MIBG Research Articles

Liver metastasized pancreatic neuroendocrine tumor in a 17-year-old female: A case report.

Pancreatic neuroendocrine tumors (PNETs) are rare and often misdiagnosed due to their vague symptoms and tumor heterogeneity. Early detection using computed tomography (CT) is essential, particularly in regions without access to advanced diagnostic tools like immunohistochemistry and genetic testing. Neuroendocrine tumors (NETs) are rare tumors in adults and extremely rare in the pediatric population, as pancreatic NETs (pNETs) have an incidence rate of <0.1 per million. We present a case of a 17-year-old female with a liver metastasized pNET. A 17-year-old female with a history of intermittent abdomen-back pain presented to the clinic with severe upper abdominal pain radiating to the shoulder. The routine tests were normal. An ultrasound showed multiple lesions in the liver, which were confirmed by a computed tomography (CT) that uncovered a pancreatic lesion too. A liver biopsy proved it was a metastasized pNET with positive NET markers on IMC staining. The metaiodobenzylguanidine (MIBG) scan flared the liver lesion. The patient was started on Octreotide long-acting release (LAR) 30 mg once monthly. The rarity of these tumors makes their diagnosis difficult, but they should not be omitted and must be considered when there are long-lasting symptoms that are not compatible with common illnesses. These tumors are curable in their early stages.

A New Perspective in Diagnosis of Neuroendocrine Tumors and Pseudo Pheochromocytomas, Understanding the Biology Behind a Mislabeled Medical Terminology

Recently the incidence of undiagnosed hypertension that does not fit into either category of essential hypertension or secondary hypertension is becoming largely increased. Most of these cases are attributed to anxiety or forms of panic attacks associated with high blood pressure. Some in fact are lethal yet clinicians have been challenged to know the real cause of the disease. The term pseudopheochromocytoma widely used for patients who have typical presentation of pheochromocytoma but yet no concrete evidence of disease manifested in their imaging or lab reports to suggest increased production of adrenaline or neurepinephrine, as seen in typical pheochromocytomas. These patients suffer from life threatening attacks of hypertension, yet the only medical revenue offered are anxiolytics, or tricyclic antidepressants. Here we review a case of suspected pheochromocytoma and we present a novel theory about the real player behind all cases of pseudopheochromocytomas. Since in contrast to all other tumors, performing a tissue biopsy is detrimental in the case of pheochromocytomas, and therefore no one logically considers a tissue biopsy for adrenal gland, liquid biopsy( NETest by WREN Laboratory) is a great substitute with high accuracy to replace the tissue biopsy. We conclude that performing liquid biopsy on all cases of pseudopheochromocytoma is essentially life saving and can lead the clinician to appropriate course of action, when the other labs and functional imaging are inconclusive or negative. This is the very perfect example of why the traditional thinking of required presence of metanephrines in urine or blood, and nuclear studies(Dotetate scan/ Octrascan/ MiBG scan, etc…) for diagnosis of pheochromocytoma and surgical interventions depending on such tests is outdated.

The relationship between lung MIBG uptake and clinical response to renal denervation

Abstract Background Renal denervation (RDN) reduces the sympathetic overdrive and can optimize blood pressure control in patients with difficult-to-treat hypertension (DTH). However, a substantial proportion of patients undergoing RDN do not show a clinical response to the procedure, making it critical to identify novel and more accurate predictors. The metaiodobenzylguanidine (MIBG) scintigraphy allows non-invasive assessment of sympathetic nerve activity. Yet, studies evaluating the heart and kidney MIBG uptake as predictors of clinical response to RDN provided conflicting results, and a comprehensive evaluation of the MIBG uptake in different organs of DTH patients undergoing RDN is lacking. Purpose To explore if a more comprehensive evaluation of MBG uptake in the kidneys, heart and lungs can predict the clinical response to RDN. Methods Eighteen patients with DTH underwent evaluation of their clinical and pharmacological history, office and ambulatory BP values and levels of cardiovascular risk factors. A rest echocardiography, carotid vascular ultrasound and MIBG scintigraphy were also performed before RDN. The patient’s pharmacological history and office and ambulatory BP values were re-evaluated after 3 months from RDN. We considered responders (R) those subjects with a significant reduction of the office BP values on stable BP-lowering treatment or a reduced burden of BP-lowering medications while maintaining optimal control of the office BP. Results Ten patients could be classified as R (1 woman, mean age 49±10 years), while 7 were non-responders (NR, 2 women, mean age 53±8 years). The reduction in office systolic and diastolic BP (baseline vs 3 months) was significantly larger in R vs NR (p=0.01 for both). The burden of BP-lowering medications after the procedure was reduced by 39% in R, compared to 2% in NR (p&amp;lt;0.01). Responders had a higher baseline HR and prevalence of carotid atherosclerosis than NR (p&amp;lt;0.05 for both). In early MIBG acquisitions, the lung/mediastinum ratio on both sides showed higher MIBG uptake in R vs NR (p&amp;lt;0.05). There was a higher MIBG uptake in the right vs. left lung in the whole population and in R vs NR. In late acquisitions, only the left side showed a significant difference between R and NR (p&amp;lt;0.05). The associations between the lung/mediastinum ratio MIBG uptake and response to RDN remained significant after adjusting for the baseline clinical predictors of the RDN response. All other MIBG scintigraphy parameters were similar between groups. Conclusions Our results suggest that RDN might be less effective in patients with an advanced burden of hypertension-mediated target organ damage and confirm a higher HR as a reliable predictor of the clinical response to the procedure. We also document a novel association between the lung/mediastinum ratio MIBG uptake and response to RDN that, if confirmed in future studies, might provide a novel marker to improve the selection of patients undergoing RDN.

