Standard therapy or additionally radioactive iodine (131I) therapy; which will stop the recurrence of glioblastoma multiforme (GBM)?

Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumour. The average survival time for a patient diagnosed with GBM, using standard treatment methods, is several months. Authors of the article pose a direct question: Is it possible to treat GBM solely with radioactive iodine (¹³¹I) therapy without employing the sodium iodide symporter (NIS) gene? After all, NIS has been detected not only in the thyroid but also in various tumours. The main author of this article (A.C.), with the assistance of her colleagues (physicians and pharmacologists), underwent ¹³¹I therapy after prior iodine inhibition, resulting in approximately 30% reduction in tumour size as revealed by magnetic resonance imaging (MRI). Classical therapy for GBM encompasses neurosurgery, conventional radiotherapy, and chemotherapy (e.g. temozolomide). Currently, tyrosine kinase inhibitors (imatinib, sunitinib, and sorafenib) are being used. Additionally, novel drugs such as crizotinib, entrectinib, or larotrectinib are being applied. Recently, personalised multimodal immunotherapy (IMI) based on anti-tumour vaccines derived from oncolytic viruses has been developed, concomitant with the advancement of cellular and molecular immunology. Thus, ¹³¹I therapy has been successfully employed for the first time in the case of GBM recurrence.

Predictors of bone mineral density in patients receiving glucocorticoid replacement for Addison's disease.

PURPOSE: Patients receiving long-term glucocorticoid (GC) treatment are at risk of osteoporosis, while bone effects of substitution doses in Addison's disease (AD) remain equivocal. The project was aimed to evaluate serum bone turnover markers (BTMs): osteocalcin, type I procollagen N-terminal propeptide (PINP), collagen C-terminal telopeptide (CTX), sclerostin, DKK-1 protein, and alkaline phosphatase (ALP) in relation to bone mineral density (BMD) during GC replacement. METHODS: Serum BTMs and hormones were assessed in 80 patients with AD (22 males, 25 pre- and 33 postmenopausal females) on hydrocortisone (HC) substitution for ≥3 years. Densitometry with dual-energy X-ray absorptiometry covered the lumbar spine (LS) and femoral neck (FN). RESULTS: Among BTMs, only PINP levels were altered in AD. BMD Z-scores remained negative except for FN in males. Considering T-scores, osteopenia was found in LS in 45.5% males, 24% young and 42.4% postmenopausal females, while osteoporosis in 9.0%, 4.0% and 21.1%, respectively. Lumbar BMD correlated positively with body mass (p = 0.0001) and serum DHEA-S (p = 9.899 × 10-6). Negative correlation was detected with HC dose/day/kg (p = 0.0320), cumulative HC dose (p = 0.0030), patient's age (p = 1.038 × 10-5), disease duration (p = 0.0004), ALP activity (p = 0.0041) and CTX level (p = 0.0105). However, only age, body mass, ALP, serum CTX, and sclerostin remained independent predictors of LS BMD. CONCLUSION: Standard HC substitution does not considerably accelerate BMD loss in AD patients and their serum BTMs: CTX, osteocalcin, sclerostin, DKK-1, and ALP activity remain within the reference ranges. Independent predictors of low lumbar spine BMD, especially ALP activity, serum CTX and sclerostin, might be monitored during GC substitution.

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

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

Serum Phosphorus and Calcium as Biomarkers of Disease Status in Acromegaly.

Acromegaly is a chronic disease caused by the hypersecretion of growth hormone (GH), leading to changes in the growth of visceral tissues and glucose impairment. Serum biomarkers that correlate with disease status are still unclear. This study aims to assess the potential of phosphorus and calcium as biomarkers in the clinical evaluation of patients with acromegaly and clarify their relationship with SAGIT and other common biomarkers. We retrospectively analyzed data from 306 medical records of patients with acromegaly hospitalized between 2015 and 2020. Factors such as patient biometrics, duration of disease, SAGIT score, tumor size, GH, insulin-like growth factor 1 (IGF-1), calcium, phosphorus, parathormone, and vitamin D were analyzed concerning current disease status (naïve, non-remission, remission). The results showed that serum phosphorus significantly correlated with IGF-1 and SAGIT scores for patients with active acromegaly. Specifically, the best predictor for the remission of acromegaly was a phosphorus level < 3.98 mg/dL and serum calcium levels < 9.88 mg/dL. Based on logistic regression, the higher the serum phosphorus level, the lower the odds of achieving remission (an increase in one unit leads to a decrease in the chance of about 80%). In conclusion, phosphorus and calcium can be effective biochemical markers for predicting disease status in acromegaly.

