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Endocrinology, Diabetes & Metabolism... Jan 2024Functioning gonadotroph tumors are rare neoplasms that can cause ovarian hyperstimulation syndrome (OHSS) in women of reproductive age. Here, we present a case of a...
SUMMARY
Functioning gonadotroph tumors are rare neoplasms that can cause ovarian hyperstimulation syndrome (OHSS) in women of reproductive age. Here, we present a case of a follicle-stimulating hormone (FSH)-producing pituitary neuroendocrine tumor (PitNET) with irregular menstrual cycles and OHSS in a Japanese woman. A 34-year-old woman with bilateral multi-cystic ovarian mass was referred to our hospital for ovarian surgery. The imaging feature of magnetic resonance imaging (MRI) of the ovary and elevated estradiol levels with normal FSH and low luteinizing hormone (LH) levels led us to suspect the presence of a functioning gonadotroph PitNET. MRI revealed a 19-mm pituitary tumor, and increased tracer uptake was observed in the pituitary lesion on 111In-pentetreotide scintigraphy. Transsphenoidal tumor resection resulted in the resolution of the ovarian enlargement, normalization of her menstrual cycles, and spontaneous pregnancy. Immunohistochemistry (IHC) of the resected tumor for pituitary transcription factors, including steroidogenesis factor 1 (SF1) and estrogen receptor alpha, demonstrated positive immunoreactivity, whereas IHC for pituitary-specific positive transcription factor 1 was negative, suggesting that the tumor belonged to the SF1 lineage of PitNETs (gonadotroph tumor). The tumor cells showed positive expression of FSHβ, while LHβ was mostly negative. Consistent with the high pituitary tumor uptake observed on 111In-pentetreotide scintigraphy, the pituitary tumor showed positive expression of somatostatin receptor 2A. Detailed clinical and histological evaluations will provide useful information to understand these rare functioning gonadotroph tumors better.
LEARNING POINTS
Functioning gonadotroph tumors are very rare neuroendocrine tumors of pituitary origin. Women of reproductive age presenting with bilateral multi-cystic ovarian enlargement, irregular menstrual cycles, and hyperestrogenemia under unsuppressed follicle-stimulating hormone (FSH) levels should be evaluated for FSH-producing tumor. Raising awareness of OHSS due to functioning gonadotroph tumors is crucial to prevent unnecessary ovarian surgery. Comprehensive histological analysis may provide useful information to better understand the characteristics of functioning gonadotroph tumors.
PubMed: 38421932
DOI: 10.1530/EDM-23-0119 -
Pharmaceuticals (Basel, Switzerland) Nov 2023(1) Background: In neuroendocrine tumors (NETs), somatostatin receptor subtype 2 is highly expressed, which can be targeted by a radioactive ligand such as...
(1) Background: In neuroendocrine tumors (NETs), somatostatin receptor subtype 2 is highly expressed, which can be targeted by a radioactive ligand such as [Lu]Lu-1,4,7,10-tetraazacyclododecane-,',″,‴,-tetraacetic acid-[Tyr,Thr]-octreotide (Lu-DOTA-TOC) and, more recently, by a lead specific chelator (PSC) containing Pb-PSC-PEG-TOC (PSC-TOC). The molar activity (A) can play a crucial role in tumor uptake, especially in receptor-mediated uptake, such as in NETs. Therefore, an investigation of the influence of different molar activities of Pb-PSC-TOC on cell uptake was investigated. (2) Methods: Optimized radiolabeling of Pb-PSC-TOC was performed with 50 µg of precursor in a NaAc/AcOH buffer at pH 5.3-5.5 within 15-45 min at 95° C. Cell uptake was studied in AR42 J, HEK293 sst2, and ZR75-1 cells. (3) Results: Pb-PSC-TOC was radiolabeled with high radiochemical purity >95% and high radiochemical yield >95%, with A ranging from 0.2 to 61.6 MBq/nmol. The cell uptake of Pb-PSC-TOC (A = 38 MBq/nmol) was highest in AR42 J (17.9%), moderate in HEK293 sstr (9.1%) and lowest in ZR75-1 (0.6%). Cell uptake increased with the level of A. (4) Conclusions: A moderate A of 15-40 MBq/nmol showed the highest cell uptake. No uptake limitation was found in the first 24-48 h. Further escalation experiments with even higher A should be performed in the future. It was shown that A plays an important role because of its direct dependence on the cellular uptake levels, possibly due to less receptor saturation with non-radioactive ligands at higher A.