Rationale for irradiation of persisting oligo-skeletal metastases to improve survival of metastatic neuroblastoma patients with a poor response to chemotherapy: A retrospective study.

Persistent metaiodobenzylguanidine (mIBG)-positive skeletal metastases post induction in high-risk neuroblastoma correlate with a poor outcome. The aim of this study was to investigate the potential rationale for a prospective randomized study evaluating the impact on event-free survival of the irradiation of residual oligo-skeletal metastases. Patients over 1year with a stage M neuroblastoma treated between 2000 and 2020 at Gustave Roussy were identified. Patients with a positive mIBG scan at diagnosis and persistent skeletal metastases after high-dose chemotherapy (HDC) were included. Data were retrospectively collected and mIBG scans reviewed by two nuclear medicine physicians. Persistent skeletal uptake after HDC was observed in 30/201 patients (15%). Four patients reached a complete response at the end of maintenance treatment and did not relapse (median follow-up [FU] 8years [1.8-11.8]), while two patients had progressive disease during maintenance. Among the 24 patients with persistent skeletal uptakes at the end of treatment, seven had a persistent response (median FU 8.2years [4-15.6]). Median SIOPEN (International Society of Paediatric Oncology European Neuroblastoma) scores post consolidation and at the end of treatment were, respectively, 2 [1-6] and 2 [0-4] for patients with persistent responses compared to 4 [1-28] and 2 [1-17] for patients with progressive diseases. Median SIOPEN score at progression was 34 [2-56]. Our study underlines that only a minority of patients had persistent skeletal mIBG-positive scans after HDC. Recurrence mainly occurred in disease sites present at diagnosis that cleared with chemotherapy. On-therapy control of the disease is the main challenge. These results highlight the complexity of conducting a randomized study exploring this strategy.

Radioligand therapy in sympathetic-adrenal-medullary axis tumors: state of art and perspectives.

The approval in 2017 by the European Medicines Agency (EMA) and in 2018 by the US Food and Drug Administration (FDA) of radioligand therapy (RLT) led to its wide application in therapeutic management of neuroendocrine neoplasms (NENs). However, the indications are currently limited to certain specific histotypes belonging to the broader NEN's family, mainly advanced well-differentiated gastro-entero-pancreatic NENs. As a consequence, several other tumors of the NEN spectrum that can potentially benefit, due to their biological characteristics, from RLT are still ineligible and can be considered "RLT-orphans". Among those, the subgroup of NENs originating from the sympathetic-adrenal-medullary (SAM) axis can be listed. This paper discusses the state of art and perspectives of the theragnostic applications in pheochromocytomas and paragangliomas, considering both the traditional theragnostic model - with radiolabelled metaiodobenzylguanidine (MIBG) - and the innovative one with radiolabeled somatostatin analogs (SSAs), that will hopefully become available for these patients in the near future.

