The cycle effect quantified: reduced tumour uptake in subsequent cycles of [177Lu]Lu-HA-DOTATATE during peptide receptor radionuclide therapy.

BACKGROUND: Clear evidence regarding the effect of reduced tumour accumulation in later peptide receptor radionuclide therapy (PRRT) cycles is lacking. Therefore, we aimed to quantify potential cycle effects for patients treated with [177Lu]Lu-HA-DOTATATE using a population pharmacokinetic (PK) modelling approach. METHODS: A population PK model was developed using imaging data from 48 patients who received multiple cycles of [177Lu]Lu-HA-DOTATATE. The five-compartment model included a central, kidney, spleen, tumour and lumped rest compartment. Tumour volume and continued use of long-acting somatostatin analogues (SSAs) were tested as covariates in the model. In addition, the presence of a cycle effect was evaluated by relating the uptake rate in a specific cycle as a fraction of the (tumour or organ) uptake rate in the first cycle. RESULTS: The final PK model adequately captured observed radioactivity accumulation in kidney, spleen and tumour. A higher tumour volume was identified to increase the tumour uptake rate, where a twofold increase in tumour volume resulted in a 2.3-fold higher uptake rate. Also, continued use of long-acting SSAs significantly reduced the spleen uptake rate (68.4% uptake compared to SSA withdrawal (10.5% RSE)). Lastly, a cycle effect was significantly identified, where tumour uptake rate decreased to 86.9% (5.3% RSE) in the second cycle and even further to 79.7% (5.6% RSE) and 77.6% (6.2% RSE) in the third and fourth cycle, respectively, compared to cycle one. CONCLUSIONS: Using a population PK modelling approach, the cycle effect of reduced tumour uptake in subsequent PRRT cycles was quantified. Our findings implied that downregulation of target receptors is probably not the major cause of the cycle effect, due to a plateau in the decrease of tumour uptake in the fourth cycle.

Dosimetry and pharmacokinetics of [177Lu]Lu-satoreotide tetraxetan in patients with progressive neuroendocrine tumours.

PURPOSE: To evaluate the dosimetry and pharmacokinetics of the novel radiolabelled somatostatin receptor antagonist [177Lu]Lu-satoreotide tetraxetan in patients with advanced neuroendocrine tumours (NETs). METHODS: This study was part of a phase I/II trial of [177Lu]Lu-satoreotide tetraxetan, administered at a median cumulative activity of 13.0 GBq over three planned cycles (median activity/cycle: 4.5 GBq), in 40 patients with progressive NETs. Organ absorbed doses were monitored at each cycle using patient-specific dosimetry; the cumulative absorbed-dose limits were set at 23.0 Gy for the kidneys and 1.5 Gy for bone marrow. Absorbed dose coefficients (ADCs) were calculated using both patient-specific and model-based dosimetry for some patients. RESULTS: In all evaluated organs, maximum [177Lu]Lu-satoreotide tetraxetan uptake was observed at the first imaging timepoint (4 h after injection), followed by an exponential decrease. Kidneys were the main route of elimination, with a cumulative excretion of 57-66% within 48 h following the first treatment cycle. At the first treatment cycle, [177Lu]Lu-satoreotide tetraxetan showed a median terminal blood half-life of 127 h and median ADCs of [177Lu]Lu-satoreotide tetraxetan were 5.0 Gy/GBq in tumours, 0.1 Gy/GBq in the bone marrow, 0.9 Gy/GBq in kidneys, 0.2 Gy/GBq in the liver and 0.8 Gy/GBq in the spleen. Using image-based dosimetry, the bone marrow and kidneys received median cumulative absorbed doses of 1.1 and 10.8 Gy, respectively, after three cycles. CONCLUSION: [177Lu]Lu-satoreotide tetraxetan showed a favourable dosimetry profile, with high and prolonged tumour uptake, supporting its acceptable safety profile and promising efficacy. TRIAL REGISTRATION: NCT02592707. Registered October 30, 2015.

Lutetium [177Lu]-DOTA-TATE in gastroenteropancreatic-neuroendocrine tumours: rationale, design and baseline characteristics of the Italian prospective observational (REAL-LU) study.

