Theranostics in Neuroendocrine Neoplasms: The Multifaceted Aspects Integrating Imaging, Therapy, and Dosimetry.

Contemporary short-term post-operative outcomes after resection of entero-pancreatic NETs: a population-based study.

Shifts in Urbanicity-Based Access to Radiotracers for Neuroendocrine Tumors.

Altered vasomotor function and endothelial impairment in a neuroendocrine tumor mouse model.

Systemic radionuclide therapy has become a cornerstone in the management of advanced gastro-entero-pancreatic neuroendocrine tumours (GEP-NETs). Following the establishment of β-emitting peptide receptor radionuclide therapy (PRRT) as an effective treatment for somatostatin receptor positive NETs, recent clinical and translational advances have substantially expanded its therapeutic scope. Several pivotal randomised trials published within the past 18 months justify a reassessment of radionuclide treatment strategies in GEP-NETs. Recently published results of randomised phase III trials support a broader and more strategic use of PRRT, such as in selected high-grade well differentiated NETs. Direct comparisons of PRRT and targeted therapies redefine therapeutic sequencing. Radiosensitising combinations and next-generation theranostic platforms, including alpha-emitting radionuclides, are entering late-phase development. Radionuclide therapy in GEP-NETs is transitioning from a late-line option toward a flexible, biology-driven treatment strategy with important implications for clinical practice.

SSTR-PET is routinely used to select patients with neuroendocrine neoplasms (NEN) for peptide receptor radionuclide therapy (PRRT). As the kidneys are organs at risk, this study evaluated whether renal uptake on pre-therapeutic SSTR-PET/CT reflects split or global renal function and correlates with renal absorbed dose during [177Lu]Lu-DOTA-TATE therapy. In this retrospective study, 85 NEN patients treated with [177Lu]Lu-DOTA-TATE between 2013 and 2023 were included. All underwent SSTR-PET/CT using [18F]SiTATE, [68Ga]Ga-DOTA-TATE, or [68Ga]Ga-DOTA-TOC plus serum kidney function tests and [99mTc]Tc-MAG3 scintigraphy. Renal PET uptake was compared with serum and scintigraphic kidney parameters. In 30 patients, renal absorbed dose was estimated using post-treatment SPECT/CT. Renal uptake on SSTR-PET/CT moderately correlated with split renal function assessed by [99mTc]Tc-MAG3 across all tracers, particularly using SUVmean ([18F]SiTATE (r = 0.462; p = 0.010); [68Ga]Ga-DOTA-TATE (r = 0.515; p = 0.004); [68Ga]Ga-DOTA-TOC (r = 0.546; p = 0.004)). No relevant correlation was observed between total renal PET uptake and tubular extraction rate, eGFR, or serum creatinine. Renal PET uptake showed moderate correlations with mean absorbed doses in selected tracer cohorts ([18F]SiTATE; r = 0.585; p = 0.076; [68Ga]Ga-DOTA-TATE; r = 0.649; p = 0.049). A strong negative correlation between TER and absorbed dose was seen only for [18F]SiTATE (r = - 0.768; p = 0.010). SSTR-PET/CT showed moderate potential to estimate pre-therapeutic split renal function and renal absorbed dose. However, global renal function could not be reliably estimated using PET/CT. Larger studies are warranted to validate PET/CT-based kidney assessment for individualized PRRT planning.

Molecular imaging of the somatostatin receptor (SSTR) plays a key role in the management of patients with neuroendocrine neoplasms in general, and neuroendocrine tumours in particular. Over the last 2 decades, gallium-68 labelled somatostatin analogues have revolutionised SSTR imaging through the advent of SSTR positron emission tomography (PET), leading to better staging and theranostic imaging. Recent advances in the development of PET SSTR tracers continue to change the field, with novel tracers labelled with different radionuclides such as fluorine-18 and copper-64, or based on new antagonist vector molecules. The advent of these innovations generates questions, such as which tracers can be used in clinical practice, how to compare scans performed with different tracers, or can antagonists be used to select patients for peptide receptor radionuclide therapy? This 'controversy paper' from the European Neuroendocrine Tumor Society provides an overview of the relevant evidence to answer these questions, and provides guidance to clinicians and nuclear medicine physicians for contemporary use of SSTR PET.

Tumor immune microenvironment in cervical cancer: Histological subtype-specific immune landscapes and therapeutic implications.

