ResearchPad - tumor-biology:-diagnostics-therapies-endocrine-neoplasias-and-hormone-dependent-tumors https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[SUN-141 Altitude as the Second Hit on the Appearance of Paragangliomas]]> https://www.researchpad.co/article/elastic_article_8769 Paragangliomas are rare neuroendocrine tumors with a high degree of inheritance. These neoplasms arise from the extra-adrenal autonomic paraganglion and can secrete catecholamines. Many patients debut with symptoms of hypertensive crisis, tachycardia, dyspnea, headache and intense sweating. However, many tumors that are derived from the parasympathetic system are asymptomatic. Supported on the genetic basis are classified into two conglomerates: conglomerate I are those that have mutations and alter the response to hypoxia. Cluster II has a more syndromatic component, with alteration in the function of complex signaling pathways. A study based on histopathological diagnoses was carried out between 2007 and 2017 at a hospital in Bogotá (Colombia) 2600 meters above sea level, which documented 108 cases of paragangliomas that were predominantly located at the carotid level (76%), with a 4.7:1 ratio between women and men. 93.2% of the patients came from geographical locations with heights above 2,500m above sea level. Most of the tumors were asymptomatic. We draw attention to the fact that paragangliomas are probably more frequent than clinically diagnosed and the influence of the environment on the development of these tumors is highlighted, with a special contribution of oxygen pressure as a second event that contributes to the formation of the tumor.

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<![CDATA[SUN-136 Clinico-Pathological Features, Treatment Modalities and Survival of Patients with Malignant Insulinoma: A Multicenter Study]]> https://www.researchpad.co/article/elastic_article_8756 Introduction: management of malignant insulinoma is challenging due to the need to control both hypoglycemic syndrome and tumor growth. Literature data is limited to small series.

Aim of the study: to analyze clinical-pathological characteristics, treatment modalities and prognosis of patients with malignant insulinoma.

Materials and methods: Multicenter retrospective study on 31 patients (M 61.3%) diagnosed between 1988 and 2017.

Results: The mean age at diagnosis was 48 ± 15 years. In 5 cases (16.1%) the hypoglycemic syndrome occurred after 46 ± 35 months from the diagnosis of NET, in 26 (83.9%) cases it led to the diagnosis of NET, of which 11 cases (42.3%) with mean diagnostic delay of 32.7 ± 39.8 months. The majority ​​of the NET were G2 (70.8 %) and in the pancreatic body-tail (78.6%). The mean NET diameter was 41 ± 31 mm. Metastases were widespread in 40.7%, only hepatic in 37%, only lymph nodal in 18.5%..Surgical treatment was performed in 21/31 (67.7%) with hypoglycemic control in 42.9%. Except for 2 patients with curative surgery, the others underwent further different lines of therapies including somatostatin analogues (SA), Peptide Receptor Radionuclide Therapy (PRRT), everolimus, chemotherapy, TAE/TACE/RFA, radiotherapy. PRRT was performed in 14/31 (45.1%) with complete (42.9 %) or partial (50%) syndrome control.

The median follow-up was 60 months. The 5-year survival rate was 62%. The median overall survival (OS) was 40 months. No significant difference in OS was observed according to the site of primary tumour and its dimension. A trend towards increased survival was found according to grading (5-year OS 100% for G1, 77% for G2, 33% for G3). Patients with Ki-67 ≤ 10% had a significant higher survival rate compared to patient with Ki-67 >10% (5-year OS rate 87% vs 43%, p: 0.03). As regards the type of treatment, patients who underwent surgery had a higher survival rate than those who did not (5-year OS 76% vs 31.7%, p= 0.006). Moreover, patients receiving PRRT as II line treatment had a better prognosis than those who underwent it in further lines, although the 5-year OS was not significantly different (80% vs 25% respectively, p=0.057).

Conclusions: Our study includes the largest series of patients with malignant insulinomas up to now reported. The hypoglycemic syndrome may occur after years in initially non-functioning NETs, or be misunderstood with delayed diagnosis of NETs. Surgical treatment and Ki67 <10% are prognostic factors associated with better survival. PPRT seems to be promising in the control of hypoglycemic syndrome.

