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European Journal of Nuclear Medicine... Dec 2023Tumor resection represents the first-line treatment for symptomatic meningiomas, and the extent of resection has been shown to be of prognostic importance. Assessment of...
PURPOSE
Tumor resection represents the first-line treatment for symptomatic meningiomas, and the extent of resection has been shown to be of prognostic importance. Assessment of tumor remnants with somatostatin receptor PET proves to be superior to intraoperative estimation with Simpson grading or MRI. In this preliminary study, we evaluate the prognostic relevance of postoperative PET for progression-free survival in meningiomas.
METHODS
We conducted a post hoc analysis on a prospective patient cohort with resected meningioma WHO grade 1. Patients received postoperative MRI and [Ga]Ga-DOTA-TATE PET/CT and were followed regularly with MRI surveillance scans for detection of tumor recurrence/progression.
RESULTS
We included 46 patients with 49 tumors. The mean age at diagnosis was 57.8 ± 1.7 years with a male-to-female ratio of 1:1.7. Local tumor progression occurred in 7/49 patients (14%) after a median follow-up of 52 months. Positive PET was associated with an increased risk for progression (*p = 0.015) and a lower progression-free survival (*p = 0.029), whereas MRI was not. 20 out of 20 patients (100%) with negative PET findings remained recurrence-free. The location of recurrence/progression on MRI was adjacent to regions where postoperative PET indicated tumor remnants in all cases. Gross tumor volumes were higher on PET compared to MRI (*p = 0.032).
CONCLUSION
Our data show that [Ga]Ga-DOTA-TATE PET/CT is highly sensitive in revealing tumor remnants in patients with meningioma WHO grade 1. Negative PET findings were associated with a higher progression-free survival, thus improving surveillance. In patients with tumor remnants, additional PET can optimize adjuvant radiotherapy target planning of surgically resected meningiomas.
Topics: Humans; Male; Female; Middle Aged; Positron Emission Tomography Computed Tomography; Meningioma; Prognosis; Gallium Radioisotopes; Progression-Free Survival; Prospective Studies; Neoplasm Recurrence, Local; Meningeal Neoplasms; World Health Organization; Retrospective Studies; Organometallic Compounds
PubMed: 37642702
DOI: 10.1007/s00259-023-06400-3 -
TouchREVIEWS in Endocrinology Apr 2024Injectable somatostatin receptor ligands (iSRL) are the most frequently utilized medical therapy in patients with acromegaly; however, satisfaction rates are suboptimal.... (Review)
Review
Injectable somatostatin receptor ligands (iSRL) are the most frequently utilized medical therapy in patients with acromegaly; however, satisfaction rates are suboptimal. Injections can result in local erythema, discomfort and subcutaneous nodule formation, encompassed with the inconvenience of attending either primary or secondary care medical facilities for injections every 4 weeks. Some patients also note breakthrough of acromegaly-related symptoms towards the end of the injection cycle. To improve acceptance and ultimately improve wellbeing of these individuals, two oral SRLs, oral octreotide capsules (OOC) and paltusotine, have been developed. The OOC combines an enteric coating to allow delivery to the small intestines and a transient permeability enhancer to enable oral bioavailability. Comparable octreotide levels are obtained with twice-daily OOC and subcutaneous octreotide 100 µg. Phase III studies show OOC to maintain equivalent biochemical control in at least 60% of patients previously receiving a stable dose of iSRL. In longer-term studies, the response to OOC was durable up to 3 years. Paltusotine is a novel potent orally available non-peptidyl somatostatin receptor subtype-2 ligand. Studies in healthy volunteers show dose-dependent suppression of growth hormone-releasing hormone-induced growth hormone secretion and suppression of insulin-like growth factor-I (IGF-I) with repeat doses. In the recent phase II study, patients with acromegaly who were partial responders (IGF-I 1.0 - 2.5 x upper limit of normal) to monotherapy with iSRL when switched to once-daily paltusotine maintained control of IGF-I within 20% of baseline or lower in 87% after 13 weeks. Adverse events with both OOC and paltusotine were reflective of those recognized with iSRL and occurred at a similar frequency. OOC and paltusotine are well-received additions to the therapeutic armamentarium in medical therapy for the management of acromegaly; however, further data on efficacy, tumour control and shrinkage are required to allow positioning of this medication within the management algorithm for acromegaly.
