Peptide Receptor Radioligand Therapy Research Articles

Real-Life Use of [68Ga]Ga-DOTANOC PET/CT in Confirmed and Suspected NETs from a Prospective 5-Year Electronic Archive at an ENETS Center of Excellence: More Than 2000 Scans in More Than 1500 Patients.

The recent introduction of novel treatments for advanced neuroendocrine tumors (NETs) and the well-established impact of clinical case discussion within dedicated multidisciplinary teams indicates the need to promote the centralization of rare diseases, such as NENs (neuroendocrine neoplasms). Data on the real-life use of and indications for [68Ga]Ga-DOTANOC PET/CT were collected from a prospective monocentric 5-year electronic archive including consecutive patients with confirmed and suspected NETs (September 2017 to May 2022). Overall, 2082 [68Ga]Ga-DOTANOC PET/CT scans (1685 confirmed NETs, 397 suspected NETs) were performed in 1537 patients. A high positivity rate was observed across different clinical settings (approximately 70%). Approximately 910/2082 scans were requested by the local oncology ward (851 confirmed NETs, 59 suspected NETs). The following observations were found: (i) the detection rate across all indications was 73.2% (higher for staging, peptide receptor radioligand therapy (PRRT) selection, and treatment response assessment); (ii) in suspected NETs, PET was more often positive when based on radiological findings. This systematic data collection in a high-volume diagnostic center represents a reliable cohort reflecting the global trends in the use of [68Ga]Ga-DOTANOC PET/CT for different clinical indications and primary tumor sites, but prompts the need for further multicenter data sharing in such a rare and slowly progressive disease setting.

GRPR-targeting radiotheranostics for breast cancer management.

Breast Cancer (BC) is the most common cancer worldwide and, despite the advancements made toward early diagnosis and novel treatments, there is an urgent need to reduce its mortality. The Gastrin-Releasing Peptide Receptor (GRPR) is a promising target for the development of theranostic radioligands for luminal BC with positive estrogen receptor (ER) expression, because GRPR is expressed not only in primary lesions but also in lymph nodes and distant metastasis. In the last decades, several GRPR-targeting molecules have been evaluated both at preclinical and clinical level, however, most of the studies have been focused on prostate cancer (PC). Nonetheless, given the relevance of non-invasive diagnosis and potential treatment of BC through Peptide Receptor Radioligand Therapy (PRRT), this review aims at collecting the available preclinical and clinical data on GRPR-targeting radiopeptides for the imaging and therapy of BC, to better understand the current state-of-the-art and identify future perspectives and possible limitations to their clinical translation. In fact, since luminal-like tumors account for approximately 80% of all BC, many BC patients are likely to benefit from the development of GRPR-radiotheranostics.

Carcinoid tumors outside the abdomen.

Neuroendocrine tumors (NETs) are epithelial malignancies that can arise from multiple tissues. Gastrointestinal (GI) NETs are the most common; in this review of extra-abdominal carcinoid tumors, we focus our discussion on bronchial and thymic carcinoid tumors. Bronchial carcinoid tumors comprise a quarter of all NETs and less than 2% of all lung cancers. Thymic carcinoid tumors are extremely rare, accounting for 5% of thymic tumors. Both bronchial and thymic carcinoid tumors are histologically classified as either typical or atypical based on their mitotic rate (less than 2 or 2-10 mitoses per 10 high-powered fields (HPF), respectively). Both bronchial and thymic carcinoids can present with symptoms of obstruction and potentially carcinoid syndrome. The gold standard of management of bronchial and thymic carcinoid tumors is surgical resection. For patients with advanced disease, first-line systemic therapy is generally somatostatin analog monotherapy with octreotide or lanreotide. In patients with refractory disease, therapy generally involves peptide receptor radioligand therapy, everolimus, or cytotoxic chemotherapy. There are ongoing, prospective trials comparing the mainstays of systemic therapy for these patients, as well as ongoing evaluations of immune checkpoint inhibitors and multi-kinase inhibitors. Prognosis for both bronchial and thymic carcinoid tumors depends on histologic grade, local versus invasive disease, and extent of metastases. Herein we provide a summary of the pathophysiologic and clinical background, the current state of the field in diagnosis and management, and note of key ongoing prospective trials for patients with bronchial and thymic carcinoid tumors.

Amino acid extravasation: a rare red flag to keep in mind during peptide receptor radioligand therapy (PRRT) with [177Lu]Lu-DOTATATE.

A 64 years-old woman with intestinal neuroendocrine tumor (NET) and multiple liver metastases was referred for peptide receptor radioligand therapy (PRRT) with [177Lu]Lu-DOTATATE. A few days after the third cycle of PRRT, erythema and swelling in the injection site is occurred which progressed up to one-month post-therapy. The cutaneous lesion was managed by a plastic surgeon with topical treatment. Amino acid extravasation could have devastating effects and should always be considered in patients who underwent PRRT and who receive amino acids for nephroprotection.

