Peptide Receptor Radionuclide Therapy Research Articles

Treatment of MiNEN with peptide receptor radionuclide therapy

Treatment of MiNEN with peptide receptor radionuclide therapy

Management of carcinoid flare events following peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumours (NET): our experience at the christie NHS foundation trust

Management of carcinoid flare events following peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumours (NET): our experience at the christie NHS foundation trust

Toxicity manifestations encountered in peptide receptor radionuclide therapy setting.

Peptide receptor radionuclide therapy (PRRT) has demonstrated immense promise as a treatment for patients with neuroendocrine tumors (NET) who have somatostatin receptor (SSTR) expression. PRRT significantly reduces tumor growth, stabilizes the disease, and prolongs survival in a significant percentage of patients with metastatic/advanced NET. It produces an important beneficial effect on the quality of life (QOL) and effectively alleviates symptoms in patients with NET. Overall, PRRT is typically well-tolerated and most of the side effects are usually transient and subside on their own. It is, however, crucial to be cognizant of the potential toxicities associated with this treatment. This awareness will enable physicians to promptly detect, effectively manage, and prevent these toxicities by identifying high-risk factors in NET patients. This review provides an in-depth overview for clinicians managing NET about the toxicity of PRRT. The toxicities are stratified into acute, subacute, and long-term based on their onset following PRRT. Potential high-risk factors in order to treat effectively and prevent these toxicities in NET patients are presented including the management strategy. This review also discusses novel insights, perspectives, and recent advancements in predicting, preventing, and managing toxicity associated with PRRT, while offering prospective future research directions to minimize clinical toxicity and maximize the therapeutic benefits of PRRT as a treatment strategy for NET patients.

Somatostatin receptor-linked α-particle therapy in neuroendocrine tumours.

The incidence and prevalence of neuroendocrine tumours (NETs) are on the rise, but to date, only complete surgical resection is curative. Among the various therapeutic options for metastatic disease, peptide receptor radionuclide therapy (PRRT), linking a radioactive moiety to an octreotide derivative, has been shown to be highly efficacious and a well-tolerated therapy, improving progression-free survival and prolonging overall survival. Nevertheless, complete responses are rare, and the current β-particle emitters have non-optimal radiobiological properties. A new generation of α-particle-emitting radionuclides is being developed, with the advantages of very high energy and a short path length. We survey the most recent developments in this field, summarising the result of currently performed studies in this potentially ground-breaking novel form of therapy for NETs.

Assessment of response to PRRT including anatomical and molecular imaging as well as novel biomarkers.

Peptide receptor radionuclide therapy (PRRT) is an effective treatment for both oncological and hormone control and is a widely accepted standard of care treatment for patients with neuroendocrine neoplasms (NEN). Its use is anticipated to increase significantly, and this demands accurate tools and paradigms to assess treatment response post PRRT. This article outlines the current role and future developments of anatomical, molecular imaging and biomarkers for response assessment to PRRT, highlighting the challenges and provides perspectives for the need to focus on a multimodality, multidisciplinary and individualised approach for patients with this complex heterogeneous disease.

Peptide Receptor Radionuclide Therapy Improves Survival in Patients Who Progress After Resection of Gastroenteropancreatic Neuroendocrine Tumors.

Peptide receptor radionuclide therapy (PRRT) is an effective treatment for advanced gastroenteropancreatic (GEP) neuroendocrine tumors (NETs). We investigated a 2-decade experience with PRRT to determine whether PRRT confers a survival advantage to patients who progress after surgery versus other therapies. We identified patients from our clinic who had resection/cytoreduction of GEP-NETs, then disease progression by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. The Kaplan-Meier method assessed progression-free survival (PFS) and overall survival (OS), calculated from progression after surgery (no-PRRT group) or the start of PRRT. Cox regression with time-dependent covariates controlled for immortal time bias and other confounders. Overall, 237 patients progressed after surgery; 95 received PRRT and 142 did not. No differences existed in sex, T or Nstage, tumor grade/differentiation, primary site, or time to progression; 94% of PRRT patients had metastases at diagnosis versus 77% in the no-PRRT group. Median PFS was longer in the PRRT group versus the no-PRRT group (32.4 vs. 11.0 months, p<0.001), as was median OS (49.8 vs. 38.4 months; p=0.009). In subgroup analysis, the PRRT group had improved PFS in small bowel NETs and pancreatic NETs. Time-dependent covariate analysis revealed a lower risk of death associated with PRRT (hazard ratio 0.61, p=0.028) after adjusting for sex, age, Mstage, tumor grade, and primary site. Surgical resection and cytoreduction is an effective treatment for patients with GEP-NETs, but most patients with metastatic disease develop recurrent disease. Surgery followed by PRRT after progression conferred superior PFS and OS over no PRRT/other therapies, and is an effective strategy for managing patients with GEP-NETs.