PubMed: 38812672
DOI: 10.17925/EE.2023.20.1.3 -
International Journal of Molecular... Feb 2024The overexpression of one or more somatostatin receptors (SSTR) in human tumors has provided an opportunity for diagnosis and therapy with somatostatin-like radionuclide...
The overexpression of one or more somatostatin receptors (SSTR) in human tumors has provided an opportunity for diagnosis and therapy with somatostatin-like radionuclide carriers. The application of "pansomatostatin" analogs is expected to broaden the clinical indications and upgrade the diagnostic/therapeutic efficacy of currently applied SSTR-prefering radioligands. In pursuit of this goal, we now introduce two bicyclic somatostatin-14 (SS14) analogs, AT5S (DOTA-Ala-Gly-c[Cys-Lys-Asn-c[Cys-Phe-DTrp-Lys-Thr-Cys]-Thr-Ser-Cys]) and AT6S (DOTA-Ala-Gly-c[Cys-Lys-c[Cys-Phe-Phe-DTrp-Lys-Thr-Phe-Cys]-Ser-Cys]), suitable for labeling with trivalent radiometals and designed to sustain in vivo degradation. Both AT5S and AT6S and the respective [In]In-AT5S and [In]In-AT6S were evaluated in a series of in vitro assays, while radioligand stability and biodistribution were studied in mice. The 8/12-mer bicyclic AT6S showed expanded affinity for all SSTR and agonistic properties at the SSTR, whereas AT5S lost all affinity to SSTR. Both [In]In-AT5S and [In]In-AT6S remained stable in the peripheral blood of mice, while [In]In-AT6S displayed low, but specific uptake in AR4-2J tumors and higher uptake in HEK293-SSTR tumors in mice. In summary, high radioligand stability was acquired by the two disulfide bridges introduced into the SS14 motif, but only the 8/12-mer ring AT6S retained a pansomatostatin profile. In consequence, [In]In-AT6S targeted SSTR-/SSTR-positive xenografts in mice. These results call for further research on pansomatostatin-like radioligands for cancer theranostics.
Topics: Animals; Humans; Mice; HEK293 Cells; Neoplasms; Receptors, Somatostatin; Somatostatin; Tissue Distribution
PubMed: 38339198
DOI: 10.3390/ijms25031921 -
Cancers Apr 2024Pancreatic ductal adenocarcinoma (PDAC), one of the deadliest cancers, presents significant challenges in diagnosis and treatment due to its aggressive, metastatic... (Review)
Review
Pancreatic ductal adenocarcinoma (PDAC), one of the deadliest cancers, presents significant challenges in diagnosis and treatment due to its aggressive, metastatic nature and lack of early detection methods. A key obstacle in PDAC treatment is the highly complex tumor environment characterized by dense stroma surrounding the tumor, which hinders effective drug delivery. Nanotechnology can offer innovative solutions to these challenges, particularly in creating novel drug delivery systems for existing anticancer drugs for PDAC, such as gemcitabine and paclitaxel. By using customization methods such as incorporating conjugated targeting ligands, tumor-penetrating peptides, and therapeutic nucleic acids, these nanoparticle-based systems enhance drug solubility, extend circulation time, improve tumor targeting, and control drug release, thereby minimizing side effects and toxicity in healthy tissues. Moreover, nanoparticles have also shown potential in precise diagnostic methods for PDAC. This literature review will delve into targeted mechanisms, pathways, and approaches in treating pancreatic cancer. Additional emphasis is placed on the study of nanoparticle-based delivery systems, with a brief mention of those in clinical trials. Overall, the overview illustrates the significant advances in nanomedicine, underscoring its role in transcending the constraints of conventional PDAC therapies and diagnostics.
PubMed: 38672671
DOI: 10.3390/cancers16081589 -
European Journal of Nuclear Medicine... Aug 2023Metastatic neuroendocrine tumors (NETs) overexpressing type 2 somatostatin receptors are the target for peptide receptor radionuclide therapy (PRRT) through the...