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<![CDATA[SUN-LB24 Clinical Performance of Multiplatform Mutation Panel MicroRNA Risk Classifier in Indeterminate Thyroid Nodules]]> https://www.researchpad.co/article/elastic_article_8653 Introduction: We evaluated the clinical performance of an expanded mutation panel in combination with microRNA classification (MPTX) for the management of indeterminate thyroid nodules. Methods: MPTX included testing of fine needle aspirates with a combination of ThyGeNEXT® mutation panel for strong and weak driver oncogenic changes and ThyraMIR® microRNA risk classifier. MPTX test status (positive or negative) and MPTX clinical risk classifications (low, moderate, or high risk) were determined blind to patient outcomes. Surgical pathology and clinical follow-up records of patients from multiple centers were used to determine patient outcomes. MPTX performance was assessed by Kaplan Meier analysis for cancer-free survival of patients, with risk of malignancy determined by hazard ratios (HR). Results: Our study included 140 patients with AUS/FLUS or FN/SFN nodules, of which 13% had malignancy. MPTX negative test status and MPTX low risk results conferred a high probability (94%) that patients would remain cancer free. MPTX positive test status (HR 11.2, P<0.001) and MPTX moderate risk results (HR 8.5, P=0.001) were significant risk factors for malignancy, each conferring a 53% probability of malignancy. MPTX high risk results elevated risk of malignancy even more so, conferring a 70% probability of malignancy (HR 38.5, P<0.001). Conclusions: MPTX test status accurately stratifies patients for risk of malignancy. Further classification using MPTX clinical risk categories enhances utility by accurately identifying patients at low, moderate, or high risk of malignancy at the low rate of malignancy encountered when clinically managing patients with indeterminate thyroid nodules.

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<![CDATA[SUN-139 Luminescence-Based Drug Screen for Novel Androgen Receptor Antagonists for Prostate Cancer Therapy]]> https://www.researchpad.co/article/elastic_article_7193 The development and maintenance of the adult prostate is dependent on the action of androgens, which mediate its effect by binding to the androgen receptor (AR). Dysregulation in the AR signaling axis disrupts transcriptional homeostasis, shifting the balance towards uncontrolled proliferation and driving the progression towards prostate cancer (PCa). The prominent role of AR signaling in prostate carcinogenesis led to the development of androgen deprivation therapy (ADT) as the primary treatment strategy for managing PCa. Despite the success of ADT in early PCa cases, most patients develop resistance to ADT and the cancer ultimately recurs towards a lethal state termed castration-resistant prostate cancer (CRPC). Remarkably, AR signaling is still active in CRPC, suggesting that the progression towards CRPC is still reliant on AR activity. Current treatments are ineffective against CRPC, highlighting the need for alternative therapeutics that can combat the resistant nature of CRPC. To address the need for innovative approaches against CRPC, we used a robust luminescence-based bioassay that can identify novel AR antagonists. We screened plant extracts derived from local fauna by measuring their effect on AR-driven activity using a luciferase-based reporter assay in HeLa cells stably overexpressing hAR (HeLa-hAR). To identify candidate hits, HeLa-hAR cells were treated with DHT to induce AR-dependent luciferase activity, DHT with the AR antagonist bicalutamide as a positive control, and DHT plus the plant extracts. We identified one extract, A32, which showed significant inhibition of AR-dependent luciferase activity without having deleterious effects on cell viability. Secondary validation tests also showed that A32 exhibits a dose-dependent inhibition of AR-driven reporter activity. When testing the effect of A32 on gene expression in LNCaP cells, we observed a down-regulation in the expression of canonical AR target genes such as PSA to degrees similar to bicalutamide. These results suggest that A32 may be an AR antagonist or may target the AR signaling axis. Collectively, this study establishes the use of a luminescence-based reporter assay for the identification of novel AR antagonists from a plant extract library.

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<![CDATA[SUN-140 TMEPAI Inhibits SMAD 2/3 Mediated Muscle Wasting]]> https://www.researchpad.co/article/elastic_article_7132 Inhibition of myostatin and activin activity using ligand traps, such as soluble receptors, follistatin and propeptides, can markedly increase skeletal muscle mass in healthy mice and ameliorate wasting in models of cancer cachexia and muscular dystrophy. Though effective, clinical translation of these approaches has been hindered by off-target effects. Toward the goal of developing tissue-specific myostatin/activin interventions, we explored the ability of transmembrane prostate androgen-induced (TMEPAI) to promote growth of skeletal muscle. TMEPAI, a transcriptional target of activin in muscle, is a known inhibitor of TGF-β1-mediated SMAD 2/3 signalling. In this study we show that TMEPAI also blocks activin A, activin B, myostatin and GDF-11 in vitro activity. Adeno-associated viral (AAV) gene delivery of TMEPAI into healthy mice increased local muscle mass by as much as 30%. Increased muscle mass was attributed to hypertrophy of fibres in TMEPAI-expressing muscles, and was coincident with an upregulation in markers of protein synthesis (pAkt, pMTOR, p70S6K). The ability of TMEPAI to block activation of the canonical activin/myostatin-SMAD 2/3 axis, was demonstrated by co-injecting AAV6:activin A and AAV6:TMEPAI into healthy mice. In this setting, TMEPAI blocked activin-induced phosphorylation of SMAD3 and associated skeletal muscle wasting. Finally, delivery of AAV6:TMEPAI into tibialis anterior muscles of mice bearing C26 tumours prevented muscle atrophy normally associated with this model. The results support that viral gene delivery of TMEPAI can effectively increase muscle mass via inactivation of the activin/myostatin-SMAD 2/3 pathway.