Technetium 99m PSMA Superscan Mimicking a Bone Scan Gone Wrong.

Imaging of metastatic castrate-resistant prostate cancer to select patients suitable for peptide receptor radioligand therapy can be performed with both SPECT and PET PSMA radiotracers. Although PET radiotracers generally have higher sensitivity and spatial resolution, SPECT tracers can be an effective alternative when PET/CT systems are unavailable in the clinical setting. We present a case of a 43-year-old male, who was referred to our facility for workup for radioligand PSMA therapy. His Tc-99m PSMA images revealed diffuse bone infiltration in a pattern mimicking a bone scan.

Severe Thrombocytopenia in Patients With Advanced Neuroendocrine Tumor Treated With Peptide Receptor Radioligand Therapy.

BackgroundPeptide receptor radioligand therapy (PRRT) was Food and Drug Administration approved in 2018 for the treatment of unresectable somatostatin receptor–positive gastroenteropancreatic neuroendocrine tumors (NETs) and provides an important option for patients with advanced disease. A known adverse effect of this treatment is hematologic toxicity, although usually transient. We present 3 patients with metastatic gastroenteropancreatic NETs treated with PRRT who were evaluated for severe persistent thrombocytopenia.MethodsThree patients who commenced therapy with PRRT were known to proceed to a bone marrow (BM) biopsy for persistent severe thrombocytopenia and were included in this study. These patients were identified retrospectively and evaluated for their tumor properties, including immunohistochemical markers, treatment modalities, and clinical outcomes.ResultsAll 3 patients had metastatic NETs that progressed on prior lines of therapy and were treated with 1 to 4 doses of 177Lu-DOTATATE 7.4 GBq (200 mCi) before developing grade 3 (25,000 to 50,000/μL) refractory thrombocytopenia. All patients had concurrent bone metastases, and 2 of the 3 had baseline grade 1 thrombocytopenia. In all 3 cases, BM biopsy documented widespread tumor infiltration.ConclusionsSevere refractory thrombocytopenia after PRRT is rare and may result from numerous known causes, including radiation-induced myelotoxicity, myelodysplastic syndrome, and tumor BM infiltration. We present 3 cases of thrombocytopenia related to persistent or progressive BM metastasis. Although known bone metastasis is not a contraindication to PRRT, thrombocytopenia may be a manifestation of tumor progression and should be considered when making decisions about continuation of therapy.

Secretin Receptor as a Target in Gastrointestinal Cancer: Expression Analysis and Ligand Development.

Secretin was originally discovered as a gastrointestinal peptide that stimulates fluid secretion from the pancreas and liver and delays gastric emptying. In disease, a secretin receptor (SCTR) was found to occur as a splice variant in gastrinoma and pancreatic adenocarcinoma. Overexpression of SCTR has been described for gastrinomas, carcinoid tumors of the lung and cholangiocarcinoma. SCTR therefore is considered a candidate target for molecular tumor imaging as well as for peptide receptor radioligand therapy (PRRT) in a number of oncological indications. The aim of this study was to characterize SCTR expression in esophageal and pancreatic cancer, demonstrating for the first time high SCTR overexpression in these tumor types. In total, 65 of 70 pancreatic ductal adenocarcinoma tissues stained strongly positive for SCTR in immunohistochemistry, as did most of the 151 esophageal cancer samples, with minor influence of grading in both entities. In addition, the aim of this study was to further delineate residues in human secretin that are critical for binding to and activation of human SCTR. For a potential development of short and metabolically stable analogs for clinical use, it was intended to probe the peptide for its capacity to incorporate deletions and substitutions without losing its affinity to SCTR. In a systematic approach, a library of 146 secretin variants containing single amino acid substitutions as well as truncations on either end was tested in β-arrestin2-GFP translocation and fluorescent ligand internalization assays employing high-content analysis, in cAMP assays which run in agonist and antagonist mode, and in radioligand binding. The main structural determinants of SCTR binding and activation were localized to the N-terminus, with His1, Asp3 being among the most sensitive positions, followed by Phe6, Thr7 and Leu10. Aminoterminal truncation caused a rapid decline in receptor activity and most of these variants proved to be partial agonists showing antagonistic properties. In this study, the most potent novel antagonist showed an IC50 of 309 ± 74 nM in the β-arrestin2-GFP translocation assay on human SCTR while remaining a weak partial agonist. Future studies will have to demonstrate the utility of further enhanced secretin analogues as tracers for in vivo imaging and therapy.

