Avid Uptake Research Articles

Two‐Dimensional Transition Metal Dichalcogenides Trigger Trained Immunity in Human Macrophages through Epigenetic and Metabolic Pathways

Trained immunity is a recently described phenomenon whereby cells of the innate immune system undergo long-term epigenetic and/or metabolic reprogramming following a short-term interaction with microbes or microbial products. Here, it is shown that 2D transition metal dichalcogenides (TMDs) trigger trained immunity in primary human monocyte-derived macrophages. First, aqueous dispersions of 2D crystal formulations of MoS2 and WS2 are tested, and no cytotoxicity is found despite avid uptake of these materials by macrophages. However, when macrophages are pre-exposed to TMDs, followed by a resting period, this causes a marked modulation of immune-specific gene expression upon subsequent challenge with a microbial agent (i.e., bacterial lipopolysaccharides). Specifically, MoS2 triggers trained immunity through an epigenetic pathway insofar as the histone methyltransferase inhibitor methylthioadenosine reverses these effects. Furthermore, MoS2 triggers an elevation of cyclic adenosine monophosphate (cAMP) levels in macrophages and increased glycolysis is also evidenced in cells subjected to MoS2 training, pointing toward a metabolic rewiring of the cells. Importantly, it is observed that MoS2 triggers the upregulation of Mo-dependent enzymes in macrophages, thus confirming that Mo is bioavailable in these cells. In conclusion, MoS2 is identified as a novel inducer of trained immunity. Thus, TMDs could potentially be harnessed as immunomodulatory agents.

The thiosemicarbazone, DpC, broadly synergizes with multiple anti-cancer therapeutics and demonstrates temperature- and energy-dependent uptake by tumor cells

BackgroundThe di-2-pyridylketone thiosemicarbazones, di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), demonstrate potent and selective anti-tumor activity. In fact, DpC entered Phase I clinical trials for advanced and resistant tumors. MethodsThis investigation examined the activity of these thiosemicarbazones in five tumor cell-types compared to nine clinically used chemotherapeutics and also in combination with these drugs. ResultsDp44mT and especially DpC demonstrated potent anti-proliferative activity that was significantly greater than a range of standard anti-cancer therapeutics. As most anti-cancer drugs are given in combination, further studies were performed to examine the synergistic activity of DpC or Dp44mT with these chemotherapeutics. Combination experiments revealed broad synergy between Dp44mT or DpC upon addition of these drugs, with a sequential protocol of treating first with standard chemotherapies followed by incubation with the thiosemicarbazones being optimal. However, combining DpC and Dp44mT resulted in a pronounced antagonistic drug interaction. To dissect the mechanism of this latter effect, custom-prepared 14C-DpC was implemented and examined for its uptake by cells. The avid uptake of 14C-DpC by tumor cells observed at 37 °C was suppressed at 4 °C and by the metabolic inhibitor, sodium fluoride, suggesting a temperature- and energy-dependent mechanism. Furthermore, competition studies using an excess of unlabeled Dp44mT or DpC inhibited 14C-DpC or 14C-Dp44mT uptake, respectively, suggesting these ligands utilize the same carrier/receptor, antagonizing the internalization of each other. Conclusions and general significanceThese studies demonstrate the potent and broad anti-proliferative activity of Dp44mT and particularly DpC, and are important for establishing optimized combinations with standard chemotherapies.

Recurrent Multi-territorial Acute Ischemic Stroke due to Cardiac Angiosarcoma.

A 64-year-old man with hypertension, hyperlipidemia, and diabetes mellitus presented on 2 separate occasions with recurrent acute ischemic strokes in multiple vascular territories (Figure 1). Transthoracic echocardiogram revealed a 4.2 × 2.1 cm left atrial mass with heterogenous contrast enhancement on heart MRI (Figure 2). A PET scan showed corresponding avid uptake in the left atrium with widespread bone, skin, and pulmonary metastases. Left ischial bone biopsy was consistent with angiosarcoma.

Primary seminoma arising in the posterior mediastinum: a diagnostic challenge

Primary mediastinal germ cell tumors are a rare finding, and one third of them are seminomas. Seminomas are found in the anterior mediastinum, whereas they are extremely rare within the posterior compartment. Most clinicians would not consider a primary seminoma in the differential diagnosis of a posterior mediastinal mass, as only two cases have been reported in literature. Here we present the case of a 57-year-old male with a primary seminoma arising in the left posterior mediastinum. He was asymptomatic and the mass was an incidental finding. Positron emission tomography (PET) revealed a small area with an avid tracer uptake. Transthoracic needle aspiration led to a non-diagnostic result. Due to the strong suspect of malignancy, a surgical excision was chosen to obtain a diagnosis. He underwent complete excision, and pathology report demonstrated a mediastinal seminoma. Subsequent further staging did not reveal any other location of the disease. Given the complete excision of the primary tumor, active surveillance was the treatment of choice. The patient is free of disease 48 months after diagnosis.

