Ulrich Knigge

Atypical lung carcinoid (AC) is widely accepted to recur more often after radical resection than typical lung carcinoid (TC). However, their recurrence rates have never been compared in a multi-state competing risks model. We retrospectively reviewed files from patients with AC and TC who had been radically resected at our European Neuroendocrine Tumor Society Center of Excellence between 2009 and 2020. We estimated the recurrence rates between the AC and TC patients counting unrelated death as a competing event using Aalen–Johansen estimates and compared them using a multi-state Cox model. Finally, we analyzed all AC and TC recurrences as to resection type, pathological stage, resection margin, recurrence site, and time to recurrence. The study included 217 patients, of whom 194 had TC and 23 had AC. The median follow-up was 9.4 years. The AC patients experienced recurrence at a higher rate (hazard ratio [HR] 16.0, 95% confidence interval [CI] 5.3–47.9, p < 0.001). Correspondingly, the 5- and 10-year recurrence rates were 18% and 32% for AC and merely 1.0% and 2.4% for TC. In patients without nodal involvement, AC recurred at a considerably higher rate (HR 41.2, 95% CI 8.7–194.8, p < 0.001) than TC. In both AC and TC, most recurrences were distant and occurred in patients with a resection margin less than 2 cm. We conclude that AC recurs more often than TC, even in patients without nodal involvement at surgery, suggesting that all AC patients regardless of their pathological stage should undergo close follow-up care after surgery.

This case report presents a 40-year-old patient with a vasoactive intestinal peptide (VIP) secreting high grade (Ki-67 39%) neuroendocrine tumor (NET) from the pancreas, for whom successful liver transplantation (LT) was carried out 8 years after resection of the primary tumor due to massive liver metastases. The transplantation was done as rescue therapy due to rapid progression and a devastating clinical condition requiring intravenous supplementation for 20 hours daily. The latest imaging carried out 18 months after transplantation is without signs of recurrence, and the patient is in good health with undetectable levels of VIP. According to the guidelines, LT is only recommended if Ki-67 is <20% and if there has been tumor control for more than 6 months prior to transplantation. Our case illustrates that LT is an option that should be considered for selected NET patients without extrahepatic involvement regardless of tumor grade and clinical condition.

The present report describes the history of a 58-year-old woman with a rapidly progressing neuroendocrine pancreatic tumor (initially G2) presenting with extensive liver, bone, and lymph node metastases. Previous treatments included chemotherapy, hemithyroidectomy for right lobe metastasis, Peptide Receptor Radionuclide Therapy (PRRT) with [¹⁷⁷Lu]Lu-DOTATATE, Lanreotide, Everolimus, and liver embolization. Due to severe disease progression, after a liver biopsy revealing tumor grade G3, PRRT with the somatostatin receptor antagonist LM3 was initiated. [⁶⁸Ga]GaDOTA-LM3 PET/CT showed intense tracer uptake in the liver, pancreatic tumor, lymph nodes, and bone metastases. Three TANDEM-PRRT cycles using [¹⁷⁷Lu]LuDOTA-LM3 and [²²⁵Ac]AcDOTA-LM3, administered concurrently, resulted in significant improvement, notably in liver metastases, hepatomegaly reduction, the complete regression of bone and lymph node metastases, and primary tumor improvement. Partial remission was confirmed by positron emission tomography/computed tomography, chest–abdomen–pelvis contrast-enhanced computed tomography, and magnetic resonance of the abdomen, with marked clinical improvement in pain, energy levels, and quality of life, enabling full resumption of physical activity.

Background: Given the rarity and heterogeneity of pancreatic neuroendocrine neoplasms (pNEN), treatment algorithms and sequencing are primarily guided by expert opinions with limited evidence. Aim: To investigate overall survival (OS), median progression-free survival (mPFS), and prognostic factors associated with the most common medical treatments for pNEN. Methods: Retrospective single-center study encompassing patients diagnosed and monitored between 2000 and 2020 (n = 192). Results: Median OS was 36 (95% CI: 26–46) months (99 months for grade (G) 1, 62 for G2, 14 for G3, and 10 for neuroendocrine carcinomas). Patients treated with somatostatin analogues (SSA) (n = 59, median Ki-67 9%) had an mPFS of 28 months. Treatment line (HR (first line as reference) 4.1, 95% CI: 1.9–9.1, p ≤ 0.001) emerged as an independent risk factor for time to progression. Patients with a Ki-67 index ≥10% (n = 28) had an mPFS of 27 months. Patients treated with streptozocin/5-fluorouracil (STZ/5FU) (n = 70, first-line treatment n = 68, median Ki-67 10%) had an mPFS of 20 months, with WHO grade serving as an independent risk factor (HR (G1 (n = 8) vs. G2 (n = 57)) 2.8, 95% CI: 1.1–7.2, p-value = 0.031). Median PFS was 21 months for peptide receptor radionuclide therapy (PRRT) (n = 41, first line n = 2, second line n = 29, median Ki-67 8%), 5 months for carboplatin and etoposide (n = 66, first-line treatment n = 60, median Ki-67 80%), and 3 months for temozolomide-based therapy (n = 56, first-line treatment n = 17, median Ki-67 30%). Conclusion: (1) Overall survival was, as expected, highly dependent on grade; (2) median PFS for SSA was around 2.5 years without difference between tumors with Ki-67 above or below 10%; (3) STZ/5FU as first-line treatment exhibited a superior mPFS of 20 months compared to what has historically been reported for targeted treatments; (4) PRRT in G2 pNEN achieved an mPFS similar to first-line chemotherapy; and (5) limited treatment efficacy was observed in high-grade tumors when treated with carboplatin and etoposide or temozolomide.

