BACKGROUND:Peptide receptor radionuclide and targeted therapy are both approved treatment options for patients with metastatic gastroenteropancreatic neuroendocrine tumours (GEP NETs), but clinical evidence for preferred sequencing is scarce. The COMPETE trial evaluated the efficacy and harms of peptide receptor radionuclide therapy ([177Lu]Lu-edotreotide) versus targeted molecular therapy (everolimus) in patients with advanced, progressive, somatostatin receptor-positive GEP NETs. METHODS:This phase 3, open-label, superiority trial included patients aged 18 years or older with treatment-naive or previously treated unresectable or metastatic (or both) grade 1-2 GEP NETs. Patients were enrolled from 49 specialist neuroendocrine tumour treatment centres across 14 countries in Africa, Europe, North America, and Oceania and randomised (2:1) to intravenous [177Lu]Lu-edotreotide (7·5 ± 0·7 GBq every 3 months, maximum four cycles) or oral everolimus (10 mg/day) for up to 30 months. Random assignment was via a central, web-based randomisation system (block size of 6) and stratified by primary tumour origin and previous therapy. The primary endpoint was progression-free survival, assessed via blinded independent central review in all randomly assigned patients at 30 months. Harms were assessed in all enrolled patients who received at least one dose of a study drug. This study was registered with ClinicalTrials.gov (NCT03049189) and is no longer recruiting. FINDINGS:Between April 13, 2017, and June 20, 2022, 324 patients were enrolled and 309 patients (including 168 [54%] male patients and 141 [46%] female patients) were randomly assigned to treatment: 207 to the [177Lu]Lu-edotreotide group and 102 to the everolimus group. The median follow-up for progression-free survival was 27·5 months (IQR 19·6-30·4) for the [177Lu]Lu-edotreotide group and 21·2 months (8·9-29·4) for the everolimus group. Median progression-free survival was significantly longer with [177Lu]Lu-edotreotide versus everolimus (23·9 months [95% CI 18·7-30·0] vs 14·1 months [9·2-20·9]; stratified hazard ratio 0·67 [95% CI 0·48-0·95]; p=0·022). Treatment-related adverse events occurred in 178 (82%) of 217 patients in the [177Lu]Lu-edotreotide group and 96 (97%) of 99 patients in the everolimus group. 40 (18%) patients in the [177Lu]Lu-edotreotide group and 40 (40%) in the everolimus group had at least one treatment-related grade 3-4 adverse event. The most common treatment-related adverse events in the [177Lu]Lu-edotreotide group were diarrhoea and nausea (both 79 [36%] patients) and asthenia (66 [33%] patients), whereas those in the everolimus group were diarrhoea (45 [45%] patients), asthenia (36 [36%] patients), and anaemia (27 [27%] patients). No treatment-related deaths occurred in either study group. INTERPRETATION:[177Lu]Lu-edotreotide led to statistically significant and clinically meaningful improvements in progression-free survival. Efficacy and harms results support the use of [177Lu]Lu-edotreotide in early lines of therapy in patients with advanced, progressive GEP NETs. FUNDING:ITM Solucin.

Neuroendocrine neoplasms (NEN) comprise well-differentiated neuroendocrine tumours (NET) and neuroendocrine carcinomas (NEC), whose distinction is clinically critical. Although c-MYC alterations have been implicated in NEC pathogenesis, its expression across NEC subtypes and anatomical sites, as well as in NET, remains incompletely defined. We analysed c-MYC immunohistochemically in 1380 resected NEN using the immunoreactive score (IRS: negative 0–1, weak 2–3, moderate 4–8, strong 9–12). Overall, c-MYC positivity (IRS ≥ 2) was observed in 13.3% of NEN. Expression was detected in 43% of NEC (164/381), including strong staining in 19.4%, whereas it was rare in NET and pulmonary carcinoids (20/999; 2%; p ≤ 0.001 ). Within NEC, c-MYC expression was enriched in LCNEC and MiNEN compared with SCNEC and Merkel cell carcinoma ( p ≤ 0.001 ) and occurred more often in gastroenteropancreatic than in pulmonary NEC (57.6% vs. 37.3%; p ≤ 0.001 ). Among NET, G3 tumours showed the highest positivity rate (6/35; 17.1%), although this was significantly lower than in NEC ( p ≤ 0.001 ), with strong expression observed in only one NET G3 (2.9%). No association between c-MYC expression and survival was identified in either NEC or NET. Our study confirms c-MYC expression as a common event in NEC and highlights differences across histological subtypes and anatomical sites, while demonstrating its absence in most low-proliferative NET. A subset of NET G3 tumours exhibits weak to moderate c-MYC expression at levels far below those seen in NEC, suggesting that strong c-MYC positivity may support an NEC classification in borderline cases but does not represent a definitive discriminatory marker.