Acute toxoplasmosis mimicking metastatic lymphadenopathy of sarcoma

Abstract Introduction: Clear cell sarcoma is a rare malignant neoplasm with the potential to metastasize to lymph nodes. We report herein a case of acute toxoplasmosis that mimicked metastatic lymphadenopathy from treated clear cell sarcoma on 18F-fluorodeoxyglucose positron emission tomography/computed tomography. Toxoplasmosis is usually asymptomatic in immunocompetent hosts. Acute acquired toxoplasmosis clinically manifests as lymphadenopathy predominantly involving the cervical nodes. Patient concerns: A 45-year-old woman underwent resection of subcutaneous clear cell sarcoma of the right knee. PET/CT performed four years after surgery revealed multiple sites of lymphadenopathy with avid FDG uptake in the right neck, left axilla, left pulmonary hilum, and right inguinal regions. The patient was afebrile and asymptomatic. Metastases were suspected and excisional biopsy of a left axillary node was performed. Diagnoses: Histopathological examination revealed reactive lymphadenitis, suggesting toxoplasmic infection without evidence of malignancy. Serum levels of toxoplasmic immunoglobulin (Ig)M antibodies were high. Serum IgG antibodies were significantly elevated in six weeks from the PET/CT examination. The patient had a cat at home, which could have represented the source of infection. Interventions: The patient was carefully monitored using regular imaging examinations. Outcomes: FDG accumulations resolved spontaneously on follow-up examination one year later. Conclusion: We report a case in which toxoplasmic lymphadenitis mimicked malignant lymphadenopathy. Lymphadenopathy at a distant site from the primary malignancy with FDG avidity may be due to infectious or inflammatory conditions, creating false-positive results.

Relative Enhancement Ratio of Portal Venous Phase to Unenhanced CT in the Diagnosis of Lipid-poor Adrenal Adenomas.

Background The development of an accurate, practical, noninvasive, and widely available diagnostic approach to characterize lipid-poor adrenal lesions (greater than 10 HU at unenhanced CT) remains an ongoing demand. Purpose To investigate whether combined assessment of unenhanced and portal venous phase CT allows for the differentiation of lipid-poor adrenal adenomas from nonadenomas. Materials and Methods Patients with lipid-poor adrenal lesions who underwent unenhanced and portal venous phase CT with a single-energy scanner between January 2016 and March 2020 were identified retrospectively. For each lesion, the unenhanced and contrast-enhanced attenuation were measured; the absolute enhancement (contrast-enhanced minus unenhanced attenuation [HU]) and relative enhancement ratio ([absolute enhancement divided by unenhanced attenuation] × 100%) were calculated. The sensitivity achieved at 95% specificity to distinguish adenomas from nonadenomas was determined with receiver operating characteristic curve analysis and compared among parameters with use of the McNemar test. Results A total of 220 patients (mean age ± standard deviation, 66 years ± 12; 134 men) with 131 lipid-poor adenomas and 89 nonadenomas were analyzed. The sensitivity (achieved at 95% specificity) of the relative enhancement ratio (86% [113 of 131 adenomas; 95% CI: 79, 92] at a threshold of >210%) was higher than that of unenhanced attenuation (50% [66 of 131 adenomas; 95% CI: 42, 59] at a threshold of ≤21 HU), contrast-enhanced attenuation (3% [four of 131 adenomas; 95% CI: 1, 8] at a threshold of >120 HU), and absolute enhancement (24% [32 of 131 adenomas; 95% CI: 17, 33] at a threshold of >74 HU; all P < .001). The sensitivities of the relative enhancement ratio were 100% (58 of 58 adenomas; 95% CI: 94, 100), 83% (52 of 63 adenomas; 95% CI: 71, 91), and 30% (three of 10 adenomas; 95% CI: 7, 65) for adenomas measuring unenhanced attenuation of more than 10 HU up to 20 HU, 21-30 HU, and more than 30 HU, respectively. Conclusion A relative enhancement ratio threshold of greater than 210%, measured at unenhanced and portal venous phase CT, accurately differentiated lipid-poor adenomas from nonadenomas, particularly for lesions with unenhanced attenuation of 10-30 HU. © RSNA, 2021 Online supplemental material is available for this article.

Sugar-originated carbon nanodots selectively damage the tumor and enhance the sensitivity of chemotherapy

Blocking the tumor energy metabolism is expected to be a potential cancer treatment strategy. However, developing a single and simple nanoparticle system to directly block the tumor energy metabolism with good biosafety and high potential for clinical application remains absence. Herein, a technique is described for the preparation of sugar-originated carbon nanodots (sCND) which is inspired by the traditional cooking skill of pork braised in brown sauce, where the sucrose caramelizes in the hot vegetable oil. The special preparation endows sCND with some glucose residues on their surfaces and optical nanodot properties, which enable the GLUT1-mediated glioma-targeted accumulation that can be monitored by in vivo imaging. Subsequently, sCND can hamper the avid uptake of glucose into the tumor. This blocks the tumor energy metabolism, impairs tumor growth and enhances sensitivity to chemotherapy as shown in two tumor models (glioma and hepatoma). Additionally, this kind of carbon nanodots possesses a favorable biosafety profile, including low cytotoxicity, almost no hematotoxicity and tissue damaging potential. It is edible due to the special preparation and structure similar to the traditional cooking style. This work reports a simple method to produce advanced therapeutic carbon nanodots with favorable biodistribution and biosafety, which will pave the way for a powerful platform with future clinical applications.

