Treatment Of Neuroendocrine Tumors Research Articles

P-P10 The survival benefit of pancreatic enzyme replacement therapy in adult patients undergoing treatment of pancreatic neuroendocrine tumours

Abstract Background Patients with pancreatic neuroendocrine tumours (pNETs), treated with somatostatin analogues (SSAs) or pancreaticoduodenectomy, are at risk of exocrine pancreatic insufficiency. This is frequently undiagnosed but can be treated with pancreatic enzyme replacement therapy (PERT). PERT improves survival and nutritional status in other exocrine pancreatic insufficiency-associated conditions such as pancreatic adenocarcinoma. This single-centre retrospective cohort study aimed to establish whether PERT increases survival or weight maintenance in SSA or pancreaticoduodenectomy-treated patients with pNETs. Methods Departmental databases identified patients (n = 82) diagnosed with pNETs between 2009 and 2019 and managed with SSAs and/or pancreaticoduodenectomy. Their baseline characteristics, treatments and outcomes were established from clinical records. Cases (n = 47) received PERT 3 months after either pancreaticoduodenectomy or commencement of SSAs, controls (n = 35) did not. Overall survival was analysed using the Kaplan-Meier method, the log-rank test and multivariable Cox regression. Percentage monthly weight changes were compared using the Mann-Witney U test. The cohort was investigated as a whole and stratified by intervention (pancreaticoduodenectomy or SSAs) as more cases having undergone pancreaticoduodenectomy was a potential confounder. Results Median survival was not reached in either group. Cases experienced significantly greater 5-year overall survival (81% vs 53%, p = 0.010), however, PERT was not independently associated with survival (Hazard ratio 0.47, 95% CI 0.17-1.30, p = 0.143). Cases showed superior median weight maintenance (+0.04% vs -0.10% per month, p = 0.013), but had lower mean baseline weights (70.0kg vs 81.9kg, p = 0.003). Considering SSA-treated patients (n = 55) only, cases (n = 27) showed greater median weight maintenance (+0.04% vs -0.21% per month, p = 0.025) and a trend towards improved median overall survival (55.5, 95% CI 10.3-100.7 vs 47.7, 95% CI 19.1-76.4 months, p = 0.054). Conclusions PERT may improve the maintenance of weight and therefore nutrition in patients with pNETs, treated with SSAs or pancreaticoduodenectomy. PERT may also convey a survival benefit in this same population, however, due to the numerous factors which affect survival, this study appears underpowered to reliably explore this outcome. Further studies are required to accurately define the use and benefits of PERT in this population.

A Physiologically Based Pharmacokinetic Model for In Vivo Alpha Particle Generators Targeting Neuroendocrine Tumors in Mice.

In vivo alpha particle generators have great potential for the treatment of neuroendocrine tumors in alpha-emitter-based peptide receptor radionuclide therapy (α-PRRT). Quantitative pharmacokinetic analyses of the in vivo alpha particle generator and its radioactive decay products are required to address concerns about the efficacy and safety of α-PRRT. A murine whole-body physiologically based pharmacokinetic (PBPK) model was developed for 212Pb-labeled somatostatin analogs (212Pb-SSTA). The model describes pharmacokinetics of 212Pb-SSTA and its decay products, including specific and non-specific glomerular and tubular uptake. Absorbed dose coefficients (ADC) were calculated for bound and unbound radiolabeled SSTA and its decay products. Kidneys received the highest ADC (134 Gy/MBq) among non-target tissues. The alpha-emitting 212Po contributes more than 50% to absorbed doses in most tissues. Using this model, it is demonstrated that α-PRRT based on 212Pb-SSTA results in lower absorbed doses in non-target tissue than α-PRRT based on 212Bi-SSTA for a given kidneys absorbed dose. In both approaches, the energies released in the glomeruli and proximal tubules account for 54% and 46%, respectively, of the total energy absorbed in kidneys. The 212Pb-SSTA-PBPK model accelerates the translation from bench to bedside by enabling better experimental design and by improving the understanding of the underlying mechanisms.

