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.

18F-fluorodeoxyglucose and 18F-sodium fluoride positron emission tomography imaging in assessing early stages of aortic valve degeneration after transcatheter aortic valve implantation.

INTRODUCTION: Transcatheter aortic valve implantation (TAVI) is a standard treatment for severe aortic stenosis, primarily in elderly patients. With an increasing number of procedures and younger patients, understanding the valve degeneration and its risk factors becomes crucial. OBJECTIVES: We aimed to utilize 18F­sodium fluoride (18F­NaF) and 18F­fluorodeoxyglucose (18F­FDG) positron emission tomography/computed tomography (PET/CT) to evaluate early TAVI valve degeneration. PATIENTS AND METHODS: In this prospective study with a prespecified follow­up protocol, 71 TAVI patients underwent baseline transthoracic and transesophageal echocardiography, and PET/CT with 18F­NaF and 18F­FDG. Of these, 31 patients completed 24­month control examinations, while the others were lost to mortality and the COVID­19 pandemic. We measured PET tracer activity and compared 18F­NaF and 18F­FDG PET/CT uptake at baseline and 24­month follow­up. RESULTS: PET/CT and echocardiography data were analyzed for 31 of the 71 enrolled TAVI patients at a median age of 84 years (interquartile range, 80-86). After TAVI, an improvement in the valve function was observed. During follow­up, the valve function remained stable. PET/CT demonstrated an increase in 18F­FDG maximal uptake in the inner (tissue­to­background ratio, P = 0.009) and outer (P = 0.01) sides of the TAVI valve stent, but no difference in 18F­NaF maximal activity (inner, P = 0.17; outer, P = 0.57). CONCLUSIONS: Twenty­four months post­TAVI, an increase in 18F­FDG uptake, indicative of inflammation, was observed in the valve, while the uptake of the calcification marker (18F­NaF) remained stable. Theseobservations might suggest early stages of TAVI valve degeneration, although further investigation is required to confirm this interpretation.

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.

Pituitary stalk metastasis of a neuroendocrine tumour of unknown origin.

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Update of the diagnostic and therapeutic guidelines for gastro-entero-pancreatic neuroendocrine neoplasms (recommended by the Polish Network of Neuroendocrine Tumours) [Aktualizacja zalecen ogólnych dotyczacych postepowania diagnostyczno-terapeutycznego w nowotworach neuroendokrynnych ukladu pokarmowego (rekomendowane przez Polska Siec Guzów Neuroendokrynnych)].

Continuous progress in the diagnostics and treatment of neuroendocrine neoplasms (NENs), the emerging results of new clinical trials, and the new guidelines issued by medical societies have prompted experts from the Polish Network of Neuroendocrine Tumours to update the 2017 recommendations regarding the management of neuroendocrine neoplasms. This article presents the general recommendations for the management of NENs, resulting from the findings of the experts participating in the Fourth Round Table Conference, entitled "Polish Guidelines for the Diagnostics and Treatment of Neuroendocrine Neoplasms of the gastrointestinal tract, Zelechów, June 2021". Drawing from the extensive experience of centres treating these cancers, we hope that we have managed to formulate the optimal method of treating patients with NENs, applying the latest reports and achievements in the field of medicine, which can be effectively implemented in our country. The respective parts of this work present the approach to the management of: NENs of the stomach and duodenum (including gastrinoma), pancreas, small intestine, and appendix, as well as large intestine.

Pancreatic neuroendocrine neoplasms - update of the diagnostic and therapeutic guidelines (recommended by the Polish Network of Neuroendocrine Tumours) [Nowotwory neuroendokrynne trzustki - uaktualnione zasady diagnostyki i leczenia (rekomendowane przez Polska Siec Guzów Neuroendokrynych)].

In this paper, we present the current guidelines for the diagnostics and management of pancreatic neuroendocrine neoplasms (PanNENs) developed by Polish experts providing care for these patients in everyday clinical practice. In oncological diagnostics, in addition to biochemical tests, molecular identification with the use of NETest liquid biopsy and circulating microRNAs is gaining importance. Both anatomical and functional examinations (including new radiopharmaceuticals) are used in imaging diagnostics. Histopathological diagnosis along with immunohistochemical examination still constitute the basis for therapeutic decisions. Whenever possible, surgical procedure is the treatment of choice. Pharmacological management including biotherapy, radioisotope therapy, targeted molecular therapy and chemotherapy are important methods of systemic therapy. Treatment of PanNENs requires a multidisciplinary team of specialists in the field of neuroendocrine neoplasms.