PURPOSE: Gastroenteropancreatic -neuroendocrine tumours (GEP-NETs) are commonly treated with surgical resection or long-term therapies for tumour growth control. Lutetium [177Lu]-DOTA-TATE was approved for the treatment of GEP-NETs after the phase III NETTER 1trial demonstrated improved progression free survival, objective response rates and health-related quality of life (HRQoL) compared to high-dose somatostatin analogues. No real-world data exist on prescribing habits and clinically significant endpoints for [177Lu]Lu-DOTA-TATE treatment in Italy. REAL-LU is a multicentre, long-term observational study in patients with unresectable/metastatic GEP-NETs progressing on standard therapies in Italian clinical practice. A pre-specified interim analysis was performed at the end of the enrolment period, data from which are described herein. METHODS: Overall duration of REAL-LU will be approximately 48 months, with 12- and 36-month recruitment and follow-up periods, respectively. The primary objective is to evaluate [177Lu]Lu-DOTA-TATE effectiveness in terms of progression-free survival. Secondary objectives include safety, impact on HRQoL, and identification of prognostic factors. This pre-specified interim analysis describes patient profiles, at the end of enrollment, of those prescribed [177Lu]Lu-DOTA-TATE for GEP-NETs in Italy. RESULTS: Among 161 evaluable patients, mean age was 64.7 ± 10.3 years at study entry, 83.8% presented with no clinical signs of disease at physical examination, and most had minor disease symptoms. All patients had metastatic disease, most commonly in the liver (83.9%) with a median of two metastatic sites. In 90.7% of patients, the disease was stage IV, and 68.3% had ≥ 1 target lesion. [177Lu]Lu-DOTA-TATE was prescribed mainly as second-line therapy (61.6%) and following surgery (58.4%). HRQoL assessments revealed high levels of functioning and low levels of symptoms at baseline; 50.0% of patients were symptom-free at study entry. CONCLUSION: The characteristics of patients who received [177Lu]Lu-DOTA-TATE in Italy are similar to those of the GEP-NET population of NETTER 1 with trial but with a higher proportion of patients with a grade 2 (71%). With regard to the tumor grade profile, our study cohort appears to be closer to that of NETTER-2 study population which included patients with G2 or G3 advanced GEP-NETs (i.e. Ki-67 ≥ 10% and ≤ 55%). Further analysis of effectiveness and safety can be anticipated as REAL-LU data mature. STUDY REGISTRATION: ClinicalTrials.gov, NCT04727723; Study Registration Date: 25 January, 2021; https://clinicaltrials.gov/study/NCT04727723?cond=NCT04727723&rank=1.

Sarcopenia and Neuroendocrine Neoplasms.

PURPOSE OF THE REVIEW: To summarise the current literature regarding the presence of sarcopenia in patients with neuroendocrine neoplasms (NENs). These are uncommon cancers separated into well-differentiated neuroendocrine tumours (NETs) and poorly differentiated neuroendocrine carcinoma (NECs). For the diagnosis of sarcopenia, there needs to be low muscle strength and low muscle quantity/quality. RECENT FINDINGS: Five studies exist describing either low muscle strength or low muscle quantity in patients with NETs. The studies used different techniques to analyse muscle strength and muscle quantity, included heterogeneous populations, and performed the analysis at different time points following the diagnosis of the NET. Only 2 studies regarding patients with NECs could be found, both included mainly patients with a mixed adenoneuroendocrine carcinoma (MiNEN) and are, therefore, difficult to interpret for patients with a NEC. The main findings of this review are to describe the presence of sarcopenia in patients with NENs. However, results should be interpreted with caution, and future research should focus on the correct technique, homogenous population and same time point.

PREF-NET: a patient preference and experience study of lanreotide autogel administered in the home versus hospital setting among patients with gastroenteropancreatic neuroendocrine tumours in the UK.

PURPOSE: PREF-NET reported patients' experience of Somatuline® (lanreotide) Autogel® (LAN) administration at home and in hospital among patients with gastroenteropancreatic neuroendocrine tumours (GEP-NETs). METHODS: PREF-NET was a multicentre, cross-sectional study of UK adults (aged ≥ 18 years) with GEP-NETs receiving a stable dose of LAN, which comprised of (1) a quantitative online survey, and (2) qualitative semi-structured interviews conducted with a subgroup of survey respondents. The primary objective was the description of overall patient preference for home versus hospital administration of LAN. Secondary objectives included describing patient-reported opinions on the experience and associated preference for each administration setting, and the impact on healthcare utilisation, societal cost, activities of daily living and health-related quality of life (HRQoL). RESULTS: In the primary analysis (80 patients; mean age 63.9 years), 98.7% (95% confidence interval [CI]: 96.1-100.0) of patients preferred to receive LAN at home, compared with 1.3% (95% CI: 0.0-3.9) who preferred the hospital setting. Among participants, over half (60.3%) received their injection from a non-healthcare professional. Most patients (79.5% [95% CI: 70.5-88.4]) reported a positive effect on HRQoL after the switch from hospital to home administration. Qualitative interviews (20 patients; mean age 63.6 years) highlighted that patients preferred home administration because it improved overall convenience; saved time and costs; made them feel more comfortable and relaxed, and less stressed; and increased confidence in their ability to self-manage their treatment. CONCLUSION: Almost all patients preferred to receive LAN treatment at home rather than in hospital with increased convenience and psychological benefits reported as key reasons for this preference.