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<![CDATA[SUN-132 KLF5 Is a Poor Prognostic Marker and Therapeutic Target for Middle Eastern Papillary Thyroid Carcinoma]]> https://www.researchpad.co/article/elastic_article_6984 Thyroid cancer is the second most common malignancy among females in Saudi Arabia, with Papillary thyroid carcinoma (PTC) accounting for 80-90%. The Kruppel-like factor 5 (Klf5) is a transcription factor that play a critical role in cell transformation, proliferation and oncogenesis. Immunohistochemical analysis of KLF5 was performed in 1219 PTC cases. KLF5 over-expression was noted in 65.1% (793/1219) of PTCs, and was significantly associated with tall-cell variant (p <0.0001), extrathyroidal extension (p = 0.0003), lymph node metastasis (p < 0.0001) and stage IV tumors (p < 0.0001). Significant association was also noted with HIF-1α over-expression (p = 0.0492). Interestingly, KLF5 over-expressing tumors showed poor disease-free survival (p = 0.0066). Functional studies in PTC cell lines showed that KLF5 co-immunoprecipitated with HIF-1α. Knockdown of KLF5 decreased the expression of HIF-1α while KLF5 was not affected by HIF-1α inhibition, suggesting that KLF5 is a functional upstream of HIF-1α. Down-regulation of KLF5 using specific inhibitor, ML264 or siRNA inhibited cell invasion and migration. In addition, treatment of PTC cell lines with ML264 resulted in inhibition of proliferation and induction of apoptosis in a dose-dependent manner. Furthermore, silencing of KLF5 significantly decreased the self-renewal ability of spheroids generated from PTC cells. Our findings confer that KLF5 may be a potential therapeutic target for the treatment of papillary thyroid cancer.

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<![CDATA[SUN-142 Clinical Characteristics of Patients Diagnosed with Functional Neuroendocrine Tumors Treated at a Tertiary National Referral Center in Mexico]]> https://www.researchpad.co/article/elastic_article_6966 Neuroendocrine tumors (NET) represent up to 0.5% of all new cancers and can be functional or non-functional. Epidemiologic data on NET in Mexico is very limited. To delineate the clinical characteristics of patients with functional NET at a tertiary national referral center in Mexico we performed a retrospective cohort study (January 1987-June 2019). The target study population was adults with functional NET with biochemical and histopathological confirmation. Results: 126 patients with functional NET were included in this study. The median follow-up was 47.4 months (IQR 10.8 to 93.7). Most were female (64.3%). The mean age at diagnosis was 46.3 ± 14.48 years. The most frequent insulinomas (59.5%), followed by (12.7%) carcinoid tumors, gastrinomas (11.1%), ACTHomas (10.3%), VIPomas (2.4%) glucagonomas (2.4%) and PPomas (1.6%). Nineteen subjects (15.1%) had genetic syndromes, mainly MEN1 (89.5%); and 8.7% had other neoplasms, most frequently non-functional gastrointestinal (GI) carcinoids (36.3%) and thyroid cancer (18.8%). The median duration of symptoms prior to diagnosis was 24 months (IQR 7.75 to 48). The most common locations were, the GI tract (86.5%), whereas 7.1% were outside the GI tract and 6.4% were of unknown primary origin. Functional NETs outside GI tract were localized primarily in lungs

(66.6%). Functional pancreatic NETs occurred more commonly in the tail (39.6%). 24.6% had locoregional or distant metastasis during follow-up. The most frequent metastatic sites were liver (86.5%), regional lymph nodes (59.8%) and bone (13.5%). The most common treatment was surgery (87.3%, with 13.6% ≥2), followed by 18.3% somatostatin receptor analogues and 11.1% cytotoxic chemotherapy. Most subjects (73%) had complete remission with first line therapy, but 14.1% had recurrence at a median of 50.7 months (IQR 15.4 to 97.6). Subjects with an incomplete remission progressed after a median of 14.85 months (IQR 10 to 38.9). Conclusions: The clinical characteristics of functional NET treated at a tertiary center in Mexico are similar to those in other population and geographic locations described in the literature.