8355 Pheochromocytoma In The Elderly: A Mini Case Series

Abstract Disclosure: S. Nabi: None. A. Golash: None. P. Panwar: None. G. Powner: None. C. Schiteanu: None. C. George: None. M. Vallabhaneni: None. B.G. Issa: None. A. Clark: None. D. Bailey: None. J. Waldron: None. F.W. Hanna: None. Diagnosis and management of pheochromocytoma in the older population is challenging due to the co-morbidities and general age-related frailty. We present a mini case series of four patients aged 72 to 86 years who presented to our tertiary referral center at the University Hospitals of North Midlands UK, between 2019 and 2022.The case series documents the challenges of managing pheochromocytoma in this population, emphasizing how close monitoring, regular follow ups and collaboration between different members of the multidisciplinary team helped to achieve the desirable outcomes in these cases. Case 1: Adrenal incidentaloma in 84-year-old female. Background of hypertension and diabetes mellitus. History of occasional palpitations. Investigations showed raised plasma and urinary metanephrines. MIBG scan confirmed pheochromocytoma and after adequate alpha and beta blockade underwent successful laparoscopic surgery. No intra or post operative complications and showed good recovery. Discharged on the 5th day post operative. Case 2: 82-year female under cardiology with non-ST elevation myocardial infarction. Background of hypertension, chronic kidney disease and gastroesophageal reflux disease. Initial presentation with shortness of breath, sweating and swelling lower limbs. Normal coronary arteries on angiography, so investigated for possible excess catecholamine production. Had significantly raised 24-hour urinary normetadrenaline. Paraaortic paraganglioma confirmed on MIBG SPECT scan. Initially opted for medical treatment however quality of life worsened over the next year and eventually underwent robot assisted excision. Procedure was uneventful with good post-operative recovery. Was able to go home 2 days after the procedure. Case 3: 72-year-old female referred with right adrenal incidentaloma. Background of hypertension, diabetes mellitus, hypothyroidism, asthma, arthritis and Ca breast treated 10 years ago. Results showed raised plasma metanephrines, subsequently, MIBG scan revealed a 3 cm right adrenal nodule with increased uptake. Full alpha and beta blockade achieved before she underwent surgical treatment with no complications. Discharged on the 3rd day post op. Case 4: An 80-year-old male was referred with left adrenal incidentaloma. History of diabetes, chronic kidney disease, ischemic heart disease and heart failure, recent myocardial infarction and atrial fibrillation. Biochemical and radiological investigations confirmed pheochromocytoma. He was started on alpha blockade that proved difficult to achieve due to underlying co-morbidities. The patient needed close monitoring by the endocrine team and was finally established on adequate alpha and beta blockade. Due to significant risks associated with the procedure, the patient decided not to proceed with the surgery and opted for medical management. Remains under active follow up. Presentation: 6/2/2024

8358 A Diagnostic Challenge: Occult Paraganglioma Misdiagnosed as Pheochromocytoma Leading to Unnecessary Adrenalectomy

Abstract Disclosure: A.R. Kasireddy: None. S. Alshami: None. S. Gummalla: None. C. Balasubramaniapandian: None. J.A. Henske: None. A. Albashaireh: None. Background: Pheochromocytomas and paragangliomas are rare neuroendocrine tumors. Catecholamine-secreting paragangliomas, like pheochromocytomas, can present with hypertension, sweating and episodic headaches. Thoughtful consideration must be given to distinguish between the two and potentially avoid a critical misdiagnosis. Case: A 61-year-old woman with hypertension and diabetes presented for evaluation of glomus jugulare discovered on CT of the head during evaluation of worsening hearing loss and tinnitus. She reported a longstanding history of episodic headaches, palpitations, anxiety spells and excessive sweating with more recent onset of ear fullness. When symptoms first presented, she had a left adrenalectomy 3 years prior. CT abdomen at that time showed 1.8 x 2.2 cm left adrenal nodule with a density of 12.2 HU and early contrast washout. Plasma metanephrines were normal but normetanephrines were elevated at 5.1 nmol/L (nl: less than 0.9 nmol/L). 24-hour urine metanephrines were normal but normetanephrines were elevated to 892mcg/24h (nl: 122-676 mcg/24h). MIBG scan was done and showed increased activity in the left adrenal nodule. Decision was made to proceed with left adrenalectomy. Surgical pathology was benign. Present evaluation after discovery of the glomus tumour with worsening symptoms showed normal plasma metanephrines, elevated plasma normetanephrines at 1529.9 pg/ml (0- 285.2 pg/ml), elevated plasma norepinephrine at 3280 pg/ml (0-874 pg/ml), with normal dopamine and epinephrine levels. CT head showed a 3 x 2.7 x 2.1 cm lytic destructive mass within the petrous temporal bone at the left skull base containing multiple internal calcifications. Given the lab and imaging findings, paraganglioma was diagnosed. Genetic testing revealed SDHB mutation. Neurosurgery consultants determined that the tumour was not amenable to resection. She was treated with radiation therapy, alpha blockade, and close blood pressure monitoring. Discussion: This case highlights the importance of reviewing the degree of hormonal elevations as well as the pattern of elevation to obtain a correct diagnosis. Paragangliomas commonly secrete normetanephrines rather than metanephrines and are often not immediately localized. Understanding the most likely genetic mutations when a paraganglioma is suspected can direct appropriate choice of radionuclide scanning agents. In this case, an earlier diagnostic scan may have prevented unnecessary adrenalectomy and facilitated earlier discovery of the paraganglioma. Presentation: 6/2/2024