Lutetium-177 Dotatate-Induced Hemolytic Anemia and Myelodysplastic Syndrome

Lutetium-177 (177Lu) dotatate is a type of peptide receptor radioligand therapy (PRRT) using radiolabeled somatostatin for patients with progressive somatostatin receptor-positive gastrointestinal neuroendocrine tumors. While cases of therapy-related myeloid neoplasms (t-MN) have been described as a consequence of 177 Lu dotatate, there are no reports of hemolytic anemia associated with therapy. We present a case of a 68-year-old woman with metastatic low-grade neuroendocrine tumor who presented four weeks after the second dose of 177Lu dotatate with progressive fatigue and dyspnea. Laboratory workup was remarkable for hemolytic anemia. Lutetium-177 dotatate-induced hemolysis was suspected after ruling out other causes. Corticosteroid treatment was initiated with improvement in hemoglobin, and dose-reduced PRRT was planned upon discharge. Six months into the treatment course of 177Lu dotatate, macrocytic anemia was noticed on routine follow-up with normal vitamin B12 and folic acid levels. A bone marrow biopsy was done, revealing myelodysplastic syndrome (MDS) features. Given the temporal relationship between drug introduction and the objective findings, early-onset 177Lu dotatate-induced MDS was diagnosed with a plan for close hematologic follow-up. Myelodysplastic syndrome should be suspected when megaloblastic anemia develops in patients with previous 177Lu dotatate therapy. The latency period between initial treatment and MDS diagnosis reported in the literature ranges between 15 months to seven years. Apart from the unusually early onset of MDS, what is unique about our case is the development of hemolytic anemia after administration of PRRT. The clinical course and the brisk response to steroid therapy, suggest other mechanisms of PRRT toxicity besides DNA breaks, genetic mutations, and myelosuppression by an immune-mediated component that likely plays a role in 177Lu dotatate toxicity. Further investigation and monitoring are needed to identify the frequency of such adverse events and the pathophysiology of their occurrence.

Phase I dose-escalation study of AlphaMedix for targeted-alpha-emitter therapy of PRRT-naive neuroendocrine patients.

4117 Background: Peptide-receptor-radioligand-therapy (PRRT) has been shown to increase the progression-free-survival (PFS) of neuroendocrine patients, however the objective response rate is rather low. The targeted-alpha-emitter therapy (TAT) of NETs can increase the ORR and induce partial or complete tumor response. In this abstract, we present results of the safety and efficacy of AlphaMedix (212Pb-DOTAMTATE) done in PRRT-naïve patients with SSTR-expressing NETs (FDA IND 135150). Methods: The phase 1 dose escalation study (IND 135150) was designed according to a 3+3 dose-escalation scheme (30% increase of the dose in each subsequent cohort). We enrolled PRRT naïve subjects with biopsy-proven unresectable or metastatic SSTR-expressing NETs from different primary sites (midgut, rectal, pancreas, and lung) with at least one measurable lesion. Response to treatment was measured per RECIST 1.1 criteria and the effect on quality of life was measured with the EORTC-QLQ-C30 QOL questionnaire. Results: A total of 20 PRRT naïve subjects (10 men and 10 women; median age 60 ( range 27-80)) have been treated to date. 10 subjects in MAD4 cohort received at least three cycles of 212Pb-DOTAMTATE at the highest dose level of 67.6 µCi/kg/cycle. Of these, 6/10 subjects (60%) have completed all four-cycles of treatment. Radiographic evaluation of these six-MAD4 patients reveal an ORR in 5 out of 6 subjects (83.3%) per RECIST 1.1 criteria (1CR, 4PR, 1SD) in addition to a 100% response according to 68Ga-DOTATATE-PET/CT-imaging, defined as complete resolution of SSTR-positive lesions (CR) or Partial Response (PR) defined as resolution of most active lesions or substantially decreased SUV (>25%). No progression of disease was noted in the first six subjects enrolled in the MAD4 cohort who have completed treatment. All six-patients have 100% PFS up to 22 months (for the first 3-subjects in MAD4) and up to 19 months (next 3-patients). Except for mild-to-moderate, reversible hair loss, there were no other clinically significant drug related AE, or SAE. The most frequent AEs of any grade (> 4 subjects) reported include fatigue (35%), hyperglycemia (30%), lymphopenia (30%) alopecia (30%), and diarrhea (20%). Five grade 3 AEs were reported (back pain, dysarthria, dyspnea, acute kidney injury), no grade 4 AEs, and one grade 5 AE was reported. There was a significant improvement in the quality of life, reduction of pain, shortness of breath in the majority of subjects, with increase of energy. Conclusions: This F-I-H clinical study of AlphaMedix shows that PRRT with 212Pb is feasible, well tolerated, and provides substantial reduction in tumor burden to patients with unresectable, metastatic SSTR-expressing NETs. Dramatic improvement in tumor burden and a positive impact on quality of life were seen in all of the PRRT naïve subjects who AlphaMedix at the highest dose tested. Clinical trial information: NCT03466216.