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<![CDATA[SUN-118 Somatostatin Agonist Conjugated to the Evans Blue Moiety Is a Superior Analog in the Diagnosis and Treatment of Tumors Characterized by High Somatostatin Receptor Expression]]> https://www.researchpad.co/article/elastic_article_6905 Background: Radiolabeled somatostatin (SST) analogs have been proven to be effective in the diagnosis and treatment of neuroendocrine tumors (NETs), which are characterized by high somatostatin receptor (SSTR2) expression. At present, there are several SST analogs available that differ from each other in the affinity for SSTR2 and tumor retention time. To date, only a single SST agonist -DOTA-TATE- has been approved by the FDA for imaging and treatment of NETs. Recent studies have shown that addition of Evans blue (EB) moiety to an SST agonist results in superior uptake and increased retention time within the tumors. The goal of our study was to compare the diagnostic and therapeutic efficacy of three different radiolabeled SST analogs in a tumor mice model: EB-TATE - a novel modified agonist; DOTA-TATE - an agonist and JR11 - an antagonist. Methods: A rat pancreatic cell line (AR42J), characterized by high SSTR2 expression, was used to create a subcutaneous xenograft mice model. The AR42J cells formed sizable tumors within two weeks post-injection. The 86Y-EB-TATE, 68Ga-DOTA-TATE, and 68Ga-DOTA-JR11 were used to determine standard uptake values by positron emission tomography (PET) imaging. For treatment purposes, the SST analogs were labeled with 177Lu to generate 177Lu-EB-TATE, 177Lu-DOTA-TATE and 177Lu-DOTA-JR11. The mice were assigned to treatment groups based on comparable tumor volume at baseline and received two doses (0.5mCi) of the 177Lu-labeled analogs one week apart. Tumor measurements were performed twice per week and the mice were euthanized if their tumor burden exceeded 2 cm at any point in the study or after 6 weeks - landmark of the end of the study. Results: Among the three analogs tested, the novel SST analog 86Y-EB-TATE was characterized by 4.3- and 3.7- fold higher tumor uptake in comparison to 68Ga-DOTA-TATE (p<0.001) and 68Ga-DOTA-JR11 (p<0.001), respectively. There was no significant difference between the uptake of 68Ga-DOTA-TATE and 68Ga-DOTA-JR11 (p=0.9). Consistently with higher tumor uptake on imaging, 177Lu-EB-TATE-treated mice responded to the treatment with an overall 86.5±13.2% reduction in the tumor volume after two weeks post-therapy. On the contrary, despite therapy with 177Lu-DOTA-TATE and 177Lu-DOTA-JR11, the mice treated with these agents presented with tumor progression exceeding 2 cm and were euthanized. Consequently, the progression-free survival (PFS) was significantly longer in 177Lu-EB-TATE group (24±0 days) compared with 177Lu-DOTA-TATE (7.7±2.6 days, p<0.001) and 177Lu-DOTA-JR11 (6.3±3 days, p<0.001). There was no difference in PFS between 177Lu-DOTA-TATE and 177Lu-DOTA-JR11-treated mice (p=0.3). Conclusion: EB-TATE is characterized by superior diagnostic and therapeutic efficacy in comparison to DOTA-TATE and DOTA-JR11. EB-TATE might be used as imaging and therapeutic agent in tumors characterized by high SSTR2 expression.

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<![CDATA[SUN-133 Intratumoral Expression of Steroid Receptors, CD68+ Macrophages and Mdm2 in Different Molecular-Biological Types of Endometrial Cancer]]> https://www.researchpad.co/article/elastic_article_6852 Background and aims: In Risk Classifier for Endometrial Cancer/EC (ProMisE) 4 molecular biological types of this tumor are described recently [1,2,3] and need an additional research, including evaluation of hormone-associated characteristics of both tumor tissue and patients [4]. Aim of the work was a study of estrogen (ER) and progesterone (PR) receptors in comparison with CD68+ macrophage infiltration (which promotes the invasion of tumor cells into the myometrium [5]) and expression of MDM2 protein, a negative regulator of p53 [6], in EC types presented in the ProMisE classification. Materials and methods: The tumor tissue of 218 EC patients included in the study (mean age 60.6 years) was assigned according to the data of genetic and immunohistochemical analysis to the types of carcinomas with gene POLE mutations, deficiency of mismatch repair proteins (MMR-D), expression (positive or diffuse) of p53 oncoprotein and to the type without characteristic molecular profile, WCMP. Immunohistochemistry was used also for evaluation of ER (Ventana antibodies, clone SP1) and PR (Ventana antibodies, clone 1E2) according to Allred, MDM2 (antibodies ABCAM, dilution 1:200) and macrophage marker CD68 (DAKO antibodies, clone CD8/144B). Results: According to the averaged data, the highest expression of ER and PR was found in EC types MMR-D and WCMP, and the lowest, respectively, in types POLE and p53+. Most often, positive expression of MDM2 (in 93.2% and 96.9% of studied cases) was detected respectively in MMR-D and p53+ type of EC, indicating, therefore, a positive relationship between MDM2 and the presence of steroid receptors in the first of these types (MMR-D) and negative - in the second of them (p53+). Expression of CD68+ macrophages demonstrated (contrary to the EC types POLE and p53+) a tendency to the lower values in types MMR-D and WCMP (128.0 ± 8.1 and 113.5 ± 6.3 cond.un.), i.e. in tumors with potential sensitivity to estrogen. Conclusions: The results indicate the importance of taking into account of both - the molecular biological type of the EC as well as the role of microenvironment of tumor cells, including the colonization of the neoplasm tissue by macrophages (and possibly lymphocytes) and the features of hormonal signal transmission in it. For further analysis, it is desirable to consider also the EC histotype, as one of the factors underlying various prognostic groups of this tumor [7].

