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.

Hemicolectomy versus appendectomy for patients with appendiceal neuroendocrine tumours 1-2 cm in size: a retrospective, Europe-wide, pooled cohort study.

BACKGROUND: Awareness of the potential global overtreatment of patients with appendiceal neuroendocrine tumours (NETs) of 1-2 cm in size by performing oncological resections is increasing, but the rarity of this tumour has impeded clear recommendations to date. We aimed to assess the malignant potential of appendiceal NETs of 1-2 cm in size in patients with or without right-sided hemicolectomy. METHODS: In this retrospective cohort study, we pooled data from 40 hospitals in 15 European countries for patients of any age and Eastern Cooperative Oncology Group performance status with a histopathologically confirmed appendiceal NET of 1-2 cm in size who had a complete resection of the primary tumour between Jan 1, 2000, and Dec 31, 2010. Patients either had an appendectomy only or an appendectomy with oncological right-sided hemicolectomy or ileocecal resection. Predefined primary outcomes were the frequency of distant metastases and tumour-related mortality. Secondary outcomes included the frequency of regional lymph node metastases, the association between regional lymph node metastases and histopathological risk factors, and overall survival with or without right-sided hemicolectomy. Cox proportional hazards regression was used to estimate the relative all-cause mortality hazard associated with right-sided hemicolectomy compared with appendectomy alone. This study is registered with ClinicalTrials.gov, NCT03852693. FINDINGS: 282 patients with suspected appendiceal tumours were identified, of whom 278 with an appendiceal NET of 1-2 cm in size were included. 163 (59%) had an appendectomy and 115 (41%) had a right-sided hemicolectomy, 110 (40%) were men, 168 (60%) were women, and mean age at initial surgery was 36·0 years (SD 18·2). Median follow-up was 13·0 years (IQR 11·0-15·6). After centralised histopathological review, appendiceal NETs were classified as a possible or probable primary tumour in two (1%) of 278 patients with distant peritoneal metastases and in two (1%) 278 patients with distant metastases in the liver. All metastases were diagnosed synchronously with no tumour-related deaths during follow-up. Regional lymph node metastases were found in 22 (20%) of 112 patients with right-sided hemicolectomy with available data. On the basis of histopathological risk factors, we estimated that 12·8% (95% CI 6·5 -21·1) of patients undergoing appendectomy probably had residual regional lymph node metastases. Overall survival was similar between patients with appendectomy and right-sided hemicolectomy (adjusted hazard ratio 0·88 [95% CI 0·36-2·17]; p=0·71). INTERPRETATION: This study provides evidence that right-sided hemicolectomy is not indicated after complete resection of an appendiceal NET of 1-2 cm in size by appendectomy, that regional lymph node metastases of appendiceal NETs are clinically irrelevant, and that an additional postoperative exclusion of metastases and histopathological evaluation of risk factors is not supported by the presented results. These findings should inform consensus best practice guidelines for this patient cohort. FUNDING: Swiss Cancer Research foundation.

Prevalence and severity of diabetic retinopathy in pregnant women with diabetes-time to individualize photo screening frequency.

AIMS: To evaluate the prevalence and severity of diabetic retinopathy including macular oedema in pregnant women with diabetes and to identify women in whom the frequency of retinal screening can be reduced to minimize the burden of health care visits. METHODS: A cohort study of 348 women with pre-existing diabetes were routinely screened with retinal photo in early (12 weeks) and late pregnancy (27 weeks). Diabetic retinopathy was classified in five stages in accordance with National Danish Guidelines based on the eye with the highest retinopathy level. Sight-threatening retinopathy was defined as the presence of proliferative retinopathy and/or clinically significant macular oedema (CSMO). RESULTS: Retinopathy was present in 52% (116/223) vs. 14% (17/125), with sight-threatening retinopathy in 16% (35/223) vs. 6% (7/125) of women with type 1 and type 2, respectively. Women without retinopathy in early and late pregnancy were characterized by shorter diabetes duration (p < 0.0001 and p = 0.008) and predominance of type 2 diabetes. Amongst the 50% (175/348) of the cohort having no retinopathy in early pregnancy and HbA1c<53 mmol/mol (7.0%), none developed sight-threatening retinopathy and 94% (165/175) remained without any retinopathy during pregnancy. Development of sight-threatening retinopathy was mainly observed in women with retinopathy in early pregnancy. Treatment for sight-threatening retinopathy was given to a minority (2.7 and 2.4%, respectively). CONCLUSION: Good glycaemic control and no retinopathy was seen in a large proportion of women in early pregnancy and none of these women developed sight-threatening retinopathy. The frequency of retinal screening can probably be safely reduced during pregnancy in these women.

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.

Galectin-3 and fibulin-1 in systolic heart failure - relation to glucose metabolism and left ventricular contractile reserve.