Lynch syndrome (LS), a well-known cancer risk syndrome, is caused by deleterious germline mutations in the mismatch repair genes. LS predispose patients to various types of cancers including colon adenocarcinoma. We discuss the case of a woman with LS who also developed a non-functioning pancreatic neuroendocrine tumor (P-NET) following primary colon adenocarcinoma. Multiple liver lesions were discovered 6 months following surgical excision the pancreatic mass and were later determined to be a neuroendocrine tumor. Liver lesions shrank after treatment with octreotide and Lutetium-177 vipivotide tetraxetan. She is in remission and takes positron emission tomography scans every 6 months for monitoring. This case highlights the importance of LS genetic testing, the function of microsatellite instability (MSI) as a screening marker, and the need for additional study on the relationship between LS and P-NETs, particularly through advanced molecular testing to confirm lesion relationships. The role of microsatellite instability (MSI) as a screening marker, and personalized treatment approaches like immunotherapy for dMMR tumors. Understanding these correlations may assist in early discovery, surveillance, and customized treatment for patients dealing with LS-associated malignancies.

Minimally Invasive Surgery/Robotic Surgery in Small Bowel Cancer.

VIPoma is an extremely rare functioning pancreatic neuroendocrine tumor. Therefore, data regarding treatment and outcome are very limited. Aim (s): This multicenter study aimed to analyze clinical characteristics, real-world management, and outcomes of patients with VIPoma. Patients with VIPoma treated in a 20-year period at 14 referral centers for neuroendocrine tumors (NET) were collected in the ENETS Database. Clinical characteristics, therapeutic interventions, and outcomes were analyzed retrospectively. Disease-free survival (DFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Of 70 patients, 59 (54% male) with a median age of 55 years were included. Forty-six (78%) patients were diagnosed due to the classical watery diarrhea-hypokalemia-achlorhydria (WDHA) syndrome, and 40 (68%) presented with distant metastases at diagnosis. Fifty-two (88%) had serum VIP levels >2 times the upper normal limit and the median Ki-67 index was 5% (range 1%-40%). Surgery of the primary VIPoma was performed in 32 (54%), with curative intent in 22 (37%). In patients with stage I-III disease (n = 19), long-term cure was achieved in only 26% (5/19), with a median DFS of 81 (95%-CI: 1-215) months and 10-year OS of 78% (95%-CI: 61%-100%). In stage IV patients (n = 53, 40 at diagnosis, 13 disease progression), the sequence and type of 354 treatment lines varied, while SSA (n = 77, 22%), loco-regional liver-directed therapy (n = 72, 20%), and chemotherapy (n = 69, 19%) were most often applied. Median OS for patients with stage IV at diagnosis was 142 (95%-CI: 87-not available (NA)) months with 10-year survival of 50% (95%-CI: 35%-73%). Patients with VIPoma treated at NET centers have relatively favorable survival, even with distant metastases at diagnosis, although long-term cure rates remain low.

Molecular theranostics has revolutionized the field of personalized medicine, specifically augmenting "precision oncology" and is now integral in the management of malignancies like differentiated thyroid carcinoma, neuroendocrine tumors, and metastatic carcinoma prostate. The potential of theranostics is huge with possible applications in a variety of tumors, including at their early stages. This article will focus on the advancements in nuclear theranostics-highlighting the expanded indications of already established radionuclide therapies like peptide receptor radionuclide therapy (PRRT), prostate specific membrane antigen radioligand therapy (PRLT), and meta-iodobenzylguanidine therapy (MIBG therapy); and also on novel radiolabeled theranostic agents targeting fibroblast activated protein (FAPI-based radiopharmaceuticals), chemokine receptor targeting agents (pentixfor/pentixather), integrins, cholecystokinin receptors and their potential applications.

Dual-tracer PET/CT and cocktail therapy with [177Lu]Lu-FAP2286 and [177Lu]Lu-DOTATATE in G3 Neuroendocrine Tumors (NET).

Port site metastasis is an uncommon but clinically relevant complication, particularly associated with minimally invasive surgery for abdomino-pelvic malignancies, often indicating poor prognosis and necessitating prompt evaluation for potential surgical intervention. Proposed mechanisms include direct tumor implantation, aerosolization during pneumoperitoneum, surgical wound contamination, and immune alterations. In this report, we describe a case of a 48-year-old man who developed SSTR-expressing port site metastases, occurring 4 years and 4 months following laparoscopic resection of an ileal neuroendocrine tumor (NET). This case highlights the importance of long-term SSTR-based PET imaging surveillance in NET patients following minimally invasive surgery, even in the absence of symptoms or early biochemical relapse.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a disorder characterized by neuroendocrine cell hyperplasia, tumorlets and tumors, manifesting as lung nodules, chronic cough, and airflow obstruction. Often misdiagnosed as asthma, DIPNECH lies at the cross-section of oncology, obstructive airway disease and interstitial lung disease. With the increasing use of CT scans leading to higher rates of lung nodule detection, it is important for clinicians to be familiar with DIPNECH. The evidence base in DIPNECH is sparse and limited to retrospective case series. In the last 5 years, clinical experiences in large academic centers have been published describing variability in clinical presentation and pulmonary function, use of DOTATATE scans, efficacy of somatostatin analogs, and principles of surveillance imaging. More awareness of DIPNECH is needed among pulmonary clinicians. Apart from the usual presentation of cough with lung nodules and spirometric obstruction in women, patients also present with dyspnea and/or restrictive patterns on PFTs. Variability in diagnosis and management is widespread. Multidisciplinary assessment is helpful in guiding management. Multicenter and multispecialty collaboration is needed to establish best practices and improve clinical management.