A NEW HYPOTHESIS IN THE TREATMENT OF RECURRENT GLIOBLASTOMA MULTIFORME (GBM). PART 1: INTRODUCTION.

Modern treatment of glioblastoma multiforme (GBM) is based on neurosurgical methods combined with radiotherapy and chemotherapy. The prognosis for patients with GBM is extremely poor. Often, complete removal of the tumor is impossible and it often recurs. Therefore, in addition to standard regimens, modern methods such as modulated electrohyperthermia, monoclonal antibodies and individualised multimodal immunotherapy (IMI) based on vaccines and oncolytic viruses are also used in the treatment of GBM. Radioiodine therapy (RIT) also holds out hope for an effective treatment of this extremely aggressive brain tumor. The expression of the sodium iodide symporter (NIS) gene has been proven to have a positive effect on the treatment of selected cancers. Research confirm the presence of expression of this gene in GBM cells, although only in animal studies. Is it possible and therapeutically effective to treat GBM with RIT without the use of an exogenous NIS gene? The safety of therapy is relevant, as the only more serious adverse effect may be hypothyroidism. The use of RIT requires further clinical studies in patients. Perhaps it is worth revolutionizing GBM therapy to give sufferers a "new life".

A NEW HYPOTHESIS IN THE TREATMENT OF RECURRENT GLIOBLASTOMA MULTIFORME (GBM). PART 2: IS THERE AN ALTERNATIVE THERAPY OPTION IN RECURRENT GM WHEN ALL STANDARD TREATMENTS HAVE BEEN EXHAUSTED?

Glioblastoma multiforme (GBM) is the most aggressive and malignant brain tumor. The average survival time for a patient diagnosed with GBM, using standard treatment methods, is several months. Besides the routinely applied treatments such as neurosurgery, radiotherapy, and chemotherapy, progress is being made in the field of oncology, offering hope for improved treatment outcomes. New treatment methods include individualized multimodal immunotherapy (IMI) and modulated electro-hyperthermia. The coauthor of the above series of articles (parts 1 and 2) - A.Cz. presents the concept of a new, potentially breakthrough treatment option for recurrent GBM. A.Cz. was diagnosed with GBM in August 2021. Exhaustion of standard treatment methods, as well as immunotherapy and virotherapy, only provided temporary relief. Unfortunately, after a few months, the disease recurred. Having little to lose, A.Cz. accepted an ablative dose of 2960 MBq (80 mCi) of I131, based on available literature data. Three days before the administration of radioiodine therapy (RIT), A.Cz. prophylactically blocked the thyroid's ability to absorb the radioisotope. In June 2023, approximately 7 weeks after receiving single I131 dose, the MRI examination confirmed a 30% reduction in the tumor's size. Based on this, one can speculate that Iodine-131 therapy may be an alternative treatment option for GBM patients in the future. However, this hypothesis requires confirmation in further clinical studies.

The influence of various endocrine disruptors on the reproductive system.

Various stimulants (VS) are chemicals that disrupt the endocrine system - endocrine homeostasis of the reproductive system - which also known as endocrine-disrupting chemicals (EDCs). These substances are found in the human body, in both the blood and urine, amniotic fluid, or, among others, the adipose tissue. This article presents the current state of knowledge of the effect of EDCs and additional factors such as smoking, alcohol consumption, and cannabis on the gonads. The article is an overview of the impact of EDCs and their mechanism of action, with particular emphasis on gonads, based on databases such as PubMed, EMBASE and Google Scholar, and Web of Science available until May 2022. The impact of human exposure to bisphenol A (BPA) is not fully understood, but it has been shown that phthalates show a negative correlation in anti-androgenic activity in the case of men and women for the anti-Müllerian hormone (AMH). Smoking cigarettes and passive exposure to tobacco have a huge impact on the effects of endocrine disorders in both women and men, especially during the reproductive time. Also, the use of large amounts of cannabinoids during the reproductive years can lead to similar disorders. It has been documented that excessive alcohol consumption leads to disturbed function of the hypothalamus-pituitary-gonadal axis (HPG). Excess caffeine consumption may adversely affect male reproductive function, although this is not fully proven. Therefore, the following publication presents various stimulants (BPA, phthalates, nicotine, alcohol, cannabis) that disrupt the function of the endocrine system and, in particular, affect the function of the gonads.