References:

1.Talhouk A, McAlpine JN. Gynecol Oncol Res Pract. 2016; 3:14.

2. Talhouk et al., Cancer. 2017; 123(5):802–813.

3. Kommoss FK et al., Br J Cancer. 2018;119(4):480–486.

4. Berstein et al. Future Oncol. 2019; 15(12):1335–1346.

5. Jing X. et al. Immunol Cell Biol. 2019; 97(6):563–576.

6. Zou X. et al. Medicine (Baltimore).2018;97(49):e13273.

7. Bosse T. et al. Am J Surg Pathol. 2018 May;42(5):561–568.

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<![CDATA[SUN-115 Distinct DNA Methylation Signature in Neuroendocrine Tumors of Different Primary Sites and Hereditary Predisposition]]> https://www.researchpad.co/article/elastic_article_6727 Objective

There is scant data of the genome-wide methylome alterations in neuroendocrine tumors (NET). Thus, the goal of this study was to compare the DNA methylation signature of NETs with respect to various primary sites and inherited genetic predisposition syndromes including von Hippel-Lindau (VHL) and multiple endocrine neoplasia type 1 (MEN1).

Methods

Genome-wide DNA methylation analysis of 96 NETs (primary and metastatic) was performed by using the Illumina Infinium EPIC Array. Principal component analysis (PCA) and unsupervised clustering analyses were performed to identify distinct methylome signatures. The methylation status of genetic drivers such as APC were assessed by primary site.

Results

A total of 835,424 CpGs methylation sites were quantified. Hypermethylated CpG sites were detected more frequently in sporadic vs. MEN1-related vs. VHL-related NETs, respectively (p < 0.001 for all comparisons), while hypomethylated CpGs sites were more common in VHL-related NETs vs. sporadic and MEN1-related NETs (p<0.001 for both comparisons).

Small-intestinal NETs (SINETs) had the most differences at CpGs with the highest number of hyper- and hypomethylated CpG sites, followed by duodenal NETs (DNETs) and pancreatic NETs (PNETs, p<0.001 for all comparisons). PCA showed distinct clustering of SINETs and three NETs of unknown primary. Sporadic, VHL-related and MEN1-related PNETs formed distinct groups on PCA. VHL-related NETs clustered separately showing pronounced CpG hypomethylation, while sporadic and MEN1-related NETs clustered together showing relative CpG hypermethylation. In a subgroup analysis, MEN1-related SINETs, DNETs and gastric NETs had distinct methylome signatures, respectively, with complete separation by PCA and unsupervised hierarchical clustering. Furthermore, we found CpG hypermethylation in the APC (adenomatous polyposis coli) gene, specifically in the 1A promoter, with higher methylation levels in gastric- and DNETs vs. SINETs, PNETs and NETs of unknown primary (p < 0.001 for all comparisons).

Conclusion

Various primary NET sites and genetically predisposed MEN1-related NETs have distinct DNA CpG methylation signatures. The methylome signatures identified in this study may be useful for non-invasive molecular characterization of NETs, through DNA methylation profiling of biopsy samples or circulating tumor DNA.

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<![CDATA[SUN-134 Estrogen Induces Granulocytic Myeloid Derived Suppressor Cell Production to Potentially Modulate Lymphangioleiomyomatosis (LAM) Tumor Progression]]> https://www.researchpad.co/article/elastic_article_6443 Affecting almost exclusively women, lymphangioleiomyomatosis (LAM) is a rare lung disease characterized by estrogen-sensitive metastatic smooth muscle cell-like adenomas that grow slowly, resulting in cystic lung change and loss of pulmonary function. LAM tumors are caused by mutations in tuberous sclerosis complex 1 or 2 genes (TSC1 or TSC2). Mutations in TSC1 or TSC2 genes results in deficient inhibitory regulation of the mammalian target of rapamycin complex 1 (mTORC1), which in turn leads to increased mTORC1 activity and cell proliferation. There is no consensus amongst LAM researchers regarding the origin of these estrogen receptor-positive smooth muscle like LAM cells; however, we previously reported inactivation of TSC2 in the mouse uterus results in notable LAM features in the setting of primary myometrial tumors. Approximately 50% of the TSC2-null mice had metastatic myometrial tumors present in the lung, suggesting that LAM tumor cells might in fact originate from the uterus, thus explaining the female sexual dimorphism, the estrogen sensitivity, and the metastatic nature of the LAM tumors.

