Recurrence Rates and Patterns after Radical Resection of Lung Carcinoids.

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.

Semaglutide treatment of hypothalamic obesity - a real-life data study.

PURPOSE: Patients with tumors involving the hypothalamic region are at high risk of developing morbid obesity due to disturbances in the appetite regulative nuclei in hypothalamus. We evaluated the effect of the Glucagon-like peptide 1 (GLP-1) analogue semaglutide in patients with hypothalamic obesity. METHODS: We recorded weight changes from real-time data before and after treatment with semaglutide in patients with hypothalamic obesity from our outpatient clinic at the Department of Endocrinology at Rigshospitalet, from September 2020 to November 2023. RESULTS: A total of 26 patients were included in this study (15 females, median age at initiation of semaglutide was 52 (range 18-65) years). Body mass index (BMI) at initial diagnosis was median 25 (range 20-38) kg/m2 while BMI at initiation of semaglutide was median 38 (range 28-58) kg/m2. All but one patient lost weight during semaglutide treatment with a mean weight loss of 13.4 kg (95% CI 10.3-16.5 kg, p = < 0.001) after 12 months corresponding to a loss in BMI of 4.4 kg/m2 (95% CI 3.4-5.4 kg/m2, p = < 0.001) with a median dosage of semaglutide of 1.6 (range 0.5-2.5) mg. Fifteen patients (58%) lost more than 10% and two patients (8%) lost more than 20% of initial body weight, respectively. CONCLUSION: Treatment with semaglutide shows promising results in reducing body weight in patients with acquired hypothalamic obesity. Whether the weight reduction remains stable after long time follow-up needs further investigation.

Successful liver transplantation as rescue therapy in a patient with metastases from a vasoactive intestinal peptide producing neuroendocrine tumor.

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.

Acromegaly management in the Nordic countries: A Delphi consensus survey.

OBJECTIVE: Acromegaly is associated with increased morbidity and mortality if left untreated. The therapeutic options include surgery, medical treatment, and radiotherapy. Several guidelines and recommendations on treatment algorithms and follow-up exist. However, not all recommendations are strictly evidence-based. To evaluate consensus on the treatment and follow-up of patients with acromegaly in the Nordic countries. METHODS: A Delphi process was used to map the landscape of acromegaly management in Denmark, Sweden, Norway, Finland, and Iceland. An expert panel developed 37 statements on the treatment and follow-up of patients with acromegaly. Dedicated endocrinologists (n = 47) from the Nordic countries were invited to rate their extent of agreement with the statements, using a Likert-type scale (1-7). Consensus was defined as ≥80% of panelists rating their agreement as ≥5 or ≤3 on the Likert-type scale. RESULTS: Consensus was reached in 41% (15/37) of the statements. Panelists agreed that pituitary surgery remains first line treatment. There was general agreement to recommend first-generation somatostatin analog (SSA) treatment after failed surgery and to consider repeat surgery. In addition, there was agreement to recommend combination therapy with first-generation SSA and pegvisomant as second- or third-line treatment. In more than 50% of the statements, consensus was not achieved. Considerable disagreement existed regarding pegvisomant monotherapy, and treatment with pasireotide and dopamine agonists. CONCLUSION: This consensus exploration study on the management of patients with acromegaly in the Nordic countries revealed a relatively large degree of disagreement among experts, which mirrors the complexity of the disease and the shortage of evidence-based data.

Impressive Response to TANDEM Peptide Receptor Radionuclide Therapy with 177Lu/225AcDOTA-LM3 Somatostatin Receptor Antagonist in a Patient with Therapy-Refractory, Rapidly Progressive Neuroendocrine Neoplasm of the Pancreas.

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.

Effects of Peptide Receptor Radiotherapy in Patients with Advanced Paraganglioma and Pheochromocytoma: A Nation-Wide Cohort Study.