PURPOSE
Metastatic neuroendocrine tumors (NETs) overexpressing type 2 somatostatin receptors are the target for peptide receptor radionuclide therapy (PRRT) through the theragnostic pair of Ga/Lu-DOTATATE. The main purpose of this study was to develop machine learning models to predict therapeutic tumor dose using pre therapy Ga -PET and clinicopathological biomarkers.
METHODS
We retrospectively analyzed 90 segmented metastatic NETs from 25 patients (M14/F11, age 63.7 ± 9.5, range 38-76) treated by Lu-DOTATATE at our institute. Patients underwent both pretherapy [Ga]Ga-DOTA-TATE PET/CT and four timepoints SPECT/CT at ~ 4, 24, 96, and 168 h post-Lu-DOTATATE infusion. Tumors were segmented by a radiologist on baseline CT or MRI and transferred to co-registered PET/CT and SPECT/CT, and normal organs were segmented by deep learning-based method on CT of the PET and SPECT. The SUV metrics and tumor-to-normal tissue SUV ratios (SUV_TNRs) were calculated from Ga -PET at the contour-level. Posttherapy dosimetry was performed based on the co-registration of SPECT/CTs to generate time-integrated-activity, followed by an in-house Monte Carlo-based absorbed dose estimation. The correlation between delivered Lu Tumor absorbed dose and PET-derived metrics along with baseline clinicopathological biomarkers (such as Creatinine, Chromogranin A and prior therapies) were evaluated. Multiple interpretable machine-learning algorithms were developed to predict tumor dose using these pretherapy information. Model performance on a nested tenfold cross-validation was evaluated in terms of coefficient of determination (R), mean-absolute-error (MAE), and mean-relative-absolute-error (MRAE).
RESULTS
SUV showed a significant correlation (q-value < 0.05) with absorbed dose (Spearman ρ = 0.64), followed by TLSUV (SUV of total-lesion-burden) and SUV (ρ = 0.45 and 0.41, respectively). The predictive value of PET-SUV in estimation of posttherapy absorbed dose was stronger compared to PET-SUV, and SUV_TNRs in terms of univariate analysis (R = 0.28 vs. R ≤ 0.12). An optimal trivariate random forest model composed of SUV, TLSUV, and total liver SUV (normal and tumoral liver) provided the best performance in tumor dose prediction with R = 0.64, MAE = 0.73 Gy/GBq, and MRAE = 0.2.
CONCLUSION
Our preliminary results demonstrate the feasibility of using baseline PET images for prediction of absorbed dose prior to Lu-PRRT. Machine learning models combining multiple PET-based metrics performed better than using a single SUV value and using other investigated clinicopathological biomarkers. Developing such quantitative models forms the groundwork for the role of Ga -PET not only for the implementation of personalized treatment planning but also for patient stratification in the era of precision medicine.
Topics: Humans; Middle Aged; Aged; Positron Emission Tomography Computed Tomography; Gallium Radioisotopes; Octreotide; Retrospective Studies; Organometallic Compounds; Neuroendocrine Tumors; Biomarkers
PubMed: 37171633
DOI: 10.1007/s00259-023-06252-x -
Science Advances Feb 2024G protein-coupled receptor 39 (GPR39) senses the change of extracellular divalent zinc ion and signals through multiple G proteins to a broad spectrum of downstream...
G protein-coupled receptor 39 (GPR39) senses the change of extracellular divalent zinc ion and signals through multiple G proteins to a broad spectrum of downstream effectors. Here, we found that GPR39 was prevalent at inhibitory synapses of spinal cord somatostatin-positive (SOM) interneurons, a mechanosensitive subpopulation that is critical for the conveyance of mechanical pain. GPR39 complexed specifically with inhibitory glycine receptors (GlyRs) and helped maintain glycinergic transmission in a manner independent of G protein signalings. Targeted knockdown of GPR39 in SOM interneurons reduced the glycinergic inhibition and facilitated the excitatory output from SOM interneurons to spinoparabrachial neurons that engaged superspinal neural circuits encoding both the sensory discriminative and affective motivational domains of pain experience. Our data showed that pharmacological activation of GPR39 or augmenting GPR39 interaction with GlyRs at the spinal level effectively alleviated the sensory and affective pain induced by complete Freund's adjuvant and implicated GPR39 as a promising therapeutic target for the treatment of inflammatory mechanical pain.