Peptide Receptor Radionuclide Therapy and clinical associations with renal and hematological toxicities and survival in patients with neuroendocrine tumors: an analysis from two U.S. medical centers

PurposeRenal and hematological toxicity are side effects and dose-limiting factors of Peptide Receptor Radionuclide Therapy (PRRT). We aimed to assess the changes in renal and hematological function and associations with survival in neuroendocrine tumor (NET) patients treated with PRRT.MethodsA retrospective cohort of 448 NET patients treated with either 177Lu-DOTATATE or 90Y-DOTATOC were followed for changes of renal and hematological function. Renal function was assessed by monitoring changes in serum creatinine, blood urea nitrogen and estimated glomerular filtration rate. Hematological function was determined by examining changes in white blood cell counts (WBC), platelet counts, and hemoglobin levels over time. Piecewise linear mixed effect models were applied to model the longitudinal repeated measurements of renal and hematological function. Overall survival (OS) and progression-free survival (PFS) were modelled using Cox proportional hazard regressions.ResultsOf the 448 PRRT treated patients, 335 received 177Lu-DOTATATE (74.78%) and 113 were treated with 90Y-DOTATOC (25.22%). Comparing patients treated with 177Lu-DOTATATE to those treated with 90Y-DOTATOC, renal function did not differ significantly prior to, during or after PRRT. Compared with patients treated with 90Y-DOTATOC, significantly decreased indicators of hematological function were observed in those treated with 177Lu-DOTATATE prior to and during PRRT treatment (WBC: estimate, -0.10, 95% CI, -0.15 to -0.05; P < 0.001; platelet count: estimate, -2.53, 95% CI, -3.83 to -1.24; P < 0.001), and no significant recovery was observed in hematological function post PRRT. Individuals who received 177Lu-DOTATATE tended to have a longer PFS (hazard ratio, 0.47, 95%CI: 0.28–0.79, P = 0.004) compared with 90Y-DOTATOC, but there was no difference in OS.ConclusionThere was no significant renal, but minor hematological toxicity, in patients treated with 177Lu-DOTATATE compared with 90Y-DOTATOC. Compared to 90Y-DOTATOC, 177Lu-DOTATATE appears to enhance PFS, but not OS. Treatment with 177Lu-DOTATATE may necessitate follow-up for hematological toxicity irrespective of other therapies prior to PRRT.

Ablative Dose Y90 Radiation Segmentectomy for Treatment of Neuroendocrine Liver Metastases

PurposeTo assess the safety and efficacy of Y90 radiation segmentectomy (RS) for neuroendocrine tumor liver metastases (NELMs). Materials and MethodsThis single-institution retrospective study included 18 patients with 23 liver tumors not amenable to resection or ablation, who underwent RS between 2009 and 2021. Tumor grades by Ki-67/mitotic indices were Grade I (n=9/23, 39%), Grade II (n=10/23, 45%) and Grade III (n=4/23, 17%). Eleven patients (61%) were previously treated with somatostatin analogs, five (28%) with chemotherapy, and two (11%) with peptide receptor radionuclide therapy. Safety was assessed with pre/post liver chemistries, blood counts and clinical adverse events (AEs) using National Cancer Institute Common Terminology Criteria for AEs v5.0. Tumor response was assessed per Response Evaluation Criteria in Solid Tumors 1.1 and modified RECIST criteria. Kaplan-Meier analysis was used to estimate median overall survival (OS), progression-free survival (PFS), and time to progression (TTP) from the date of Y90. ResultsMedian follow-up was 31.9 months. Grade 1 fatigue was observed in 13/18 patients (72%), with 1/18 patient (6%) experiencing grade 3 fatigue. Three patients (17%) exhibited grade 3 lymphopenia. No other grade 3 or any grade 4 AE was observed. Tumor objective response was achieved in 83% of patients by RECIST size criteria and 100% by mRECIST enhancement criteria. Median OS was 69.4 months (95% CI, 23.1-99.4) and median PFS was 12.2 months (95% CI, 4.6-28.8). Median overall TTP was 13.0 months (95% CI, 4.6-45.1), with median treated tumor TTP not reached. ConclusionY90 RS demonstrates high rates of antitumor response with a favorable toxicity profile and durable OS in the treatment of NELMs.