MTOR Inhibitors as Radiosensitizers in Neuroendocrine Neoplasms.

Peptide receptor radioligand therapy (PRRT) has evolved as an important second-line treatment option in the management of inoperable and metastatic neuroendocrine neoplasms (NEN). Though high radiation doses can be delivered to the tumors, complete remission is still rare. Radiosensitization prior to PRRT is therefore considered to be a promising strategy to improve the treatment effect. In this study, effect and mechanism of mTOR inhibitors were investigated in a comprehensive panel of five NEN cell lines (BON, QGP-1, LCC-18, H727, UMC-11), employing assays for cellular proliferation, clonogenic survival, cell cycle modification and signaling. mTOR inhibition lead to growth arrest with a biphasic concentration-response pattern: a partial response at approximately 1 nM and full response at micromolar concentrations (8–48 µM). All cell lines demonstrated elevated p70S6K phosphorylation yet also increased phosphorylation of counterregulatory Akt. The pulmonary NEN cell line UMC-11 showed the lowest induction of phospho-Akt and strongest growth arrest by mTOR inhibitors. Radiation sensitivity of the cells (50% reduction versus control) was found to range between 4 and 8 Gy. Further, mTOR inhibition was employed together with irradiation to evaluate radiosensitizing effects of this combination treatment. mTOR inhibition was found to radiosensitize all five NEN cells in an additive manner with a moderate overall effect. The radiation-induced G2/M arrest was diminished under combination treatment, leading to an increased G1 arrest. Further investigation involving a suitable animal model as well as radioligand application such as 177Lu-DOTATATE or 177Lu-DOTATOC will have to demonstrate the full potential of this strategy for radiosensitization in NEN.

Concept proposal for a six-tier integrated dual tracer PET-CT (68Ga-PSMA and FDG) image scoring system ('Pro-PET' score) and examining its potential implications in metastatic castration-resistant prostate carcinoma theranostics and prognosis.

To develop and examine a scoring system in metastatic castration-resistant prostate carcinoma (mCRPC) that integrates findings of both 68Ga-prostate-specific membrane antigen (PSMA) and flurodeoxyglucose (FDG) PET-CT imaging in a single combined parameter and referred to as the 'Pro-PET' score. A six-tier integrated dual tracer PET-CT (68Ga-PSMA and FDG) Image Scoring System ('Pro-PET' score) was conceptualized, based on the findings of both 68Ga-PSMA-11 and FDG PET-CT in patients of mCRPC. This proposed integrated scoring was examined in a retrospective analytical study assessing mCRPC patients (n = 47) referred for 177Lu-PSMA-617 peptide receptor radioligand therapy (PRLT) and had both FDG and 68Ga-PSMA PET-CT undertaken within 15 days of each other without any interim treatment intervention. The 'Pro-PET' score grades and subgrades were assigned and compared with clinical data, such as histopathology, Gleason score, serum prostate-specific antigen (PSA), treatment response (symptomatic, biochemical, metabolic and anatomical) and survival [overall survival (OS) and progression-free survival (PFS)]. The Pro-PET score significantly correlated with symptomatic (P = 0.05), biochemical (P = 0.05), metabolic (P = 0.001) and anatomical (P = 0.012) responses, PFS (P = 0.03) and OS (P = 0.027). On multivariate analysis, histopathology, Gleason score and PSA as individual parameters were not significantly associated with OS and PFS, whereas the Pro-PET score was found to have a significant association (P = 0.001 for PFS and 0.011 for OS). The 'Pro-PET' scoring system integrating dual tracer PET-CT imaging findings in a single parameter appeared as a potentially promising prognostic marker that has the potential to enhance the objectivity and scientific basis of prostate carcinoma theranostics and prognostication.

Abstract CT159: First-in-human dose escalation of AlphaMedixTM for targeted alpha-emitter therapy of neuroendocrine tumors