Topics: Humans; Neurons; Pain; Receptors, G-Protein-Coupled; Receptors, Glycine; Signal Transduction; Spinal Cord
PubMed: 38306424
DOI: 10.1126/sciadv.adj3808 -
International Journal of Molecular... Oct 2023Insulinomas are rare functional pancreatic neuroendocrine tumours, which metastasize in 10% of cases. As predicting the prognosis can be challenging, there is a need for...
Insulinomas are rare functional pancreatic neuroendocrine tumours, which metastasize in 10% of cases. As predicting the prognosis can be challenging, there is a need for the determination of clinicopathological factors associated with metastatic potential. The aim of this study is to evaluate the glucagon-like peptide-1 receptor (GLP-1R) expression in insulinomas and to analyse its association with clinicopathological features and patient outcome. This retrospective study involves pancreatic tumour tissue samples from fifty-two insulinoma patients. After histological re-evaluation, formalin-fixed paraffin-embedded tissue samples were processed into tissue microarrays and stained immunohistochemically with a monoclonal GLP-1R antibody. Forty-eight of the forty-nine (98%) non-metastatic tumours expressed GLP-1R, while one non-metastatic, multiple endocrine neoplasia type 1 (MEN1)-related tumour and all three of the metastatic tumours lacked GLP-1R expression. The lack of GLP-1R expression was associated with impaired overall survival, larger tumour diameter, higher Ki-67 PI and weaker insulin staining. Somatostatin receptor 1-5 expression did not differ between GLP-1R-positive and GLP-1R-negative insulinomas. In conclusion, the lack of GLP-1R expression is associated with metastatic disease and impaired survival in insulinoma patients. Thus, GLP-1R expression could be a useful biomarker in estimating the metastatic potential of the tumour and the prognosis of surgically treated patients.
Topics: Humans; Antibodies, Monoclonal; Glucagon-Like Peptide-1 Receptor; Insulin; Insulinoma; Pancreatic Neoplasms; Retrospective Studies
PubMed: 37894845
DOI: 10.3390/ijms242015164 -
Quantitative Imaging in Medicine and... Oct 2023The imaging of somatostatin receptors (SSTRs) plays a significant role in imaging neuroendocrine tumors (NETs). However, there has been no clear definition on whether it...
BACKGROUND
The imaging of somatostatin receptors (SSTRs) plays a significant role in imaging neuroendocrine tumors (NETs). However, there has been no clear definition on whether it is necessary to withdraw somatostatin analogs (SSAs) before SSTRs imaging. We aimed to assess whether nonradioactive SSAs affect the uptake of radiolabeled SSAs on imaging for NETs patients.
METHODS
The databases of PubMed, Embase, and Web of Science (WoS) were searched until March 12, 2022 to identify eligible studies. Maximum standardized uptake values (SUVmax) in tumor and normal tissues were extracted, pooled, and compared before and after SSAs treatment. The change of tumor-to-background/liver ratio was also described. The quality of each study was assessed using the revised Quality Assessment of Diagnostic Accuracy Studies-2 tool.
RESULTS
A total of 9 articles involving 285 patients were included and 5 studies using Gallium-68-labeled [1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid]-D-Phe-Tyr-Thr-octreotide (Ga-DOTATATE) were used for pooled evaluation. We found a significantly decreased SUVmax in the liver (9.56±2.47 7.62±2.12, P=0.001) and spleen (25.74±7.14 20.39±6.07, P=0.006) after SSAs treatment whereas no significant differences were observed in the uptake of thyroid, adrenal, and pituitary gland. For either primary tumor sites or metastases, the SUVmax did not change significantly before and after SSAs treatment. The tumor-to-liver/background ratio increased following SSAs therapy. High heterogeneity was observed across the studies, mainly due to inherent diversity of study design, sample size, and scanning technique.
CONCLUSIONS
Based on current evidence, long-acting SSAs therapy before imaging has no effect on the uptake of radiolabeled SSAs at tumor primary sites and metastatic lesions, but results in a significant reduction of uptake in the liver and spleen. These findings may implicate the unnecessary discontinuation of SSAs before radiolabeled SSAs imaging.