Metastatic Malignant Paraganglioma of Rare Sites Failed on Conventional Treatments Demonstrating Beneficial Response to 177Lu-DOTATATE PRRT

AbstractThe incidence of paraganglioma (PGL) is rising due to better imaging modalities employed for evaluating incidentaloma and surveillance of the asymptomatic carriers. Benign and malignant PGLs often cannot be reliably diagnosed on histology alone, and the documentation of metastases is important in the diagnosis of malignancy. Advancement in genomics has improved our understanding of PGL. 68Ga-DOTATATE positron emission tomography (PET)/computed tomography (CT) scan shows a significant superior detection rate compared with other conventional functional and anatomical imaging modalities, can detect rare sites of primary disease in PGL, and also aids in patient selection for peptide receptor radionuclide therapy (PRRT). PRRT is increasingly used in metastatic setting with good symptomatic and biochemical response and disease stabilization in metastatic PGL patients. We present a series of three patients with PGLs located in rare primary sites (sigmoid colon, urinary bladder, and carotid body space), which showed recurrence of disease on conventional treatments and developed metastatic disease in the lymph nodes, liver, skeleton, and lungs. PRRT with 177Lu-DOTATATE achieved symptom control, favorable biochemical and imaging responses, and increased progression-free and overall survival rate in the described patients.

Intraarterial Administration of Peptide Receptor Radionuclide Therapy in Patients with Advanced Meningioma: Initial Safety and Efficacy.

Peptide receptor radionuclide therapy (PRRT) is a treatment option for patients with advanced meningioma. Recently, intraarterial application of the radiolabeled somatostatin receptor agonists has been introduced as an alternative to standard intravenous administration. In this study, we assessed the safety and efficacy of intraarterial PRRT in patients with advanced, progressive meningioma. Methods: Patients with advanced, progressive meningioma underwent intraarterial PRRT with [177Lu]Lu-HA-DOTATATE. The safety of PRRT was evaluated according to the Common Terminology Criteria for Adverse Events version 5.0. Treatment response was assessed according to the proposed Response Assessment in Neuro-Oncology criteria for meningiomas and somatostatin receptor-directed PET/CT. Results: Thirteen patients (8 women, 5 men; mean age, 65 ± 13 y) with advanced meningioma underwent 1-4 cycles (median, 4 cycles) of intraarterial PRRT with [177Lu]Lu-HA-DOTATATE (mean activity per cycle, 7,428 ± 237 MBq; range, 6,000-7,700 MBq). Treatment was well tolerated with mainly grade 1-2 hematologic toxicity. Ten of 13 patients showed radiologic disease control at follow-up after therapy (1/10 complete remission, 1/10 partial remission, 8/10 stable disease), and 9 of 13 patients showed good control of clinical symptoms. Conclusion: Intraarterial PRRT in patients with advanced meningioma is feasible and safe. It may result in improved radiologic and clinical disease control compared with intravenous PRRT. Further research to validate these initial findings and to investigate long-term outcomes is highly warranted.

Prognostic value of interim [68Ga]Ga-DOTA-TOC PET/CT in patients with neuroendocrine tumour who underwent peptide receptor radionuclide therapy.

This study evaluated the prognostic value of basal and interim [68Ga]Ga-DOTA-TOC PET/CT in patients with locally advanced or metastatic neuroendocrine tumour (NET) who received peptide receptor radionuclide therapy (PRRT). Patients with NET who received PRRT with [177Lu]Lu-DOTA-TATE at our institution were retrospectively reviewed. Among them, patients who underwent both basal and interim (after two cycles of PRRT) [68Ga]Ga-DOTA-TOC PET/CT were included. Alongside clinicopathologic parameters, PET parameters of maximum standardised uptake value (SUVmax), tumour-to-liver ratio (TLR), whole tumour volume (WTV) and total receptor expression (TRE: WTV multiplied by mean standardised uptake value) were obtained from basal and interim [68Ga]Ga-DOTA-TOC PET/CT, and their proportional changes (∆) were assessed for associations with progression-free survival (PFS) using Kaplan-Meier analysis, log-rank tests, and a Cox proportional-hazards regression model. Twenty-four patients were finally included (10 men and 14 women, median age of 56.5 years, age range 32-74 years). Among them, 16 patients (66.7%) experienced disease progression. In univariate analysis, high ∆WTV (≥ -10%, hazard ratio [HR] = 3.053 [1.003-9.289], p = 0.049) and high ∆TRE (≥ -21%, HR = 3.567 [1.144-11.122], p = 0.028) were significantly associated with shorter PFS. In multivariate analyses adjusted for WHO grade, high ∆WTV (HR = 3.345 [1.055-10.601], p = 0.043) and high ∆TRE (HR = 3.894 [1.194-12.695], p = 0.024) were significant predictors of shorter PFS. The study demonstrates that basal and interim [68Ga]Ga-DOTA-TOC PET/CT scans, through proportional changes in WTV and TRE, effectively predict PFS in neuroendocrine tumour patients receiving PRRT. Question Peptide receptor radionuclide therapy is utilised for patients with somatostatin receptor-positive well-differentiated neuroendocrine tumours; however, prognostic predictors are not well established. Findings Progression-free survival was significantly associated with the proportional change in whole tumour volume and total receptor expression between basal and interim [68Ga]Ga-DOTA-TOC PET/CT. Clinical relevance Interim [68Ga]Ga-DOTA-TOC PET/CT can serve as a valuable imaging method to predict prognosis of peptide receptor radionuclide therapy.