Abstract:Neuroendocrine tumors of the gastrointestinal tract, including those of the pancreas, comprise a broad spectrum of potentially malignant neoplasms that are being diagnosed with increasing incidence. This article provides an overview of these tumors-and describes, in particular, endoscopic treatment options as well as the standards and recent developments in systemic therapies.

OBJECTIVE:Most neuroendocrine neoplasms (NENs) are sporadic and occur predominantly in older patients. Early-age disease onset has been increasingly observed in NENs. We aimed to assess the clinical features and outcomes of young adults with sporadic NENs. DESIGN:This is a retrospective study that gathered 20 institutions from 12 countries under the auspices of Women in NET (WiN) ENETS group. METHODS:Young patients aged 18-40 years diagnosed with sporadic NENs (well and poorly differentiated) from 2010 to 2020 were enrolled. Patients with appendiceal and type 1 gastric NETs, hereditary syndromes, synchronous malignancy, pheochromocytoma, paraganglioma, and medullary thyroid cancer were excluded. Descriptive statistics, comparisons between groups, survival, and Cox multivariable analysis were performed. RESULTS:Overall, 478 young patients with sporadic NENs were enrolled. Localised (62%, n = 249), well-differentiated (92%, n = 433), non-functioning tumours (81%, n = 384), and women (58%, n = 277) were more prevalent. The pancreas was the most common primary site (33%, n = 159). Metastatic disease at diagnosis was more often found in men than women (47%, n = 78 vs. 33%, n = 78, P = .004). Five-year overall survival was 82%. Overall survival was significantly longer in women than men (P = .019), as well as in rectal (P = .00245) and lung (P = .0027) primary tumours compared to pancreatic NENs. The multivariable analysis identified stage, Ki-67, morphology, and gender as independent predictors of survival. CONCLUSIONS:Young patients with NENs often present with well-differentiated and localised tumours, thereby increasing the probability of curative surgical resection. Prospective research into molecular biology is needed to identify distinct NEN features in young adults and determine risk factors to tailor effective treatment strategies.

Background and Purpose Personalized medicine is guided by an expanding array of molecular targets. This study investigates whether larger next-generation sequencing (NGS) gene panels (> 1 Mb) yield more clinically relevant therapy options in molecular tumor boards (MTB) compared to smaller panels. Patients and Methods We analyzed 281 consecutive patients using a 430-gene DNA panel (1.3 Mb) combined with a RNA-fusion panel and compared the findings to a 185-gene DNA panel (618 kb). Results Molecular alterations were detected in 97.2% of tumors with either oncogenic variants and/or gene fusions. Among these, 170 (60.5%) received a molecular-stratified therapy recommendation from the local MTB. Only 8.8% depended on the expanded 430-gene DNA panel, and additionally identified actionable variants in five additional genes. High TMB alone enabled 4.1% of MTB recommendations. Conclusion Our findings indicate that sufficient genomic coverage in DNA panels is essential for reliable TMB calculation, defining a minimal standard for genomic cancer care.

Ziel/Aim: Gastroenteropancreatic neuroendocrine tumors (GEP-NET) are a rare disease [1] [2]. Current guidelines recommend treatment with somatostatin receptor (SSTR) targeting radioligand therapy (RLT) [1] [3]. SSTR-RLT is available as 177Lu-radiolabeled somatostatin analogues locally compounded by hospitals (non-licensed product) and as EMA approved product with standardized formulation and application. Limited real-world data exist on the German care situation with SSTR-RLT.