Distinct In Vitro Binding Profile of the Somatostatin Receptor Subtype 2 Antagonist [177Lu]Lu-OPS201 Compared to the Agonist [177Lu]Lu-DOTA-TATE.

Treatment of neuroendocrine tumours with the radiolabelled somatostatin receptor subtype 2 (SST2) peptide agonist [177Lu]Lu-DOTA-TATE is effective and well-established. Recent studies suggest improved therapeutic efficacy using the SST2 peptide antagonist [177Lu]Lu-OPS201. However, little is known about the cellular mechanisms that lead to the observed differences. In the present in vitro study, we compared kinetic binding, saturation binding, competition binding, cellular uptake and release of [177Lu]Lu-OPS201 versus [177Lu]Lu-DOTA-TATE using HEK cells stably transfected with the human SST2. While [177Lu]Lu-OPS201 and [177Lu]Lu-DOTA-TATE exhibited comparable affinity (KD, 0.15 ± 0.003 and 0.08 ± 0.02 nM, respectively), [177Lu]Lu-OPS201 recognized four times more binding sites than [177Lu]Lu-DOTA-TATE. Competition assays demonstrated that a high concentration of the agonist displaced only 30% of [177Lu]Lu-OPS201 bound to HEK-SST2 cell membranes; an indication that the antagonist binds to additional sites that are not recognized by the agonist. [177Lu]Lu-OPS201 showed faster association and slower dissociation than [177Lu]Lu-DOTA-TATE. Whereas most of [177Lu]Lu-OPS201 remained at the cell surface, [177Lu]Lu-DOTA-TATE was almost completely internalised inside the cell. The present data identified distinct differences between [177Lu]Lu-OPS201 and [177Lu]Lu-DOTA-TATE regarding the recognition of receptor binding sites (higher for [177Lu]Lu-OPS201) and their kinetics (faster association and slower dissociation of [177Lu]Lu-OPS201) that explain, to a great extent, the improved therapeutic efficacy of [177Lu]Lu-OPS201 compared to [177Lu]Lu-DOTA-TATE.

Theragnostic radionuclides: a clinical perspective.

The concept of theragnostics goes back to the earliest days of nuclear medicine, with [123I/131I]iodide in thyroid disease and [123I/131I]MIBG in phaeochromocytoma being examples in long-term use. However, in recent years there has been a great expansion in the application of theragnostics, beginning with [68Ga/177Lu]-labelled somatostatin peptides for evaluation and treatment of neuroendocrine tumors. We are currently seeing the rapid development of [68Ga/177Lu]PSMA theragnostics in metastatic prostate cancer. While these applications are very promising, there are a number of practicalities which must be addressed in the development and introduction of novel theragnostics. The physical half-lives of the diagnostic and therapeutic radionuclides must be appropriate for imaging and delivery of targeted cell killing, respectively. The types of radioactive emissions are critical; beta particles can traverse several millimeters but also risk damaging non-target tissues, while alpha particles deliver their energy over a much shorter path length, a few cell diameters, and must be more directly targeted. It must be practical to produce the therapeutic radionuclide and the final radiopharmaceutical and deliver them to the final user within an appropriate time-frame determined by half-life and stability. The biodistribution of the agent must demonstrate adequate accumulation and retention in the target tissue with clearance from adjacent and/or radio-sensitive normal tissues. The commercial success of recently introduced theragnostics suggests a rosy future for personalized medicine.

Sunitinib-Induced Hypothyroidism and Survival in Pancreatic Neuroendocrine Tumors