Interestingly, flow cytometry revealed large numbers of granulocytic myeloid derived suppressors cells (G-MDSCs) in the blood and myometrial tumors of uterine-specific Tsc2 null mice. MDSCs are known to accumulate in the setting of chronic inflammation caused by trauma, infection, and various cancers. This granulocytic subtype not only has the capacity to suppress anti-tumor immune cells of the tumor microenvironment, but also directly promotes tumor cell malignant neoplasicity. We found that Tsc2-null myometrial tumors required MDSCs for normal progression, as MDSC depletion or inhibition of MDSC recruitment reduced tumor growth. We have showed that these tumors expressed estrogen receptors and were exquisitely sensitive to estrogen, while other studies demonstrate that G-MDSCs are also positively influenced by estradiol. Therefore, we hypothesized that, in addition to direct effects of estrogen on tumor cells, estrogen also stimulates tumor growth by promoting MDSC production in the bone marrow. We have developed a technique to stimulate MDSC production from mouse bone marrow. Using this strategy, we found that estradiol is indeed a potent promotor of G-MDSC production. These effects occurred in both male and female bone marrow. Employing both pharmacologic agents and bone marrow from ERα; knockout mice, we showed that ERα; is necessary for promoting a G-MDSC fate for immature myeloid cells and precursors. Thus, estradiol may have duel effects in LAM, both directly promoting tumor growth and indirectly upregulating MDSC production, which in turn promotes tumor growth. We propose that these estrogen effects on MDSC production are not limited to LAM and may be important regulators of tumor growth in many tissues.

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<![CDATA[SUN-116 The Role of <sup>68</sup>Gallium DOTATATE PET/CT Versus <sup>18</sup>F-FDOPA PET/CT in the Imaging of Neuroendocrine Neoplasms in Patients with Multiple Endocrine Neoplasia Type 1 (MEN1)]]> https://www.researchpad.co/article/elastic_article_6439 Background: Neuroendocrine neoplasms (NEN) are a heterogenous group of tumors. Patients with the multiple endocrine neoplasia type 1 (MEN1) syndrome often manifest with simultaneous functional and non-functional NEN in various endocrine glands. In MEN1, nuclear medicine plays an important role in the diagnostic work-up and localization of NEN. Little is known about the comparative efficacy of 68Ga-Dotatate PET/CT (DOTA) versus 18F-FDOPA PET/CT (FDOPA) and both versus non-nuclear medicine imaging (CT and MRI) in the identification of primary and metastatic NEN.

Methods: This prospective MEN1 cohort study evaluated 15 germline MEN1 mutation-positive patients. Subjects were imaged using CT, MRI, DOTA and 18F-FDOPA. Radiological review with a multidisciplinary team was performed for each patient.

Results: One-hundred twenty-nine total lesions were identified using any of the four scans. DOTA sensitivity was 69% (89/129; 95% CI 61% to 76%) with a mean standardized uptake value (SUV) of 33.9 ± 30.1, FDOPA sensitivity was 18% (23/129; 95% CI 12% to 25%) with mean SUV of 12.1 ± 15.16. DOTA identified an additional 50 lesions not seen on CT (of which MRI detected 8 lesions with an average size 0.95 cm ± 0.48; 3 pancreatic, 2 duodenal, 2 liver, and 1 lymph node) and identified 55 lesions not seen on MRI (of which CT identified 13 with a mean size of 1.1 cm ± 0.45; 1 lung, 4 pancreatic, 2 duodenal, 1 liver, and 5 lymph nodes). Overall, CT detected 51.2% (66/129) of lesions (mean 0.61 cm ± 0.73; 95% CI 43% to 60%) and MRI detected 39.5% (51/129; 0.47 cm ± 0.71; 95% CI 32% to 48%), and there was no significant difference in the size of lesions detected (p=0.18). Analysis by organ NEN revealed equal sensitivity between FDOPA and DOTA for lung carcinoid, detecting 33% (4/12) of lesions, while CT detected 92% (11/12) of lesions. In the duodenum, DOTA identified 100% (11 /11) of lesions, while FDOPA had poor sensitivity (9%) in this location. Within the pancreas, DOTA has a sensitivity of 81% (31/38), while FDOPA had a sensitivity of 21% (8/38). CT localized 42% (16/38) of pancreatic lesions, of which MRI missed 6. Interestingly, DOTA missed 7 pancreatic lesions all approximately 1cm or larger, which is previously unrecognized (range 0.9 - 1.8cm). Twenty-three liver metastases were detected on anatomic imaging (CT identified 14, while MRI detected 15, with only 9 overlapping lesions). DOTA identified 60% (14/23) of lesions, of which 3 lesions were missed by CT and MRI. However, DOTA was more sensitive in the liver than FDOPA which only detected 2 lesions. FDOPA detected one lesion in the adrenal (0.9cm) that was not seen on DOTA.