Delta-like ligand 3 (DLL3) is frequently expressed in pulmonary small cell neuroendocrine carcinoma (SCNEC) and has emerged as a promising therapeutic target. However, limited data on DLL3 expression in other neuroendocrine neoplasms (NEN), such as extrapulmonary SCNEC, large cell neuroendocrine carcinomas (LCNEC), mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN), gastroenteropancreatic neuroendocrine tumours (GEP-NET), and pulmonary carcinoids, impedes an estimation if other types of NEN might be suitable candidates for anti-DLL3 therapies. We evaluated DLL3 expression in 1294 NEN and 479 non-neuroendocrine carcinomas, correlating the findings with histological subtypes, tumour localisation, and overall survival (OS). Furthermore, we explored the concordance of DLL3 expression during metastatic progression in 67 paired primary NEN and metastases. DLL3 expression was significantly higher in NEC (64.0%) compared to GEP-NET and pulmonary carcinoids (10.1%, p < 0.001), particularly in SCNEC (80.4%), followed by LCNEC (62.6%) and MiNEN (28.6%). DLL3 was common in pulmonary carcinoids (41.5%), but rare in GEP-NET (5.1%) and non-neuroendocrine carcinomas (1.3%). Overall DLL3 expression was highly concordant between metastases and corresponding primary NEN (92.5%, p < 0.001). In univariable analyses, DLL3-expressing pulmonary carcinoids (p = 0.005) and GEP-NET (p = 0.018) were associated with decreased OS, but this was not retained in multivariable analyses adjusting for stage and grade (p = n. s.). No prognostic impact was observed in pulmonary (p = 0.708) or GEP-NEC (p = 0.87). Our study highlights significant differences in DLL3 expression across NEN subtypes and localisations, with largely concordant expression in metastases. DLL3-based therapies may be effective in many NEC and pulmonary carcinoids, while DLL3 appears to be a minor therapeutic target for GEP-NET and non-neuroendocrine carcinomas.

BACKGROUND:Complete resection is the only chance for cure in small intestine neuroendocrine neoplasms (SI-NEN). Previous ENETS guidelines proposed standards for the surgery of SI-NEN, which should be followed to provide long-term disease-free survival. AIM:To analyze the results of reintervention for locoregional SI-NEN (stages I-III) after suboptimal initial resection. METHODS:Perioperative characteristics of all patients who underwent surgical reintervention after suboptimal initial resection (SIR) of locoregional SI-NEN were retrieved from a prospective database. Patient characteristics, initial and redo procedures, imaging before reintervention, pathological results of SIR, and after reintervention, including missed primary tumors and lymph node metastases, were retrospectively analyzed. RESULTS:During a 15 years period, 21 of 93 (22%) patients had surgical reinterventions after SIR. In 20 of 21 (95%) cases, the initial resection was performed outside an ENETS center of excellence. Ten (48%) of those cases were emergency operations because of the bowel obstruction or bowel bleeding. Seven SIR (33%) cases were performed laparoscopically, and in another 5 (24%) cases, a complete endoscopic mucosa resection was performed. Imaging before reintervention visualized residual disease in 15 of 21 (71%) patients. Surgical reintervention included either lymphadenectomy alone (LAD, n = 3) or small bowel resection plus systematic LAD (n = 12) or right hemicolectomy/ileocecal resection with systematic LAD (n = 6), respectively. In 19 of 21 (90%) patients, a R0 resection could be achieved. One patient (5%) experienced postoperative clinically relevant complications. According to pathology, in 10 (48%) patients lymph node metastases, in 6 (29%) patients additional primary tumors, and in 5 (24%) patients, both lymph nodes metastases and primary tumors were left behind in the SIR. After mean follow-up of 52 months, 16 (76%) of 21 patients were free of disease, 4 (19%) patients were alive with disease, and 1 patient deceased of an unrelated cause. CONCLUSION:The proposed standards to resect locoregional SI-NEN should be followed to avoid SIR, although the prognosis after adequate surgical reintervention is good.

Non-functioning pancreatic neuroendocrine tumors (NF-pNETs) significantly contribute to the premature death of multiple endocrine neoplasia type 1 (MEN1) patients. Reliable prognostic markers are not yet available. MicroRNAs (miRNA) and long-non-coding (lnc) RNAs, transported by extracellular vesicles, are emerging as new prognostic tools. This study aimed to analyze the clinical characteristics, the exosomal-miRNA 451 (exo-miR451) and the lnc-RNA nuclear paraspeckle assembly transcript 1 (NEAT1_1, 3.7 kB) in the mild and aggressive courses of MEN1-NFpNET disease. Patient characteristics were assessed regarding an aggressive course of disease. In addition, exo-miR451 and exo-lnc-NEAT1_1 expression levels were quantified in serum by RT-qPCR and correlated with clinical data. Immunohistochemistry results of STAT3 (signal transducer and activator of transcription 3), regulated by NEAT1, were performed in NF-pNET tissue and correlated with exo-lnc-NEAT1_1 expression. Among 66 MEN1 patients with NF-pNETs, 13 (20%) had an aggressive disease course. No significant differences in patient characteristics were observed between those with aggressive (n = 13) and mild (n = 53) disease (all p > .5). Exosomal miRNA-451 was dysregulated in 55% (n = 23) of cases, showing a trend toward higher upregulation in the aggressive group (36% vs. 19%), although this difference was not statistically significant (p = .215). Exo-NEAT1_1 was overexpressed in 42% (16/38) of patients, without significant differences between groups (p = .0523). However, exo-NEAT1_1 expression strongly correlated with STAT3 immunohistochemical staining (p = .001). Although no prognostic marker could be identified, we show for the first time that the STAT3-NEAT1 pathway plays a role in MEN1-associated NF-pNET tumorigenesis.