AbstractSunitinib has been approved for the treatment of pancreatic neuroendocrine tumors, renal-cell carcinoma, and gastrointestinal stromal tumors. The elevation of thyroid-stimulating hormone serum levels is a common side effect. Studies suggest a correlation between sunitinib-induced hypothyroidism and treatment outcome in patients with renal-cell carcinoma and gastrointestinal stromal tumors. This study assessed whether sunitinib-induced hypothyroidism is a predictive marker of the objective response rate, progression-free survival, and overall survival in pancreatic neuroendocrine tumor patients. Twenty-nine patients treated with sunitinib for advanced pancreatic neuroendocrine tumors were included. The incidence of sunitinib-induced hypothyroidism was 33%. The median progression-free survival of patients who developed hypothyroidism was 16 months (95% confidence interval: 6.2–25.8 months) as compared with six months among euthyroid patients (95% confidence interval: 0.1–12.2 months) (p=0.02). The median overall survival was 77 months (95% confidence interval: 31.4–122.6 months) in hypothyroid patients but 12 months (95% confidence interval: 5.9–18.1 months) in subjects with euthyroidism (p=0.001). The median overall survival from the time of initial diagnosis ranged from 247 months in patients with hypothyroidism to 65 months in euthyroid subjects (p=0.015). Elevated thyroid-stimulating hormone levels are a prognostic biomarker of improved outcomes of sunitinib therapy in pancreatic neuroendocrine tumor patients.

Treatment for gastrointestinal and pancreatic neuroendocrine tumours: a network meta-analysis.

Several available therapies for neuroendocrine tumours (NETs) have demonstrated efficacy in randomised controlled trials.However, translation of these results into improved care faces several challenges, as a direct comparison of the most pertinent therapies is incomplete. To evaluate the safety and efficacy of therapies forNETs, to guide clinical decision-making, and to provide estimates of relative efficiency of the different treatment options (including placebo) and rank the treatments according to their efficiency based on a network meta-analysis. We identified studies through systematic searches of the following bibliographic databases:the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library; MEDLINE (Ovid); and Embase from January 1947to December 2020. In addition,we checked trial registriesfor ongoing or unpublished eligible trials and manually searched for abstracts from scientific and clinical meetings. We evaluated randomised controlled trials (RCTs) comparing two or more therapies in people with NETs (primarily gastrointestinal and pancreatic). Two review authors independently selected studies and extracted data to a pre-designed data extraction form. Multi-arm studies were included in the network meta-analysis using the R-package netmeta. We separately analysed two different outcomes (disease control and progression-free survival) and two types of NET (gastrointestinal and pancreatic NET) in four network meta-analyses.A frequentist approach was used to compare the efficacy of therapies. We identified 55 studies in 90 records in the qualitative analysis, reporting 39 primary RCTs and 16 subgroup analyses. We included 22 RCTs, with 4299participants, that reported disease control and/or progression-free survival in the network meta-analysis. Precision-of-treatment estimates and estimated heterogeneity were limited, although the risk of bias was predominantly low. The network meta-analysis of progression-free survival found nine therapies for pancreatic NETs: everolimus (hazard ratio [HR], 0.36 [95% CI, 0.28 to 0.46]), interferon plus somatostatin analogue (HR, 0.34 [95% CI, 0.14 to 0.80]), everolimus plus somatostatin analogue (HR, 0.38 [95% CI, 0.26 to 0.57]), bevacizumab plus somatostatin analogue (HR, 0.36 [95% CI, 0.15 to 0.89]), interferon (HR, 0.41 [95% CI, 0.18 to 0.94]), sunitinib (HR, 0.42 [95% CI, 0.26 to 0.67]), everolimus plus bevacizumab plus somatostatin analogue (HR, 0.48 [95% CI, 0.28 to 0.83]), surufatinib (HR, 0.49 [95% CI, 0.32 to 0.76]), and somatostatin analogue (HR, 0.51 [95% CI, 0.34 to 0.77]); and six therapies for gastrointestinal NETs: 177-Lu-DOTATATE plus somatostatin analogue (HR, 0.07 [95% CI, 0.02 to 0.26]), everolimus plus somatostatin analogue (HR, 0.12 [95%CI, 0.03 to 0.54]), bevacizumab plus somatostatin analogue (HR, 0.18 [95% CI, 0.04 to 0.94]), interferon plus somatostatin analogue (HR, 0.23 [95% CI, 0.06 to 0.93]), surufatinib (HR, 0.33 [95%CI, 0.12 to 0.88]), and somatostatin analogue (HR, 0.34 [95% CI, 0.16 to 0.76]), with higher efficacy than placebo. Besides everolimus for pancreatic NETs, the results suggested an overall superiority of combination therapies, including somatostatin analogues. The results indicate that NET therapies have a broad range of risk for adverse events and effects on quality of life, but these were reported inconsistently. Evidence from this network meta-analysis (and underlying RCTs) does not support any particular therapy (or combinations of therapies) with respect to patient-centred outcomes(e.g. overall survival and quality of life). The findings from this study suggest that a range of efficient therapies with different safety profiles is available for people with NETs.