12394 "Sugar And Tumors: A Case Report On New-onset Diabetes In Metastatic Pheochromocytoma With Elevated Dopamine Levels"

Abstract Disclosure: B. Agrawal: None. V. mehta: None. R. naseem: None. M. Renzu: None. R. rashid: None. Introduction: Metastatic pheochromocytoma is a rare neuroendocrine tumor with potential complication of new-onset diabetes mellitus (DM). We present a case highlighting the challenges in managing a patient with metastatic pheochromocytoma and concurrent DM. Case presentation: A 66-year-old male with a history of hypertension and gout initially presented in 2010 with an adrenal mass, later identified as pheochromocytoma and resected. In 2018, he presented with bilateral leg pain, revealing metastatic disease-causing spinal cord compression along with metastatic lung nodules and metastasis in adrenalectomy bed. Despite interventions including T6,7,8 laminectomy in 2020 and radiation therapy, metastases persisted. In 2024, he presented with polyuria, polydipsia, and hyperglycemia (blood glucose &amp;gt;500 mg/dL). Laboratory findings showed elevated a1c of 15 in addition to elevated normetanephrines, metanephrines, and dopamine with levels of 3880, 48 and 488 respectively. He was diagnosed with new-onset DM and started on insulin therapy in addition to metformin and jardiance. Discussion: Secondary diabetes mellitus (DM) in secretory pheochromocytoma occurs in approximately 50% of cases, manifesting from mild insulin resistance to severe presentation like DKA. Epinephrine-secreting tumors contribute to glucose intolerance by activating beta receptors, thereby stimulating gluconeogenesis. Patients with higher levels of epinephrine and preoperative glucose intolerance were more prone to developing postoperative hypoglycemia, requiring close monitoring during the postoperative period. Additionally, research by DiSalvo et al. Epinephrine-secreting tumors have a more significant impact on hyperglycemia by impairing insulin secretion and stimulation GLP-1. Tumor resection has been found to be more effective effective in restoring normal glucose homeostasis in these patients. Dopamine-secreting pheochromocytomas are rare neoplasms characterized by the presence of immature catecholamine vesicles that inhibit dopamine conversio owing to localized dopamine beta hydroxylase. Typically presenting around the age of 48, these tumors often lack excess catecholamines, leading to atypical symptoms such as local discomfort or pain from tumor compression. These neoplasms are less detectable on metaiodobenzylguanidine (MIBG) scans, necessitating positron emission tomography (PET) for accurate diagnosis. Surgical resection is the treatment, with preoperative management involving metyrosine instead of alpha blockers. These tumors are frequently diagnosed late, often in a malignant stage, contributing to poor prognosis Conclusion: Overall, understanding the complex interplay between catecholamines and glucose metabolism is crucial for the comprehensive management of patients with pheochromocytoma and secondary DM. Presentation: 6/1/2024

12325 Adrenocortical Carcinoma Masquerading As Pheochromocytoma In A Patient With Congenital Adrenal Hyperplasia

Abstract Disclosure: E.M. Niedzialkowska: None. A.A. Banka: None. Introduction: The development of adrenocortical carcinoma (ACC) in patients with congenital adrenal hyperplasia (CAH) is rare. The patients with CAH are at increased risk of adrenal tumors which is attributed to ACTH stimulation of adrenal gland if the disease is not appropriately treated. ACC cases mistaken for pheochromocytomas have been reported in the literature and are attributed to the variety of immunohistochemical markers expressed by the tumors. Case description:59 y.o female with salt-wasting CAH diagnosed at the age of 2 (21-hydroxylase deficiency) on hydrocortisone supplementation reported to the hospital due to episodes of sweating, tachycardia and hypertension. Work up revealed mildly elevated plasma normetanephrine 1 nmol/l (N &amp;lt;0.9), urine normetanephrine 1762 mcg (N&amp;lt;899), VMA 11.2 mcg/24hr (N 3.3-7.2). MRI of the abdomen revealed 2 left adrenal masses of 3.7 and 2.4 cm, right adrenal gland hyperplasia and low T1 and T2 enhancement. I-123 MIBG revealed increased activity and thickness of the right adrenal gland and no significant uptake on the left with nodular masses. The patient underwent left adrenalectomy with pathological report consistent with pheochromocytoma due to positive chromogranin and synaptophysin staining and moderate Ki activity. A year later follow up imaging showed an enhancing mass up to 7 cm at the suprarenal fossa invading the left kidney that was positive for nodular adrenocortical hyperplasia per pathology report. The patient continued to have elevated 17-OH- progesterone (2740 ng/l, N &amp;lt;51) despite compliance with her steroid therapy and suppressed ACTH. She underwent mass resection along with nephrectomy, splenectomy, partial colectomy and partial pancreatectomy. Pathology report was positive for adrenocortical carcinoma (positive chromogranin, synaptophysin, CAM 5.2, polycystic cytokeratin, Ki positive in greater than 10% of the tumor cells) with renal and regional lymph node invasion and colonic metastases. The patient was started on mitotane therapy but a year later PET scan was positive for liver and omental metastases and was subsequently started on carboplatin/etoposide followed by streptozocin/adriamycin with initial good response, however repeat PET a year afterwards showed progression of the liver lesions, metastases to omentum and metastatic lesion to calvarium and the patient expired soon afterwards. Discussion: CAH predisposes patients to adrenal tumors which is attributed to increased ACTH stimulation of the adrenal gland but ACC in this population is extremely rare. In very rare cases ACC can present clinically as pheochromocytoma with elevated catecholamine levels and positive synaptophysin and chromogranin staining which poses a clinical challenge. Both CAH and ACC can lead to increased androgen levels and ACTH levels can help to differentiate the origin of the hyperandrogenemia. Presentation: 6/2/2024