Gastroenteropancreatic Neuroendocrine Tumor with Peritoneal Metastasis: A Review of Current Management.

Peritoneal metastasis in gastroenteropancreatic neuroendocrine tumors poses a significant clinical challenge, with limited data guiding management strategies. We review the existing literature on surgical and systemic treatment modalities for peritoneal metastasis from gastroenteropancreatic neuroendocrine tumors. Surgical interventions, including cytoreductive surgery, have shown promise in improving symptom control and overall survival-particularly in cases in which 70% cytoreduction can be achieved. Hyperthermic intraperitoneal chemotherapy remains controversial due to a paucity of high-level evidence and a lack of consensus for routine use. The use of systemic therapy in the setting of peritoneal metastasis from gastroenteropancreatic neuroendocrine tumors is extrapolated from high-quality evidence for its use in the setting of the solid organ metastasis of this disease. The use of somatostatin analogs for symptom control and some antiproliferative effects is supported by large clinical trials. Additional strong evidence exists for the use of interferon-alpha, everolimus, and sunitinib, particularly in pancreatic neuroendocrine tumors. Cytotoxic chemotherapy and peptide receptor radionuclide therapy may be used in select cases, though as an emerging treatment modality, the optimal sequence of peptide receptor radionuclide therapy within the existing algorithms is unknown. Significant gaps in understanding and standardized management exist, particularly for those patients presenting with peritoneal metastasis, and targeted research to optimize outcomes in this population is needed.

To Perform, or Not to Perform Interim PET: Questioning the Impact of Midtherapy Evaluation During PRRT in GEP-NET Patients.

This study aimed to analyze the impact of interim evaluation on the continuation of 177Lu-based peptide receptor radionuclide therapy (PRRT) in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and to survey its usage across German university hospitals. In 119 GEP-NET patients who underwent PRRT, we retrospectively assessed the results and therapeutic impact of restaging performed after 2 cycles using MRI/CT/somatostatin receptor imaging. Therapeutic decisions based on interim PET results were made in multidisciplinary tumor board meetings. Additionally, an online survey was conducted among 37 German university hospitals regarding their interim evaluation practices, focusing on the change in management. Of 119 patients, 83 completed 4 PRRT cycles; 36 stopped after 2: 27 showed PD, 3 had PR leading to surgery, 5 experienced toxicity, and 1 died. Those completing 4 cycles showed a median PFS of 38.0 months (95% confidence interval, 32.2-43.8). Seventeen of 37 surveyed hospitals routinely used interim evaluation. In a survey among 37 German university hospitals, 62% reported offering PRRT for GEP-NET patients, with 74% of these performing a routinely interim evaluation after 2 cycles of PRRT, primarily using PET/CT imaging techniques. Interim PET after 2 PRRT cycles helps to identify early progression in GEP-NET patients. Standardizing interim evaluation practices could enhance the comparability of clinical outcomes and optimize patient management.

ESR Essentials: role of PET/CT in neuroendocrine tumors-practice recommendations by the European Society for Hybrid, Molecular and Translational Imaging.