Prevalence of Increased FDG PET/CT Axillary Lymph Node Uptake Beyond 6 Weeks after mRNA COVID-19 Vaccination.

Ipsilateral avid axillary lymph node uptake at FDG PET/CT persists in 29% (49 of 169) of patients between 7 to 10 weeks after the second dose of the mRNA-based BNT162b2 COVID-19 vaccination.

P031 Whipple's disease: a multidisciplinary conundrum

Abstract Background/Aims A 45-year-old male patient presented in 2015 with a six-month history of relapsing and remitting polyarthralgia. Hand X-rays appeared normal. Serology showed mildly elevated inflammatory markers. Autoimmune profile including anti-CCP antibody, rheumatoid factor and ANA was negative. His initial diagnosis was palindromic rheumatism. He was under watchful waiting in rheumatology clinic having declined a trial of hydroxychloroquine, when in 2018 he developed severe epigastric pain. Over the subsequent 18 months he was noted to have dramatic weight loss, fatigue and drenching night sweats. Methods Investigations showed microcytic anaemia with elevated inflammatory markers (Hb 98 g/L, CRP 161 mg/L, ESR 68 mm/hr). Serum ACE, bone profile, thyroid function and urate levels were normal. Chest X-ray was unremarkable. HIV and hepatitis screening was negative. Endoscopy with jejunal biopsy was performed, with mild gastritis only on histopathology and normal D2 biopsies. He was found to be H pylori positive, and notably felt his B-symptoms much improved with triple antibiotic and PPI eradication therapy. CT abdomen demonstrated widespread mesenteric lymphadenopathy. Para-aortic lymph node biopsy showed non-necrotising granulomata suggestive of either sarcoidosis or an infective etiology such as tuberculosis (TB). Given the clinical picture, the patient was commenced on high dose oral prednisolone and methotrexate for suspected sarcoidosis. Results The patient made some clinical improvement, particularly with regards to arthralgia, however his B-symptoms returned with any reduction in steroid dose. Serology showed worsening anaemia with iron and folate deficiency, and increasing inflammatory markers. We therefore decided to perform a PET CT and refer to Haematology for consideration of a lymphoproliferative disease. PET CT demonstrated lymphadenopathy without avid uptake. A second lymph node biopsy was performed which showed florid histiocytic infiltration within which there were numerous PAS positive particles consistent with Whipple's disease. This was confirmed as tropheryma whipplei on PCR. Whipple's disease is a rare systemic infectious disease causing arthralgia, diarrhoea, abdominal pain and weight loss. Treatment consists of antibiotic therapy. On further questioning, the patient had grown up on a farm. There is a known association with Whipple's disease in the agricultural community as it is a soil-borne organism. Conclusion Our patient has made an excellent recovery. He remains under the care of our rheumatology team and the London School of Tropical Medicine and Hygiene. Treatment plan is 12 months of combined therapy with doxycycline and hydroxychloroquine. He underwent a lumbar puncture to rule out meningeal Whipple disease. We have also commenced sulfasalazine for persistent arthritis, which we feel could be a reactive phenomenon. Our key learning points from this case were to use a stepwise approach to diagnosis, involve relevant specialty teams and that it in complex cases it is useful to go back to the history. Disclosure F. Baldeweg: None. A. Nuttall: None. D. Arul: None. A. Childerhouse: None.

Breast cancer in multiple endocrine neoplasia type 1 (MEN1).