Traction-assisted hybrid endoscopic submucosal dissection for small rectal neuroendocrine tumors

Endoscopic resection is conducted as a first-line treatment for localized small rectal neuroendocrine tumors (NETs) [1] [2] [3]. However, NETs involve the deep mucosa and submucosa; a sufficient tumor-free vertical margin is required for R0 resection in endoscopic treatment. Recently, we developed the traction-assisted hybrid endoscopic submucosal dissection (ESD) procedure for gastrointestinal tumors [4]. Herein, we present a case of a small rectal NET successfully treated by traction-assisted hybrid ESD ([Video 1]).

NIMG-61. CLINICAL UTILITY OF SOMATOSTATIN RECEPTOR PET IMAGING BIOMARKERS FOR CHARACTERIZATION OF MENINGIOMA AMONG INCIDENTAL CNS LESIONS

Abstract BACKGROUND Somatostatin receptor (SSTR) PET/CT is utilized with increasing frequency in the clinical treatment of neuroendocrine tumors. Incidental CNS lesions are commonly noted and presumed to be meningiomas, however 68Gallium (Ga-68)-DOTATATE radionuclide use lacks specificity for meningioma identification. Currently there is no established SSTR-based imaging criteria for classification of incidental CNS lesions. METHODS We retrospectively analyzed patients across clinical and radiological databases at Mayo Clinic who had undergone both Ga-68-DOTATATE PET/CT and brain MR imaging who had an incidental CNS lesion identified with clinical or radiographic prediction of meningioma. Known meningioma diagnoses prior to imaging were excluded. Imaging indication, semi-quantitative measures, and corresponding clinical history were analyzed to identify metrics impacting both the predictive and descriptive utility of SSTR-based imaging as compared to corresponding MRI prediction in incidental CNS lesions. RESULTS Among 59 patients with a CNS lesion identified on both imaging modalities, most scans were performed for a history of neuroendocrine tumor (71%). Cases with concordant lesion type prediction of meningioma between imaging modalities (N = 25) displayed a higher median SUV max and Krenning score on Ga-68-DOTATATE PET compared to cases with concordant prediction of other lesions (N=10) or discordant prediction of meningioma (N=24). Ga-68-DOTATATE was more likely to discordantly predict meningioma as compared to the corresponding patient MRI in cases with lower SUV max values. The addition of Qclear technology was significantly associated with diagnostic clarification in cases of imaging discordant tumor type prediction. Prior cranial radiation or use of a somatostatin mimetic did not affect quantitative radiographic measures in lesion characterization, and MRI-based tumor size was similar across groups. CONCLUSION The continued development of SSTR-based imaging biomarker signatures across incidental CNS lesion subtypes will further define the role of this imaging modality in the clinical diagnosis and management of presumed meningiomas.

Use of [177Lu]Lu-DOTA-TATE in the treatment of gastroenteropancreatic neuroendocrine tumours: Results of a UK cost-effectiveness modelling study

