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European Journal of Nuclear Medicine... May 2024Somatostatin receptor (SSTR) imaging features are predictive of treatment outcome for neuroendocrine tumor (NET) patients receiving peptide receptor radionuclide therapy...
Models using comprehensive, lesion-level, longitudinal [Ga]Ga-DOTA-TATE PET-derived features lead to superior outcome prediction in neuroendocrine tumor patients treated with [Lu]Lu-DOTA-TATE.
PURPOSE
Somatostatin receptor (SSTR) imaging features are predictive of treatment outcome for neuroendocrine tumor (NET) patients receiving peptide receptor radionuclide therapy (PRRT). However, comprehensive (all metastatic lesions), longitudinal (temporal variation), and lesion-level measured features have never been explored. Such features allow for capturing the heterogeneity in disease response to treatment. Furthermore, models combining these features are lacking. In this work we evaluated the predictive power of comprehensive, longitudinal, lesion-level GA-SSTR-PET features combined with a multivariate linear regression (MLR) model.
METHODS
This retrospective study enrolled NET patients treated with [Lu]Lu-DOTA-TATE and imaged with [Ga]Ga-DOTA-TATE at baseline and post-therapy. All lesions were segmented, anatomically labeled, and longitudinally matched. Lesion-level uptake and variation in uptake were measured. Patient-level features were engineered and selected for modeling of progression-free survival (PFS). The model was validated via concordance index, patient classification (ROC analysis), and survival analysis (Kaplan-Meier and Cox proportional hazards). The MLR was benchmarked against single feature predictions.
RESULTS
Thirty-six NET patients were enrolled and stratified into poor and good responders (PFS ≥ 25 months). Four patient-level features were selected, the MLR concordance index was 0.826, and the AUC was 0.88 (0.85 specificity, 0.81 sensitivity). Survival analysis led to significant patient stratification (p<.001) and hazard ratio (3⨯10). Lastly, in a benchmark study, the MLR modeling approach outperformed all the single feature predictors.
CONCLUSION
Comprehensive, lesion-level, longitudinal GA-SSTR-PET analysis, combined with MLR modeling, leads to excellent predictions of PRRT outcome in NET patients, outperforming non-comprehensive, patient-level, and single time-point feature predictions.
MESSAGE
Neuroendocrine tumor, peptide receptor radionuclide therapy, Somatostatin Receptor Imaging, Outcome Prediction, Treatment Response Assessment.
PubMed: 38795121
DOI: 10.1007/s00259-024-06767-x -
FEBS Letters May 2024Neuronostatin suppresses the differentiation of white preadipocytes. However, the role of neuronostatin in brown adipose tissue remains elusive. Therefore, we...
Neuronostatin suppresses the differentiation of white preadipocytes. However, the role of neuronostatin in brown adipose tissue remains elusive. Therefore, we investigated the impact of neuronostatin on the proliferation and differentiation of isolated rat brown preadipocytes. We report that neuronostatin and its receptor (GPR107) are synthesized in brown preadipocytes and brown adipose tissue. Furthermore, neuronostatin promotes the replication of brown preadipocytes via the AKT pathway. Notably, neuronostatin suppresses the expression of markers associated with brown adipogenesis (PGC-1α, PPARγ, PRDM16, and UCP1) and reduces cellular mitochondria content. Moreover, neuronostatin impedes the differentiation of preadipocytes by activating the JNK signaling pathway. These effects were not mimicked by somatostatin. Our results suggest that neuronostatin is involved in regulating brown adipogenesis.
PubMed: 38794908
DOI: 10.1002/1873-3468.14934 -
Cancers May 2024The overexpression of somatostatin receptor type 2 (SSTR2) is a property of various tumor types. Hybrid imaging utilizing...
The overexpression of somatostatin receptor type 2 (SSTR2) is a property of various tumor types. Hybrid imaging utilizing [Ga]1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra-acetic acid (DOTA) may improve the differentiation between tumor and healthy tissue. We conducted an experimental study on 47 anonymized patient cases including 30 meningiomas, 12 PitNET and 5 SBPGL. Four independent observers were instructed to contour the macroscopic tumor volume on planning MRI and then reassess their volumes with the additional information from DOTA-PET/CT. The conformity between observers and reference volumes was assessed. In total, 46 cases (97.9%) were DOTA-avid and included in the final analysis. In eight cases, PET/CT additional tumor volume was identified that was not detected by MRI; these PET/CT findings were potentially critical for the treatment plan in four cases. For meningiomas, the interobserver and observer to reference volume conformity indices were higher with PET/CT. For PitNET, the volumes had higher conformity between observers with MRI. With regard to SBGDL, no significant trend towards conformity with the addition of PET/CT information was observed. DOTA PET/CT supports accurate tumor recognition in meningioma and PitNET and is recommended in SSTR2-expressing tumors planned for treatment with highly conformal radiation.