An international simulated-use study to assess nurses' preferences between two lanreotide syringes for patients with neuroendocrine tumours or acromegaly (PRESTO 3).

PURPOSE: PRESTO 3 evaluated nurses' preference for the Somatuline® Autogel® syringe versus the Lanreotide Pharmathen syringe after injection-pad testing. METHODS: This international simulated-use study included oncology/endocrinology nurses with ≥ 1 years' experience in managing neuroendocrine tumours (NETs) and/or acromegaly. Each nurse tested both syringes twice in a randomised order before completing an electronic survey. The primary objective was to assess overall preference (%, 95% confidence interval [CI]) for the Somatuline Autogel syringe versus the Lanreotide Pharmathen syringe. Secondary objectives included rating syringe performance and ranking the importance of syringe attributes. RESULTS: Ninety-four nurses were enrolled: mean age, 41.0 (SD, 11.5) years. The percentage of nurses stating a preference ("strong" or "slight") for the Somatuline Autogel syringe (86.2% [95% CI 77.5-92.4%]) was significantly higher than 50% (p < 0.0001). Performance rating was significantly higher for the Somatuline Autogel syringe versus Lanreotide Pharmathen syringe for 10 of the 11 attributes tested (p < 0.05). The syringe attributes considered most important when injecting patients in routine clinical practice were "easy to use from preparation to injection" (30.9%) and "comfortable to handle during use from preparation to injection" (16.0%). The attribute most commonly rated as least important was "fast administration from preparation to injection" (26.6%). CONCLUSION: Nurses strongly preferred the user experience of the Somatuline Autogel syringe over the Lanreotide Pharmathen syringe. "Ease of use" and "comfortable to handle" were the most important syringe attributes, and performance rating was significantly higher with Somatuline Autogel versus Lanreotide Pharmathen syringe for all but one attribute.

Drugs called somatostatin analogues (SSAs) can be used to treat patients with neuroendocrine tumours or acromegaly over a prolonged period of time. SSAs are given as injections and act by slowing the production of hormones by the body and in some cases reducing the growth of the tumour. To help to provide the best care possible, it is important that the syringe used for the injection is easy to use and delivers the SSA effectively. Somatuline Autogel is a syringe that can be used to inject an SSA called lanreotide. Previous studies showed that patients and nurses preferred the injection experience when using the Somatuline Autogel syringe compared with a syringe used to inject another SSA called octreotide long-acting release. A new syringe used for lanreotide injections has been developed recently by a company called Pharmathen. In the PRESTO 3 study, we compared the user experience of the Somatuline Autogel syringe and the Lanreotide Pharmathen syringe. We asked 94 nurses from Europe and the US to test both syringes, in a randomised order, using injection pads, and then to answer questions about their overall preference between the two syringes and how well the syringe performed for a set of syringe features. Overall, 86% of nurses preferred the Somatuline Autogel syringe over the Lanreotide Pharmathen syringe. Of the 11 features of the syringe that we assessed, 10 were rated higher for the Somatuline Autogel syringe than the Lanreotide Pharmathen syringe. The syringe features "ease of use" and "comfortable to handle" were considered the most important. The results of the PRESTO 3 study indicated that there is a difference in the user experience between the syringes, particularly for confidence and ease of use, and that it is important to offer syringe choices to nurses who are using SSA injections to treat patients.

Is radiomics a useful addition to magnetic resonance imaging in the preoperative classification of PitNETs?