AimTo evaluate the cost-effectiveness of [177Lu]Lu-DOTA-TATE versus relevant comparators for the treatment of neuroendocrine tumours located in the gastrointestinal tract (GI-NETs) and the pancreas (P-NETs). Materials and methodsA three-state partitioned survival model was developed to perform a cost-utility analysis of [177Lu]Lu-DOTA-TATE versus standard of care (high dose Octreotide LAR), everolimus and sunitinib. Effectiveness data for SoC, everolimus and sunitinib were obtained from published Kaplan–Meier survival curves. Given a lack of head-to-head effectiveness data, matching adjusted indirect comparisons (MAICs) were performed to population-adjust [177Lu]Lu-DOTA-TATE survival data based on prognostic factors and derive estimates of relative effectiveness. Health state utilities were estimated from real-world evidence. Drug acquisition costs were taken from nationally published sources (BNF, NICE), and administration costs were based on treatment protocols in [177Lu]Lu-DOTA-TATE studies, combined with nationally published unit costs (PSSRU, DoH reference costs). Incidence of adverse events were estimated using published sources. A discount rate of 3.5% was applied to both utilities and costs, and deterministic and probabilistic sensitivity analyses were performed. Costs were included from an NHS perspective and presented in 2017/18 GBP (and PPP Euros for base case). ResultsIn GI-NETs, the incremental cost-effectiveness ratio (ICER) of [177Lu]Lu-DOTA-TATE compared to SoC and everolimus was £26,528 (€27,672) and £24,145 (€25,186) per QALY, respectively. In P-NETs, the ICER of [177Lu]Lu-DOTA-TATE compared to SoC was £22,146 (€23,101) or £28,038 (€29,251) dependent on matched population, and £21,827 (€22,766) and £15,768 (€16,445) compared to everolimus and sunitinib, respectively. ConclusionsAt a willingness to pay threshold of £30,000, [177Lu]Lu-DOTA-TATE is likely to be a cost-effective treatment option for GI-NET and P-NET patients versus relevant treatment comparators (NHS perspective).

Pituitary function following peptide receptor radionuclide therapy for neuroendocrine tumours.

Peptide receptor radionuclide therapy (PRRT) is an increasingly used treatment for unresectable neuroendocrine tumours (NETs) that express somatostatin receptors. Normal pituitary tissue expresses somatostatin receptors so patients receiving PRRT may be at risk of developing hypopituitarism. The aim was to assess the prevalence of clinically significant hypopituitarism a minimum of 2 years following radioisotope therapy for metastatic NET. This was a multicentre study (Australia and New Zealand). Sixty‐six patients with unresectable NETs were included–34 had received PRRT and 32 comparison patients. Median follow‐up after PRRT was 68 months. Male hypogonadism was the most common hormonal abnormality (16 of 38 men [42%]) from the total cohort. Of these, seven men had primary hypogonadism (five from PRRT group) and nine had secondary hypogonadism (six in PRRT group). There was no difference in either male hypogonadism or other hormonal dysfunction between patients who had received PRRT and those that had not. Patients who have received PRRT out to 68 months following treatment do not show concerning hypopituitarism although there may be the suggestion of growth hormone deficiency developing. However, hypogonadism is common in men with NETs so the gonadal axis should be assessed in men with suggestive symptoms as the treatment of testosterone deficiency may improve the quality of life.

Long Term Efficacy and Assessment of Tumor Response of Transarterial Chemoembolization in Neuroendocrine Liver Metastases: A 15-Year Monocentric Experience.

Simple SummaryNeuroendocrine tumors (NET) are rare tumors, with long-term survival even for patients with liver metastases. Transarterial chemoembolization (TACE) is one of the most widely used treatments in this setting. The aim of the study was to assess the long-term efficacy of TACE in a large cohort of patients with NET liver metastases and to correlate imaging findings with survival. In our study including 202 patients with NET liver metastases and a mean follow-up of 8.2 years, TACE was effective to provide disease control for 26 months and a 5.3-year median overall survival (OS). Imaging responses using RECIST and mRECIST criteria were significantly correlated to OS: the median-OS was twice as long among mRECIST responders versus non-responders, with 80.5 months and 39.6 months respectively. These findings are of major importance for everyday practice as they confirm TACE’s effectiveness and usefulness of imaging evaluation to better tailor patient treatment and repeat TACE sessions whenever necessary.Background: transarterial chemoembolization (TACE) is an established treatment for neuroendocrine tumor (NET) liver metastases. The aim was to evaluate the long-term treatment efficacy of TACE for NET liver metastases, and correlate imaging response with survival. Methods: this IRB-approved, single-center, retrospective study evaluated all TACE procedures performed for NET liver metastases from 2003–2017 for imaging tumor response (RECIST and mRECIST), time to liver progression (TTLP), time to untreatable progression with TACE (TTUP), and overall survival (OS). Patient, tumor, and treatment characteristics were analyzed as prognostic factors. Survival curves according to the Kaplan–Meier method were compared by Log-rank test. Tumor responses according to RECIST and mRECIST were correlated with OS. Results: 555 TACE procedures were performed in 202 NET patients (38% grade 1, 60% grade 2) with primary tumors originating from pancreas, small bowel, and lung (39, 26, and 22% respectively). Median follow-up was 8.2 years (90–139 months). Median TTLP and TTUP were 19.3 months (95%CI 16.3–22.3) and 26.2 months (95%CI 22.3–33.1), respectively. Median OS was 5.3 years (95%CI 4.2–6.7), and was higher among mRECIST responders (80.5 months; 95%CI 64.6–89.8) than in non-responders (39.6 months; 95%CI = 32.8–60.2; p < 0.001). In multivariable analysis, age, tumor grade and liver involvement predicted worse OS, whereas administration of somatostatin analogs correlated with improved OS. Conclusion: TACE for NET liver metastases provides objective response and sustained local disease control rates. RECIST and mRECIST responses correlate with OS.