INTRODUCTION: Pheochromocytomas and paragangliomas are rare neuroendocrine tumours that originate from chromaffin cells within the adrenal medulla or extra-adrenal sympathetic ganglia. Management of disseminated or metastatic pheochromocytomas and paragangliomas continues to pose challenges and relies on limited evidence. METHOD: In this study, we report retrospective data on median overall survival (OS) and median progression-free survival (PFS) for all Danish patients treated with peptide receptor radionuclide therapy (PRRT) with 177Lu-Dotatate or 90Y-Dotatate over the past 15 years. One standard treatment of PRRT consisted of 4 consecutive cycles with 8-14-week intervals. RESULTS: We included 28 patients; 10 were diagnosed with pheochromocytoma and 18 with paraganglioma. Median age at first PRRT was 47 (IQR 15-76) years. The median follow-up time was 31 (IQR 17-37) months. Eight patients died during follow-up. Median OS was 72 months, and 5-year survival was 65% with no difference between pheochromocytoma and paraganglioma. Patients with germline mutations had better survival than patients without mutations (p = 0.041). Median PFS after the first cycle of PRRT was 30 months. For patients who previously received systemic treatment, the median PFS was 19 months, compared with 32 months for patients with no previous systemic treatment (p = 0.083). CONCLUSIONS: The median OS of around 6 years and median PFS of around 2.5 years found in this study are comparable to those reported in previous studies employing PRRT. Based on historical data, the efficacy of PRRT may be superior to 131I-MIBG therapy, and targeted therapy with sunitinib and PRRT might therefore be considered as first-line treatment in this patient group.

Changes in acromegaly comorbidities, treatment, and outcome over three decades: a nationwide cohort study.

Objective: To study the time-dependent changes in disease features of Danish patients with acromegaly, including treatment modalities, biochemical outcome, and comorbidities, with a particular focus on cancer and mortality. Methods: Pertinent acromegaly-related variables were collected from 739 patients diagnosed since 1990. Data are presented across three decades (1990-1999, 2000-2009, and 2010-2021) based on the year of diagnosis or treatment initiation. Results: Adenoma size and insulin-like growth factor I (IGF-I) levels at diagnosis did not differ significantly between study periods. The risk of being diagnosed with diabetes, heart disease, sleep apnea, joint disease, and osteoporosis increased from the 1990s to the later decades, while the mortality risk declined to nearly half. The risk of cancer did not significantly change. Treatment changed toward the use of more medical therapy, and fewer patients underwent repeat surgeries or pituitary irradiation. A statistically significant increase in the proportion of patients achieving IGF-I normalization within 3-5 years was observed over time (69%, 83%, and 88%). The proportion of patients with three or more deficient pituitary hormones decreased significantly over time. Conclusion: Modern medical treatment regimens of acromegaly as well as increased awareness and improved diagnostics for its comorbidities have led to better disease control, fewer patients with severe hypopituitarism, and declining mortality in the Danish cohort of acromegaly patients. The risk of cancer did not increase over the study period.

Responses to Medical Treatment in 192 Patients with Pancreatic Neuroendocrine Neoplasms Referred to the Copenhagen Neuroendocrine Tumour Centre in 2000-2020.

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.

Appendiceal Neuroendocrine Neoplasms: an Update for 2023.

PURPOSE OF REVIEW: To summarize the literature from the last 5 years on treatment of appendiceal neuroendocrine neoplasms (aNEN). Furthermore, to evaluate the prognostic significance of lymph node metastases, indications for adjuvant treatment, and challenges of the current follow-up regimen. RECENT FINDINGS: Simple appendectomy is sufficient in tumors < 1 cm while extended surgery is indicated in tumors > 2 cm. In a multicenter study of aNENs measuring 1-2 cm, extended surgery offered no significant prognostic advantage and is now limited to incomplete tumor resection or high-grade G2 or G3 aNEN. Follow-up remains debatable, as the use of imaging and biomarkers lacks validation. While surgical procedure is well established in aNEN tumors < 1 cm and > 2 cm, the need for extended surgery in aNEN tumors 1-2 cm is questionable. Future studies should address the prognostic impact of lymph node metastases and the optimal design and duration of follow-up.