BACKGROUND: The WHO 2021 introduced the term pituitary neuroendocrine tumours (PitNETs) for pituitary adenomas and incorporated transcription factors for subtyping, prompting the need for fresh diagnostic methods. Current biomarkers struggle to distinguish between high- and low-risk non-functioning PitNETs. We explored if radiomics can enhance preoperative decision-making. METHODS: Pre-treatment magnetic resonance (MR) images of patients who underwent surgery between 2015 and 2019 with available WHO 2021 classification were used. The tumours were manually segmented on the T1w, T1-contrast enhanced, and T2w images using 3D Slicer. One hundred Pyradiomic features were extracted from each MR sequence. Models were built to classify (1) somatotroph and gonadotroph PitNETs and (2) high- and low-risk subtypes of non-functioning PitNETs. Feature were selected independently from the MR sequences and multi-sequence (combining data from more than one MR sequence) using Boruta and Pearson correlation. Support vector machine (SVM), logistic regression (LR), random forest (RF), and multi-layer perceptron (MLP) were the classifiers used. Data imbalance was addressed using the Synthetic Minority Oversampling TEchnique (SMOTE). Performance of the models were evaluated using area under the receiver operating curve (AUC), accuracy, sensitivity, and specificity. RESULTS: A total of 222 PitNET patients (train, n = 149; test, n = 73) were enrolled in this retrospective study. Multi-sequence-based LR model discriminated best between somatotroph and gonadotroph PitNETs, with a test AUC of 0.84, accuracy of 0.74, specificity of 0.81, and sensitivity of 0.70. Multi-sequence-based MLP model perfomed best for the high- and low-risk non-functioning PitNETs, achieving a test AUC of 0.76, accuracy of 0.67, specificity of 0.72, and sensitivity of 0.66. CONCLUSIONS: Utilizing pre-treatment MRI and radiomics holds promise for distinguishing high-risk from low-risk non-functioning PitNETs based on the latest WHO classification. This could assist neurosurgeons in making critical decisions regarding surgery or alternative management strategies for PitNETs after further clinical validation.

Dual-energy CT improves differentiation of non-hypervascular pancreatic neuroendocrine neoplasms from CA 19-9-negative pancreatic ductal adenocarcinomas.

PURPOSE: To evaluate the utility of dual-energy CT (DECT) in differentiating non-hypervascular pancreatic neuroendocrine neoplasms (PNENs) from pancreatic ductal adenocarcinomas (PDACs) with negative carbohydrate antigen 19-9 (CA 19-9). METHODS: This retrospective study included 26 and 39 patients with pathologically confirmed non-hypervascular PNENs and CA 19-9-negative PDACs, respectively, who underwent contrast-enhanced DECT before treatment between June 2019 and December 2021. The clinical, conventional CT qualitative, conventional CT quantitative, and DECT quantitative parameters of the two groups were compared using univariate analysis and selected by least absolute shrinkage and selection operator regression (LASSO) analysis. Multivariate logistic regression analyses were performed to build qualitative, conventional CT quantitative, DECT quantitative, and comprehensive models. The areas under the receiver operating characteristic curve (AUCs) of the models were compared using DeLong's test. RESULTS: The AUCs of the DECT quantitative (based on normalized iodine concentrations [nICs] in the arterial and portal venous phases: 0.918; 95% confidence interval [CI] 0.852-0.985) and comprehensive (based on tumour location and nICs in the arterial and portal venous phases: 0.966; 95% CI 0.889-0.995) models were higher than those of the qualitative (based on tumour location: 0.782; 95% CI 0.665-0.899) and conventional CT quantitative (based on normalized conventional CT attenuation in the arterial phase: 0.665; 95% CI 0.533-0.797; all P < 0.05) models. The DECT quantitative and comprehensive models had comparable performances (P = 0.076). CONCLUSIONS: Higher nICs in the arterial and portal venous phases were associated with higher blood supply improving the identification of non-hypervascular PNENs.

Multiple endocrine neoplasia type 1 (MEN-1) and neuroendocrine neoplasms (NENs).

Neuroendocrine neoplasms (NENs) are relatively rare neoplasms with 6.4-times increasing age-adjusted annual incidence during the last four decades. NENs arise from neuroendocrine cells, which release hormones in response to neuronal stimuli and they are distributed into organs and tissues. The presentation and biological behaviour of the NENs are highly heterogeneous, depending on the organ. The increased incidence is mainly due to increased awareness and improved detection methods both in the majority of sporadic NENs (non-inherited), but also the inherited groups of neoplasms appearing in at least ten genetic syndromes. The most important one is multiple endocrine neoplasia type 1 (MEN-1), caused by mutations in the tumour suppressor gene MEN1. MEN-1 has been associated with different tumour manifestations of NENs e.g. pancreas, gastrointestinal tract, lungs, thymus and pituitary. Pancreatic NENs tend to be less aggressive when arising in the setting of MEN-1 compared to sporadic pancreatic NENs. There have been very important improvements over the past years in both genotyping, genetic counselling and family screening, introduction and validation of various relevant biomarkers, as well as newer imaging modalities. Alongside this development, both medical, surgical and radionuclide treatments have also advanced and improved morbidity, quality of life and mortality in many of these patients. Despite this progress, there is still space for improving insight into the genetic and epigenetic factors in relation to the biological mechanisms determining NENs as part of MEN-1. This review gives a comprehensive update of current evidence for co-occurrence, diagnosis and treatment of MEN-1 and neuroendocrine neoplasms and highlight the important progress now finding its way to international guidelines in order to improve the global management of these patients.