SummaryA 38-year-old female was identified as carrying a heterozygous pathogenic MEN1 variant (c.1304delG) through predictive genetic testing, following a diagnosis of familial hyperparathyroidism. Routine screening for parathyroid and pituitary disease was negative. However, cross-sectional imaging by CT revealed a 41 mm pancreatic tail mass. Biopsy via endoscopic ultrasound confirmed the lesion to be a well-differentiated (grade 1) pancreatic neuroendocrine tumour (pNET) with MIB1<1%. Biochemically, hyperinsulinaemic hypoglycaemia was confirmed following an overnight fast, which was subsequently managed by diet alone prior to definitive surgery. Pre-operative work-up with octreotide SPECT CT demonstrated avid tracer uptake in the pancreatic lesion and, unexpectedly, a focal area of uptake in the left breast. Further investigation, and subsequent mastectomy, confirmed ductal carcinoma in situ pT2 (23 mm) grade 1, N0 (ER positive; HER2 negative). Following mastectomy, our patient underwent a successful distal pancreatectomy to resect the pNET. Loss of heterozygosity (LOH) at the MEN1 locus was found in both the breast tumour and pNET, thereby in keeping with a 'two-hit' hypothesis of oncogenesis, a suggestive but non-definitive clue for causation. To obtain further support for a causative relationship between MEN1 and breast cancer, we undertook a detailed review of the published literature which overall supports the notion that breast cancer is a MEN1-related malignancy that presents at a younger age and histologically, is typically of ductal subtype. Currently, clinical guidance regarding breast cancer surveillance in MEN1 does not exist and further research is required to establish a clinical and cost-effective surveillance strategy).Learning pointsWe describe a case of pNET and breast cancer diagnosed at a young age of 38 years in a patient who is heterozygous for a pathogenic MEN1 variant. Loss of the wild-type allele was seen in both breast tissue and pNET specimen.Breast cancer may be an under-recognised MEN1-associated malignancy that presents at a younger age than in the general population with a relative risk of 2–3.Further research is required to determine the cost-effectiveness of breast cancer surveillance approach at a younger age in MEN1 patients relative to the general population .

A woman with visual loss, amenorrhoea and polyuria: the first reported case of nodular lymphocyte-predominant Hodgkin lymphoma presenting with hypopituitarism.

SummaryA 34-year-old woman presented 18 months post-partum with blurred vision, polyuria, amenorrhoea, headache and general malaise. Comprehensive clinical examination showed left superior temporal visual loss only. Initial investigations revealed panhypopituitarism and MRI demonstrated a sellar mass involving the infundibulum and hypothalamus. Lymphocytic hypophysitis was suspected and high dose glucocorticoids were commenced along with desmopressin and thyroxine. However, her vision rapidly deteriorated. At surgical biopsy, an irresectable grey amorphous mass involving the optic chiasm was identified. Histopathology was initially reported as granulomatous hypophysitis. Despite the ongoing treatment with glucocorticoids, her vision worsened to light detection only. Histopathological review revised the diagnosis to partially treated lymphoma. A PET scan demonstrated avid uptake in the pituitary gland in addition to splenic involvement, lymphadenopathy above and below the diaphragm, and a bone lesion. Excisional node biopsy of an impalpable infraclavicular lymph node confirmed nodular lymphocyte-predominant Hodgkin lymphoma. Hyper-CVAD chemotherapy was commenced, along with rituximab; fluid-balance management during chemotherapy (with its requisite large fluid volumes) was extremely complex given her diabetes insipidus. The patient is now in clinical remission. Panhypopituitarism persists; however, her vision has recovered sufficiently for reading large print and driving. To the best of our knowledge, this is the first reported case of Hodgkin lymphoma presenting initially as hypopituitarism.Learning pointsLymphoma involving the pituitary is exceedingly rare and, to the best of our knowledge, this is the first reported case of nodular lymphocyte-predominant Hodgkin lymphoma presenting as hypopituitarism.There are myriad causes of a sellar mass and this case highlights the importance of reconsidering the diagnosis when patients fail to respond as expected to appropriate therapeutic intervention.This case highlights the difficulties associated with managing panhypopituitary patients receiving chemotherapy, particularly when this involves large volumes of i.v. hydration fluid.

Biological Pathways as Substantiation of the Use of Copper Radioisotopes in Cancer Theranostics

Copper, a cofactor for many enzymes, is a bioelement that is involved in many main biochemical processes; although high levels of copper promote the proliferation of cancer cells. Further development of radiopharmaceuticals based on copper radioisotopes depend on understanding and taking advantage of its biochemical pathways in oncogenesis. As with other radiometals used in molecular imaging and/or targeted therapy, biological vectors are employed to transport copper radioisotopes to a target, aiming for high specific uptake at tumor sites and precise delivery of ionizing radiation. Evidence of the clinical utility of copper radioisotopes in the ionic form CuCl2 were also proven in an in vivo study of the copper metabolism, guiding personalized copper-chelating treatment in cancer patients and in imaging pathological sites associated with copper imbalance. Five of the copper radioisotopes have gained interest for nuclear medicine applications, based on their emissions, energies, and half-lives, as they can be produced with pharmaceutical-grade quality. The uptake mechanism, kinetics, and metabolic parameters are important findings in molecular imaging, which are decisive when designing individualized targeted radiotherapy for dose calculations of high linear energy transfer Auger electrons and β− emissions of 64Cu and 67Cu. As radiation deposits a high amount of energy within the intra-cellular space, the biochemical involvement of copper determines targets in drug design and validation. The biochemical pathways depict copper metabolism in normal cells and highlight its increased activity in tumor progression and angiogenesis. The avid uptake of copper into inter- and intra-mitochondrial spaces, as constituents of cytochrome C oxidase, substantiate the selection of 64/67CuCl2 as theranostic agents.

