The dominant location of the primary tumor was the tail of the pancreas (43.18%), especially in the subgroup with the disease recurrence (56.25%). The relationship between the largest dimension of the tumor with a division of 4 cm and the relapse was close to statistical significance (p=0.077). Recurrence was associated with a larger tumor 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 The most important predictive factors of the NET G2 recurrence after radical surgery were Ki67 over 5% and the largest dimension of tumor over 4cm.

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.

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.

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.