Atypical carcinoid (AC) is a rare neuroendocrine neoplasm of the lung, which exhibits a varying malignant potential. In this study, we aimed to identify the prognostic thresholds of the mitotic count and Ki-67 labeling index for recurrence and survival in AC. We retrospectively reviewed 78 patients who had been radically resected for AC and calculated said thresholds using time-dependent receiver operating characteristic curves and the Youden index. We then dichotomized the patients into groups of above or below these thresholds and estimated the cumulative incidences of the groups using the Aalen–Johansen estimator. We compared the groups using univariable and multivariable Fine–Gray subdistribution hazard models. Our findings show that more patients recurred and died from this disease if their mitotic count exceeded three and four mitoses per 2 mm², respectively, or if their Ki-67 labeling index exceeded 14% and 11%, respectively. Both thresholds independently predicted survival (p < 0.001 and p = 0.015, respectively). These thresholds may serve as a valuable tool for clinicians and researchers in making treatment plans and predicting outcomes for patients with AC.

Background: Small intestinal neuroendocrine tumors (siNET) are one of the most common neuroendocrine neoplasms. Radical surgery is the only curative treatment. Method: We utilized a single-center study including consecutive patients diagnosed from 2000 to 2020 and followed them until death or the end of study. Disease-specific survival and recurrence-free survival (RFS) were investigated by Cox regression analyses with the inclusion of prognostic factors. Aims/primary outcomes: We identified three groups: (1) disease specific-survival in the total cohort (group1), (2) RFS and disease-specific survival after intended radical surgery (group2), (3) disease specific-survival in patients with unresectable disease or residual tumor after primary resection (group3). Results: In total, 615 patients, with a mean age (SD) 65 ± 11 years were included. Median (IQR) Ki-67 index was 4 (2–7)%. Median disease-specific survival in group1 was 130 months. Median RFS in group2 was 138 months with 5- and 10-year RFS rates of 72% and 59% with age, plasma chromogranin A (p-CgA) and Ki-67 index as prognostic factors. The ten year disease-specific survival rate in group2 was 86%. The median disease-specific survival in group3 was 85 months with age, Ki-67 index, p-CgA and primary tumor resection as prognostic factors. When proliferation was expressed by WHO grade, no difference was observed between G1 vs. G2 for any of the primary outcomes. Conclusions: Recurrence rates remained high 5–10 years after surgery (group2) supporting long-term follow-up. Median disease-specific survival in patient with unresectable disease (group3) was 7 years, with a favorable impact of primary tumor resection. Our data does not support the current grading system since no significant prognostic information was detected in G1 vs. G2 tumors.

Introduction: The prognosis and impact of different prognostic factors in pancreatic neuroendocrine neoplasms (pNEN) remain controversial. Aim: To investigate prognostic factors for recurrence-free survival and disease-specific survival in patients with pNEN, divided into three groups: patients undergoing surveillance (tumor size < 2 cm, group 1), patients followed after curative-intended surgery (group 2), and patients with unresectable disease or residual tumors after resection (group 3). Method: A single-center retrospective study including consecutive patients over a 20-year period. Multivariate Cox regression analyses were performed to identify risk factors. Results: 413 patients were included, with a mean (SD) age of 62 ± 14 years. In group 1 (n = 51), median (IQR) follow-up was 29 (21–34) months, and tumor size was 1.0 (0.8–1.4) cm. One progressed and had a tumor resection. In group 2 (n = 165), follow-up 59 (31–102) months, median tumor size 2 (1.2–3.4) cm, median Ki-67 index 5 (3–10)%, the 5-year recurrence rate was 21%. Tumor size (p < 0.001), Ki-67 index (p = 0.02), and location in the pancreatic head (p < 0.001) were independent risk factors. In group 3 (n = 197), follow-up 19 (6–46) months, median tumor size 4.2 (2.6–7.0) cm, Ki-67 index 17 (9–64)%, the median disease-specific survival was 22 (6–75) months—99 in NET G1; 54 in NET G2; 14 in NET G3; and 6 months in neuroendocrine carcinomas (NEC). Age (p = 0.029), plasma chromogranin A (p = 0.014), and proliferation, expressed by grade (p = 0.001) and Ki-67 index (p < 0.001), were risk factors. Conclusion: Growth in pNET < 2 cm requiring surgery was observed in 1/51. Tumor size, Ki-67 index, and location in the head were prognostic factors for disease recurrence, while age, plasma chromogranin A, and proliferation predicted mortality in patients with unresectable disease or residual tumors after resection.