Transcriptome of GH-producing pituitary neuroendocrine tumours and models are significantly affected by somatostatin analogues.

Pituitary neuroendocrine tumours (PitNETs) are neoplasms of the pituitary that overproduce hormones or cause unspecific symptoms due to mass effect. Growth hormone overproducing GH-producing PitNETs cause acromegaly leading to connective tissue, metabolic or oncologic disorders. The medical treatment of acromegaly is somatostatin analogues (SSA) in specific cases combined with dopamine agonists (DA), but almost half of patients display partial or full SSA resistance and potential causes of this are unknown. In this study we investigated transcriptomic landscape of GH-producing PitNETs on several levels and functional models-tumour tissue of patients with and without SSA preoperative treatment, tumour derived pituispheres and GH3 cell line incubated with SSA to study effect of medication on gene expression. MGI sequencing platform was used to sequence total RNA from PitNET tissue, pituispheres, mesenchymal stromal stem-like cells (MSC), and GH3 cell cultures, and data were analysed with Salmon-DeSeq2 pipeline. We observed that the GH-producing PitNETs have distinct changes in growth hormone related pathways related to its functional status alongside inner cell signalling, ion transport, cell adhesion and extracellular matrix characteristic patterns. In pituispheres model, treatment regimens (octreotide and cabergoline) affect specific cell proliferation (MKI67) and core functionality pathways (RYR2, COL8A2, HLA-G, ARFGAP1, TGFBR2). In GH3 cells we observed that medication did not have transcriptomic effects similar to preoperative treatment in PitNET tissue or pituisphere model. This study highlights the importance of correct model system selection for cell transcriptomic profiling and data interpretation that could be achieved in future by incorporating NGS methods and detailed cell omics profiling in PitNET model research.

A phase I/II study of the safety and efficacy of [177Lu]Lu-satoreotide tetraxetan in advanced somatostatin receptor-positive neuroendocrine tumours.

PURPOSE: We present the results of an open-label, phase I/II study evaluating the safety and efficacy of the novel somatostatin receptor (SSTR) antagonist [177Lu]Lu-satoreotide tetraxetan in 40 patients with previously treated, progressive neuroendocrine tumours (NETs), in which dosimetry was used to guide maximum administered activity. METHODS: This study was conducted in two parts. Part A consisted of 15 patients who completed three cycles of [177Lu]Lu-satoreotide tetraxetan at a fixed administered activity and peptide amount per cycle (4.5 GBq/300 µg). Part B, which included 25 patients who received one to five cycles of [177Lu]Lu-satoreotide tetraxetan, evaluated different administered activities (4.5 or 6.0 GBq/cycle) and peptide amounts (300, 700, or 1300 µg/cycle), limited to a cumulative absorbed radiation dose of 23 Gy to the kidneys and 1.5 Gy to the bone marrow. RESULTS: Median cumulative administered activity of [177Lu]Lu-satoreotide tetraxetan was 13.0 GBq over three cycles (13.1 GBq in part A and 12.9 GBq in part B). Overall, 17 (42.5%) patients experienced grade ≥ 3 treatment­related adverse events; the most common were lymphopenia, thrombocytopenia, and neutropenia. No grade 3/4 nephrotoxicity was observed. Two patients developed myeloid neoplasms considered treatment related by the investigator. Disease control rate for part A and part B was 94.7% (95% confidence interval [CI]: 82.3-99.4), and overall response rate was 21.1% (95% CI: 9.6-37.3). CONCLUSION: [177Lu]Lu-satoreotide tetraxetan, administered at a median cumulative activity of 13.0 GBq over three cycles, has an acceptable safety profile with a promising clinical response in patients with progressive, SSTR-positive NETs. A 5-year long-term follow-up study is ongoing. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02592707. Registered October 30, 2015.