6695 When Pheochromocytoma Presents As Acute Renal Failure, With Complete Resolution, A Case Report

Abstract Disclosure: U.A. Siddiqui: None. D. Deyar: None. D. Bondarenko: None. M. Ahmad: None. K.K. Lessard: None. Pheochromocytomas and paragangliomas (PPGL), are rare neuroendocrine tumors (0.66/ 100,000 cases), often characterized by paroxysmal hypertension and associated symptoms. While cardiac complications have been well-documented in the literature, there is limited information regarding acute renal failure. We explore a unique case of pheochromocytoma presenting initially with hypertensive crisis, but also with an unexpected journey into acute renal failure and subsequent recovery. 62-year-old hispanic male without known past medical history presents to the emergency department with chest pain, epigastric pain, dyspnea, and emesis. He was tachypneic, febrile (101°F), hypoxic (83% on room air), and profoundly hypertensive (188/112 mmHg). CT scan showed pneumonia as well as a 7cm complex mass within the left adrenal gland. Admitting labs showed metabolic acidosis, acute kidney injury (Cr 2.52mg/dL) and elevated troponins. Echocardiogram showed a reduced ejection fraction 45-50% and coronary angiography showed mild nonocclusive coronary artery disease. MRI visualized a solid left adrenal mass measuring 6.8cm with enhanced, mixed T1/T2 signaling and drop out inconsistent with adenoma. Adrenal labs revealed ACTH 125 pg/mL (9-46 pg/mL) and cortisol 27mcg/dL free metanephrine (MN) 1,422 pg/mL (&amp;lt;57 pg/mL), and free normetanephrine (NMN) &amp;gt;20,000 pg/mL (&amp;lt;148 pg/mL), total free MN + NMN &amp;gt;40,000 pg/mL (&amp;lt;205 pg/mL). Preoperative MIBG scan showed increased tracer activity of the left adrenal consistent with pheochromocytoma. Alpha blockade was performed using doxazosin and carvedilol was continued. Unfortunately, he developed oliguria and rising creatinine ( 7.4mg/DL). Kidney biopsy showed findings of acute tubular necrosis and mild fibrosis. Hemodialysis was initiated, receiving 12 sessions prior to undergoing open left adrenalectomy with mass resection on day 22 of admission. Post-operative blood pressure was managed with volume re-expansion and tapering of alpha blocker. Within 72 hours, renal function fully recovered and dialysis was discontinued. Follow up metanephrines are within normal limits and genetic testing results remain pending. Cases of acute renal failure and PPGL are scarce, and this case report contributes to the topic. Mortality in p is usually due to cardiovascular complications such as stroke, cardiomyopathy, and dysrhythmia [2]. Renal complications result from hypertensive nephrosclerosis or nephrotic syndrome. To date, only one case report from 1961 exists on acute tubular necrosis and PPGL [3]. We present an interesting case of pheochromocytoma complicated by hypertensive crisis and acute renal failure requiring dialysis. Resection of the pheochromocytoma normalized renal function. This demonstrates the importance of timely resection of the tumor and meticulous blood pressure management to ensure optimal outcomes. Presentation: 6/2/2024

Urodynamic study and its correlation with cardiac meta-iodobenzylguanidine (MIBG) in body-first and brain-first subtypes of Parkinson's disease.