ENETS standardized (synoptic) reporting for radiological imaging in neuroendocrine tumours.

This expert consensus document represents an initiative by the European Neuroendocrine Tumor Society (ENETS) to provide guidance for synoptic reporting of radiological examinations critical to the diagnosis, grading, staging and treatment of neuroendocrine neoplasms (NENs). Template drafts for initial tumor staging and follow‐up by computed tomography (CT) and magnetic resonance imaging (MRI) were established, based on existing institutional and organisational reporting templates relevant for NEN imaging, and applying the RadLex lexicon of radiological information (Radiological Society of North America), for consistency regarding the radiological terms. During the ENETS Scientific Advisory Board meeting 2018, the template drafts were subject to iterative interdisciplinary discussions among experts in imaging, surgery, gastroenterology, oncology and pathology. Members of the imaging group stated a strong preference for a combination of limited and standardised options by way of drop‐down menus. Separate templates were produced for the initial work‐up and for follow‐up, respectively. To provide a detailed description of the radiological findings of the primary tumor and its local extension and spread, different templates were developed for bronchial, pancreatic and gastrointestinal NENs for CT and MRI, respectively. Each template was structured in 10 sections: clinical details, comparative imaging modality, acquisition technique, primary tumor findings, regional lymph node metastases, distant metastases, TNM classification, reference lesions according to RECIST 1.1, additional findings and conclusion. Two templates were developed for follow‐up, for CT and MRI, respectively, and were specifically focused on assessment of therapy response. These included a qualitative response assessment, such as decrease of vascularisation and presence of necrosis, and a quantitative assessment according to RECIST 1.1 and the modified RECIST (mRECIST) for assessing tumor response following transarterial chemoembolisation.

Gastric Neuroendocrine Tumor Treatment and Survival Outcomes Is Determined by Facility Type

Gastric Neuroendocrine Tumor Treatment and Survival Outcomes Is Determined by Facility Type

RHAMMB-mediated bifunctional nanotherapy targeting Bcl-xL and mitochondria for pancreatic neuroendocrine tumor treatment

The incidence of pancreatic neuroendocrine tumor (PNET) has continued to rise. Due to their indolent feature, PNET patients often present with incurable, metastatic diseases. Novel therapies are urgently needed. We have previously shown that Receptor for Hyaluronic Acid-Mediated Motility isoform B (RHAMMB) and Bcl-xL are upregulated in PNETs and both of them promote PNET metastasis. Because RHAMM protein is undetectable in most adult tissues, we hypothesized that RHAMMB could be a gateway for nanomedicine delivery into PNETs. To test this, we developed a RHAMMB-targeting nanoparticle (NP). Inside this NP, we assembled small interfering RNA (siRNA) against Bcl-xL (siBcl-xL) and mitochondria-fusing peptide KLA. We demonstrated that RHAMMB-positive PNETs picked up the RHAMMB-targeting NPs. siBcl-xL or KLA alone killed only 30% of PNET cells. In contrast, a synergistic killing effect was achieved with the co-delivery of siBcl-xL and KLA peptide in vitro. Unexpectedly, siBcl-xL induced cell death before reducing Bcl-xL protein levels. The systemically injected RHAMMB-targeting NPs carrying siBcl-xL and KLA peptide significantly reduced tumor burden in mice bearing RHAMMB-positive PNETs. Together, these findings indicate that the RHAMMB-targeting nanotherapy serves as a promising drug delivery system for PNET and possibly other malignancies with upregulated RHAMMB. The combination of siBcl-xL and KLA peptide can be a therapy for PNET treatment.