Background: Approximately 10% of patients with small intestine neuroendocrine neoplasms (SI-NENs) present with locally advanced, unresectable symptomatic disease. The present study analyzed the results of debulking of the mesenteric mass in such patients. Methods: Patients operated on for locally advanced SI-NEN disease were identified from the prospective database of the ENETS Center of Excellence Marburg based on the review of imaging results and operative notes. “Locally advanced” was defined as mesenteric disease involving the mesenteric root above the level of the horizontal part of the duodenum and/or extending into the retroperitoneum. Patient characteristics, operations, and outcomes were retrospectively analyzed. Results: 29 of 202 (14%) operated SI-NEN patients (79% male) operated on, with a median age of 63 (46–78) years, had symptomatic locally advanced disease and presented with either abdominal pain (76%) and/or symptoms of obstruction (38%). Imaging revealed a mesenteric mass >10 mm above the level of the pars descendens duodeni in 15 (52%) patients, with tumor-related obstruction of the superior mesenteric vein in 17 (59%) patients. Fourteen (48%) patients had had previous surgery with primary tumor resection (n = 10) or diagnostic or bypass procedures (n = 4). Debulking of the mesenteric mass with (n = 26) or without (n = 2) bowel resection was performed 28 patients; the remaining patient underwent only resection of the ischemic bowel. Median operating time was 262 (156–411) minutes. Four (14%) patients had clinically relevant postoperative complications; one patient died perioperatively. A total of 27/29 (93%) patients reported improvement in preoperative abdominal symptoms. After a median follow-up of 28 (1–142) months, 21 (72%) patients were alive with disease. Conclusions: Debulking of the mesenteric mass in locally advanced symptomatic SI-NENs is a challenging procedure, but most patients benefit in terms of bowel symptoms.

Supplementary Table S1. Representativeness of Study Participants.

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are rare malignancies deriving from the endocrine system in the gastrointestinal tract including the pancreas. Prognosis is greatly heterogenous due to its dependency on various factors, most importantly stage and differentiation. Several studies report an alarming rise in incidence in the past decade. Despite there being some therapeutical options, best therapy sequence still needs to be defined, particularly for unresectable and/or intermediate and high-grade NENs. Peptide receptor radionuclide therapy (PRRT) was approved in Europe and USA in 2017 and 2018, respectively. Studies with real-world systematic data on characteristics and treatment patterns of PRRT-receiving patients was non-existent at the time of this writing. In this retrospective study, we identified within the German NET-Registry 203 patients diagnosed with GEP-NEN having received PRRT from 1995 to 2023. We assessed general clinical patient characteristics, disease-specific characteristics, treatments and outcomes. To obtain a more up-to-date picture of treatment modalities and outcomes, a subgroup of the study population was allocated to the "therapy cohort," defined by patients with date of first diagnosis between 2010 and 2023 (open cohort). Mean age of the study population was 58 years (SD 12 years) with 51.7% being men. Most patients had a WHO performance score of 0 to 1 (41.4% and 50.5%, respectively). Most NEN cases were of small intestine/pancreatic origin (46.3% and 45.3%, respectively) and displayed well/moderate differentiation (55.3%). Ki-67 was generally within the 3% to 20% range (57.92%). Most patients presented with metastasis at diagnosis (73.9%). Somatostatin analogs (SSAs), chemotherapy and surgery were the most common non-PRRT therapy options (65.3%, 60.2%, and 50.0%, respectively). PRRT was most often applied as third- or second-line therapy (42.3% and 36.6%, respectively), usually after surgery and/or SSA treatment. As PRRT had been administered using different regimens, tumor response evaluation showed mixed responses. Given the low sample size and considerable amount of missing response data, no correlation analysis between PRRT sequencing and tumor response could be performed. Overall, the clinical characteristics and treatment patterns tend to follow trends observed in other studies or medical guidelines. Finally, this study presents real-world data that more accurately describes GEP-NEN disease in Germany and treatment modalities after PRRT's approval.