NT-proBNP as a neuroendocrine tumor biomarker: beyond heart failure.

Introduction: Neuroendocrine tumors (NETs) are rare neoplasms that occur in various locations throughout the body. Despite their usually benign character, they might manifest with distant metastases. N-terminal prohormone of brain natriuretic peptide (NT-proBNP) has previously been described as a useful biomarker in diagnosing carcinoid heart disease (CHD), a common advanced NETs manifestation. We observed plasma concentrations of NT-proBNP in metastatic midgut NETs over a 4-year period. Objectives: We aimed to explore NT-proBNP concentrations in states of varying levels of cell proliferation and disease status. Our goal was to investigate NT-proBNP's role in predicting disease progression in relation to previous research and up-to-date scientific guidelines. Patients and methods: We performed a retrospective multivariate analysis of NT-proBNP concentrations in 41 midgut NETs patients treated with somatostatin analogs, all with liver metastases. NT-proBNP concentrations were measured in every patient across 16 evenly distanced time points over a 48-month period and were compared to variables such as sex, age, grading, Ki-67, primary tumor location, and CT findings. Results: NT-proBNP concentrations correlated positively with higher liver tumor burden, higher grading, high Ki-67 levels, and with progressive disease in CT. There were no differences in NT-proBNP levels with regard to primary location (ileum vs jejunum), sex, and age. Conclusion: We conclude that NT-proBNP is a useful analyte for monitoring NETs progression, due to its increased concentration in scenarios implying increased cellular proliferation. These long-term follow-up results align with previous findings and suggest an additional role for NT-proBNP in diagnostic algorithms, beyond a CHD biomarker.

Circulating Neuroendocrine Tumor Biomarkers: Past, Present and Future.

Neuroendocrine tumors are a heterogeneous group of neoplasms originating from the diffuse endocrine system. Depending on primary location and hormonal status, they range in terms of clinical presentation, prognosis and treatment. Functional tumors often develop symptoms indicating an excess of hormones produced by the neoplasm (exempli gratia insulinoma, glucagonoma and VIPoma) and can be diagnosed using monoanalytes. For non-functional tumors (inactive or producing insignificant amounts of hormones), universal biomarkers have not been established. The matter remains an important unmet need in the field of neuroendocrine tumors. Substances researched over the years, such as chromogranin A and neuron-specific enolase, lack the desired sensitivity and specificity. In recent years, the potential use of Circulating Tumor Cells or multianalytes such as a circulating microRNA and NETest have been widely discussed. They offer superior diagnostic parameters in comparison to traditional biomarkers and depict disease status in a more comprehensive way. Despite a lot of promise, no international standards have yet been developed regarding their routine use and clinical application. In this literature review, we describe the analytes used over the years and cover novel biomarkers that could find a use in the future. We discuss their pros and cons while showcasing recent advances in the field of neuroendocrine tumor biomarkers.

Relationship between thyroid hormones and central nervous system metabolism in physiological and pathological conditions.

Thyroid hormones (THs) play an important role in the regulation of energy metabolism. They also take part in processes associated with the central nervous system (CNS), including survival and differentiation of neurons and energy expenditure. It has been reported that a correlation exists between the functioning of the thyroid gland and the symptoms of CNS such as cognitive impairment, depression, and dementia. Literature data also indicate the influence of THs on the pathogenesis of CNS diseases, such as Alzheimer's disease, epilepsy, depression, and Parkinson's disease. This review describes the relationship between THs and metabolism in the CNS, the effect of THs on the pathological conditions of the CNS, and novel options for treating these conditions with TH derivatives.

Is eNAMPT/visfatin a potential serum marker of papillary thyroid cancer?