Сучасні аспекти діагностики та лікування нейроендокринних пухлин шлунка

Нейроендокринні пухлини (НЕП) шлунка виникають рідко, їх частка становить 7–8 % усіх НЕП, хоча останніми роками частота виникнення зростає, що, можливо, пов’язано із покращенням методів діагностики. Завдяки магнітно-резонансній, комп’ютерній, позитронно-емісійній томографії, застосуванню сучасних радіофармакологічних препаратів вдається виявити та локалізувати НЕП. Хірургічна резекція залишається найефективнішим методом лікування нейроендокринних пухлин, метою якого є видалення первинної пухлини та, за наявності, метастазів. З успіхом використовуються консервативне лікування та локорегіонарні методи: внутрішньом’язові ін’єкції аналогів соматостатину тривалої дії, радіочастотна термоабляція, емболізація та локальна променева терапія. НЕП шлунка потребують подальшого дослідження: кращого розуміння молекулярно-генетичних шляхів, що впливають на розвиток усіх типів уражень; подальшої розробки фармакологічних препаратів і проведення рандомізованих контрольованих досліджень лікарських засобів, що вже існують; необхідні додаткові клінічні дослідження для визначення найкращих стратегій лікування. Зростаюча частота нейроендокринних пухлин шлунка робить ці питання ще більш актуальними. Наведена стаття, присвячена цій проблемі, базується на даних значної кількості проспективних і неконтрольованих досліджень, клінічних рекомендацій European Neuroendocrine Tumor Society (ENETS), інструкцій National Comprehensive Cancer Network (NCCN), з використанням пошукового ресурсу PubMed.

Progress and Future Directions with Peptide-Drug Conjugates for Targeted Cancer Therapy.

We review drug conjugates combining a tumor-selective moiety with a cytotoxic agent as cancer treatments. Currently, antibody-drug conjugates (ADCs) are the most common drug conjugates used clinically as cancer treatments. While providing both efficacy and favorable tolerability, ADCs have limitations due to their size and complexity. Peptides as tumor-targeting carriers in peptide-drug conjugates (PDCs) offer a number of benefits. Melphalan flufenamide (melflufen) is a highly lipophilic PDC that takes a novel approach by utilizing increased aminopeptidase activity to selectively increase the release and concentration of cytotoxic alkylating agents inside tumor cells. The only other PDC approved currently for clinical use is 177Lu-dotatate, a targeted form of radiotherapy combining a somatostatin analog with a radionuclide. It is approved as a treatment for gastroenteropancreatic neuroendocrine tumors. Results with other PDCs combining synthetic analogs of natural peptide ligands with cytotoxic agents have been mixed. The field of drug conjugates as drug delivery systems for the treatment of cancer continues to advance with the application of new technologies. Melflufen provides a paradigm for rational PDC design, with a targeted mechanism of action and the potential for deepening responses to treatment, maintaining remissions, and eradicating therapy-resistant stem cells.

Сучасні можливості діагностики і лікування нейроендокринних пухлин шлунково-кишкового тракту і підшлункової залози

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Evaluation of Laparoscopy Combined with Intraoperative Gastroscopic Local Gastrectomy in the Treatment of Gastric Neuroendocrine Tumors