PubMed: 38791956
DOI: 10.3390/cancers16101877 -
International Journal of Molecular... May 2024A novel nanotechnology-based drug delivery system (DDS) targeted at pancreatic cancer cells was developed, characterized, and tested. The system consisted of liposomes...
A novel nanotechnology-based drug delivery system (DDS) targeted at pancreatic cancer cells was developed, characterized, and tested. The system consisted of liposomes as carriers, an anticancer drug (paclitaxel) as a chemotherapeutic agent, and a modified synthetic somatostatin analog, 5-pentacarbonyl-octreotide, a ligand for somatostatin receptor 2 (SSTR2), as a targeting moiety for pancreatic cancer. The cellular internalization, cytotoxicity, and antitumor activity of the DDS were tested in vitro using human pancreatic ductal adenocarcinoma (PDAC) cells with different expressions of the targeted SSTR2 receptors, and in vivo on immunodeficient mice bearing human PDAC xenografts. The targeted drug delivery system containing paclitaxel exhibited significantly enhanced cytotoxicity compared to non-targeted DDS, and this efficacy was directly related to the levels of SSTR2 expression. It was found that octreotide-targeted DDS proved exceptionally effective in suppressing the growth of PDAC tumors. This study underscores the potential of octreotide-targeted liposomal delivery systems to enhance the therapeutic outcomes for PDAC compared with non-targeted liposomal DDS and Paclitaxel-Cremophor EL, suggesting a promising avenue for future cancer therapy innovations.
Topics: Animals; Humans; Pancreatic Neoplasms; Receptors, Somatostatin; Mice; Cell Line, Tumor; Paclitaxel; Liposomes; Drug Delivery Systems; Xenograft Model Antitumor Assays; Octreotide; Somatostatin; Nanotechnology; Antineoplastic Agents; Carcinoma, Pancreatic Ductal
PubMed: 38791582
DOI: 10.3390/ijms25105545 -
Radiologie (Heidelberg, Germany) Jul 2024Neuroendocrine tumors of the pancreas have a broad biological spectrum. The treatment decision is based on an optimal diagnosis with regard to the local findings and...
BACKGROUND
Neuroendocrine tumors of the pancreas have a broad biological spectrum. The treatment decision is based on an optimal diagnosis with regard to the local findings and possible locoregional and distant metastases. In addition to purely morphologic imaging procedures, functional parameters are playing an increasingly important role in imaging.
OBJECTIVES
Prerequisites for optimal imaging of the pancreas, technical principles are provided, and the advantages and disadvantages of common cross-sectional imaging techniques as well as clinical indications for these special imaging methods are discussed.
MATERIALS AND METHODS
Guidelines, basic and review papers will be analyzed.
RESULTS
Neuroendocrine tumors of the pancreas have a broad imaging spectrum. Therefore, there is a need for multimodality imaging in which morphologic and functional techniques support each other. While positron emission tomography/computed tomography (PET/CT) can determine the presence of one or more lesions and its/their functional status of the tumor, magnetic resonance imaging (MRI) efficiently identifies the location, relationship to the main duct and the presence of liver metastases. CT allows a better vascular evaluation, even in the presence of anatomical variants as well as sensitive detection of lung metastases.
CONCLUSIONS
Knowledge of the optimal combination of imaging modalities including clinical and histopathologic results and dedicated imaging techniques is essential to achieve an accurate diagnosis to optimize treatment decision-making and to assess therapy response.
Topics: Humans; Magnetic Resonance Imaging; Multimodal Imaging; Neuroendocrine Tumors; Pancreatic Neoplasms; Positron Emission Tomography Computed Tomography; Tomography, X-Ray Computed
PubMed: 38789854
DOI: 10.1007/s00117-024-01316-x -
Archives of Endocrinology and Metabolism May 2024Hemangioblastomas associated with von Hippel-Lindau (VHL) disease are frequently multiple and recur during prolonged follow-up. Currently, no systemic treatment is... (Review)
Review
Expression of somatostatin receptors in hemangioblastomas associated with von Hippel-Lindau disease as a novel diagnostic, therapeutic, and follow-up opportunity: A case report and literature review.