Conclusion: DOTA imaging proved to be superior to FDOPA, CT and MRI overall in detecting NENs in MEN1, specifically in the duodenum. Pancreatic NEN missed by DOTA may represent higher grade tumors and may benefit from 18FDG PET/CT imaging.

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<![CDATA[SUN-114 Successful Long-Term Medical Management of Insulinomas]]> https://www.researchpad.co/article/elastic_article_6364 Background: Insulinomas are usually benign, solitary tumors. Surgical resection is the treatment of choice and only method of cure. Surgical cure is not possible with unresectable metastatic disease, unlocalizable disease, or contraindications to surgery. Long-term medical management may be required. Clinical Cases: Patient 1: A 57-year-old female was diagnosed at age 42 when imaging confirmed a 2.4cm insulinoma in the pancreatic tail and two lesions in the right hepatic lobe. She underwent distal pancreatectomy with splenectomy, and hepatic wedge resection. Follow-up imaging showed two new hepatic lesions. She underwent chemoembolization with resolution of her symptoms. By age 48, her symptoms returned. Imaging showed new lesions in the liver, not amenable to embolization. She was placed on Octreotide 20mg IM monthly and her symptoms resolved soon after initiation of therapy. She has since had an unremarkable clinical course. Additional therapies have been deferred as follow-up imaging has not shown disease progression. Patient 2: A 48-year-old female was diagnosed at age 37. CT and MRI did not find a source. A DOPA-PET showed increased uptake in head and tail of the pancreas. An 8-hour ex-laparotomy with EUS and palpation of the pancreas did not localize a mass. A second surgery, with 75% removal of the distal pancreas, including the tail and body, did not relieve her symptoms. She had unsuccessful trials of verapamil, verapamil with low-dose diazoxide, and octreotide. She started diazoxide 300mg daily, but had fluid retention and tachycardia. Her dose was decreased to 200mg daily and HCTZ 25mg daily was started. Due to persistent symptoms, prednisone was started at 5mg in the morning and 2.5mg in the afternoon, which gave symptom relief. At her request it was decreased to 5mg daily. By age 42 she had self-decreased it to 2.5 mg daily, but continued her other meds. She endorsed the return of symptoms, but felt she could manage them without increasing her dose. At age 44, as part of a clinical trial, an MRI and nuclear medicine study showed a 9mm lesion in the head of the pancreas. Another exploratory surgery did not find a lesion. Currently, she is on the same medication regiment with strict diet and frequent meals. She endorses only rare hypoglycemic episodes. Conclusion: The patients have been managed with medical therapy for 15 and 11 years respectively. Long-term survival data of patients with metastatic insulinoma indicates that prolonged survival is unlikely; however, most data is from the 1990s or earlier. It does not incorporate new medical treatments, or advancements in technology and the field of medicine. Patients who are not candidates for surgical cure, may have better survival rates and undergo longer courses of medical management. Additionally, while oral prednisone is not standard therapy for insulinoma, there are cases of its use to control hypoglycemia when other treatments are exhausted.

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<![CDATA[SUN-137 Clonal Status of Multigland Disease Primary Hyperparathyroidism]]> https://www.researchpad.co/article/elastic_article_6164 Primary hyperparathyroidism (PHPT) is a common endocrine disorder that arises due to single or multiple parathyroid gland disease (MGD). The molecular mechanism(s) of parathyroid neoplasia are incompletely understood and both monoclonal (mono-X) and polyclonal (poly-X) parathyroid tumors have been described using methylation-sensitive PCR of X-linked Human Androgen Receptor (HUMARA) alleles. Our previous investigations of parathyroid tumor clonal status has shown that poly-X tumors are common and are associated with MGD in patients with non-familial PHPT (Shi et al. 2014 & 2018). This work examined the clonal status of the dominant gland and the clonal relationship of multiple tumors from the same patient has not been examined. The goal of the current study was to determine the clonal relationship of parathyroid tumors from PHPT patients with MGD. Banked parathyroid tissues from twenty-nine PHPT patients with MGD were examined in this study. Clonal status (mono-X vs poly-X) of multiple abnormal parathyroid glands from each patient was determined using a modification of the HUMARA assay used in our prior work. Briefly, methylation-sensitive PCR of HUMARA alleles was performed followed by fragment analysis using Capillary-Electrophoresis performed. Raw fragment sizing data analyzed using Peak Scanner software. Classification of samples as either mon-X or poly-X was made as described in (Shattuck et al.) Of 29 PHPT patients with MGD, 13 (45%) had pure mono-X, 5 (17%) had pure poly-X, and 11 (38%) had a mixture of mono-X and poly-X tumors. Five of 29 patients had three or more abnormal glands evaluated: 3 had mixture of poly-X and mono-X, 2 had pure mono-X tumors, and none were pure polyclonal-X. Eighteen (62%) out of 29 patients had paired upper or lower double adenomas. Of these, 9 (50%) were pure mono-X, 4 were pure poly-X, and 5 were mixed mono-X/poly-X. In 2 patients with multiple mono-X tumors, allele distribution was not the same in different abnormal glands. Our previous work has demonstrated that among patients with non-familial PHPT, poly-X parathyroid tumors are common and are associated with MGD. Our new data extend these findings to show that the clonal relationship between multiple parathyroid tumors from the same patient is complex and may reflect the emergence of single or multiple tumors from a background of parathyroid hyperplasia, or other mechanism(s). Future studies to explore the mechanisms behind these apparent clonal relationships are warranted and ongoing. Reference: (1) Shi et al., PNAS 2014, 201319742. (2) Shi et al., Surgery 2018, 9-14. (3) Shattuck. N Engl J Med 2005, 2406-12.