Neuroendocrine neoplasms of the appendix (aNET) are rare tumors that are often diagnosed by pathology as an incidental finding after appendectomy for acute appendicitis. Several guidelines proposed risk criteria to indicate oncological completion surgery after appendectomy. The aim of this study was to evaluate the reliability of proposed criteria for completion surgery of aNET. Patients with aNET treated at ENETS center of excellence Marburg between 2002 and 2022 were retrieved from a prospective data base. Demographic data, histopathological findings, including formerly proposed criteria to indicate oncological completion surgery, histological results of the completion resection and disease-free survival were evaluated. 82 patients with a median age of 35 (range 8–82) years were analysed. 72 (88

Abstract Purpose: Neuroendocrine neoplasms grade 3 (NEN G3) are rare tumors with poor prognosis and no established second-line therapy. The role of immune checkpoint blockade in these aggressive tumors remains unclear. Patients and Methods: The phase II AveNEC study evaluated the effect of avelumab (AVE, 10 mg/kg i.v. every 2 weeks) in 60 patients with well-differentiated high-grade neuroendocrine tumors (N = 22) or poorly differentiated neuroendocrine carcinomas (N = 38) progressing after ≥1 prior chemotherapy (excluding Merkel cell carcinoma and small cell lung cancer). Results: The best overall response according to immune-related Response Evaluation Criteria in Solid Tumors (iRECIST) was partial response (PR) in three (5%) and stable disease (SD) in nine (15%) patients, with a disease control rate at 16 weeks of 15% (3 PRs; 6 SDs) and a median duration of response of 4.3 months. Six (10%) patients achieved SD or PR for >6 months and two for >1 year. Response rates were similar regardless of differentiation, Ki-67 expression, or primary localization. The median progression-free survival was 1.9 months, and the overall survival was 6.6 months. After a median follow-up of 3.6 years, only four (7%) patients were still alive; 1- and 2-year survival rates were 33% and 17%, respectively. Responders had a significantly longer overall survival of 30.2 months compared with 4.8 months in nonresponders. AVE was well tolerated, with few treatment-related grade 3/4 adverse events, and the quality of life remained stable during treatment. Conclusions: In patients with progressive high-grade NEN G3, AVE was well tolerated and provided disease control with significant clinical benefit in 15% of heavily pretreated patients.

Neuroendocrine tumors (NETs) are a rare and heterogeneous class of neoplastic lesions, but their prevalence has increased significantly over the past three decades. These tumors are aggressive and difficult to treat. Improving diagnostic efficiency and treatment effectiveness is important for patients with neuroendocrine tumors. Radiopharmaceutical therapeutic diagnostics combines diagnosis and treatment technology and has broad prospects in precision medicine, especially for the early diagnosis and treatment of tumors. To compare the diagnostic advantages of radiolabeled somatostatin receptor agonists and antagonists for liver metastases from NETs and the disease control rate in NET patients. Systematic search of PubMed, Embase, Cochrane, Ovid, Scopus, and Web of Science databases up to 29 October 2024. Clinical trials of somatostatin receptor agonists and antagonists for NET diagnosis or treatment. Following PRISMA guidelines, data were independently extracted by two researchers. Pooled diagnostic or treatment effects and 95% CIs were reported using a random-effects meta-analysis model. Effect of somatostatin receptor agonists and antagonists in detecting liver metastases and disease control rate. Risk Ratio (RR) for liver metastasis detection and Effect Size (ES) for disease control rate were calculated. From 5291 articles, 52 were included in the meta-analysis. Radiolabeled somatostatin receptor antagonists were significantly more effective than agonists in detecting liver lesions (RR = 11.57, 95% CI: 4.10, 32.67). Disease control rates were higher with antagonists (ES = 0.90, 95% CI: 0.83, 0.96) compared to agonists (ES = 0.82, 95% CI: 0.78, 0.85, z = 2.12, p = 0.03). Radiolabeled somatostatin receptor antagonists outperform agonists in diagnosing hepatic lesions and controlling disease in NETs, highlighting their clinical superiority. This meta-analysis provides critical insights into the diagnostic and therapeutic efficacy of somatostatin receptor antagonists, and may offer a potential paradigm shift in the management of neuroendocrine tumors. Nevertheless, the smaller number of studies on antagonists may limit the generalizability of the findings and underscore the need for further clinical trials to validate these results.