Abstract Introduction: Peptide Receptor Radioligand Therapy (PRRT) has been shown to be an effective treatment for patients with metastatic somatostatin receptor (SSTR) positive neuroendocrine tumors (NETs), however interest in developing alpha-emitter based therapies remains high. We present the initial safety and preliminary efficacy of this first-in-human (FIH) study of AlphaMedix™ (212Pb-DOTAMTATE), a novel somatostatin analog for Targeted Alpha-emitter Therapy (TAT), in patients with SSTR expressing NETs (FDA IND 135150). Methods: Thirteen adult subjects, 6 men and 7 women, median age 68 (range 27-75), with biopsy-proven unresectable or metastatic SSTR (+) NETs from different primary sites (small bowel, pancreas, and lung) with at least one measurable lesion were treated with a Single, weight-based, Ascending Dose (SAD) of AlphaMedix™. Dose escalation was conducted according to a classic 3+3 design. Once a partial response was observed in the SAD-3 cohort, the Multiple Ascending Dosing (MAD) began at the same dose level (3 cycles dosed every 8-weeks). Subjects who had previously received PRRT were excluded. All patients received amino acid renal protection prior to AlphaMedixTM administration. Response to treatment was measured per RECIST 1.1 and the effect on the quality of life was measured with the EORTC-QLQ-C30 QOL questionnaire. Two SAD cohorts (SAD1 and SAD2) received 30.7 and 40.0 µCi/kg respectively. MAD3 received 52.0 µCi/kg per cycle and MAD4, began dosing at 67.6 µCi/ kg for a total dose ranging from 14.7 to 16.8 mCi, across 3 cycles. Results: All 3 subjects in MAD 4 who received 67.6 µCi/ kg for 3 cycles showed partial response with 73%, 71%, and 33% decrease in size of the index lesions respectively. 68Ga DOTATATE PET/CT revealed almost a complete response in 2 subjects and a partial response in the third. No clinically significant investigational drug-related hematological and renal toxicity was noted. The most common adverse events noted were diarrhea 2/13(23%), nausea 4/13(30%), fatigue 4/13(30%), hyperglycemia 7/13(53%). Moderate hair loss was seen in 2/13 (15%) patients. Quality of life parameters suggest significant improvement in pain, energy, and shortness of breath in the majority of subjects. Conclusion: Dramatic decreases in tumor burden and a positive impact on quality of life were seen in all of the subjects who received three cycles of AlphaMedixTM at the highest dose tested. In addition, AlphaMedixTM was extremely well tolerated with only mild adverse events, most of which were attributable to the AA solution used for renal protection. This FIH study of AlphaMedixTM illustrates that PRRT with 212Pb is feasible, well-tolerated, and provides substantial reduction in tumor burden to patients with unresectable, metastatic SSTR expressing NETs Citation Format: Izabela Tworowska, Ebrahim S. Delpassand, Julien Torgue, Farah Shanoon, Jason Hurt, Rodolfo Nunez. First-in-human dose escalation of AlphaMedixTM for targeted alpha-emitter therapy of neuroendocrine tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT159.

Preclinical drug studies in MEN1-related neuroendocrine neoplasms (MEN1-NENs).

Neuroendocrine neoplasms (NENs) occur usually as sporadic tumours; however, rarely, they may arise in the context of a hereditary syndrome, such as multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant disorder characterised by the combined development of pancreatic NENs (pNENs) together with parathyroid and anterior pituitary tumours. The therapeutic decision for sporadic pNENs patients is multi-disciplinary and complex: based on the grade and stage of the tumor, various options (and their combinations) are considered, such as surgical excision (either curative or for debulking aims), biological drugs (somatostatin analogues), targeted therapies (mTOR inhibitors or tyrosine kinases (TK)/receptors inhibitors), peptide receptor radioligand therapy (PRRT), chemotherapy, and liver-directed therapies. However, treatment of MEN1-related NENs' patients is even more challenging, as these tumours are usually multifocal with co-existing foci of heterogeneous biology and malignant potential, rendering them more resistant to the conventional therapies used in their sporadic counterparts, and therefore associated with a poorer prognosis. Moreover, clinical data using standard therapeutic options in MEN1-related NENs are scarce. Recent preclinical studies have identified potentially new targeted therapeutic options for treating MEN1-associated NENs, such as epigenetic modulators, Wnt pathway-targeting β-catenin antagonists, Ras signalling modulators, Akt/mTOR signalling modulators, novel somatostatin receptors analogues, anti-angiogenic drugs, as well as MEN1 gene replacement therapy. The present review aims to summarize these novel therapeutic opportunities for NENs developing in the context of MEN1 syndrome, with an emphasis on pancreatic NENs, as they are the most frequent ones studied in MEN1-NENs models to date; moreover, due to the recent shifting nomenclature of 'pituitary adenomas' to 'pituitary neuroendocrine neoplasms', relevant data on MEN1-pituitary tumours, when appropriate, are briefly described.

Examining Absorbed Doses of Indigenously Developed 177Lu-PSMA-617 in Metastatic Castration-Resistant Prostate Cancer Patients at Baseline and During Course of Peptide Receptor Radioligand Therapy.