S2202 Post-Surgical Presentation of Zollinger–Ellison Syndrome Following Resection of Endometrioid Neuroendocrine Tumor

INTRODUCTION: Zollinger–Ellison syndrome (ZE) may present as lymph node metastases at initial presentation. Here we report a case of ZE following resection of endometrioid small cell neuroendocrine carcinoma and endometrioid adenocarcinoma. CASE DESCRIPTION/METHODS: A 76-year-old Caucasian female presented with heavy vaginal bleeding. CT scan revealed an enlarged uterus measuring 6.2 × 5.4 cm. The patient underwent uneventful laparoscopic hysterectomy with bilateral salpingo-oophorectomy and bilateral sentinel lymph node dissection. Pathological examination demonstrated stage IB mixed endometrioid adenocarcinoma and small cell neuroendocrine carcinoma. Gastrin immunostaining was negative. The patient presented three months after completing chemotherapy (one month following radiation treatment with brachytherapy) with black stool in addition to watery diarrhea for more than 6 months. The patient denied taking aspirin or nonsteroidal anti-inflammatory drug and was not taking a proton pump inhibitor (PPI). Esophagogastroduodenoscopy (EGD) demonstrated multiple non-bleeding superficial gastric ulcers with clean ulcer bases (Forrest Class III) in the antrum and prepyloric region. No ulcers were identified in the duodenum. An elevated serum gastrin level (538 pg/mL) was noted the day after EGD while not on PPI therapy. Somatostatin receptor-based imaging (Ga-68 Dotatate- PET/CT) revealed avid left paraesophageal node uptake measuring 11 × 8 mm. Stool helicobacter pylori antigen test was negative. Serum calcium (9.2 mg/dL), renal function and PTH were within normal limits. After five months, follow up EGD demonstrated two persistent (2-3 mm) clean based ulcerations in the posterior gastric wall. Gastric fluid demonstrated pH of 1 despite Pantoprazole 40 mg twice a day for 4 months. Endoscopic ultrasound examination demonstrated an ill-defined 14 × 7 mm heterogenous lymph node in the region of the lymph node noted on PET scan, which was sampled by fine needle aspiration, revealing scant lymphoid tissue insufficient for pathologic diagnosis. DISCUSSION: Here the diagnosis of ZE was based on a combination of persistent gastric ulcerations in the presence of elevated serum gastrin, gastric pH < 2, and somatostatin receptor-based imaging, despite our being unable to identify a primary lesion. Our case illustrates the importance of utilizing multiple modalities in establishing a presumptive diagnosis of ZE.Figure 1.: Multiple clean based ulcers in the gastric antrum and prepyloric region.Figure 2.: Persistent clean based ulcerations in the gastric antrum.Figure 3.: Left paraesophageal node uptake (Ga-68 Dotatate- PET/CT).

SALIVARY ADENOID CYSTIC CARCINOMA: AN UNCOMMON SALIVARY-TYPE OF LUNG CANCER

SESSION TITLE: Medical Student/Resident Lung Cancer Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Adenoid cystic carcinoma (ACC) is a rare salivary gland-type lung malignancy with an estimated incidence of 0.04-0.2% [1]. Tumors typically occur in the major airways and may have submucosal invasion [2]. Common presenting symptoms include chest pain, hemoptysis, and dyspnea. We report a patient with non-specific chest pain found to have primary ACC of the lung. CASE PRESENTATION: A 55-year-old female non-smoker with history of hypertension and diabetes presented with worsening headache, neck, chest, and back pain following a motor vehicle accident four days prior. She further clarified that she had been experiencing left-sided chest pain radiating to her left shoulder for one year. Physical examination was remarkable only for midline neck and back tenderness. Initial labs were unremarkable. Chest radiography identified a left sided suprahilar opacity. This prompted a computed tomography (CT) scan of her chest which demonstrated a 2.9 x 2.3cm left sided suprahilar mass with splaying of the underlying vascular structures [Figure 1A]. Positron emission tomography CT scan showed avid fluorodeoxyglucose uptake in the left upper lobe [Figure 1B]. Bronchoscopy was performed which revealed a smooth mass within the left main bronchus that had increased vascularity with narrow band imaging [Figure 2]. Endobronchial biopsies confirmed ACC and prompted referral for a left upper lobe lobectomy. Pathological analysis was consistent with a Grade II, moderately differentiated adenoid cystic carcinoma. Surgical margins and 0/23 lymph nodes were negative for malignancy. She was ultimately staged pT2N0M0 with an R0 resection. On follow-up with hematology-oncology, it was determined that the patient would not require adjuvant chemoradiation. She remains on active surveillance without any evidence of tumor recurrence at 12-month follow-up. DISCUSSION: Diagnosis and staging for ACC requires a combination of radiographic imaging and bronchoscopy with biopsy. Histological sub-types include cribriform, tubular, and solid, the latter being more aggressive [2]. Surgical resection is the cornerstone of management providing the best prognosis. A case series of 26 patients who underwent R0 surgical resection of primary ACC observed an overall survival rate of 91.7% at 5-years [3]. A similar benefit was also seen with adjuvant radiotherapy in R1 resections. In those who are not surgical candidates, survival is 0% at 5-years. In non-surgical patients, chemoradiation is often ineffective as ACC responds poorly to currently available chemotherapeutics. CONCLUSIONS: ACC is an uncommon type of lung cancer. Tumors have a high likelihood of submucosal extension and local recurrence. Complete surgical resection offers the best prognosis. In contrast, chemoradiation has a limited role in non-surgical candidates. Reference #1: W. D. Travis, L. B. Travis, and S. S. Devesa, “Lung cancer,” Cancer, vol. 75, no. 1 S, pp. 191–202, 1995, doi: 10.1002/1097-0142(19950101)75:1+<191::AID-CNCR2820751307>3.0.CO;2-Y. Reference #2: H. Inoue, A. Iwashita, H. Kanegae, K. Higuchi, Y. Fujinaga, and I. Matsumoto, “Peripheral pulmonary adenoid cystic carcinoma with substantial submucosal extension to the proximal bronchus,” Thorax, vol. 46, no. 2, pp. 147–148, 1991, doi: 10.1136/thx.46.2.147. Reference #3: M. M. Hu, Y. Hu, J. B. He, and B. L. Li, “Primary adenoid cystic carcinoma of the lung: Clinicopathological features, treatment and results,” Oncol. Lett., vol. 9, no. 3, pp. 1475–1481, Mar. 2015, doi: 10.3892/ol.2015.2859. DISCLOSURES: No relevant relationships by Ethan Karle, source=Web Response No relevant relationships by Armin Krvavac, source=Web Response No relevant relationships by Michael Nance, source=Web Response No relevant relationships by Tarang Patel, source=Web Response