Lower urinary tract symptoms (LUTS) are frequently observed in patients with Parkinson's disease (PD), but the underlying mechanism remains elusive. The concept of "body-first" and "brain-first" subtypes in PD has been proposed, but the correlation of PD subtype with LUTS remains unclear. We aimed to investigate the disparities in urological dysfunctions between body-first and brain-first subtypes of PD using urodynamic studies (UDS). We reviewed patients with PD (disease duration <3 years) who had undergone UDS and completed urological questionnaires (Overactive Bladder Symptom Score [OABSS] and International Prostate Symptom Score [IPSS]) and a voiding diary. Patients were categorized as having body-first or brain-first PD based on cardiac sympathetic denervation (CSD) using cardiac meta-iodobenzylguanidine (MIBG) uptake and the presence of rapid eye movement sleep behavior disorder (RBD), assessed using a questionnaire (PD with CSD and RBD indicating the body-first subtype). A total of 55 patients with PD were categorized into body-first PD (n = 37) and brain-first PD (n = 18) groups. The body-first PD group exhibited smaller voiding volume and first desire volume (FDV) than the brain-first PD group (p < 0.05 in both). Also, the body-first PD group had higher OABSS and IPSS scores, and higher prevalence of overactive bladder diagnosed by OABSS, compared to the brain-first PD group. In multiple linear regression, cardiac MIBG uptake was positively correlated with FDV and voiding volume andnegatively correlated with OABSS and IPSS (p < 0.05 in all). Patients with the body-first PD subtype exhibited more pronounced overactive bladder symptoms and impaired storage function in the early stage of disease. Additionally, cardiac MIBG was significantly associated with urological dysfunction.

Thyroid dysfunction in patients diagnosed with neuroblastoma who received MIBG scans

Thyroid dysfunction in patients diagnosed with neuroblastoma who received MIBG scans

Difference in gut microbial dysbiotic patterns between body-first and brain-first Parkinson's disease

BackgroundThis study aims to identify distinct microbial and functional biomarkers characteristic of body-first or brain-first subtypes of Parkinson's disease (PD). This could illuminate the unique pathogenic mechanisms within these subtypes. MethodsIn this cross-sectional study, we classified 36 well-characterized PD patients into body-first, brain-first, or undetermined subtypes based on the presence of premotor REM sleep behavior disorder (RBD) and cardiac meta-iodobenzylguanidine (MIBG) uptake. We then conducted an in-depth shotgun metagenomic analysis of the gut microbiome for each subtype and compared the results with those from age- and sex-matched healthy controls. ResultsSignificant differences were found in the gut microbiome of body-first PD patients (n = 15) compared to both brain-first PD patients (n = 9) and healthy controls. The gut microbiome in body-first PD showed a distinct profile, characterized by an increased presence of Escherichia coli and Akkermansia muciniphila, and a decreased abundance of short-chain fatty acid-producing commensal bacteria. These shifts were accompanied by a higher abundance of microbial genes associated with curli protein biosynthesis and a lower abundance of genes involved in putrescine and spermidine biosynthesis. Furthermore, the combined use of premotor RBD and MIBG criteria was more strongly correlated with these microbiome differences than the use of each criterion independently. ConclusionsOur findings highlight the significant role of dysbiotic and pathogenic gut microbial alterations in body-first PD, supporting the body-first versus brain-first hypothesis. These insights not only reinforce the gut microbiome's potential as a therapeutic target in PD but also suggest the possibility of developing subtype-specific treatment strategies.

Long-standing preservation of levodopa response in progressive supranuclear palsy

The clinical and neuropathological characteristics of progressive supranuclear palsy (PSP) with preservation of levodopa (L-dopa) response are described in this report. We present the case of a 73-year-old Japanese man with a 13-year history of dopa-responsive Parkinsonism and abnormalities observed in metaiodobenzylguanidine (MIBG) myocardial scintigraphy, suggesting Parkinson's disease. However, autopsy results revealed PSP pathology, including tuft-shaped astrocytes and globose-type neurofibrillary tangles, without Lewy body pathology. The degeneration was moderately to severely distributed in the globus pallidus, subthalamic nucleus, and substantia nigra, whereas striatal degeneration was mild. These findings suggest an intact response to L-dopa therapy throughout the patient's lifetime. Pathological examination of cardiac sympathetic nerves revealed intact nerves, suggesting functional involvement in the MIBG abnormality. This study provides further evidence of the clinical and pathological heterogeneity of PSP. Homozygosity for both the rs564309-C allele at TRIM11 and the rs2242367-G allele at SLC2A13 might have played a protective role. This case indicates a protracted course-PSP, which may hold promise for future treatments.