Aim: The objective of this study was to estimate the absorbed doses to the normal organs and tumor lesions in metastatic castration-resistant prostate cancer (mCRPC) patients treated with indigenously developed 177Lu-PSMA-617 that could establish optimal treatment protocol with minimum risk to the dose-limiting organs. Furthermore, attempt was also made to compare radiation absorbed doses for normal organs and tumor lesions in subsequent cycles of 177Lu-PSMA-617 peptide receptor radioligand therapy (PRLT) in the same group of patients during the course of treatment. Methods: A total of 30 patients of proven mCRPC were enrolled for this prospective study. These patients received up to 5 cycles of treatment with 177Lu-PSMA-617 PRLT (1 cycle for 13 patients, 2 cycles for 9 patients, 3 cycles for 3 patients, and 5 cycles for 5 patients), at 11-12-week intervals between the two successive therapies. The patients underwent postadministration whole-body scintigraphy at five time points: 0.5 (prevoid), 2, 12, 24, and 72/96 h (postvoid). From time-activity curves generated by drawing regions of interests on the images, number of disintegrations was determined. Tumor masses were estimated from pretherapeutic 68Ga-PSMA-11 positron emission tomography-computed tomography images. Absorbed doses for organs and tumors were calculated using OLINDA 2.0 software. Results: The average activity of 177Lu-PSMA-617 (mean ± SD) administered per patient per cycle was 4.94 ± 0.45 GBq. The mean absorbed organ doses (mean ± SD) from first therapy cycle in Gy/GBq were as follows: kidneys 0.52 ± 0.16, spleen 0.17 ± 0.07, liver 0.08 ± 0.05, salivary glands 0.53 ± 0.30, lacrimal glands 1.45 ± 0.85, nasal mucosa membrane 0.46 ± 0.19, urinary bladder 0.23 ± 0.02, and bone marrow 0.04 ± 0.03. The mean effective dose for whole body from first therapy cycle was 0.05 ± 0.03 Sv/GBq. Among all the normal organs, lacrimal glands received the highest absorbed dose. The median dose for all lesions, bone lesions, lymph nodes, primary site, liver lesion, lung lesion, and soft tissue deposit from first therapy cycle was determined to be 4.17, 4.23, 3.96, 4.36, 10.27, 0.78, and 4.68 Gy/GBq respectively. Absorbed doses received by the normal organs in five consecutive cycles follow three different trends, (a) for kidneys, salivary glands, and nasal mucous membrane, absorbed doses increased from first therapy cycle to second therapy cycle and then slowly decreased in subsequently therapy cycles; (b) for spleen, liver, and lacrimal glands, absorbed doses decreased with the successive therapy cycles; and (c) in case of bone marrow, bladder, and whole body, mean absorbed dose almost remained constant in each therapy cycle. Absorbed doses to the lesions gradually decreased with increase of the number of therapy cycles. Conclusions: The organ and tumor absorbed doses of 177Lu-PSMA-617 in mCRPC patients were found to be comparable to the data reported in the literature. The highest absorbed organ dose was observed in lacrimal glands and being a dose limiting organ, a cumulative activity up to 32.5 GBq (878 mCi) of 177Lu-PSMA-617 in 4-5 therapy cycles appears safe and feasible to achieve full therapeutic window.

Posttherapeutic Critical Organ Dosimetry of Extensive 177Lu-PSMA Inhibitor Therapy With Metastatic Castration-Resistant Prostate Cancer

Lu-PSMA inhibitor peptide receptor radioligand therapy (RLT) is playing an increasing role in metastatic castration-resistant prostate cancer. We aimed to estimate the absorbed radiation doses for critical organs (eg, kidneys, parotid glands, submandibular glands, and lacrimal glands) of patients treated with 4 to 6 cycles by Lu-PSMA inhibitor RLT, retrospectively, and to evaluate the findings extensively in order to determine the critical organ radiation-absorbed limitations and the number of prospective RLT. A total of 51 cycles Lu-PSMA inhibitor RLT in 10 patients was analyzed. Therapies have been applied in 4 to 6 cycles with 8 to 10 weeks' intervals. Dosimetric estimates of kidneys, parotid glands, submandibular glands, and lacrimal glands have been calculated based on MIRD scheme pamphlet no. 16. Regions of interest were drawn with GE Xeleris Functional Imaging Workstation. OLINDA/EXM 1.1 simulation software was used to calculate radiation-absorbed doses. Mean radiation-absorbed doses were 0.70 ± 0.24 Gy/GBq for kidneys, 1.34 ± 0.78 Gy/GBq for parotid glands, 0.94 ± 0.45 Gy/GBq for submandibular glands, and 2.28 ± 1.29 Gy/GBq for lacrimal glands. Due to the critical target organ risks and the optimal therapy doses, patient-specific dosimetry is a deterministic factor in radionuclide therapy. Even when the absorbed kidney doses were above the ICRP critical dose limits in patients who had 4 to 6 cycles of therapy, mortality due to nephrotoxicity has not been observed. Mild increased tolerated radiation dose is acceptable for the patient groups with very low survival rate.