Clinical and Proteomic-Based Molecular Characterizations of Invasive and Noninvasive Somatotroph PitNETs.

INTRODUCTION: Somatotroph pituitary neuroendocrine tumours (PitNETs) are characterized by complex and variable biological behaviours with unpredictable patterns of growth and invasiveness. The molecular mechanisms and reliable predictors of biological markers of invasiveness remain unknown. METHODS: Seventy-two acromegaly patients were consecutively enrolled. Data-independent acquisition-based proteomics and ingenuity pathway analysis were conducted between invasive and noninvasive somatotroph PitNETs. The expression of selected biomarkers was verified in PitNET tissue, and its correlation with various clinical indicators and outcomes of these tumours was assessed. The invasive phenotypes of GH3 cells were validated in vitro. RESULTS: Patients with invasive somatotroph PitNETs were significantly younger at onset and diagnosis, with significantly higher secretion and faster growth and a lower long-term biochemical response rate than patients with noninvasive somatotroph PitNETs. Proteomic data were evaluated in a consecutively collected sample of 19 (10 invasive and 9 noninvasive somatotroph PitNETs) tumours and indicated a distinct proteomic pattern. The enriched and important pathways included IL-4, PDGF, PTEN, VEGF, PI3K/AKT, FAK, and other pathways that were significantly associated with tumour proliferation, migration, and invasion. High cathepsin Z (CTSZ) expression was found in invasive somatotroph PitNETs and significantly positively correlated with parameters of tumour invasion and growth. In Ctsz-overexpressing GH3 cells, cell proliferation, invasion, and migration were consequently increased. CONCLUSION: It is more difficult for patients with invasive somatotroph PitNETs to achieve remission than those with noninvasive somatotroph PitNETs, and proteomic data analysis has revealed the high expression of CTSZ as a contributing factor to invasive transformation and poor prognosis in somatotroph PitNETs for the first time.

Chromosome 18 Loss of Heterozygosity in Small Intestinal Neuroendocrine Tumours: Multi-Omic and Tumour Composition Analyses.

INTRODUCTION: Small intestinal neuroendocrine tumours (siNETs) are rare neoplasms which present with low mutational burden and can be subtyped based on copy number variation (CNV). Currently, siNETs can be molecularly classified as having chromosome 18 loss of heterozygosity (18LOH), multiple CNVs (MultiCNV), or no CNVs. 18LOH tumours have better progression-free survival when compared to MultiCNV and NoCNV tumours, however, the mechanism underlying this is unknown, and clinical practice does not currently consider CNV status. METHODS: Here, we use genome-wide tumour DNA methylation (n = 54) and gene expression (n = 20 matched to DNA methylation) to better understand how gene regulation varies by 18LOH status. We then use multiple cell deconvolution methods to analyse how cell composition varies between 18LOH status and determine potential associations with progression-free survival. RESULTS: We identified 27,464 differentially methylated CpG sites and 12 differentially expressed genes between 18LOH and non-18LOH (MultiCNV + NoCNV) siNETs. Although few differentially expressed genes were identified, these genes were highly enriched with the differentially methylated CpG sites compared to the rest of the genome. We identified differences in tumour microenvironment between 18LOH and non-18LOH tumours, including CD14+ infiltration in a subset of non-18LOH tumours which had the poorest clinical outcomes. CONCLUSIONS: We identify a small number of genes which appear to be linked to the 18LOH status of siNETs, and find evidence of potential epigenetic dysregulation of these genes. We also find a potential prognostic marker for worse progression-free outcomes in the form of higher CD14 infiltration in non-18LOH siNETs.

Where Are We Now with Liver Transplantation in Neuroendocrine Neoplasms? The Place of Liver Transplantation for Grades 1 and 2 Well-Differentiated Unresectable Liver Metastatic Neuroendocrine Tumours.

PURPOSE OF REVIEW: This review outlines the role of liver transplantation in selected patients with unresectable neuroendocrine tumour liver metastases. It discusses the international consensus on eligibility criteria and outlines the efforts taking place in the UK and Ireland to develop effective national liver transplant programmes for neuroendocrine tumour patients. RECENT FINDINGS: In the early history of liver transplantation, indications included cancer metastases to the liver as well as primaries of liver origin. Often, liver transplantation was a salvage procedure. The early results were disappointing, including in patients with neuroendocrine tumours. These data discouraged the widespread adoption of liver transplantation for neuroendocrine tumour liver metastases (NET LM). A few centres persisted in performing liver transplantation for patients with NET LM and in determining parameters predictive of good outcomes. Their work has provided evidence for benefit of liver transplantation in a selected group of patients with NET LM. Liver transplantation for NET LM is now accepted as a valid indication by many professional bodies, including the European Neuroendocrine Tumour Society (ENETS) and the United Network for Organ Sharing (UNOS). It is nevertheless rarely utilised. The UK and the Republic of Ireland are commencing a pilot programme of liver transplantation in selected patients. This programme will help develop the expertise and infrastructure to make liver transplantation for NET LM a routine procedure.