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<![CDATA[SUN-LB22 PLK1 as a New Treatment Target for Adrenocortical Carcinoma]]> https://www.researchpad.co/article/Nf44fd940-0f06-4b43-81bd-e26d86caad4c <![CDATA[SUN-119 Identification of Novel Mirnas Found to Be Differentially Expressed Between ATA Risk Stratification Groups in Papillary Thyroid Carcinoma]]> https://www.researchpad.co/article/N60477790-86a2-4a4c-83e9-dce151251852 <![CDATA[SUN-117 Growth Hormone-Releasing Hormone (GHRH) Deficiency Promotes Inflammation Associated Carcinogenesis]]> https://www.researchpad.co/article/N66bad4b7-08de-4d5a-ac81-63ca501b820a <![CDATA[SUN-120 Regional Hyperthermia Enhances Selective Mesenchymal Stem Cell Migration Towards the Tumor Stroma]]> https://www.researchpad.co/article/N1f476646-0f53-44f9-b421-0491fdc431c1

Abstract

The tumor homing characteristics of mesenchymal stem cells (MSCs) make them attractive vehicles for the tumor-specific delivery of therapeutic agents, such as the sodium iodide symporter (NIS). NIS is a theranostic protein that allows non-invasive monitoring of the

biodistribution of functional NIS expression by radioiodine imaging as well as the therapeutic application of

I. To enhance the actively recruitment of MSCs to growing tumor stroma and thereby trigger targeted delivery of the NIS gene to the tumor, we examined the combination with regional hyperthermia, as heat induces the secretion of immunomodulatory chemokines, cytokines and growth factors, well-known attractants of MSCs.

Human hepatocellular carcinoma cells (HuH7) were heat-treated in a water bath at 41 °C for 1h, followed by incubation at 37 °C for 0-48h. mRNA and protein levels of chemokines involved in MSC migration was analyzed by RT-PCR and ELISA. Chemotaxis of MSCs in relation to a gradient of supernatants was tested in a 3D live cell tracking migration assay. In a subcutaneous HuH7 mouse xenograft tumor model, a single systemic injection of CMV-NIS-MSCs was applied 6h, 24h, 48h after or 24h, 48h before hyperthermia treatment and tumoral

I accumulation was assessed by

I-scintigraphy.

NIS analysis of tumor sections was performed by RT-PCR and immunohistochemistry. The optimal imaging regime was then used for a

I therapy study.

Chemokine mRNA and protein analysis indicated a substantial increase in expression levels of chemokines and growth factors, involved in MSC tumor homing, after heat exposure. In addition, MSCs showed directed migration towards the supernatant of thermo-stimulated cancer cells.

, with the optimal regime, we observed a significantly increased uptake of

I in tumors of heat-treated animals (41 °C) when thermostimulated 24h after CMV-NIS-MSC injection compared to control animals (37 °C). Immunohistochemical staining of tumor sections showed strong tumoral NIS-specific immunoreactivity and RT-PCR an increased NIS mRNA expression in heat-treated tumors, thereby confirming tumor-selective, temperature-dependent MSC migration. CMV-NIS-MSC-mediated

I therapy combined with regional hyperthermia resulted in a reduced tumor growth that was associated with prolonged survival of regional heat-treated animals compared to normothermic mice and to the saline control group.

In summary, we have demonstrated a significantly increased, selective MSC migration towards the tumor stroma after regional hyperthermia in the

I imaging study. The combination of MSC-mediated NIS gene therapy with mild regional hyperthermia resulting in stimulated therapeutic efficacy of NIS-mediated

I therapy.

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<![CDATA[SUN-LB27 Interleukin-8 - a Possible Target for Melanoma Treatment? In-Vitro Studies Based on Human Melanoma Cell Models]]> https://www.researchpad.co/article/Nf785fb6d-bedb-4c8a-bd65-659f6e57bef0 <![CDATA[SUN-143 Prostatic Acid Phosphatase Is Not Regulated by Androgens During Prostate Development and Tumorigenesis]]> https://www.researchpad.co/article/Nf86d53d8-a83d-4c8d-8a1b-f6a50b8ba119