Neuroendocrine neoplasms (NEN) originate from the secretory cells of the neuroendocrine system, with the majority arising in the gastrointestinal tract and pancreas. Given the heterogeneity in the biological behavior and morphological differentiation of these tumors, advanced imaging techniques are crucial for supporting the suspected diagnosis, accurate staging, and monitoring therapy. As most well-differentiated NEN demonstrate overexpression of somatostatin receptors (SSR) on the cell surface, SSR-directed PET/CT is considered the reference standard for imaging of this particular entity. SSR-PET/CT should be the imaging method of choice in every NEN G1 or G2 and considered for re-staging after both potentially curative and non-curative surgeries. The extent of SSR expression is also crucial for determining a patient's eligibility for peptide receptor radionuclide therapy (PRRT). PRRT utilizes [177Lu]Lu-DOTA-TATE to target the SSR receptor and can significantly prolong progression-free survival in patients with advanced, progressive neuroendocrine tumor of the gastroenteropancreatic system (GEP-NET). PET/CT is a central component of the multidisciplinary management of NEN. Variable follow-up intervals are recommended, considering that tumors with higher proliferation rates or advanced metastatic disease require more frequent assessments. The combination with other imaging modalities, like MRI, complements SSR-PET/CT, further enhancing overall diagnostic accuracy. KEY POINTS: Somatostatin receptor-PET/CT (SSR-PET/CT) is the guideline-recommended reference standard for imaging well-differentiated neuroendocrine tumors (NET). SSR-PET/CT should be the diagnostic imaging of choice for staging and post-therapy re-staging of grade 1 or 2 NET (G1 or G2). Variable follow-up intervals are recommended for NET G1 and G2. Tumors with higher proliferation rates or advanced metastatic disease necessitate more frequent assessments.

7166 EFFECT OF ANTI-NEOPLASTIC THERAPIES ON CARCINOMA AND AGGRESSIVE PITUITARY TUMORS : A SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract Disclosure: V.D. Nunes-Nogueira: None. A.R. Cardoso: None. A.C. Zimmermann: None. Introduction: Approximately 10% of the pituitary adenomas can have an aggressive behavior and 0.2% can present metastasis, being classified as pituitary carcinomas. Objective: Evaluate the tumor control obtained by anti-neoplastic therapies that are still little explored in the context of carcinoma and aggressive pituitary tumors. Methods: A systematic review according to the Joanna Briggs Institute has been conducted. We have included studies that evaluated patients with carcinoma or aggressive pituitary tumors who underwent treatment with at least one of the following therapies: Temozolomide, VEGF Inhibitors, Peptide Receptor Radionuclide Therapy (PRRT), Everolimus, Immune Checkpoint Inhibitors, EGFR Inhibitors, Capecitabine and temozolomide (CAPTEM). The main outcome assessed by the study was the frequency of tumor response according to the RECIST protocol classification. Embase, Medline, LILACS, and CENTRAL were our source databases. Proportional meta-analyses were performed to calculate the overall frequencies of complete remission (CR), partial remission (PR; minimum shrinkage of 30%), stable disease (SD) and progression disease (PD). We used Stata Software 18, the updated command “metaprop_one” and fit the logistic normal random effect model. Results: None clinical trial was found, and sixty case report/case series were included. The most frequent therapy used was temozolomide (101 patients), followed by PRRT, pembrolizumab, lapatinib, CAPTEM, bevacizumab, ipilimumab/ nivolumab and everolimus, with respectively 9, 6 ,6, 6, 4, 3 and 1 individuals. The majority of patient in temozolomide studies had prolactinomas (40/101), followed by Cushing’s disease (25/101), the overall frequency of CR with this drug was 1% (ch^2=2.7; p=0.049, Predictive Interval (PI) 1% to 93%, 7 events), PR was 45% ( ch^2=1.8, p=0.091, PI= 8-89%, 46 events), SD 14% (CI 95%=5 a 33%, 20 events), and PD was 25% (95%CI: 14-40%, 28 events). Two patients receiving CAPTEM presented CR, no other studies presented this outcome. In the PRRT studies, the overall frequency of PR was 22% (95%CI 6 to 58%) and PD was 44% (95%CI 18 to 75).Conclusion: Temozolomide has been the therapy most frequent used in the management of carcinoma and aggressive pituitary tumor, being PR the most frequent outcome, followed by PD and SD, with low percentage of CR. The other drugs approached by this review showed similar poor response although they were less tested in the context of this neoplasms. Presentation: 6/2/2024