Purpose: The role of nicotinamide phosphoribosyltransferase (NAMPT)/visfatin in a more aggressive course of many malignancies has been proven. Previous studies have noticed the importance of visfatin in thyroid neoplastic tissue, but the diagnostic and prognostic value of its serum concentration has not been investigated so far. Our study aimed to consider whether extracellular NAMPT (eNAMPT) could be a potential serum marker in recurrent papillary thyroid cancer (PTC). Methods: It was a prospective observational study with consecutive enrolment. We recruited 100 patients with PTC after thyroidectomy with postoperative 131I ablation and 100 healthy controls. Also, 50 randomly selected patients underwent laboratory assessment (including eNAMPT serum concentration by ELISA Assay Kit, TSH, free thyroid hormones, TSH-stimulated thyroglobulin Tg, antibodies - TgAbs, TPOAb) and body composition analysis twice: at admission and 6 months after being on suppressive levothyroxine doses. TSH-stimulated Tg of 1 ng/ml was defined as the cutoff value for predicting disease status as complete remission (n = 55) and recurrent or persistent structural disease (n = 45). Results: The visfatin serum concentrations in patients diagnosed with PTC and in healthy subjects were not statistically significantly different (p = 0.9425). The eNAMPT levels were also similar in disease-free patients and the ones with tumour relapse. Besides, ROC curve analysis did not detect eNAMPT as a biomarker of PTC. Conclusion: We have not found visfatin as a potential serum marker of papillary thyroid cancer. Also, eNAMPT has no prognostic value in assessing the risk of disease recurrence or metastasis in PTC management.

Determination of neuron-specific enolase in patients with midgut-type tumour treated with somatostatin analogues.

INTRODUCTION: The biochemical diagnosis of neuroendocrine tumours (NETs) uses assays of specific and nonspecific markers. Nonspecific markers include, among others, neuron-specific enolase (NSE). The aim of this study was to evaluate NSE in patients with midgut type tumours treated with somatostatin analogues. MATERIAL AND METHODS: The study group of patients with NETs of the small intestine included 41 patients. Grade G1 was found in 19 cases, while G2 was seen in the remaining 22 cases. Liver metastases were found in all patients studied. The examined group of patients was treated with somatostatin analogues receiving octreotide LAR at a dose of 30 mg. The control of biochemical parameters was performed every 3 months and imaging examinations every 6 months. The Immuno-Biological Laboratories kit was used for determination of NSE concentration, where reference values were 12.5-25 ng/mL. RESULTS: In the G1 group of patients, the median value of NSE concentration was 134.67 ng/mL, while in the G2 group, the value was 234.55 ng/mL and was significantly higher than in the G1 group (p = 0.003). In the determination of NSE concentration values according to the degree of liver involvement, in the group of patients with 10% liver involvement, the median value of NSE concentration was 143.21 ng/mL, while in the group with 25% liver involvement, the value was 251.82 ng/mL (p < 0.001). In the analysis of NSE concentration assessment in patients with disease progression, the median value was 234.65 ng/mL compared to the group with disease stabilization, where the median NSE value was significantly lower and amounted to 136.27 ng/mL (p < 0.001). CONCLUSIONS: In our study, we observed that NSE concentration values were significantly higher among patients with NET midgut type tumour with histological grade G2 and in patients with 25% liver involvement and progression of the disease process.

Is low radioiodine uptake a contraindication to radioiodine therapy in patients with benign thyroid disease?

BACKGROUND: Radioiodine therapy (131I) is a standard procedure in the treatment of hyperthyroidism in the course of Graves' disease or toxic nodules. However, the use of 131I in patients with low radioiodine uptake (RAIU) may be controversial. OBJECTIVES: To determine the influence of lithium carbonate (Li) on iodine kinetics. MATERIAL AND METHODS: Patients with hyperthyroidism and low RAIU (< 30%) were divided into 2 groups: a Li(-) group of 305 patients not receiving Li adjuvant therapy and a Li(+) group of 264 patients receiving adjuvant therapy. The serum concentrations of free triiodothyronine (fT3), free thyroxine (fT4) and thyroid stimulating hormone (TSH) were assessed at baseline, 24 h, 48 h, 72 h and 96 h, and 1, 6 and 12 months after 131I therapy. The RAIU was assessed after 5 h, 24 h, 48 h, 72 h, and 96 h. RESULTS: Levels of fT3 in the Li(+) group compared to the Li(-) group were significantly higher at baseline, lower after 48 h, 72 h, 96 h and 1 month, and did not differ significantly after 24 h, 6 months and 12 months. Levels of fT4 in the Li(+) group compared to the Li(-) group were significantly higher at baseline, lower after 24 h, 48 h, 72 h, 96 h and 1 month, and not differ significantly after 6 and 12 months. The RAIU in the hyperthyroidism Li(-) and Li(+) groups, respectively, was 11.9 ±5.6% compared to 23.9 ±10.1% (p < 0.001) after 5 h; 25.9 ±8.3% compared to 40.5 ±12.4% (p < 0.05) after 24 h; 7.8 ±8.1% compared to 40.9 ±13.7% (p < 0.05) after 48 h; 26.2 ±10.2% compared to 39.5 ±11.2% (p < 0.01) after 72 h; and 24.7 ±7.1% compared to 37.4 ±10.1% (p < 0.01) after 96 h. CONCLUSIONS: Adjuvant therapy with Li in patients with hyperthyroidism caused a significant increase in RAIU and positive changes in the fT3 and fT4 profiles. The use of lithium carbonate prior to the inclusion of 131I in hyperthyroid patients with low RAIU should be considered.