PubMed: 38004470
DOI: 10.3390/ph16111605 -
Cancers Mar 2024The United States Food and Drug Administration (FDA) has approved a plethora of peptide-based drugs as effective drugs in cancer therapy. Peptides possess high... (Review)
Review
The United States Food and Drug Administration (FDA) has approved a plethora of peptide-based drugs as effective drugs in cancer therapy. Peptides possess high specificity, permeability, target engagement, and a tolerable safety profile. They exhibit selective binding with cell surface receptors and proteins, functioning as agonists or antagonists. They also serve as imaging agents for diagnostic applications or can serve a dual-purpose as both diagnostic and therapeutic (theragnostic) agents. Therefore, they have been exploited in various forms, including linkers, peptide conjugates, and payloads. In this review, the FDA-approved prostate-specific membrane antigen (PSMA) peptide antagonists, peptide receptor radionuclide therapy (PRRT), somatostatin analogs, antibody-drug conjugates (ADCs), gonadotropin-releasing hormone (GnRH) analogs, and other peptide-based anticancer drugs are analyzed in terms of their chemical structures and properties, therapeutic targets and mechanisms of action, development journey, administration routes, and side effects.
PubMed: 38473389
DOI: 10.3390/cancers16051032 -
Frontiers in Endocrinology 2023The significance of neuroendocrine (NE) markers in triple-negative breast cancer (TNBC) patients has not been investigated. This study aims to clarify the incidence and...
BACKGROUND
The significance of neuroendocrine (NE) markers in triple-negative breast cancer (TNBC) patients has not been investigated. This study aims to clarify the incidence and prognostic significance of NE marker expression in TNBC, determine its association with other clinicopathological parameters, and further explore the pathological features and potential treatment options for TNBC patients expressing NE markers.
METHODS
Clinicopathological data were collected from 396 TNBC patients undergoing radical breast cancer surgery at Peking Union Medical College Hospital from January 2002 to December 2014, with a final follow-up in July 2019. Immunohistochemistry (IHC) staining was performed for NE markers including chromogranin A (CgA) and synaptophysin (Syn). For TNBC patients with positive NE marker expression, IHC staining was then performed for alpha-thalassemia/mental retardation X-linked (ATRX), O(6)-methylguanine-methyltransferase (MGMT), somatostatin receptor 2 (SSTR2), and programmed death receptor-ligand 1 (PD-L1). The chi-square or Fisher exact test was used to evaluate the correlations between NE marker expression and other parameters. Survival curves were plotted using the Kaplan-Meier (K-M) method to assess the prognostic significance of NE markers in TNBC.
RESULTS
NE marker-positive staining was observed in 7.6% (30/396) of all TNBC cases. Only 0.5% (2/396) cases had ≥ 90% neoplastic cells expressing NE markers. Positive NE marker expression was associated with negative basal-like marker expression. K-M survival analysis showed that the NE marker-positive TNBC patients had higher disease-free survival (DFS) rates than the NE marker-negative patients at the same stage. Among the 30 NE marker-positive TNBC cases, 13.3% and 26.7% showed negative IHC staining for ATRX and MGMT, respectively, while 13.3% had a 3+ score for SSTR2 IHC staining. For PD-L1 IHC staining, 13.3% of the 30 TNBC cases were higher than 10 scores in Combined Positive Score (CPS), and 10.0% were higher than 10% in Tumor Cell Proportion Score (TPS).
CONCLUSION
There was a small proportion of TNBC patients expressing NE markers. TNBC patients with positive NE marker expression had a better prognosis than the negative group at the same stage. TNBC cases with positive NE marker expression may potentially benefit from immunotherapy or somatostatin analogue treatment.