6799 RZ358 Therapy. A Novel Approach to Hyperinsulinemia in Metastatic Neuroendocrine Tumor Patients

Abstract Disclosure: J. Noreña: None. T. Akcan: None. S. Patel: None. W. Madeleine: None. S. Shaheen: None. M. Tan: None. RZ358, an intravenously administered monoclonal antibody, targets a unique allosteric site on the insulin receptor. It is under investigation for hypoglycemia due to congenital hyperinsulinism. We present a case of its efficacy in treating refractory hyperinsulinemic-hypoglycemia (HH) due to a metastatic pancreatic neuroendocrine tumor (pNET). Clinical Case: A 50-year-old woman with a 6-year history of HH initially presented in 2016 with epigastric pain and was diagnosed with gastrin secreting pNET pT3N1. After Whipple surgery and cholecystectomy. A well-differentiated, WHO grade 2 NET, positive in immunohistochemistry for AE1/3, synaptophysin and Ki-67 index of 9.2% was confirmed. She presented recurrent disease with liver metastasis requiring somatostatin analogue Lanreotide. Subsequently despite Lanreotide, hypoglycemia persisted, and 72-hour fast confirmed HH. DOTATATE scan showed progression to new liver lesions. Everolimus was started and subsequently peptide receptor radionuclide therapy (PRRT) with fair hypoglycemia control. Unfortunately, her disease progressed. Oral glucose, cornstarch, and diazoxide failed. After a left hepatectomy and transarterial chemoembolization, her severe hypoglycemia improved briefly. Despite high-dose dexamethasone (up to 4 mg daily), octreotide 400 mcg every 8 hours, and high-calorie total parenteral nutrition (TPN) (over 800 grams of carbohydrates daily), she required multiple hospitalizations for persistent symptomatic hypoglycemia. Moreover, these therapies led to significant side effects, including recurrent episodes of volume overload, 240 pounds weight gain over a year, and Cushingoid features. Given RZ358's reports in reversing HH in rodents, humans, and a recent report of successful use in a malignant insulinoma case, we aimed to start RZ358 in our patient. We obtained, emergency use authorization from the FDA, IRB of Stanford University School of Medicine approval, and patient written informed consent. RZ358 was started at 6 mg/kg biweekly, along with octreotide, dexamethasone, and TPN. RZ358 dosage was later increased to 9 mg/kg weekly, allowing a substantial reduction in dexamethasone to physiological doses and a 50% reduction in TPN carbohydrate requirements. She achieved normoglycemia and returned home, but missing a single weekly RZ358 dose caused recurrent severe hypoglycemia until the next dose administration.As her disease progressed, the patient opted for comfort care, discontinuing TPN and RZ358. Conclusion: RZ358 represents a novel and unique treatment option for refractory HH in patients with metastatic NETs and can improve clinical outcomes when standard interventions fail. This case underscores the potential of RZ358, a monoclonal antibody, to treat HH beyond its approved use for congenital cases, suggesting its applicability to cases of hyperinsulinemia secondary to NETs in adults. Presentation: 6/2/2024

9286 RZ358 Therapy. A Novel Approach To Hyperinsulinemia In Metastatic Neuroendocrine Tumor Patients

Abstract Disclosure: J. Noreña: None. T. Akcan: None. S. Patel: None. M. Welsh: None. S. Shaheen: None. M. Tan: None. RZ358, an intravenously administered monoclonal antibody, targets a unique allosteric site on the insulin receptor. It is under investigation for hypoglycemia due to congenital hyperinsulinism. We present a case of its efficacy in treating refractory hyperinsulinemic-hypoglycemia (HH) due to a metastatic pancreatic neuroendocrine tumor (pNET). Clinical Case: A 50-year-old woman with a 6-year history of HH initially presented in 2016 with epigastric pain and was diagnosed with gastrin secreting pNET pT3N1. After Whipple surgery and cholecystectomy. A well-differentiated, WHO grade 2 NET, positive in immunohistochemistry for AE1/3, synaptophysin and Ki-67 index of 9.2% was confirmed. She presented recurrent disease with liver metastasis requiring somatostatin analogue Lanreotide. Subsequently despite Lanreotide, hypoglycemia persisted, and 72-hour fast confirmed HH. DOTATATE scan showed progression to new liver lesions. Everolimus was started and subsequently peptide receptor radionuclide therapy (PRRT) with fair hypoglycemia control. Unfortunately, her disease progressed. Oral glucose, cornstarch, and diazoxide failed. After a left hepatectomy and transarterial chemoembolization, her severe hypoglycemia improved briefly. Despite high-dose dexamethasone (up to 4 mg daily), octreotide 400 mcg every 8 hours, and high-calorie total parenteral nutrition (TPN) (over 800 grams of carbohydrates daily), she required multiple hospitalizations for persistent symptomatic hypoglycemia. Moreover, these therapies led to significant side effects, including recurrent episodes of volume overload, 240 pounds weight gain over a year, and Cushingoid features. Given RZ358's reports in reversing HH in rodents, humans, and a recent report of successful use in a malignant insulinoma case, we aimed to start RZ358 in our patient. We obtained, emergency use authorization from the FDA, IRB of Stanford University School of Medicine approval, and patient written informed consent. RZ358 was started at 6 mg/kg biweekly, along with octreotide, dexamethasone, and TPN. RZ358 dosage was later increased to 9 mg/kg weekly, allowing a substantial reduction in dexamethasone to physiological doses and a 50% reduction in TPN carbohydrate requirements. She achieved normoglycemia and returned home, but missing a single weekly RZ358 dose caused recurrent severe hypoglycemia until the next dose administration.As her disease progressed, the patient opted for comfort care, discontinuing TPN and RZ358. Conclusion: RZ358 represents a novel and unique treatment option for refractory HH in patients with metastatic NETs and can improve clinical outcomes when standard interventions fail. This case underscores the potential of RZ358, a monoclonal antibody, to treat HH beyond its approved use for congenital cases, suggesting its applicability to cases of hyperinsulinemia secondary to NETs in adults. Presentation: 6/2/2024