Outlook for 615 Small Intestinal Neuroendocrine Tumor Patients: Recurrence Risk after Surgery and Disease-Specific Survival in Advanced Disease.

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.

Desmopressin Dose Requirements in Adults with Congenital and Acquired Central Diabetes Insipidus.

Central diabetes insipidus is a rare disorder characterized by a deficiency of vasopressin. The first line drug to treat this disorder is a synthetic analogue of vasopressin, desmopressin.The primary aim of this retrospective register study was to compare desmopressin dose requirements in patients with acquired and congenital DI, and secondly to assess the influence of BMI on dose requirement and risk of hyponatremia with different drug administrations. We included all patients with suspected DI attending the endocrine department at Rigshospitalet, Copenhagen, Denmark in 2022. We identified 222 patients who were included whereof 130/222 (58.6%) were females and median age was 53 years (IQR 35 to 63). The etiology included 7/222 (3.2%) congenital and 215/222 (96.8%) acquired. After converting nasal and sublingual doses to equivalent oral doses, the median daily dose requirement was 600 µg in patients with congenital etiology compared to 200 µg in patients with acquired etiology (p=0.005). We found no association between BMI and desmopressin dose requirements (p=0.6). During the past 12 months, 66/215 (30.7%) had sodium levels<136 mmol/l including 20/215 (9.3%) with sodium levels<131 mmol/l. No increased risk of hyponatremia was found, when nasal and oral were compared (p=0.9). Daily desmopressin dose requirements were higher in patients with congenital DI compared to patients with acquired DI. However, this result was associated with uncertainty due to the small congenital group. BMI did not influence daily dose requirements and nor did type of administration influence the risk of hyponatremia.

Imaging surveillance in multiple endocrine neoplasia type 1: Ten years of experience with somatostatin receptor positron emission tomography.

Guidelines for multiple endocrine neoplasia type 1 (MEN1) recommend intensive imaging surveillance without specifying a superior regimen, including the role of somatostatin receptor imaging (SRI) with positron emission tomography (PET). The primary outcomes were to: (1) Assess change in treatment of duodenal-pancreatic neuroendocrine neoplasms (DP-NENs), bronchopulmonary NENs, and thymic tumors attributed to use of SRI PET/computed tomography (CT) and (2) estimate radiation from imaging and risk of cancer death attributed to imaging radiation. This was a retrospective single center study, including all MEN1 patients, who had had at least one SRI PET/CT. A total of 60 patients, median age 42 (range 21-54) years, median follow-up 6 (range 1-10) years were included. Of 470 cross sectional scans (MRI, CT, SRI PET/CT), 209 were SRI PET/CT. The additional information from SRI PET had implications in 1/14 surgical interventions and 2/12 medical interventions. The estimated median radiation dose per patient was 104 (range 51-468) mSv of which PET contributed with 13 (range 5-55) mSv and CT with 91 mSv (range 46-413 mSv), corresponding to an estimated increased median risk of cancer death of 0.5% during 6 years follow-up. SRI PET had a significant impact on 3/26 decisions to intervene in 60 MEN1 patients followed for a median of 6 years with SRI PET/CT as the most frequently used modality. The surveillance program showed a high radiation dose. Multi-modality imaging strategies designed to minimize radiation exposure should be considered. Based on our findings, SRI-PET combined with CT cannot be recommended for routine surveillance in MEN1 patients.

Natural History of Non-Functioning Pituitary Adenomas: A Systematic Review and Meta-Analysis.