Topics: Humans; Triple Negative Breast Neoplasms; B7-H1 Antigen; Prognosis; Disease-Free Survival; Mastectomy
PubMed: 38125789
DOI: 10.3389/fendo.2023.1205631 -
Therapeutic Advances in Medical Oncology 2023Somatostatin receptor (SSTR) positron emission tomography (PET) is a cornerstone of neuroendocrine tumor (NET) management. Hybrid PET/magnetic resonance imaging (MRI) is...
BACKGROUND
Somatostatin receptor (SSTR) positron emission tomography (PET) is a cornerstone of neuroendocrine tumor (NET) management. Hybrid PET/magnetic resonance imaging (MRI) is now available for NET-imaging, next to PET/computed tomography (CT).
OBJECTIVES
To determine whether CT or MRI is the best hybrid partner for [Ga]Ga-DOTATATE PET.
DESIGN
Monocentric, prospective study.
METHODS
Patients received a same-day [Ga]Ga-DOTATATE PET/CT and subsequent PET/MRI, for suspicion of NET, (re)staging or peptide receptor radionuclide therapy-selection. The union (PET) of malignant lesions detected on PET and PET was the reference standard. Concordance of detection of malignant lesions in an organ was measured between PET and CT and PET and MRI. Seven bins were used to categorize the number of malignant lesions, containing following ordinal variables: 0, 1, 2-5, 6-10, 11-20, >20 countable and diffuse/uncountable. The difference in number of malignant lesions was obtained as the difference in bin level ('Δbin') between PET and CT and PET and MRI with a Δbin closer to zero implying a higher concordance rate.
RESULTS
Twenty-nine patients were included. Primary tumors included 17 gastroenteropancreatic-NETs, 1 colon neuroendocrine carcinoma, 7 lung-NETs and 2 meningiomas. Patient level concordance with PET was 96% for MRI and 67% for CT ( = 0.039). Organ level concordance with PET was 74% for MRI and 40% for CT ( < 0.0001). In bone, there was a higher concordance rate for MRI compared to CT, 92% and 33%, respectively ( = 0.016). Overall, a mean Δbin of 0.5 ± 1.1 for PET/MRI and 1.4 ± 1.2 for PET/CT ( < 0.0001) was noted. In liver, a mean Δbin of 0.0 ± 1.1 for PET/MRI and 1.7 ± 1.2 for PET/CT was observed ( = 0.0078). In bone, a mean Δbin closer to zero was observed for PET/MRI compared to PET/CT, 0.6 ± 1.4 and 2.0 ± 1.5, respectively ( = 0.0098).
CONCLUSIONS
Compared to SSTR PET/CT, SSTR PET/MRI had a higher patient and organ level concordance for malignant tumoral involvement and number of malignant lesions, with a clear added value in bone and liver specifically.
PubMed: 37885461
DOI: 10.1177/17588359231189133 -
Seminars in Nuclear Medicine Mar 2024Peptide receptor radionuclide therapy (PRRT) today is a well-established treatment strategy for patients with neuroendocrine tumors (NET). First performed already more... (Review)
Review
Peptide receptor radionuclide therapy (PRRT) today is a well-established treatment strategy for patients with neuroendocrine tumors (NET). First performed already more than 30 years ago, PRRT was incorporated only in recent years into the major oncology guidelines, based on its proven efficacy and safety in clinical trials. Following the phase 3 NETTER-1 trial, which led to the final registration of the radiopharmaceutical Luthatera® for G1/G2 NET patients in 2017, the long-term results of the phase 3 NETTER-2 trial may pave the way for a new treatment option also for advanced G2/G3 patients as first-line therapy. The growing knowledge about the synergistic effect of combined therapies could also allow alternative (re)treatment options for NET patients, in order to create a tailored treatment strategy. The evolving thera(g)nostic concept could be applied for the identification of patients who might benefit from different image-guided treatment strategies. In this scenario, the use of dual tracer PET/CT in NET patients, using both [F]F-FDG/[Ga]Ga-DOTA-somatostatin analog (SSA) for diagnosis and follow-up, is under discussion and could also result in a powerful prognostic tool. In addition, alternative strategies based on different metabolic pathways, radioisotopes, or combinations of different medical approaches could be applied. A number of different promising "doors" could thus open in the near future for the treatment of NET patients - and the "key" will be thera(g)nostic!