Clinical presentation and management of primary ovarian neuroendocrine tumor in multiple endocrine neoplasia type 1.

SummaryMultiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant condition characterized by parathyroid, anterior pituitary and enteropancreatic endocrine cell tumors. Neuroendocrine tumors occur in approximately in 5–15% of MEN1 patients. Very few cases of ovarian NETs have been reported in association with clinical MEN1 and without genetic testing confirmation. Thirty-three-year-old woman with MEN1 was found to have right adnexal mass on computed tomography (CT). Attempt at laparoscopic removal was unsuccessful, and mass was removed via a minilaparotomy in piecemeal fashion. Pathology showed ovarian NET arising from a teratoma. Four years later, patient presented with recurrence involving the pelvis and anterior abdominal wall. She was treated with debulking surgery and somatostatin analogs (SSAs). Targeted DNA sequencing analysis on the primary adnexal mass as well as the recurrent abdominal wall tumor confirmed loss of heterozygosity (LOH) at the MEN1 gene locus. This case represents to our knowledge, the first genetically confirmed case of ovarian NET arising by a MEN1 mechanism in a patient with MEN1. Extreme caution should be exercised during surgery as failure to remove an ovarian NET en masse can result in peritoneal seeding and recurrence. For patients with advanced ovarian NETs, systemic therapy options include SSAs, peptide receptor radioligand therapy (PRRT) and novel agents targeting mammalian target of rapamycin (mTOR) and vascular endothelial growth factor (VEGF).Learning points:Ovarian NET can arise from a MEN1 mechanism, and any adnexal mass in a MEN1 patient can be considered as a possible malignant NET.Given the rarity of this disease, limited data are available on prognostication and treatment. Management strategies are extrapolated from evidence available in NETs from primaries of other origins.Care should be exercised to remove ovarian NETs en bloc as failure to do so may result in peritoneal seeding and recurrence.Treatment options for advanced disease include debulking surgery, SSAs, TKIs, mTOR inhibitors, PRRT and chemotherapy.

SAT-LB060 Clinical Presentation and Management of Primary Ovarian Carcinoids in Multiple Endocrine Neoplasia Type 1

Introduction MEN1 is an autosomal dominant condition characterized by parathyroid, anterior pituitary and enteropancreatic endocrine cell tumors. Carcinoids occur in 5-15% patients, majority of which are of foregut origin (thymus, bronchus, stomach and duodenum). Only 1 case of ovarian carcinoid has been reported in association with MEN1, and was not confirmed with genetic testing. Case report A 33-year-old female with a macroprolactinoma and primary hyperparathyroidism was referred to us with a presumptive diagnosis of MEN1. Genetic testing showed a heterozygous germline mutation in the MEN1 gene, c.219_220delCG (frameshift leading to premature protein truncation). She had no family history consistent with MEN1. EGD showed two submucosal nodules in the duodenum with confirmed histology of gastrinomas. CT demonstrated 8.7 x 7.7 cm right adnexal mass containing foci of soft tissue density and calcification. Laparoscopic resection was attempted but the mass was too large to be delivered en-bloc. Operative approach was changed to a minilaparotomy and the mass was delivered in a piecemeal fashion. Pathology demonstrated a benign dermoid cyst with neuroendocrine tumor consistent with carcinoid extending into peri-ovarian tissues. 4 years later, she presented with a lower abdominal palpable mass. CT showed an irregular, avidly enhancing 11.7 x 8.7 cm pelvic mass, extending through the anterior abdominal wall into the subcutaneous fat with satellite lesions within the anterior subcutaneous abdomen. The CT abnormalities corresponded to abnormally elevated In-111 pentetreotide uptake. Biopsy of one of the subcutaneous lesions showed metastatic neuroendocrine neoplasm with Ki67 index of 2%. Targeted genetic analysis for the patient’s MEN1 mutation using DNA samples isolated from the primary adnexal mass as well as the recurrent abdominal wall tumor demonstrated predominantly mutant sequence in both specimens, confirming LOH at the MEN1 gene locus. 5 months later, the patient presented with obstructive uropathy from nodal metastases. She underwent debulking surgery via exploratory laparotomy, panniculectomy, resection of metastatic abdominal wall tumors and abdominal wall reconstruction. Post operatively, FDG-PET scan showed few scattered disease foci. She was commenced on monthly octreotide injections. Conclusions This case represents to our knowledge, the first genetically confirmed case of ovarian carcinoid arising by a MEN1 mechanism. Ovarian carcinoid should be considered as a differential in MEN1 patients with adnexal mass. Extreme caution should be exercised during surgical resection, as failure to remove an ovarian carcinoid en masse can result in peritoneal seeding and recurrence. For patients with advanced disease, systemic therapy options include somatostatin receptor analogs, peptide receptor radioligand therapy, and novel agents targeting mTOR and VEGF. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Systemic Therapy for Low-grade Pulmonary Neuroendocrine Tumor