Objective: To analyze the clinical effect of laparoscopy combined with intraoperative gastroscopic local gastrectomy in the treatment of gastric neuroendocrine tumors. Methods: A total of 100 patients with gastric neuroendocrine tumors that were treated in the Affiliated Hospital of Chifeng University from January 2016 to March 2021 were selected as the research subjects. They were divided into two groups by the digital table method. The control group underwent laparoscopic partial gastrectomy while the research group underwent laparoscopy combined with intraoperative gastroscopic partial gastrectomy. The curative effects of the two groups were compared. Results: There was no significant difference in the number of surgical lymph node dissections between the two groups (p &gt; 0.05); the amount of bleeding in the research group was lower than that in the control group; the operation time, time taken to get out of bed, gastrointestinal function recovery time, time taken for first eating, and hospital stay were shorter than those in the control group (p &lt; 0.05); the incidence of complications and the recurrence rate in the research group were lower than those in the control group (p &lt; 0.05). Conclusion: Laparoscopy combined with intraoperative gastroscopic local gastrectomy in the treatment of gastric neuroendocrine tumors has significant clinical effect and high safety.

Comparative Analysis on the Curative Effect of Endoscopic Submucosal Dissection and Mucosal Resection in the Treatment of Gastric Neuroendocrine Tumor

Objective: To study the therapeutic effect of endoscopic submucosal dissection and mucosal resection on gastric neuroendocrine tumor. Methods: A hundred patients with gastric neuroendocrine tumor that were treated in the Affiliated Hospital of Chifeng University from January 2016 to May 2021 were randomly selected for this research. They were divided into two groups, which were the control group (endoscopic mucosal resection) and the study group (endoscopic submucosal dissection), by the digital table method. The curative effects of the two groups were observed and compared. Results: Before operation, there were no significant differences in serum CgA, TNF-?, and IL-6 between the two groups, p &gt; 0.05. After surgical treatment, the operation time and hospital stay of the patients in the study group were shorter than those in the control group, the amount of surgical bleeding was also less compared to the control group, and the complete tumor resection rate was higher than that in the control group (p &lt; 0.05); the levels of IL-6 and CgA of the study group were lower than those in the control group, while the levels of TNF-? were higher than those of the control group, p &lt; 0.05; the postoperative complication rate of the study group was lower than that of the reference group (p &lt; 0.05). Conclusion: Endoscopic submucosal dissection is more effective for gastric neuroendocrine tumors. The resection rate of the tumor is high, and the operation risk is low.

90Y radioembolization in the treatment of neuroendocrine neoplasms: Results of an international multicenter retrospective study.

In neuroendocrine neoplasms (NENs), the presence of distant metastases has a severe impact on survival leading to a relevant decrease in the 5-y survival rate. Here, 90Y radioembolization (90Y RE) might be an important treatment option; however, data to support clinical benefits for 90Y RE are scarce. Therefore, the purpose of this study was to analyze the use of 90Y RE in NEN patients with hepatic metastases in an international, multicenter retrospective analysis and assess the potential role of 90Y RE in a multimodal treatment concept. Methods: In total, 297 angiographic evaluations in NEN patients before 90Y RE were analyzed. Baseline characteristics and parameters derived from imaging evaluation and 90Y RE were analyzed. Tumor response was assessed using RECIST 1.1, and survival data were collected. Mean overall survival (OS) between different groups was compared using Kaplan-Meier curves and the log rank test. A P value of less than 0.05 indicated statistical significance. Results: After 90Y RE, the disease control rate according to RECIST 1.1 was 83.5% after 3 mo and 50.9% after 12 mo. OS in the entire population was 38.9 ± 33.0 mo. High tumor grade (P < 0.006) and high tumor burden (P= 0.001) were both associated with a significant decrease in OS. The presence of extrahepatic metastases (P = 0.335) and the type of metastatic vascularization pattern (P = 0.460) had no influence on OS. Patients who received 90Y RE as second-line therapy had a slightly longer but not statistically significant OS than patients who had 90Y RE in a salvage setting (44.8 vs. 30.6 mo, P= 0.078). Hepatic and global progression-free survival after 90Y RE was significantly decreased in heavily pretreated patients, compared with patients with second-line therapy (P = 0.011 and P= 0.010, respectively). Conclusion: 90Y RE could be an important alternative to peptide receptor radionuclide therapy as second-line treatment in patients with progressive liver-dominant disease pretreated with somatostatin analogs.