PubMed: 38490913
DOI: 10.1053/j.semnuclmed.2024.02.002 -
Frontiers in Immunology 2024Somatostatin (SST) is a peptide hormone primarily synthesized in the digestive and nervous systems. While its impact on the endocrine system is well-established,...
INTRODUCTION
Somatostatin (SST) is a peptide hormone primarily synthesized in the digestive and nervous systems. While its impact on the endocrine system is well-established, accumulating evidence suggests a crucial role for SST and its analogues in modulating immune responses. Despite this, the precise mechanism through which SST regulates T cells has remained largely unknown.
METHODS
To elucidate the impact of SST on human T cells, we conducted a series of experiments involving cell culture assays, molecular analyses, and metabolic profiling. Human T cells were treated with SST, and various parameters including proliferation, cytokine production, and metabolic activities were assessed. Additionally, we employed pharmacological inhibitors and genetic manipulations to dissect the signaling pathways mediating SST's effects on T cells.
RESULTS
We showed that SST diminishes T-cell proliferation by influencing IL-2 production and T-cell mitochondrial respiration, while having no discernible impact on TCR-induced glycolysis. Our findings also identified that the regulatory influence of SST on T-cell responses and metabolism is contingent on its receptor, SSTR3. Moreover, we demonstrated that SST governs T-cell responses and metabolism by acting through the T-cell metabolic checkpoint GSK3.
DISCUSSION
Our study provides novel insights into the immunoregulatory function of SST in human T cells, highlighting the complex interplay between hormonal signaling and immune regulation. Understanding the molecular mechanisms underlying SST's effects on T cells may offer therapeutic opportunities for manipulating immune responses in various pathological conditions.
Topics: Humans; Glycogen Synthase Kinase 3; T-Lymphocytes; Somatostatin; Signal Transduction; Cell Proliferation
PubMed: 38426092
DOI: 10.3389/fimmu.2024.1322670 -
Molecular Pharmaceutics Nov 2023Small cell lung cancer (SCLC) is a neuroendocrine tumor with a high degree of malignancy. Due to limited treatment options, patients with SCLC have a poor prognosis. We...
Small cell lung cancer (SCLC) is a neuroendocrine tumor with a high degree of malignancy. Due to limited treatment options, patients with SCLC have a poor prognosis. We have found, however, that intravenously administered octreotide (Oct) armed with astatine-211 ([At]SAB-Oct) is effective against a somatostatin receptor 2 (SSTR2)-positive SCLC tumor in SCLC tumor-bearing BALB/c nude mice. In biodistribution analysis, [At]SAB-Oct achieved the highest concentration in the SCLC tumors up to 3 h after injection as time proceeded. A single intravenous injection of [At]SAB-Oct (370 kBq) was sufficient to suppress SSTR2-positive SCLC tumor growth in treated mice by inducing DNA double-strand breaks. Additionally, a multitreatment course (370 kBq followed by twice doses of 370 kBq for a total of 1110 kBq) inhibited the growth of the tumor compared to the untreated control group without significant off-target toxicity. Surprisingly, we found that [At]SAB-Oct could up-regulate the expressions of calreticulin and major histocompatibility complex I (MHC-I) on the tumor cell membrane surface, suggesting that α-particle internal irradiation may activate an endogenous antitumor immune response through the regulation of immune cells in the tumor microenvironment, which could synergically enhance the efficacy of immunotherapy. We conclude that [At]SAB-Oct is a potential new therapeutic option for SSTR2-positive SCLC.
Topics: Humans; Animals; Mice; Small Cell Lung Carcinoma; Lung Neoplasms; Mice, Nude; Tissue Distribution; Receptors, Somatostatin; Antineoplastic Agents; Octreotide; Immunity; Cell Line, Tumor; Tumor Microenvironment
PubMed: 37788300
DOI: 10.1021/acs.molpharmaceut.3c00427 -
European Journal of Nuclear Medicine... Mar 2024The lead-203 (Pb)/lead-212 (Pb) elementally identical radionuclide pair has gained significant interest in the field of image-guided targeted alpha-particle therapy for...