Iodine-131 Metaiodobenzylguanidine (MIBG) and NP-59 uptakes in the Rat Normal Tissues: Increase of Cholesterol uptake in Cold-Activated Brown Adipose Tissue

Objective Aim: NP-59 (I-131-6ß-iodomethyl-19-norcholesterol) and MIBG (I-131-metaiodobenzylguanidine) both are useful to detect tumors. There is a great need to understand their distributions in normal organs and tissues as well as ways to reduce normal uptakes in tumor imaging and/or treatment. Activated Brown Adipose tissue (BAT) has been promising for its role in optimal treatment of obesity and hypercholesterolemia. The study of cholesterol uptake in BAT may have a significant impact in managing hyperlipidemia and protecting from atherosclerosis. Materials and Methods: Male Sprague-Dawley rats weighing 250—300 g were used in the study. All animals received 25 µCi of I-131-MIBG or NP-59 by the tail vein and were killed (N = 4 - 6 each) 3, 24 or 48 hours afterwards. For cold stressed animals were kept at 6 – 8 C in a cold room overnight prior to receiving labeled MIBG or NP-59. The animal continued to stay in cold room as compared to room temperature controls. To study the effect of norepinephrine-blocking agent, reserpine (4 mg/kg, IP) was given to rats 4 hours prior to I-131-MIBG infusion. Organs were immediately dissected. Radioactivity was counted and tissue concentrations were expressed as percent kilogram (body weight) dose per gram of tissue (% Kg dose/g). Findings: Higher uptakes of I-131-MIBG were observed in organs rich in sympathetic innervation [BAT (brown adipose tissue), heart and spleen] as compared to liver and muscle. Reserpine reduced uptakes in BAT, heart, adrenals and spleen but not in liver in room temperature controls. BAT, but not in other organs, showed a paradoxical increase in reserpine-treated animal kept in cold room as compared to room temperature controls. NP-59 showed a near 6 folds increase in adrenals from 30 minutes to 48 hours and unchanged in cold stressed animals. The only tissue showed significant increases in NP-59 uptake under cold stress was BAT from 1.84 folds at 30 minutes to 1.44 folds at 48 hours (p&lt;0.05 as compared to room temperature controls). Conclusions: The uptake of MIBG is reduced in organs rich in sympathetic innervation under cold stress, but this reduction is partially blocked by reserpine. Findings may help to improve the efficacy of MIBG as a theragnostic agent. A noteworthy finding is the significant increase in NP-59, a cholesterol analog, in cold-activated BAT. This novel observation could serve as a valuable tool for studying the role of activated BAT in the overall cholesterol metabolism in humans. Furthermore, it presents a potent therapeutic avenue for mitigating hyperlipidemia and providing protection against atherosclerosis.

Impairment of Cognitive Function Increases Mortality Risk in Relation to Cardiac Sympathetic Denervation and Renal Dysfunction in Patients With Systolic Heart Failure.

In contrast to the well-known prognostic values of the cardiorenal linkage, it remains unclear whether impaired cognitive function affects cardiac prognosis in relation to cardiac sympathetic innervation and renal function in patients with heart failure (HF). A total of 433 consecutive HF patients with left ventricular ejection fraction (LVEF) <50% underwent the Mini-Mental State Examination (MMSE) and a neuropsychological test for screening of cognition impairment or subclinical dementia. Following metaiodobenzylguanidine (MIBG) scintigraphy, patient outcomes with a primary endpoint of lethal cardiac events (CEs) were evaluated for a mean period of 14.8 months. CEs were documented in 84 HF patients during follow-up. MMSE score, estimated glomerular filtration rate (eGFR) and standardized heart-to-mediastinum ratio of MIBG activity (sHMR) were significantly reduced in patients with CEs compared with patients without CEs. Furthermore, overall multivariate analysis revealed that these parameters were significant independent determinants of CEs. The cutoff values of MMSE score (<26), sHMR (<1.80) and eGFR (<47.0 mL/min/1.73 m2) determined by receiver operating characteristic (ROC) analysis successfully differentiated HF patients at more increased risk for CEs from other HF patients. Impairment of cognitive function is not only independently related to but also synergistically increases cardiac mortality risk in association with cardiac sympathetic function and renal function in patients with HF.

Substrate binding and inhibition mechanism of norepinephrine transporter.

Norepinephrine transporter (NET; encoded by SLC6A2) reuptakes the majority of the released noradrenaline back to the presynaptic terminals, thereby affecting the synaptic noradrenaline level1. Genetic mutations and dysregulation of NET are associated with a spectrum of neurological conditions in humans, making NET an important therapeutic target1. However, the structure and mechanism of NET remain unclear. Here we provide cryogenic electron microscopy structures of the human NET (hNET) in three functional states-the apo state, and in states bound to the substrate meta-iodobenzylguanidine (MIBG) or the orthosteric inhibitor radafaxine. These structures were captured in an inward-facing conformation, with a tightly sealed extracellular gate and an open intracellular gate. The substrate MIBG binds at the centre of hNET. Radafaxine also occupies the substrate-binding site and might block the structural transition of hNET for inhibition. These structures provide insights into the mechanism of substrate recognition and orthosteric inhibition of hNET.