Mistletoe extract is a widespread complementary therapy mainly used for quality-of-life improvement in cancer patients. Advanced pancreatic cancer is associated with poor quality of life and better therapies for symptomatic relief are highly needed. MISTRAL aimed to assess the impact of mistletoe extract on quality of life, body weight, observed costs and blood biomarkers in patients with advanced pancreatic cancer. MISTRAL was an investigator-initiated, phase III, randomized, double-blind, placebo-controlled, parallel-group, superiority, multicenter, clinical trial with a nested biomarker study. Registration EudraCT 2014-004552-64, NCT02948309. At 9 oncology centers, 290 participants were randomized to standard treatment (palliative chemotherapy or best supportive care) plus subcutaneous mistletoe extract or placebo. Main inclusion criteria were advanced pancreatic cancer, performance status 0-2, main exclusion criteria neuroendocrine pancreatic tumor. EORTC-QLQ-C30, EORTC-QLQ-PAN26, body weight, cost parameters and biomarkers were assessed from baseline up until 9 months. No statistically significant differences for quality of life and weight were evident between treatment arms. Parameters for observed costs for supportive and inpatient care (days at hospital, parenteral nutrition infusions, nutritional supplement drinks, number of visits of palliative home care teams, symptom-relieving medication) were similar in both arms. Thus, calculation of costs was not performed. No effect on explored biomarkers (differential blood count, lymphocyte subpopulations, C-reactive protein, albumin and Ca19-9) was found except for a statistically significant increase of eosinophils in the mistletoe arm without association to clinical effect. Since no benefit was observed, there is no clinical reason to recommend mistletoe extract in patients with advanced pancreatic cancer.

Epigenomic profiling of neuroendocrine lung cancers identifies a classical-neuroendocrine ASCL1/NKX2-1 subtype and a SOX11-associated differentiation axis linked to reduced immunogenicity.

Clinical research analysis of [225Ac]Ac-DOTATATE therapy for neuroendocrine neoplasms.

Accurate preoperative lymph node (LN) staging is critical for determining optimal surgical strategies in duodenal and pancreatic neuroendocrine neoplasms (DP-NENs). While both gallium-68-labeled somatostatin receptor (SSTR) PET/CT and contrast-enhanced CT (ceCT) offer distinct advantages for LN assessment, their comparative diagnostic accuracy remains undefined. We aimed to systematically evaluate and directly compare the diagnostic performance of 68 Ga-SSTR PET/CT and ceCT against pathologic gold standards in DP-NENs. We retrospectively analyzed 521 LNs from 136 regional stations in 42 DP-NEN patients who underwent preoperative 68 Ga-SSTR PET/CT and ceCT followed by surgical LN dissection at 2 medical centers. Pathologic validation revealed comparable detection rates for 68 Ga-SSTR PET/CT and ceCT at the patient and regional levels. However, at the individual lesion level, 68 Ga-SSTR PET/CT demonstrated significantly higher sensitivity (67.6% vs. 26.4%, P =0.008) and accuracy (96.5% vs. 94.0%). In patients with small DP-NENs (≤2cm), 68 Ga-SSTR PET/CT also exhibited superior lesion-level sensitivity (52.6% vs. 26.3%, P =0.004) and accuracy (94.0% vs. 93.5%). The size of the metastatic deposit within LNs significantly influenced 68 Ga-SSTR PET/CT detection ( P =0.036), whereas the overall LN size was associated with ceCT performance ( P =0.048). 68 Ga-SSTR PET/CT provided superior detection of lymph node metastases (LNM) compared with ceCT. Preoperative integration of 68 Ga-SSTR PET/CT, particularly in conjunction with ceCT, might enhance staging accuracy, guiding less aggressive surgical approaches and avoiding nontargeted lymphadenectomy, especially in patients with small DP-NENs.

Real-world presentation and outcomes of gastroenteropancreatic neuroendocrine neoplasms in Italy: findings from the nationwide Itanet prospective database.