Extensive Extramedullary Hematopoiesis in Thalassemia

We report the case of a 45-year-old man with thalassemia major referred for a bone scan as a workup for generalized bone pain. Tc-MDP SPECT CT showed multiple elongated soft tissue masses along the inner aspects of ribs and along both sides of dorsal spine with calcification and mild tracer uptake. There was also a large lobulated presacral soft tissue mass displacing the bladder and involving the adjacent pelvic bone. Biopsy of mildly avid tracer uptake in pelvic soft tissue mass was extramedullary hematopoiesis confirmed by biopsy.

MO055STABLE CALCIUM ISOTOPES: A NOVEL BIOMARKER OF BONE MINERAL CONTENT IN PATIENTS WITH CHRONIC KIDNEY DISEASE

Abstract Background and Aims In CKD dysregulated calcium (Ca) homeostasis is common and causally associated with reduced bone mineral density (BMD) and vascular calcification. Currently available radiological measures and biomarkers do not allow accurate evaluation of BMD. The aim of our study was to determine the sensitivity and specificity of stable Ca isotopes in determining bone mineral content. Method We measured stable Ca isotopes 44Ca and 42Ca by plasma-ionization mass-spectrometry in blood and urine. The relationship between bone Ca gain and loss is calculated using a compartment model based on Ca kinetics, and expressed as δ44/42Ca. Ca absorption from bones increases δ44/42CaBlood and δ44/42CaUrine, and resorption decreases these fractions. 104 children in CKD4-5 and on dialysis (CKD4-5D), 40 matched controls and 100 adults underwent Ca isotope measurement, bone biomarkers, dual energy x-ray absorptiometry (DXA) and tibial peripheral quantitative CT scan (pQCT), an accurate measure of cortical BMD. Results In healthy children the δ44/42CaBlood and δ44/42CaUrine were higher than in adults (p&amp;lt;0.0001), reflecting avid Ca uptake during bone formation. Since urinary Ca excretion is impaired in CKD, δ44/42CaBlood was higher and δ44/42CaUrine lower in children with CKD4-5D compared to controls (p&amp;lt;0.001 for both); Figure 1. In CKD2-5D δ44/42CaBlood positively correlated with cholecalciferol (p=0.01) and alfacalcidol (p=0.002) doses, implying increased bone Ca uptake when Ca bioavailability is increased. δ44/42CaBlood positively correlated with biomarkers of bone formation (alkaline phosphatase, p=0.05) and negatively with bone resorption markers (PTH, p=0.013; TRAP5b, p&amp;lt;0.001 and CTX, p=0.006). δ44/42CaBlood positively correlated with tibial cortical BMD-Z-score (p=0.006, R2=0.39), and DXA hip BMD-Z-score (p=0.02). On multivariable linear regression analysis significant and independent predictors of tibial cortical BMD-Z-score were δ44/42CaBlood (β=0.68, p=0.006) and PTH (β-0.39, p=0.04), together predicting 67% of the variability in BMD. Conclusion Ca isotope ratios provide a novel, non-invasive method of assessing bone mineralization. Further studies are in progress to define optimal levels of δ44/42CaBlood that can guide safe and effective treatment to prevent Ca deficiency or overload.