PubMed: 37869289
DOI: 10.21037/qims-23-477 -
Frontiers in Oncology 2023Tumor-induced osteomalacia (TIO) is a rare acquired paraneoplastic disorder characterized by hypophosphatemia resulting from tumor-secreted fibroblast growth factor-23...
OBJECTIVES
Tumor-induced osteomalacia (TIO) is a rare acquired paraneoplastic disorder characterized by hypophosphatemia resulting from tumor-secreted fibroblast growth factor-23 (FGF23). Surgical resection of the culprit TIO is the first choice of treatment. However, TIO is difficult to detect with conventional diagnostic tools due to its small size and variable location in the body. Somatostatin receptor scintigraphy (SSR) has recently emerged as a functional molecular imaging choice for TIO detection and localization. This research was undertaken to evaluate the efficacy of Tc-labeled hydrazinonicotinyl-Tyr3-octreotide (Tc-HYNIC-TOC) SPECT/CT in detecting TIO.
METHODS
Tc-HYNIC-TOC SPECT/CT and the available clinical data of 25 patients with suspected TIO were analyzed retrospectively. The Tc-HYNIC-TOC SPECT/CT findings were compared with the post-surgical pathology diagnosis and clinical follow-up results.
RESULTS
Using Tc-HYNIC-TOC SPECT/CT, suspicious tumors were found in 18 of the 25 patients, and 15 of them underwent surgical resection. The post-operative pathology confirmed a TIO in those 13 patients whose symptoms and biochemical anomalies gradually resolved after the surgery. The remaining five patients were finally considered false positives. Moreover, the Tc-HYNIC-TOC SPECT/CT results were negative in seven patients, with six patients being true negative (4 patients were diagnosed with acquired Fanconi syndrome and 2 patients responded well to conservative therapy) and one being false negative. Therefore, the sensitivity and specificity values of Tc-HYNIC-TOC SPECT/CT in the evaluation of TIO were 92.9% (13/14) and 54.5% (6/11), respectively. The overall accuracy of Tc-HYNIC-TOC SPECT/CT for detecting TIO was 76.0% (19/25).
CONCLUSIONS
The Tc-HYNIC-TOC SPECT/CT is an accurate imaging modality for locating culprit tumors in TIO.
PubMed: 37554164
DOI: 10.3389/fonc.2023.1228575 -
Scientific Reports May 2024Chronic stress has been implicated in mental illnesses and depressive behaviors. Somatostatin 4 receptor (SSTR4) has been shown to mediate anxiolytic and depression-like...
Chronic stress has been implicated in mental illnesses and depressive behaviors. Somatostatin 4 receptor (SSTR4) has been shown to mediate anxiolytic and depression-like effects. Here, we aimed to explore the potential of SSTR4 as a diagnostic marker for chronic stress in mice. The mice were divided into single stress, chronic restraint stress, and control groups, and Sstr4 mRNA expression in the pituitary, lungs, and thymus, its protein expression in the thymus, were analyzed. Compared to controls, Sstr4 mRNA expression decreased significantly in the pituitary gland of the chronic and single-stress groups (P = 0.0181 and 0.0022, respectively) and lungs of the single-stress group (P = 0.0124), whereas it significantly increased in the thymus of the chronic-stress group (P = 0.0313). Thymic SSTR4 expression did not decrease significantly in stress groups compared to that in the control group (P = 0.0963). These results suggest that SSTR4 expression fluctuates in response to stress. Furthermore, Sstr4 mRNA expression dynamics in each organ differed based on single or chronic restraint stress-loading periods. In conclusion, this study suggests that investigating SSTR4 expression in each organ could allow for its use as a stress marker to estimate the stress-loading period and aid in diagnosing chronic stress.
Topics: Animals; Receptors, Somatostatin; Mice; Stress, Psychological; Male; Biomarkers; Thymus Gland; Pituitary Gland; RNA, Messenger; Lung; Chronic Disease; Stress, Physiological; Restraint, Physical
PubMed: 38698013
DOI: 10.1038/s41598-024-58621-7