6799 RZ358 Therapy. A Novel Approach To Hyperinsulinemia In Metastatic Neuroendocrine Tumor Patients

Abstract Disclosure: J. Noreña: None. T. Akcan: None. S. Patel: None. W. Madeleine: None. S. Shaheen: None. M. Tan: None. RZ358, an intravenously administered monoclonal antibody, targets a unique allosteric site on the insulin receptor. It is under investigation for hypoglycemia due to congenital hyperinsulinism. We present a case of its efficacy in treating refractory hyperinsulinemic-hypoglycemia (HH) due to a metastatic pancreatic neuroendocrine tumor (pNET). Clinical Case: A 50-year-old woman with a 6-year history of HH initially presented in 2016 with epigastric pain and was diagnosed with gastrin secreting pNET pT3N1. After Whipple surgery and cholecystectomy. A well-differentiated, WHO grade 2 NET, positive in immunohistochemistry for AE1/3, synaptophysin and Ki-67 index of 9.2% was confirmed. She presented recurrent disease with liver metastasis requiring somatostatin analogue Lanreotide. Subsequently despite Lanreotide, hypoglycemia persisted, and 72-hour fast confirmed HH. DOTATATE scan showed progression to new liver lesions. Everolimus was started and subsequently peptide receptor radionuclide therapy (PRRT) with fair hypoglycemia control. Unfortunately, her disease progressed. Oral glucose, cornstarch, and diazoxide failed. After a left hepatectomy and transarterial chemoembolization, her severe hypoglycemia improved briefly. Despite high-dose dexamethasone (up to 4 mg daily), octreotide 400 mcg every 8 hours, and high-calorie total parenteral nutrition (TPN) (over 800 grams of carbohydrates daily), she required multiple hospitalizations for persistent symptomatic hypoglycemia. Moreover, these therapies led to significant side effects, including recurrent episodes of volume overload, 240 pounds weight gain over a year, and Cushingoid features. Given RZ358's reports in reversing HH in rodents, humans, and a recent report of successful use in a malignant insulinoma case, we aimed to start RZ358 in our patient. We obtained, emergency use authorization from the FDA, IRB of Stanford University School of Medicine approval, and patient written informed consent. RZ358 was started at 6 mg/kg biweekly, along with octreotide, dexamethasone, and TPN. RZ358 dosage was later increased to 9 mg/kg weekly, allowing a substantial reduction in dexamethasone to physiological doses and a 50% reduction in TPN carbohydrate requirements. She achieved normoglycemia and returned home, but missing a single weekly RZ358 dose caused recurrent severe hypoglycemia until the next dose administration.As her disease progressed, the patient opted for comfort care, discontinuing TPN and RZ358. Conclusion: RZ358 represents a novel and unique treatment option for refractory HH in patients with metastatic NETs and can improve clinical outcomes when standard interventions fail. This case underscores the potential of RZ358, a monoclonal antibody, to treat HH beyond its approved use for congenital cases, suggesting its applicability to cases of hyperinsulinemia secondary to NETs in adults. Presentation: 6/2/2024