Gastroduodenal neuroendocrine neoplasms including gastrinoma - update of the diagnostic and therapeutic guidelines (recommended by the Polish Network of Neuroendocrine Tumours) [Nowotwory neuroendokrynne zoladka i dwunastnicy z uwzglednieniem gastrinoma - uaktualnione zasady postepowania (rekomendowane przez Polska Siec Guzów Neuroendokrynnych)].

After another meeting of experts of the Polish Network of Neuroendocrine Tumours, updated recommendations for the management of patients with gastric and duodenal neuroendocrine neoplasms, including gastrinoma, have been issued. As before, the epidemiology, pathogenesis and clinical symptoms of these neoplasms have been discussed, as well as the principles of diagnostic procedures, including biochemical and histopathological diagnostics and tumour localisation, highlighting the changes introduced in the recommendations. Updated principles of therapeutic management have also been presented, including endoscopic and surgical treatment, and the options of pharmacological and radioisotope treatment. The importance of monitoring patients with gastric and duodenal NENs, including gastrinoma, has also been emphasised.

Colorectal neuroendocrine neoplasms - update of the diagnostic and therapeutic guidelines (recommended by the Polish Network of Neuroendocrine Tumours) [Nowotwory neuroendokrynne jelita grubego - uaktualnione zasady diagnostyki i leczenia (rekomendowane przez Polska Siec Guzów Neuroendokrynych)].

Colorectal neuroendocrine neoplasm (CRNEN), especially rectal tumours, are diagnosed with increased frequency due to the widespread use of colonoscopy, including screening examinations. It is important to constantly update and promote the principles of optimal diagnostics and treatment of these neoplasms. Based on the latest literature and arrangements made at the working meeting of the Polish Network of Neuroendocrine Tumours (June 2021), this paper includes updated and supplemented data and guidelines for the management of CRNEN originally published in Endokrynologia Polska 2017; 68: 250-260.

Neuroendocrine neoplasms of the small intestine and the appendix - update of the diagnostic and therapeutic guidelines (recommended by the Polish Network of Neuroendocrine Tumours) [Nowotwory neuroendokrynne jelita cienkiego i wyrostka robaczkowego - uaktualnione zasady diagnostyki i leczenia (rekomendowane przez Polska Siec Guzów Neuroendokrynnych)].

Updated Polish recommendations for the management of patients with neuroendocrine neoplasms (NENs) of the small intestine (SINENs) and of the appendix (ANENs) are presented here. The small intestine, and especially the ileum, is one of the most common locations for these neoplasms. Most of them are well-differentiated and slow-growing tumours; uncommonly - neuroendocrine carcinomas. Their symptoms may be untypical and their diagnosis may be delayed or accidental. Najczesciej pierwsza manifestacja ANEN jest jego ostre zapalenie. Typical symptoms of carcinoid syndrome occur in approximately 20-30% of SINENs patients with distant metastases. In laboratory diagnostics the assessment of 5-hydroxyindoleacetic acid concentration is helpful in the diagnosis of carcinoid syndrome. The most commonly used imaging methods are ultrasound examination, computed tomography, magnetic resonance imaging, colonoscopy and somatostatin receptor imaging. Histopathological examination is crucial for the proper diagnosis and treatment of patients with SINENs and ANENs. The treatment of choice is a surgical procedure, either radical or palliative. Long-acting somatostatin analogues (SSAs) are essential in the medical treatment of functional and non-functional SINENs. In patients with SINENs, at the stage dissemination with progression during SSAs treatment, with high expression of somatostatin receptors, radioisotope therapy should be considered first followed by targeted therapies - everolimus. After the exhaustion of the above available therapies, chemotherapy may be considered in selected cases. Recommendations for patient monitoring are also presented.

Potential value of pre- and post-therapy [68Ga]Ga-DOTA-TATE PET/CT in the prognosis of response to PRRT in disseminated neuroendocrine tumors.

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.

Additional Value of [18F]FDG PET/CT in Detection of Suspected Malignancy in Patients with Paraneoplastic Neurological Syndromes Having Negative Results of Conventional Radiological Imaging.

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.

Value of Peptide Receptor Radionuclide Therapy as Neoadjuvant Treatment in the Management of Primary Inoperable Neuroendocrine Tumors.

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.

Clinical Approach to Neuroendocrine Neoplasm Associated With Ovarian Teratoma.

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.

Self-Administration of Long-Acting Somatostatin Analogues in NET Patients-Does It Affect the Clinical Outcome?

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.

Clinical challenges and dilemmas in the management of advanced pancreatic neuroendocrine tumour - the first manifestation of von Hippel-Lindau disease in a young patient.

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Heterogeneity of the Clinical Presentation of the MEN1 LRG_509 c.781C>T (p.Leu261Phe) Variant Within a Three-Generation Family.

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_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_509t1 c.781C>T /p.Leu261Phe (LRG_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.