Prediction of lymph node metastasis of well-differentiated rectal neuroendocrine tumours using multiple diagnostic modalities.

AIM: The preoperative prediction of lymph node metastasis of well-differentiated rectal neuroendocrine tumours is highly desirable and useful in defining surgical indication more accurately. We aimed to evaluate lymph node metastasis in rectal neuroendocrine neoplasms using multiple imaging modalities. METHODS: The clinical records and radiological images of 70 patients with well-differentiated rectal neuroendocrine tumours who received treatment at the University of Tokyo Hospital between 2010 and 2022 were retrospectively analysed. The relationship between evaluation by multiple imaging modalities and pathological lymph node metastasis was analysed. RESULTS: The receiver operating characteristic curves showed that a maximum lymph node diameter ≥4 mm on computed tomography and ≥8 mm on magnetic resonance imaging were the optimal predictive factors for lymph node metastasis. Accumulation in the lymph nodes on somatostatin receptor scintigraphy (P = 0.058) and Delle's findings on colonoscopy (P = 0.014) were also significant predictors of pathological lymph node positivity, and combination of multiple modalities was useful. Pathologically, lymphatic (P = 0.0030)/venous (P = 0.0007) invasion were risk factors for lymph node metastasis. CONCLUSIONS: In addition to pathological risk factors, a combination of multiple radiological imaging modalities is useful for predicting lymph node metastasis in well-differentiated rectal neuroendocrine tumours.

Plasma or serum 5-hydroxyindoleacetic acid can be used interchangeably in patients with neuroendocrine tumours.

5-hydroxyindole acetic acid, a metabolite of serotonin, is used in the diagnosis and monitoring of patients with neuroendocrine tumours, in particular patients with small intestinal neuroendocrine tumours associated with the carcinoid syndrome. Analysis of 5-hydroxyindole acetic acid was commonly performed in urine, but blood-based assays are now becoming available. The objective of this study was to assess how 5-hydroxyindole acetic acid compares in plasma and serum as a biochemical marker of neuroendocrine tumours. Twenty-four-hour urine, plasma and serum samples were obtained from 80 patients with neuroendocrine tumours and 30 healthy volunteers. We developed a liquid chromatography tandem mass spectrometry assay for plasma and serum 5-hydroxyindole acetic acid. Comparison was made between them, and their cut-off was determined using a receiver-operating characteristic curve. A close correlation was shown between plasma and serum 5-hydroxyindole acetic acid. At a cut-off of 135 nmol/l, a sensitivity of 91.2% with a specificity of 61.9% was obtained for both compared to the urinary assay. A statistically significant agreement was shown when plasma and serum 5-hydroxyindole acetic acid were compared with the currently used urine assay in patients with neuroendocrine tumours; κ = 0.675 (95% CI 0.49 to 0.86), p < 0.001 and healthy volunteers; 0.967 (95% CI 0.828 to 0.999), p = <0.001. In conclusion, 5-hydroxyindole acetic acid in plasma and serum were comparable, hence either sample type can be used interchangeably.

Appendiceal neuroendocrine neoplasms and resection of the mesoappendix: a retrospective comparative study.

PURPOSE: Incidental appendiceal neoplasms are identified in approximately 1% of the specimens of suspected appendicitis. The current institutional policy is to perform en bloc mesoappendix resection during routine laparoscopic appendicectomy allowing for staging, reducing the need for oncological right hemicolectomy (ORH). Herein, we review en bloc mesoappendicectomy in clinical practice and its effects on the rate of ORH. METHODS: We reviewed all cases of appendicectomy performed at the Auckland City Hospital between 1 May 2014 and 31 May 2019. Clinical notes and histopathological reports were reviewed. All neoplasms, surgical techniques and the need for further surgery were analysed. RESULTS: A total of 2455 appendicectomies were performed with an approximately similar number of procedures between the sexes and an overall median age of 31 years. Overall, 86% (n = 2098) of the specimens included resection of the mesoappendix, and 58 (2.4%) appendiceal neoplasms were identified. Of them, 33 (1.3%) specimens included neuroendocrine appendiceal neoplasms. Eleven (33%) patients with appendiceal neuroendocrine neoplasms were recommended ORH. One of these patients may have avoided additional surgery, whereas 3 (9.1%) patients with tumours of 10-20 mm avoided ORH because their mesoappendix was resected. CONCLUSION: At our centre, there has been a significant change in the practice of mesoappendix resection, and we support resection of the mesoappendix during appendicectomy. The procedure is technically straightforward and safe, incurs no increases in costs or time, allows for accurate tumour staging and guides decisions regarding further surgical interventions.