Opinion statement In the 2019 WHO guidelines, the classification of gastro-entero-pancreatic neuroendocrine neoplasms (GEP NEN) has changed from one being based on Ki-67 proliferation index alone to one that also includes tumor differentiation. Consequently, GEP NENs are now classified as well-differentiated neuroendocrine tumor (NET), NET G1 (Ki-67 20%), and poorly differentiated neuroendocrine carcinoma (NEC) (Ki-67 >20%). It has been suggested that NET G3 should be treated as NET G2 with respect to surgery, while surgical management of NEC should be expanded from local disease to also include patients with advanced disease where curative surgery is possible. High grade mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) have a neuroendocrine and a non-neuroendocrine component mostly with a poor prognosis. All studies evaluating the effect of surgery in NEC and MiNEN are observational and hold a risk of selection bias, which may overestimate the beneficial effect of surgery. Further, only a few studies on the effect of surgery in MiNEN exist. This review aims to summarize the data on the outcome of surgery in patients with GEP NET G3, GEP NEC and high grade MiNEN. The current evidence suggests that patients with NEN G3 and localized disease and NEN G3 patients with metastatic disease where curative surgery can be achieved may benefit from surgery. In patients with MiNEN, it is currently not possible to evaluate on the potential beneficial effect of surgery due to the low number of studies.

Arginine-Glycine-Aspartate (RGD)-recognizing cell surface integrins are involved in tumor growth, invasiveness/metastases, and angiogenesis, and are therefore an attractive treatment target in cancers. The subtype integrin α_vβ₃ is upregulated on endothelial cells during angiogenesis and on tumor cells. In vivo assessment of integrin α_vβ₃ is possible with positron emission tomography (PET). Preclinical data on radiochemical properties, tumor uptake and radiation exposure identified [⁶⁸Ga]Ga-NODAGA-E[c(RGDyK)]₂ as a promising candidate for clinical translation. In this first-in-human phase I study, we evaluate [⁶⁸Ga]Ga-NODAGA-E[c(RGDyK)]₂ PET in patients with neuroendocrine neoplasms (NEN) and breast cancer (BC). The aim was to investigate safety, biodistribution and dosimetry as well as tracer uptake in tumor lesions. A total of 10 patients (5 breast cancer, 5 neuroendocrine neoplasm) received a single intravenous dose of approximately 200 MBq [⁶⁸Ga]Ga-NODAGA-E[c(RGDyK)]₂. Biodistribution profile and dosimetry were assessed by whole-body PET/CT performed at 10 min, 1 h and 2 h after injection. Safety assessment with vital parameters, electrocardiograms and blood tests were performed before and after injection. In vivo stability of [⁶⁸Ga]Ga-NODAGA-E[c(RGDyK)]₂ was determined by analysis of blood and urine. PET images were analyzed for tracer uptake in tumors and background organs. No adverse events or pharmacologic effects were observed in the 10 patients. [⁶⁸Ga]Ga-NODAGA-E[c(RGDyK)]₂ exhibited good in vivo stability and fast clearance, primarily by renal excretion. The effective dose was 0.022 mSv/MBq, equaling a radiation exposure of 4.4 mSv at an injected activity of 200 MBq. The tracer demonstrated stable tumor retention and good image contrast. In conclusion, this first-in-human phase I trial demonstrated safe use of [⁶⁸Ga]Ga-NODAGA-E[c(RGDyK)]₂ for integrin α_vβ₃ imaging in cancer patients, low radiation exposure and favorable uptake in tumors. Further studies are warranted to establish whether [⁶⁸Ga]Ga-NODAGA-E[c(RGDyK)]₂ may become a tool for early identification of patients eligible for treatments targeting integrin α_vβ₃ and for risk stratification of patients.