肺部是神经内分泌肿瘤（neuroendocrine tumor, NET）的第二好发部位。肺类癌包括典型类癌和不典型类癌，属于低级别神经内分泌肿瘤。这一类肿瘤由于发病率较低，目前尚未得到广大医务工作者的重视。但有效的治疗不仅能提高患者的远期生存，还能控制患者症状，改善生活质量。本文分别阐述肺低级别神经内分泌肿瘤的流行病学和病理学特点、早期患者的治疗策略以及进展期患者的治疗策略。早期患者应当尽早进行手术治疗。进展期患者治疗方式包括化疗、SSAs、mTOR抑制剂、肽受体介导的放射性核素治疗、生物治疗以及靶向治疗。目前的研究结论大多来自其他部位的NETs研究外推而来，仍需针对肺低级别神经内分泌肿瘤患者进行特异性临床试验加以证实。

Evaluation of response in patients of metastatic castration resistant prostate cancer undergoing systemic radiotherapy with lutetium177-prostate-specific membrane antigen: A comparison between response evaluation criteria in solid tumors, positron-emission tomography response criteria in solid tumors, European organization for research and treatment of cancer, and MDA criteria assessed by gallium 68-prostate-specific membrane antigen positron-emission tomography-computed tomography.

Introduction:We evaluated various morphological and molecular response criteria in metastatic castration-resistant prostate cancer (PCa) patient undergoing peptide receptor radioligand therapy (PRLT) with Lutetium177-prostate-specific membrane antigen (PSMA) by using Gallium 68-PSMA positron-emission tomography-computed tomography (Ga68-PSMA PET-CT).Methods:A total of 46 pre- and 8–12 weeks’ post-PRLT Ga68-PSMA PET-CT studies were reanalyzed (23 comparisons). Prostate-specific antigen drop of ≥50% and ≥25% increase was considered as partial response (PR) and progressive disease (PD), respectively, for biochemical response (BR) while change in-between was considered as stable disease (SD). Response evaluation criteria in solid tumors 1.1 (RECIST 1.1) and MD Anderson (MDA) criteria for morphological response while PET response criteria in solid tumors 1.0 (PERCIST 1.0) and European organization for research and treatment of cancer (EORTC) criteria for molecular response were used. Kappa coefficient was derived to see the level of agreement.Results:The proportion of PD, PR, and SD by BR and RECIST criteria was 9 (39.13%), 3 (13.04%), and 11 (47.83%) and 5 (21.74%), 2 (8.70%), and 16 (69.57%), respectively. The proportion of PD, PR, and SD was same by PERCIST and EORTC criteria and which were 8 (34.78%), 5 (21.74%), and 10 (43.48%). The proportion of PD, PR, and SD by MDA criteria was 1 (4.35%), 1 (4.35%), and 21 (91.30%), respectively. Poor agreement between BR and both morphological criteria while a statistically significant agreement with both molecular criteria seen.Conclusion:We concluded that molecular criteria performed better than morphological criteria in response assessment by Ga68-PSMA PET-CT in metastatic castration resistant PCa patients undergoing PRLT.

Management of Neuroendocrine Tumors of the Pancreas

Neuroendocrine tumors (NETs) comprise a heterogeneous group of malignancies, with differences in prognosis and effective therapies. Traditionally, NETs have been characterized by tumor grade, site of primary tumor, functional status, and presence of underlying familial syndrome. However, increased feasibility and use of next-generation sequencing and other methodologies have revealed new genomic and epigenetic aberrations. In the past decade, treatment options available for metastatic well-differentiated gastroenteropancreatic NETs have expanded, with the approval of antiangiogenic and mTOR-directed targeted therapies, and our armamentarium of active therapies is likely to further increase. Optimal surgical therapy both for nonfunctional and functional PNETs has become more personalized and strategic to optimize long-term quality of life time. Management of localized metastatic PNET has become a true multidisciplinary management opportunity that all treating physicians should use. Peptide receptor radioligand therapy is an emerging treatment that uses functional imaging to personalize dosimetry to the tumor and avoid nephrotoxicity. Nevertheless, there is a critical need for further biomarkers, particularly multianalyte biomarkers, to aid in prognostication and predict efficacy of therapies. This review contains 1 figure, 1 table, and 72 references. Key Words: carcinoid tumor, islet cell carcinoma, neuroendocrine tumors, pancreatic, surgical management, medical management, metastatic, localized.