The management of non-functioning pituitary tumors (NFPTs) relies on the risk of tumor growth and new endocrinopathies. The objective of this systematic review was to assess the risk of growth, new pituitary endocrinopathies, and surgery in patients with conservatively treated NFPTs. We conducted a bibliographical search identifying studies assessing NFPTs followed conservatively. Estimates were pooled using random-effects meta-analysis reporting events per 100 person years (PYs), in case of high heterogeneity (I2>75%) only the range of observed effects was reported. We identified 30 cohort studies including 1957 patients with a mean follow-up time of 4.0 (SD 1.5) years. The overall risk of tumor growth ranged from 0.0 to 14.2/100 PYs (I2=90%), while the overall risk of new endocrinopathies was 0.9/100 PYs (95% CI. 0.5 to 1.2; I2=: 35%) and risk of surgery ranged from 0.0 to 7.7/100 PYs (I2=: 80%). Compared to microadenomas, macroadenomas had higher risk of growth (p=: 0.002), higher risk of surgery (p=: 0.006), and non-significant differences in risk of new endocrinopathies (p=: 0.15). An analysis of microadenomas found the risk of growth to be 1.8/100 PYs (95% CI. 0.9 to 2.8; I2=: 58%), the risk of new endocrinopathies 0.7/100 PYs (95% CI. 0.0 to 1.6; I2=: 37%) and the risk of surgery 0.5/100 PYs (0.1 to 0.9; I2=: 37%). These data support individualized follow-up strategies of patients with NFPTs and particularly a less rigorous follow-up of patients with microadenomas.

Prognostic value of contralateral suppression on kidney function after surgery in patients with primary aldosteronism.

BACKGROUND AND OBJECTIVE: Adrenalectomy for primary aldosteronism (PA) has been associated with decreased kidney function after surgery. It has been proposed that elimination of excess aldosterone unmasks an underlying failure of the kidney function. Contralateral suppression (CLS) is considered a marker of aldosterone excess and disease severity, and the purpose of this study was to assess the hypothesis that CLS would predict change in kidney function after adrenalectomy in patients with PA. DESIGN AND PATIENTS: Patients with PA referred for adrenal venous sampling (AVS) between May 2011 and August 2021 and who were subsequently offered surgical or medical treatment were eligible for the current study. RESULTS: A total of 138 patients were included and after AVS 85/138 (61.6%) underwent adrenalectomy while 53/138 (38.4%) were treated with MR-antagonists. In surgically treated patients the estimated glomerular filtration rate (eGFR) was reduced by 11.5 (SD: 18.5) compared to a reduction of 5.9 (SD: 11.5) in medically treated patients (p = .04). Among surgically treated patients, 59/85 (69.4%) were classified as having CLS. After adrenalectomy, patients with CLS had a mean reduction in eGFR of 17.5 (SD: 17.6) compared to an increase of 1.8 (SD: 12.8) in patients without CLS (p < .001). The association between CLS and change in kidney function remained unchanged in multivariate analysis. Post-surgery, 16/59 (27.1%) patients with CLS developed hyperkalemia compared to 2/26 (7.7%) in patients without CLS (p = .04). CONCLUSION: This retrospective study found that CLS was a strong and independent predictor of a marked reduction of eGFR and an increased risk of hyperkalemia after adrenalectomy in patients with PA.

Prospective Phase II Trial of [68Ga]Ga-NODAGA-E[c(RGDyK)]2 PET/CT Imaging of Integrin αvß3 for Prognostication in Patients with Neuroendocrine Neoplasms.