Hemangioblastomas associated with von Hippel-Lindau (VHL) disease are frequently multiple and recur during prolonged follow-up. Currently, no systemic treatment is available for these tumors. Recent studies have shown the expression of somatostatin receptors in these types of hemangioblastomas. Notably, increased somatostatin receptor expression in a tumor, as determined by peptide-receptor radionuclide imaging, is a predictive factor of response to treatment with somatostatin analogs and peptide-receptor radionuclide therapy. The aim of this study was to describe the case of a patient with increased expression of somatostatin receptors in a suprasellar hemangioblastoma associated with VHL disease and conduct a literature review on somatostatin receptor expression in patients with VHL-associated hemangioblastomas. We describe herein the case of a 51-year-old man with VHL disease who had a suprasellar hemangioblastoma detected on magnetic resonance imaging. Peptide-receptor radionuclide imaging using gallium-68-DOTATOC (Ga-DOTATOC) identified increased expression of somatostatin receptors in the suprasellar hemangioblastoma, along with multiple pancreatic neuroendocrine tumors and bilateral pheochromocytomas. The patient was treated for 1 year with lanreotide, a somatostatin analog. A repeat Ga-DOTATOC 1 year after starting lanreotide revealed decreased radiotracer uptake by the hemangioblastoma, consistent with a metabolic response. The presence of somatostatin receptors in hemangioblastomas associated with VHL disease is a novel finding. The decreased expression of these receptors after treatment with a somatostatin analog, as described in the present case, positions the somatostatin receptor as a new target for novel diagnostic, therapeutic, and follow-up opportunities in patients with VHL disease.
Topics: Humans; Hemangioblastoma; von Hippel-Lindau Disease; Receptors, Somatostatin; Male; Middle Aged; Octreotide; Cerebellar Neoplasms; Follow-Up Studies; Magnetic Resonance Imaging; Radiopharmaceuticals
PubMed: 38788146
DOI: 10.20945/2359-4292-2023-0181 -
Clinical Nuclear Medicine Jul 2024Neuroendocrine tumor (NET) typically spreads to the liver, lymph nodes, lungs, and skeleton. Brain metastasis in NET is uncommon. Therefore, each case of detected brain...
Triple Tumors (Neuroendocrine Tumor, Schwannoma, and Papillary Thyroid Carcinoma) With Brain Lesions in a Single Patient Demonstrating Avidity on 68 Ga-DOTATATE PET/CT and Their Characterization With FDG-PET/CT and Brain MRI.
Neuroendocrine tumor (NET) typically spreads to the liver, lymph nodes, lungs, and skeleton. Brain metastasis in NET is uncommon. Therefore, each case of detected brain metastases in NET is crucial for the development of treatment guidelines for these types of tumors. We present a unique case of triple tumors (NET, papillary thyroid carcinoma, and schwannoma) in a single patient who presented with neurological symptoms and somatostatin receptor-avid T2 hyperintense multiple metastatic brain lesions from NET on 68 Ga-DOTATATE-PET/CT scan and brain MRI. Despite the rarity of brain metastases in NET, we conclude that the presence of neurological sign or symptoms and/or the detection of somatostatin receptor-avid brain lesions in patients with NET should raise suspicion of brain metastases.
Topics: Humans; Positron Emission Tomography Computed Tomography; Organometallic Compounds; Thyroid Cancer, Papillary; Thyroid Neoplasms; Brain Neoplasms; Fluorodeoxyglucose F18; Magnetic Resonance Imaging; Neuroendocrine Tumors; Neurilemmoma; Carcinoma, Papillary; Female; Middle Aged; Male; Multimodal Imaging; Tomography, X-Ray Computed; Brain
PubMed: 38778465
DOI: 10.1097/RLU.0000000000005273 -
Radiologie (Heidelberg, Germany) Jul 2024Neuroendocrine neoplasms (NEN) are heterogenous with an increasing incidence in recent years. (Review)
Review
BACKGROUND
Neuroendocrine neoplasms (NEN) are heterogenous with an increasing incidence in recent years.