Prognostic predictors for recurrence following curative resection in grade I/II pancreatic neuroendocrine tumours.

INTRODUCTION: Pancreatic neuroendocrine tumours (pNETs) have an excellent long-term survival after resection, but are associated with a high recurrence rate. Identification of prognostic factors affecting recurrences would enable identifying subgroup of patients at higher risk of recurrences, who may benefit from more aggressive treatment. METHODS: A retrospective analysis of prospectively maintained database of patients undergoing pancreatectomy with curative intent for grade I and II pNETs between July 2007 and June 2021 was performed. Perioperative and long-term outcomes were analysed. RESULTS: A total of 68 resected patients of pNETs were included in this analysis. Fifty-two patients (76.47%) underwent pancreaticoduodenectomy, 10 (14.7%) patients had distal pancreatectomy, and 2 (2.9%) patients underwent median pancreatectomy, while enucleation was performed in 4 patients (5.8%). The overall major morbidity (Clavien-Dindo III/IV) and mortality rates were 33.82% and 2.94%, respectively. At a median follow-up period of 48 months, 22 (32.35%) patients had disease recurrence. The 5-year overall survival and 5-year recurrence-free survival (RFS) rates were 90.2% and 60.8%, respectively. While OS was unaffected by different prognostic factors, multivariate analysis showed that lymph node involvement, Ki-67 index ≥5%, and presence of perineural invasion (PNI) were independently associated with recurrence. CONCLUSIONS: While surgical resection gives excellent overall survival in grade I/II pNETs, lymph node positivity, higher Ki-67 index, and PNI are associated with a high risk for recurrence. Patients with these characteristics should be stratified as high risk and evaluated for more intensive follow-up and aggressive treatment strategies in future prospective studies.

Lactotroph PitNET/adenoma associated to granulomatous hypophysitis in a patient with Crohn's disease: A case report.

Granulomatous hypophysitis is a rare and poorly understood condition. Although certain cases are treated as primary pituitary autoimmune disorders, rare cases may be associated with pituitary neuroendocrine tumours (PitNETs) and systemic inflammatory diseases. Here, we report a case of a 47-year-old man that underwent endoscopic trans-sphenoidal excision of a pituitary mass diagnosed as PitNET. On histologic evaluation, the neoplasm showed an admixture of granulomas with extensive inflammatory infiltrate and lactotroph PitNET/adenoma. Careful anamnestic examination revealed a diagnosis of Crohn's disease 20 years prior. Although rarely done, both PitNET and Crohn's disease may be associated with granulomatous hypophysitis, and our patient had both conditions. During the 6-year follow-up, PitNETs and hypophysitis did not recur, while Crohn's disease was only partially controlled by medical therapy. To our knowledge, this is the first description of association of granulomatous hypophysitis, PitNET and Crohn's disease.

Neuroendocrine Neoplasms of the Gastrointestinal Tract versus Neuroendocrine Neoplasms of the Gynaecological Tract-Comparison of the Risk Factors and Non-Surgical Treatment Efficacy.

Neuroendocrine tumours of the gastrointestinal tract are rare. The incidence has increased in recent years due to improvements in diagnostic methods for detecting these lesions. These tumours have a poor prognosis, especially when detected at an advanced stage. The basis of the treatment is resection, and non-surgical treatments are also standard in the treatment process. The situation is similar in even rarer neuroendocrine tumours of the reproductive tract, which are associated with an equally poor prognosis. In this article, we focus on learning about the risk factors (including genetic mutations) that increase the risk of the disease and comparing the effectiveness of non-surgical treatments-chemotherapy, radiotherapy, peptide receptor radionuclide therapy, somatostatin analogues, and immunotherapy. The efficacy of these treatments varies, and immunotherapy appears to be a promising form of treatment; however, this requires further research.