Metformin Biodistribution: A Key to Mechanisms of Action?

Metformin has undisputed glucose-lowering effects in diabetes and an impressive safety record. It has also shown promising effects beyond diabetes, and several hundred clinical trials involving metformin are currently planned or active. Metformin targets intracellular effectors, but exactly which remain to be established, and in an era of precision medicine, an incomplete understanding of mechanisms of action may limit the use of metformin. Distribution of metformin depends on specific organic cation transporter proteins that are organ- and species-specific. Therefore, target tissues of metformin can be identified by cellular uptake of the drug, and exploring the biodistribution of the drug in humans becomes an attractive strategy to assist the many investigations into the mechanisms of action of metformin performed in animals. In this review, we combine the emerging evidence from the use of 11C-labeled metformin in humans to discuss metformin action in liver, intestines, and kidney, which are the organs with the most avid uptake of the drug.

MON-509 RET Mutations in the MEN1 Syndrome: Is It an Innocent Bystander?

IntroductionMENIN and RET mutations in MEN1 families, are rare, and, when they co-exist either mutation may predominate the clinical picture.We report a family, with both mutations, and, suspect that the RET mutation may not be an innocent bystander.Clinical CasesGM (36M): 2009: Presented with skin lesions and a lactotroph adenoma causing chiasmal compression. Treatment: Hypophysectomy and Cabergoline. This resulted in restoration of sexual function and fertility.2013: Developed hyperparathyroidism [Calcium 10.6mg% (8.5-10.5); PTH 610pg/ml (10-65); MIBG Scan: parathyroid adenomas]. Treatment: Subtotal parathyroidectomy with allotransplant.2015: Developed Zollinger-Ellison Syndrome [multiple gastric ulcers; S Gastrin: 516pg/ml; (0-180)]. Treatment: Pantoprazole.MRI Abdomen: Calcific atrophic pancreas and bilateral non-functioning adrenal adenomas.HM (32M): 2008: Skin lesions and Lactotroph adenoma. Treatment with Cabergoline resulted in restoration of sexual function and a reduction in breast and tumour size.2013: Hyperparathyroidism [Calcium 10.9mg%; PTH: 166pg/ml; Calcium excretion: 1160mg/24hrs (100-250); BMD: Osteopenia. MIBG 123 Scan: Avid uptake in Right Inferior parathyroid gland]. He underwent a subtotal parathyroidectomy with allotransplant.2015: Recurrent Hyperparathyroidism (Calcium 10.7mg%; PTH: 116pg/ml; MIBG 123 scan: Hyperfunction of the transplanted gland). Stable on treatment with Cinacalcet.Their mother, AM (42F): 1980: Detected to have a lactotroph adenoma when investigated for primary infertility and galactorrhoea. She was treated with Bromocriptine and delivered the boys in 1980 and 1984 respectively. She had recurrent renal calculi and hydronephrosis (? hyperparathyroidism). She succumbed to renal failure following surgery for a benign pancreatic cystadenoma in 1990.DiscussionWhole exome sequencing of GM and HM showed pathogenic mutations of both, MENIN and RET gene. The precise mutation was a stop gain mutation at exon 3 MENIN.C511T:p.Q171X . They (GM/HM) also harboured a mutation in the RET gene at exon 14 c. G2492T: p.G831V; g. chr10. This may be the first family in which the rare combination of these two mutations has been reported.The genomics and the clinical presentation suggest that the MENIN mutation predominates in the family, but the presence of bilateral adrenal adenomas in GM are significant on account of RET mutation. The latter may be a harbinger of serious disease in the future. The situation is further compounded by the recurrence of hyperparathyroidism in the allograft of HM. This may be caused due to chance or an unknown genetic/ epigenetic phenomenon in the two MEN mutated genes and RNA sequencing of the tumour tissue may explain the genetic phenomenon. The latter two events suggest that the RET mutations in MEN1 may not be an innocent bystander.

SAT-546 Endoscopic Ultrasound-Guided Radiofrequency Ablation (EUS-RFA) as an Alternative to Adrenalectomy for the Treatment of Aldosterone-Producing Adenomas (APAs)