OBJECTIVES
Overview on incidence, symptoms, diagnostics, grading, imaging and prognostic determinants, including factors having an impact on therapeutic management.
METHODS
Review on current literature, including original articles, reviews, guidelines and expert opinions.
RESULTS
NEN are mainly located in the gastrointestinal tract and their incidence has increased in recent years, mainly due to improved diagnostics, e.g., cross-sectional imaging. Clinical characteristics include hormone excess syndromes (carcinoid syndrome). Laboratory markers such as chromogranin A are commonly used as part of routine diagnostics, followed by endoscopic and endosonographic procedures, which also allow biopsies to be obtained. Tumor spread can be determined by contrast-enhanced computed tomography/magnetic resonance imaging (CT/MRI) or somatostatin receptor (SSRT)-PET/CT (positron emission tomography). Prognostic factors include Ki67 index, type, and grading. Resection with curative intent is the therapy of choice. In a metastasized setting, SSRT-directed treatment approaches are favored, while in dedifferentiated NEN, conventional chemotherapy is needed.
CONCLUSION
A broad diagnostic armamentarium can be offered to NEN patients and the improved diagnostic procedures have most likely caused a raising incidence in recent years. Among others, prognostic factors are Ki67 and NEN subtypes; these clinical determinants also have an impact on patient management.
Topics: Neuroendocrine Tumors; Humans; Prognosis; Incidence; Neoplasm Staging; Symptom Assessment; Clinical Relevance
PubMed: 38777918
DOI: 10.1007/s00117-024-01315-y -
European Journal of Nuclear Medicine... May 2024Gastroenteropancreatic -neuroendocrine tumours (GEP-NETs) are commonly treated with surgical resection or long-term therapies for tumour growth control. Lutetium...
Lutetium [Lu]-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 [Lu]-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 [Lu]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 [Lu]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 [Lu]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. [Lu]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.
PubMed: 38772998
DOI: 10.1007/s00259-024-06725-7 -
European Journal of Endocrinology Jun 2024The aim of this study is to compare the response to first-line medical treatment in treatment-naive acromegaly patients with pure growth hormone (GH)-secreting pituitary...
OBJECTIVE
The aim of this study is to compare the response to first-line medical treatment in treatment-naive acromegaly patients with pure growth hormone (GH)-secreting pituitary adenoma (GH-PA) and those with GH and prolactin cosecreting PA (GH&PRL-PA).
DESIGN
This is a retrospective multicentric study of acromegaly patients followed from 2003 to 2023 in 33 tertiary Spanish hospitals with at least 6 months of first-line medical treatment.
METHODS
Baseline characteristics, first-line medical treatment strategies, and outcomes were analyzed. We employed a multiple logistic regression full model to estimate the impact of some baseline characteristics on disease control after each treatment modality.
RESULTS
Of the 144 patients included, 72.9% had a GH-PA, and 27.1% had a GH&PRL-PA. Patients with GH&PRL-PA were younger (43.9 ± 15.0 vs 51.9 ± 12.7 years, P < .01) and harboring more frequently macroadenomas (89.7% vs 72.1%, P = .03). First-generation somatostatin receptor ligand (fgSRL) as monotherapy was given to 106 (73.6%) and a combination treatment with fgSRL and cabergoline in the remaining 38 (26.4%). Patients with GH&PRL-PA received more frequently a combination therapy (56.4% vs 15.2%, P < .01). After 6 months of treatment, in the group of patients under fgSRL as monotherapy, those patients with GH&PRL-PA had worse control compared to GH-PAs (29.4% vs 55.1%, P = .04). However, these differences in the rate of disease control between both groups disappeared when both received combination treatment with fgSRL and cabergoline.
CONCLUSION
In GH&PRL-PA, the biochemical control achieved with fgSRL as monotherapy is substantially worse than in patients harboring GH-PA, supporting the inclusion of cabergoline as first-line medical treatment in combination with fgSRLs in these subgroups of patients.
Topics: Humans; Acromegaly; Female; Male; Middle Aged; Retrospective Studies; Adult; Cabergoline; Treatment Outcome; Prolactin; Growth Hormone-Secreting Pituitary Adenoma; Human Growth Hormone; Adenoma; Aged; Drug Therapy, Combination; Somatostatin; Pituitary Neoplasms; Spain
PubMed: 38771697
DOI: 10.1093/ejendo/lvae053