Integrin αvß3, a subtype of the arginine-glycine-aspartate (RGD)-recognizing cell surface integrins, is upregulated on endothelial cells during angiogenesis and on tumor cells. Because of involvement in tumor growth, invasiveness and metastases, and angiogenesis, integrin αvß3 is an attractive target in cancers. In this study, we applied 68Ga-NODAGA-E[c(RGDyK)]2 for imaging of integrin αvß3 in patients with neuroendocrine neoplasms (NENs) and its potential use for prognostication. We hypothesized that 68Ga-NODAGA-E[c(RGDyK)]2 PET/CT would show tumor lesion uptake and that higher tumor lesion uptake was associated with a poorer prognosis. Methods: Between December 2017 and November 2020 we prospectively enrolled 113 patients with NEN of all grades (2019 World Health Organization classification) for 68Ga-NODAGA-E[c(RGDyK)]2 PET/CT. The scan was acquired 45 min after injection of 200 MBq of 68Ga-NODAGA-E[c(RGDyK)]2 Board-certified specialists in nuclear medicine and radiology analyzed the PET/CT measuring SUVmax in tumor lesions. Positive tumor lesions were defined as those with tumor-to-liver background ≥ 2. Maximal tumor SUVmax for each patient was used as a predictor of outcome. Patients were followed for at least 1 y to assess progression-free survival and overall survival. Results: Of 113 patients enrolled in the trial, 99 underwent 68Ga-NODAGA-E[c(RGDyK)]2 PET/CT, with 97 patients having evaluable lesions. The patients predominantly had small intestinal (64%) or pancreatic (20%) NEN and most had metastatic disease (93%). Most patients had low-grade tumors (78%), whereas 22% had high-grade tumors. During a median follow-up of 31 mo (interquartile range, 26-38 mo), 62 patients (64%) experienced disease progression and 25 (26%) patients died. In total, 76% of patients had positive tumor lesions, and of the patients with high-grade tumors 91% had positive tumor lesions. High integrin αvß3 expression, defined as an SUVmax of at least 5.25, had a hazard ratio of 2.11 (95% CI, 1.18-3.78) and 6.95 (95% CI, 1.64-29.51) for progression-free survival and overall survival, respectively (P = 0.01 for both). Conclusion: Tumor lesion uptake of 68Ga-NODAGA-E[c(RGDyK)]2 was evident in patients with all grades of NEN. High uptake was associated with a poorer prognosis. Further studies are warranted to establish whether 68Ga-NODAGA-E[c(RGDyK)]2 PET/CT may become a prediction tool for identification of patients eligible for treatments targeting integrin αvß3.

Recurrence-Free Survival and Disease-Specific Survival in Patients with Pancreatic Neuroendocrine Neoplasms: A Single-Center Retrospective Study of 413 Patients.

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.

Radiofrequency ablation of pancreatic insulinomas.

Insulinomas are rare neoplasms which may cause significant symptoms and substantially reduce quality of life. In operable patients, the current treatment is primarily surgery with either enucleation or resection of all or parts of the gland. This treatment is associated with high morbidity and long convalescence. Endoscopic ultrasound-guided radiofrequency ablation is a new and minimally invasive treatment for patients with insulinomas. The purpose of this review is to draw attention to the method and to communicate our preliminary experience with this procedure in Denmark.

Variation in serum adrenal hormones in female 21-hydroxylase deficient patients.

Background: There is no consensus regarding markers of optimal treatment or timing between glucocorticoid intake and assessment of hormone levels in the follow-up of female 21-hydroxylase deficient patients. Objective: To examine visit-to-visit repeatability in levels of adrenal hormones in adult female patients, to identify predictors of repeatability in hormone levels and to examine concordance between levels of different adrenal hormones. Method: All patients with confirmed 21-hydroxylase deficiency treated with glucocorticoids, were included. The two most recent blood samples collected on a stable dose of glucocorticoid replacement were compared. Complete concordance was defined as all measured adrenal hormones either within, below or above normal range evaluated in a single-day measurement. Results: Sixty-two patients, median age of 35 (range 18-74) years were included. All hormone levels showed moderate to excellent repeatability with an intraclass correlation coefficient between 0.80 and 0.99. Repeatability of hormone levels was not affected by the use of long-acting glucocorticoids or time of day for blood sample collection. The median difference in time between the two sample collections was 1.5 (range 0-7.5) h. Complete concordance between 17-hydroxyprogesterone, androstenedione, and testosterone was found in 21% of cases. Conclusion: During everyday, clinical practice hormone levels in adult female patients with 21-hydroxylase deficiency showed a moderate to excellent repeatability, despite considerable variation in time of day for blood sample collection. We found no major predictors of hormone level variation. Future studies are needed to address the relationship between the timing of glucocorticoid intake vs adrenal hormone levels and clinical outcome in both adults and children.

Surgery in Patients with Gastro-Entero-Pancreatic Neuroendocrine Carcinomas, Neuroendocrine Tumors G3 and High Grade Mixed Neuroendocrine-Non-Neuroendocrine Neoplasms.

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 <3%), NET G2 (Ki-67 3-20%) and NET G3 (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.