EZH2 and SMYD3 expression in papillary thyroid cancer.

Recent studies have revealed the significant role of SMYD3 and EZH2 genes in the development and aggressiveness of numerous types of malignant tumor. Therefore, the present study aimed to investigate the expression of SMYD3 and EZH2 in papillary thyroid cancer, and to determine the correlation between the expression of these genes and clinical characteristics. Resected thyroid tissue samples from 62 patients with papillary thyroid cancer were investigated. Thyroid tissue derived from the healthy regions of removed nodular goiters from 30 patients served as the control group. Reverse transcription-quantitative PCR analysis was employed to detect relative mRNA expression levels. Primer sequences and TaqMan® hydrolysis probe positions for EZH2 and SMYD3 were determined using the Roche Universal ProbeLibrary Assay Design Center version 2.50. EZH2 expression was detected in all thyroid cancer samples and in 83.3% of benign lesions. Notably, EZH2 was revealed to be upregulated in thyroid cancer tissues compared with control tissues (P=0.0002). EZH2 expression was positively correlated with tumor stage (P<0.0001; r=0.504), and multiple comparison analysis revealed that the highest expression of EZH2 was detected in samples staged pT4 (P=0.0001). SMYD3 expression was detected in all thyroid cancer samples and in 96.7% of healthy thyroid tissues; notably, the expression levels were similar in both groups. In addition, there was no correlation between SMYD3 expression and the aggressiveness of papillary thyroid cancer. In conclusion, overexpression of the EZH2 gene may be associated with the development of papillary thyroid cancer and EZH2 may be a potential therapeutic target in papillary thyroid cancer.

The Safety and Efficacy of the Repeated PRRT with [90Y]Y/[177Lu]Lu-DOTATATE in Patients with NET.

PURPOSE: The peptide receptor radionuclide therapy (PRRT) is a treatment option for patients with disseminated, inoperable G1 and G2 neuroendocrine tumours (NETs). The study aims to evaluate the safety, efficacy, and progression-free survival (PFS) of patients after retreatment (R-PRRT) and re-retreatment (RR-PRRT) with tandem isotopes [90Y]Y/[177Lu]Lu-DOTATATE. Material and Methods. Out of 99 treated patients with G1 and G2 NETs, 26 were included in the study and treated with the repeated PRRT (with 5 undergoing the re-repeated PRRT treatment) after an initial positive response to four PRRT cycles and later progression of the disease. [68Ga]Ga-DOTATATE PET/CT and CT/MRI procedures were performed before and after the treatment. Patients were treated with [90Y]Y/[177Lu]Lu-DOTATATE (1 : 1) with mixed amino acid infusion for kidney protection. Toxicity was evaluated using the CTCAE 3.0 criteria. RESULTS: The median follow-up was 88 months (the range: 42-164). The median cumulative administered activity was 22.2 GBq (the range: 17.8-30.7 GBq). Myelodysplastic syndrome occurred in one patient (3.8%), and grade 4 renal toxicity was also detected in one patient (3.8%). No other cases of grade 3 or 4 bone marrow and renal toxicity were observed. The median PFS rate was 31 months after the PRRT and 23 months following the R-PRRT. The OS rate from the diagnosis (OS-d) was 109 months and from the start of the PRRT (OS-t)-92.4 months. During the restaging, 3-6 months after the PRRT, PR, SD, and PD were observed in 19.2%, 80.8%, and 0% of the patients, respectively. After the R-PRRT, PR, SD, and PD were observed in 50%, 42.3%, and 7.7% of the patients, respectively. CONCLUSIONS: The repeated therapy with [90Y]Y/[177Lu]Lu-DOTATATE is safe and effective for patients with disseminated, inoperable G1 and G2 neuroendocrine tumours.