PURPOSE
The lead-203 (Pb)/lead-212 (Pb) elementally identical radionuclide pair has gained significant interest in the field of image-guided targeted alpha-particle therapy for cancer. Emerging evidence suggests that Pb-labeled peptide-based radiopharmaceuticals targeting somatostatin receptor subtype 2 (SSTR2) may provide improved effectiveness compared to beta-particle-based therapies for neuroendocrine tumors (NETs). This study aims to improve the performance of SSTR2-targeted radionuclide imaging and therapy through structural modifications to Tyr-octreotide (TOC)-based radiopharmaceuticals.
METHODS
New SSTR2-targeted peptides were designed and synthesized with the goal of optimizing the incorporation of Pb isotopes through the use of a modified cyclization technique; the introduction of a Pb-specific chelator (PSC); and the insertion of polyethylene glycol (PEG) linkers. The binding affinity of the peptides and the cellular uptake of Pb-labeled peptides were evaluated using pancreatic AR42J (SSTR2+) tumor cells and the biodistribution and imaging of the Pb-labeled peptides were assessed in an AR42J tumor xenograft mouse model. A lead peptide was identified (i.e., PSC-PEG-TOC), which was then further evaluated for efficacy in Pb therapy studies.
RESULTS
The lead radiopeptide drug conjugate (RPDC) - [Pb]Pb-PSC-PEG-TOC - significantly improved the tumor-targeting properties, including receptor binding and tumor accumulation and retention as compared to [Pb]Pb-DOTA-Tyr-octreotide (DOTATOC). Additionally, the modified RPDC exhibited faster renal clearance than the DOTATOC counterpart. These advantageous characteristics of [Pb]Pb-PSC-PEG-TOC resulted in a dose-dependent therapeutic effect with minimal signs of toxicity in the AR42J xenograft model. Fractionated administrations of 3.7 MBq [Pb]Pb-PSC-PEG-TOC over three doses further improved anti-tumor effectiveness, resulting in 80% survival (70% complete response) over 120 days in the mouse model.
CONCLUSION
Structural modifications to chelator and linker compositions improved tumor targeting and pharmacokinetics (PK) of Pb peptide-based radiopharmaceuticals for NET theranostics. These findings suggest that PSC-PEG-TOC is a promising candidate for Pb-based targeted radionuclide therapy for NETs and other types of cancers that express SSTR2.
Topics: Mice; Humans; Animals; Octreotide; Neuroendocrine Tumors; Radiopharmaceuticals; Tissue Distribution; Lead; Lead Radioisotopes; Receptors, Somatostatin; Chelating Agents
PubMed: 37955792
DOI: 10.1007/s00259-023-06494-9 -
Proceedings of the National Academy of... Dec 2023Somatostatin-expressing interneurons (SOMIs) in the mouse dentate gyrus (DG) receive feedforward excitation from granule cell (GC) mossy fiber (MF) synapses and provide...
Somatostatin-expressing interneurons (SOMIs) in the mouse dentate gyrus (DG) receive feedforward excitation from granule cell (GC) mossy fiber (MF) synapses and provide feedback lateral inhibition onto GC dendrites to support environment representation in the DG network. Although this microcircuitry has been implicated in memory formation, little is known about activity-dependent plastic changes at MF-SOMI synapses and their influence on behavior. Here, we report that the metabotropic glutamate receptor 1α (mGluR1α) is required for the induction of associative long-term potentiation (LTP) at MF-SOMI synapses. Pharmacological block of mGluR1α, but not mGluR5, prevented synaptic weight changes. LTP at MF-SOMI synapses was postsynaptically induced, required increased intracellular Ca, involved G-protein-mediated and Ca-dependent (extracellular signal-regulated kinase) ERK1/2 pathways, and the activation of NMDA receptors. Specific knockdown of mGluR1α in DG-SOMIs by small hairpin RNA expression prevented MF-SOMI LTP, reduced SOMI recruitment, and impaired object location memory. Thus, postsynaptic mGluR1α-mediated MF-plasticity at SOMI input synapses critically supports DG-dependent mnemonic functions.
Topics: Mice; Animals; Mossy Fibers, Hippocampal; Neuronal Plasticity; Interneurons; Long-Term Potentiation; Synapses; Somatostatin; Dentate Gyrus; Synaptic Transmission
PubMed: 38091292
DOI: 10.1073/pnas.2312752120