Imaging adjuvants in pediatric surgical oncology.

Surgery is a crucial component of pediatric cancer treatment, but conventional methods may lack precision. Image-guided surgery, including fluorescent and radioguided techniques, offers promise for enhancing tumor localization and facilitating precise resection. Intraoperative molecular imaging utilizes agents like indocyanine green to direct surgeons to occult deposits of tumor and to delineate tumor margins. Next-generation agents target tumors directly to improve specificity. Radioguided surgery, employing tracers like metaiodobenzylguanidine (MIBG), complements fluorescent techniques by allowing for detection of tumors at a greater depth. Dual-labeled agents combining both modalities are under development. Three-dimensional modeling and virtual/augmented reality aid in preoperative planning and intraoperative guidance. The above techniques show great promise to benefit patients with pediatric tumors, and their continued development will almost certainly improve surgical outcomes.

Trends in analgesia-sedation of pediatric patients receiving I-131 MIBG in the pediatric intensive care unit: A report from the Pediatric Health Information System database.

Children with neuroblastoma receiving I-131 metaiodobenzylguanidine (MIBG) therapy require sedation-analgesia for strict radiation safety precautions during MIBG infusion and clearance. We evaluated the sedation-analgesia trends of patients undergoing MIBG therapy using the Pediatric Health Information System (PHIS) database. Retrospective data from 476 patient encounters from the PHIS from 2010 to 2019. Total 240/476 (50.45%) children evaluated were under 6years of age. Compared to 2010, in 2018 there was a decrease in benzodiazepine infusion use (60% vs. 40%, p<.04), as well as a decrease in use of opiate infusion (35% vs. 25%, p<.001). Compared to 2010, in 2018 we report an increase in the use of ketamine (from 5% to 10%, p<.002), as well as an increase in dexmedetomidine use (0% vs. 30%, p<.001). Dexmedetomidine was the most used medication in the 0-3years age group compared to children older than 3years of age (14.19% vs. 5.80%, p<.001). Opiate was the most used medication in children greater than 3years compared to the 0-3-year age group (36.23 vs. 23.87, p<.05). Using PHIS data, we discovered considerable variability in the medications used for sedation in patients undergoing MIBG therapy. Although benzodiazepines and opioids were the most used agents, there was a trend toward decreasing use of benzodiazepines and opioids in these patients. Furthermore, there has been an increasing trend in the use of dexmedetomidine and ketamine.

1215 Cardiovascular Compromise and Hypertensive Crisis Secondary to Phaeochromocytoma

Abstract Phaeochromocytoma is a rare tumour of the chromaffin cells in the adrenal medulla, which secretes catecholamines. While associated with genetic disorders e.g., MEN-2, they tend to occur sporadically, and are often initially asymptomatic, found incidentally on imaging. Classical symptoms of Phaeochromocytoma include headaches, sweating, and palpitations, with sustained or paroxysmal hypertension which is refractory to a cocktail of antihypertensives. A variety of presentations have been reported in the literature including, but not limited to colitis, intracerebral haemorrhage, and PRES syndrome. We present a case of a 64-year-old man with an incidental left adrenal nodule. This radiologically indeterminate lesion was initially asymptomatic. Secretion studies revealed elevated metadrenaline levels, and an MIBG scan with positive avidity unveiled the lesion's pheochromocytoma nature. Whilst awaiting surgical intervention, the patient required emergency admission with a hypertensive crisis, presenting with left-sided flank pain and a blood pressure peaking at 220mmHg systolic. ECG findings were consistent with a myocardial infarction-like picture, and echocardiogram demonstrated regional wall motion abnormalities. CT coronary angiography revealed no significant coronary arterial disease – confirming that the patient’s presentation was in fact secondary to the pheochromocytoma. Pre-operative optimization is crucial for safe surgery. After the crisis, surgery was delayed by 6 weeks for cardiac rehabilitation. The patient was admitted a week before the procedure for optimal haemodynamics. Adrenalectomy proceeded as planned after alpha-blockade. A structured endocrine surgery clinic follow-up was established to assess the patient's ongoing recovery, and cardiovascular status. This case highlights cardiovascular implications of phaeochromocytoma, stressing a multidisciplinary approach for hypertensive crises and optimising outcomes.