e16351 Background: The prognosis of patients with neuroendocrine neoplasia (NEN) depends mainly on the proliferation index (Ki67). Patients with NEN G1 and G2 frequently survive many years, while those with NEN G3 often die within 12 months after diagnosis. For patients with NET G1/G2, a few approved treatment options are available, while for NEN G3 the choice is very limited. Among NEN G3, those with a Ki67 of > 60% respond well to platinum-based chemotherapies, while there is no trial-proven treatment option for slower-proliferating G3 tumors. The CABONEN study evaluates the tyrosine kinase inhibitor Cabozantinib, which has shown striking activity in NEN G1/G2, in NEN G3 with a Ki67 up to 60%. Here we present the efficacy and tolerability outcomes of the second per-protocol planned interim analysis. Methods: CABONEN represents a prospective, single-arm, multicenter phase II trial investigating the efficacy and safety of Cabozantinib in NEN G3 patients with a Ki67 between 20% and 60%. Primary endpoint is disease control rate (DCR) after 6 months; secondary endpoints include DCR after 3 and 12 months, progression free survival (PFS), overall survival (OS), objective response rate (ORR), time on medication (TOM), quality of life, and toxicity. Results: From December 2021 to December 2024, all 45 planned patients (21 female, 24 male) were enrolled although not all patients have reached 6 month of treatment for the primary endpoint. Of these, 39 patients had NET G3, and 6 patients had NEC Ki67low. The median age at diagnosis was 63 years (40 to 84 years). The primary tumor location was the pancreas in 53.3% (24), the GI tract in 20% (9) lung in 11.1% (5), and others in 15.5 % (7). The median Ki67 was 31% (21% to 60%). Twelve patients were therapeutically naïve (26.7%), 13 had received 1 prior therapy (28.9%) and 20 had received 2 or more therapeutic lines (44.4%). The primary end point DCR at 6 months was 83% and at 3 months 92.1% The best objective response rate was 19.5% and the median PFS was 9.7 months. During therapy, a total of 105 SAEs were observed including 74 SAE grade 3, 1 SAE grade 4, and 4 SAE grade 5, with SAEs being ileus, acute pain, cholangiosepsis, infection, small intestinal perforation, or stroke. A Data and Safety Monitoring Board could not find any new and unexpected (S)AEs and recommends continuation of the study. Conclusions: At interim analysis, Cabozantinib represents a safe and effective treatment option in patients with low proliferative NEN G3. The CABONEN study will continue to the next planned analysis. Clinical trial information: EudraCT Number: 2020-002541-41 .

INTRODUCTION:Secretion of parathormone related peptide (PTHrp) is the most common cause of tumor-associated hypercalcemia. This occurs most often in squamous cell carcinomas in the ear nose and throat, bronchial and breast carcinomas. We report a rare case of a PTHrp-producing pancreatic neuroendocrine tumor (pNET) and provide a brief review of the literature. CASE PRESENTATION:A 68-year-old female patient with epigastric pain and weight loss was diagnosed with a 11 × 8 × 9 cm tumor in the pancreatic body with infiltration of the splenic vein and consecutive portal vein thrombosis without evidence of distant metastases. An endosonographic fine needle aspiration revealed a neuroendocrine tumor G2 (Ki-67 3 %). Laboratory analyses showed an asymptomatic hypercalcemia and elevated PTHrp. Distal splenopancreatectomy, left adrenalectomy, thrombectomy of the portal vein, cholecystectomy and partial resection of the left renal vein was performed. Histopathologic examination showed a PTHrp-producing NET of the pancreas G2, pT4 pN0 M0 L0 V2 Pn0 R0. Postoperatively serum levels of PTHrp and calcium dropped to normal values. DISCUSSION:Up to date only 83 cases of PTHrp producing pNETs have been reported in the English literature. Frequently, as in the reported patient, locally advanced or already distantly metastasized tumors were present. In addition to initial drug control of hypercalcemia, surgical treatment in case of R0 resection offers long-term symptom control and should be performed, when possible. CONCLUSION:In case of a pancreatic tumor and the simultaneous occurrence of hypercalcemia, the determination of PTHrp should be considered. Surgical resection remains the only curative therapy.