Chromogranin A assessment in patients with neuroendocrine neoplasm of the small bowel and carcinoid syndrome treated with somatostatin analogues.

BACKGROUND: Chromogranin A (CgA) is one of the non-specific markers measured in the biochemical diagnostics of neuroendocrine neoplasms (NENs). OBJECTIVES: To analyze the CgA levels of patients with carcinoid syndrome who are being treated with somatostatin analogues (SSAs), depending on the histologic maturity of the neoplasm, the degree of liver involvement and the stage of the disease. MATERIAL AND METHODS: The study group comprised of 41 patients, including 29 women (70.7%) and 12 men (29.3%). All of the patients had undergone surgical removal of the primary site. Hepatic metastases were found in all patients and they all were treated with SSAs. Chromogranin A concentration was determined using the enzyme-linked immunosorbent assay (ELISA). RESULTS: Among the patients with grade 1 tumors, the mean CgA value was 298.83 ng/mL, whereas in the group with grade 2 tumors, the CgA value was 1498.44 ng/mL, which was a statistically significant difference (p < 0.001). In the group of patients with 10% liver involvement, the mean CgA value was 394.44 ng/mL, whereas in the group of patients with 25% liver involvement, this value was 1,770.63 ng/mL, demonstrating significantly higher values (p < 0.001). Among the patients with a progressing disease, the mean CgA concentration value was 1,620.78 ng/mL, whereas in the group of patients with a stable disease, these were considerably lower, amounting to 230.36 ng/mL (p < 0.001). CONCLUSIONS: Assessing CgA level in patients with carcinoid syndrome is helpful in the diagnostics and monitoring of treatment because CgA values depend on the tumor grade and the severity of the disease.

Liver metastases in gastroenteropancreatic neuroendocrine tumours - treatment methods.

Surgical approaches that allow the safe treatment of multiple, bilateral, large tumours, and that combine extirpative, ablative and interventional therapies, have expanded the population of patients with neuroendocrine tumors (NET) liver metastases (LMs) who can benefit from aggressive treatment of their liver disease. Pre-treatment staging often includes the biochemical assessment of serologic markers such as serotonin, insulin, vasoactive intestinal peptide, and chromogranin, even in patients without clinically apparent hormonal excess. Radiofrequency ablation (RFA) is a technique that involves the use of thermal energy to induce coagulation necrosis, thereby destroying tumour cells. Resection plus RFA is increasingly used in patients with bilateral NET LMs. Resection is performed for large or dominant lesions, while ablation is used to treat small lesions. Hepatic arterial embolization, typically termed transarterial embolization, and transarterial chemoembolization have been shown to induce a reduction in tumour size and to ameliorate symptoms of excess hormonal secretion.

Oncological management of advanced neuroendocrine tumours (Review).

The oncological principles of managing patients with gastroenteropancreatic neuroendocrine tumours (GEP-NETs) depends on a number of factors and requires a multidisciplinary approach. Recent data have provided additional therapeutic options, including biotherapy, traditional chemotherapy and novel targeted agents. Somatostatin analogues (SSAs) inhibit multiple cellular functions, including secretion, motility and proliferation. Interferon appears to act through several mechanisms, with antisecretory effects, immunomodulatory effects and antiproliferative functions, the latter inhibiting direct growth or attenuating angiogenesis. Opinions on when to commence chemotherapy for well differentiated GEP-NETs varies among experts. In previous years, reserving chemotherapy for patients with progressive disease (well differentiated, inoperable and/or metastatic GEP-NETs) was reasonably well argued for. Most well differentiated endocrine tumours are richly vascular and many express vascular endothelial growth factor (VEGF) receptors. In a xenograft model of a human carcinoid, treatment with an anti-VEGF monoclonal antibody was revealed to inhibit tumour growth and metastasis. As the role of angiogenesis and hypoxic-associated factors appears to be associated with tumour aggressiveness, strategies using agents which target angiogenesis have been developed. Mammalian target of rapamycin (mTOR) is a conserved serine-threonine kinase that regulates the cell cycle and metabolism in response to environmental factors. In addition, mTOR inhibition suppression was demonstrated to suppress NET growth. Each patient requires an individual approach to the choice of therapy, which should be selected depending on the severity of disease.