Primary Aldosteronism (PA) carries significant cardiometabolic risk, over and above those attributable to hypertension alone. The Endocrine Society guidelines recommend adrenalectomy in those with unilateral disease. However surgery is likely to become unsustainable in public healthcare systems as more patients are diagnosed with PA. Already, surgery may not be feasible in some patients due to co-morbidities, others are reluctant to have the whole adrenal gland removed when excess aldosterone can be localised to small APA(s) in 1 gland.The FABULAS Study explores if EUS-RFA is a safe alternative to left-sided adrenalectomy (ClinicalTrials.gov ID NCT03405025). This multicentre phase-1 study comprises 3 groups of 10 patients with proven PA and left APAs. Successive groups have an increasing benefit:risk ratio for surgery. The first 4 ablation procedures are assessed by an independent safety committee before progression into the next, overlapping group. The primary outcomes are safety and feasibility of EUS-RFA. Safety is assessed throughout the study, including measures of intra-procedure adrenomedullary activation. Efficacy is evaluated by biochemistry, home / clinic BPs, and quantitative 11C-metomidate PET-CT at baseline and 6 months post-ablation.RFA is performed using a Starmed catheter, small enough to pass through a 19-gauge needle, through the stomach. Ablation has been performed in 6 patients (median age 63-years). Mean tumour size was 17mm (range 12-36mm). Plasma metanephrine levels remained stable during RFA. 2 adverse events occurred within the first 48hours post-ablation: AF in a patient with known paroxysmal AF, and an episode of pyrexia and raised CRP attributed to tissue infarction. Both events were deemed ‘not unexpected’ by the safety committee. Most patients have benefited clinically post-ablation. This is illustrated by a 65-year-old man with previously uncontrolled hypertension despite 4 antihypertensive medications, including spironolactone. Baseline aldosterone/renin ratio (ARR) was >200 (PA likely if ARR>60). PET CT revealed a 15mm left adrenal nodule with avid metomidate uptake and an SUVmax ratio of 1.92 (SUVmax ratio >1.25 suggestive of unilateral disease). He underwent uneventful EUS-RFA. 6 months post-ablation his ARR has normalised to 26. On repeat PET CT the metomidate avid adenoma is no longer hot, with a drop in both the SUVmax measured over the APA (31 pre-, and 5 post-ablation) and a reduction in the SUVmax ratio to 1.04. Most importantly, his home BP averages 124/83mmHg and he is thrilled to be off all treatment.Retrospective reports exist of successful percutaneous and retroperitoneal RFA of APAs. FABULAS is the first prospective study, using a minimally invasive, endoscopic route. If proven to be safe and effective EUS-RFA will open the doors for more patients to receive definitive treatment, potentially even those with bilateral disease.

SUN-474 An Unusual Case of Poorly Differentiated Thyroid Carcinoma with an Excellent Prognosis

Background: Poorly differentiated thyroid carcinoma (PDTC) is a rare and aggressive subtype with morphological/behavioral features between differentiated thyroid carcinoma (DTC) and anaplastic thyroid carcinoma (ATC). Clinical case: A 43-year-old female presented with 3 cm right thyroid mass noted on US neck. FNA biopsy showed undifferentiated carcinoma, large cell type. Additional immune-stains were suggestive of ATC. Pre-surgery non-stimulated thyroglobulin (NSTG) was 311 (RR 0–55 ng/dl). Pathology post-total thyroidectomy with bilateral level VI lymph node dissection showed a 3.2 x 2.5 x 2.5 cm carcinoma with vascular and capsular invasion. Most of the mass consisted of very atypical pleomorphic cells, mitosis was difficult to find. The tumor did not show the widely invasive-destructive pattern commonly seen in ATC. An adjacent differentiated component showed predominantly follicular pattern and was described as dedifferentiated follicular carcinoma. All lymph nodes were negative for metastatic disease. Post-surgery NSTG was <0.2 (RR <0.1ng/ml as athyreotic), stimulated TG was 2.22 with negative TG antibodies. Four months later, she received 193.5 mCi radioactive iodine (RAI) therapy. The post-therapy scan showed no Iodine-131 avid uptake in neck or distant metastasis. Neck imaging and TG levels done periodically showed no structural or biochemical evidence of recurrence. Currently the patient is cancer-free for 14 years since diagnosis with no need for additional therapies. Discussion: PDTC accounts for 1–15% of all thyroid cancers. Although PDTC is rare, it is a clinically significant histological diagnosis as it represents the main cause of death from non-anaplastic follicular cell-derived thyroid carcinoma. The Turin proposal published in 2007 suggested three criteria for the diagnosis of PDTC which included the pattern of growth and high-grade features. PDTC presents more frequently with locally invasive extra-thyroidal disease, metastasis to regional lymph nodes and distant organs compared to DTC. Despite the capacity to have RAI uptake, there has been no evidence of significant improvement in survival due to tumor heterogeneity in differentiation. Recent data suggest that age more than 45 years, tumor size more than 4cm, extra-thyroidal extension, higher pathological T stage, positive margins, and distant metastasis predict worse prognosis. Conclusion: Our patient showed an excellent response to therapy in spite of having PDTC with positive margins. We hypothesize that this could be likely due to young age at the time of diagnosis, early detection of tumor while it was localized in the thyroid without distant metastasis as well as heterogeneity in the tumor with differentiated cells that are responsive to RAI. We conclude that with early detection, timely surgery, and adjuvant therapy, excellent prognosis can be achieved in patients with PDTC.