9286 RZ358 Therapy. A Novel Approach to Hyperinsulinemia in Metastatic Neuroendocrine Tumor Patients

Abstract Disclosure: J. Noreña: None. T. Akcan: None. S. Patel: None. M. Welsh: None. S. Shaheen: None. M. Tan: None. RZ358, an intravenously administered monoclonal antibody, targets a unique allosteric site on the insulin receptor. It is under investigation for hypoglycemia due to congenital hyperinsulinism. We present a case of its efficacy in treating refractory hyperinsulinemic-hypoglycemia (HH) due to a metastatic pancreatic neuroendocrine tumor (pNET). Clinical Case: A 50-year-old woman with a 6-year history of HH initially presented in 2016 with epigastric pain and was diagnosed with gastrin secreting pNET pT3N1. After Whipple surgery and cholecystectomy. A well-differentiated, WHO grade 2 NET, positive in immunohistochemistry for AE1/3, synaptophysin and Ki-67 index of 9.2% was confirmed. She presented recurrent disease with liver metastasis requiring somatostatin analogue Lanreotide. Subsequently despite Lanreotide, hypoglycemia persisted, and 72-hour fast confirmed HH. DOTATATE scan showed progression to new liver lesions. Everolimus was started and subsequently peptide receptor radionuclide therapy (PRRT) with fair hypoglycemia control. Unfortunately, her disease progressed. Oral glucose, cornstarch, and diazoxide failed. After a left hepatectomy and transarterial chemoembolization, her severe hypoglycemia improved briefly. Despite high-dose dexamethasone (up to 4 mg daily), octreotide 400 mcg every 8 hours, and high-calorie total parenteral nutrition (TPN) (over 800 grams of carbohydrates daily), she required multiple hospitalizations for persistent symptomatic hypoglycemia. Moreover, these therapies led to significant side effects, including recurrent episodes of volume overload, 240 pounds weight gain over a year, and Cushingoid features. Given RZ358's reports in reversing HH in rodents, humans, and a recent report of successful use in a malignant insulinoma case, we aimed to start RZ358 in our patient. We obtained, emergency use authorization from the FDA, IRB of Stanford University School of Medicine approval, and patient written informed consent. RZ358 was started at 6 mg/kg biweekly, along with octreotide, dexamethasone, and TPN. RZ358 dosage was later increased to 9 mg/kg weekly, allowing a substantial reduction in dexamethasone to physiological doses and a 50% reduction in TPN carbohydrate requirements. She achieved normoglycemia and returned home, but missing a single weekly RZ358 dose caused recurrent severe hypoglycemia until the next dose administration.As her disease progressed, the patient opted for comfort care, discontinuing TPN and RZ358. Conclusion: RZ358 represents a novel and unique treatment option for refractory HH in patients with metastatic NETs and can improve clinical outcomes when standard interventions fail. This case underscores the potential of RZ358, a monoclonal antibody, to treat HH beyond its approved use for congenital cases, suggesting its applicability to cases of hyperinsulinemia secondary to NETs in adults. Presentation: 6/2/2024

12533 A Rare Case of a Growth Hormone Releasing Hormone-Secreting Pulmonary Carcinoid Tumor: Clinical Presentation and Management

Abstract Disclosure: I. Yaseen: None. C. Woods: None. D.B. O'Shea: None. R.K. Crowley: None. D. O'Toole: None. H. Almeamar: None. We present a rare case of an ectopic Growth Hormone Releasing Hormone (GHRH)-secreting pulmonary neoplasm manifesting with acromegaly. A 62-year-old woman presented with Bell’s palsy. An incidental lung mass proved to be a 17.5cm carcinoid tumor, DOTATOC-avid, with bony and liver metastases, Ki67 1% on lung and bone biopsy. After pulmonary service referral to endocrinology, she was noted to have acromegalic features, the most troubling of which was macroglossia associated with mouth ulceration. IGF1 was 549ug/L (57-186), random growth hormone was 225. GHRH in serum was 1937ng/ml (reference &amp;lt; 60). MR Pituitary revealed hyperplasia.The multidisciplinary team discussion was that the lung lesion was unresectable, therefore she was commenced on somatuline autogel 120mg every 28 days and an opinion requested re suitability for Peptide Receptor Radionuclide Therapy. After 6 months of therapy IGF1 normalised to 90ug /L. GHRH reduced to 1056ng/L.Imaging at 8 months showed stability of lung primary and bone / liver metastases, with no benefit likely from PRRT at this time. This case highlights the importance of considering endocrine syndromes in the setting of a lung mass. The prevalence of acromegaly in Ireland is 69 per million people; this is the second Irish case known of GHRH-associated GH excess. Ectopic GH-secreting pulmonary tumors are a rare but important differential in patients presenting with acromegalic features. Complete surgical resection can be curative, underlining the significance of a multidisciplinary approach in management, encompassing endocrinology, thoracic surgery, and pathology. This case of successful medical management adds to the limited literature on such tumors and underscores the potential for non-pituitary neoplasms to cause systemic endocrinopathies. Presentation: 6/1/2024