BACKGROUND: Heart failure (HF) patients with diabetes (DM) have an adverse prognosis and reduced functional capacity, which could be associated with cardiac fibrosis, increased chamber stiffness and reduced left ventricular (LV) contractile reserve. Galectin-3 (Gal-3) and fibulin-1 are circulating biomarkers potentially reflecting cardiac fibrosis. We hypothesize that plasma levels of Gal-3 and fibulin-1 are elevated in HF patients with DM and are associated with reduced LV contractile reserve in these patients. METHODS: A total of 155 patients with HF with reduced ejection fraction underwent a low-dose dobutamine echocardiography and blood sampling for biomarker measurements. Patients were classified according to history of DM and an oral glucose tolerance test (OGTT) as: normal glucose tolerance (NGT) (n = 70), impaired glucose tolerance (IGT) (n = 25) and DM (n = 60). RESULTS: Galectin-3 levels were elevated in DM patients as compared to non-diabetic patients (P = 0.02), while higher fibulin-1 levels were observed in HF patients with IGF and DM (P = 0.07). Reduced LV contractile reserve was associated with increasing Gal-3 levels (ß = -0.19, P = 0.03) although, this association was attenuated after adjustment for estimated glomerular filtration rate (P = 0.66). Fibulin-1 was not associated with LV contractile reserve (P = 0.71). CONCLUSIONS: Galectin-3 and fibulin-1 levels were elevated in HF patients with impaired glucose metabolism. However, reduced LV contractile reserve among HF patients with DM does not to have an independent impact on plasma Gal-3 and fibulin-1 levels.

The influence of diabetes mellitus on midregional proadrenomedullin concentrations and prognostic value in heart failure outpatients.

BACKGROUND: Diabetes mellitus (DM) is associated with an adverse outcome in heart failure (HF). Increased concentrations of midregional proadrenomedullin (MR-proADM) have been associated with DM and are predictors of mortality in HF patients. The aim of this study was to elucidate the impact of DM on MR-proADM concentrations and the prognostic value regarding all-cause mortality and hospitalization among HF patients. METHODS AND RESULTS: We included 366 patients from an HF clinic; 69 (19%) had a history of DM and 40 (11%) had newly diagnosed DM (HbA1c ≥48 mmol/mol). The median MR-proADM concentration was unaffected by DM status (P = .20) but increased in HF patients with impaired renal function (P < .001). During a median follow-up of 55 months, 189 died, and 292 either died or were hospitalized. After adjustment for clinically relevant parameters, MR-proADM was associated with all-cause mortality (hazard ratio [HR] 1.3, 95% confidence interval [CI] 1.1-1.4; P = .01) and the combined end point of death and hospitalization (HR 1.2, 95% CI 1.1-1.4; P = .02) per 1 SD increment of ln-transformed variable. No interaction between DM and MR-proADM was found regarding mortality or hospitalization. CONCLUSIONS: Diabetes status had no impact on MR-proADM concentrations or in the predictive ability of MR-proADM in HF patients.

Long-term L-Triiodothyronine (T3) treatment in stable systolic heart failure patients: a randomised, double-blind, cross-over, placebo-controlled intervention study.

BACKGROUND: Chronic heart failure (HF) is characterized by reduced serum T3 levels and increased activity of the T3 degrading enzyme deiodinase D3. This may result in an intracellular composition of the cardiomyocyte mimicking that of hypothyroidism. Short-term T3-administration to systolic HF patients might be beneficial. QUESTION: Does long-term treatment with T3 have a beneficial effect on cardiac function and neurohormonal activation in chronic systolic HF patients with serum T3 levels below 1·6 nmol/l? DESIGN: A randomized, double-blind, cross-over, placebo-controlled intervention study with oral T3 treatment twice daily for 3 months. The T3 dose was uptitrated to a final dose avoiding reduced TSH levels. PRIMARY END-POINT: Left-ventricular ejection fraction (LVEF). METHODS: Cardiac imaging was performed using multiple gated tomographic radionuclide ventriculography (MUGA-SPECT). Neurohormonal stimulation was evaluated by plasma measurements of natriuretic peptides, aldosterone, renin, noradrenalin and copeptin levels. The patients were monitored for potential cardiac arrhythmias at the start of each treatment period. RESULTS: Thirteen patients completed the protocol. Mean LVEF was 43%, range: 37-52 and serum T3 levels 1·4 nmol/l (0·9-1·6). The T3 dose was 20 µg per day (10-40). TSH levels did not change between groups, whereas serum T3 levels increased in the active arm. Cardiac function as measured by LVEF, end-diastolic and end-systolic volumes and cardiac output did not change during T3-treatment and neither did the neurohormonal profile. There were no side-effects in terms of cardiac arrhythmias and no change in resting heart rate. CONCLUSIONS: This study does not support the hypothesis that oral T3 treatment might be beneficial to patients with chronic, stable systolic HF with a modest degree of reduced LVEF and low-normal serum T3 concentrations. The study included both functional studies of heart contractility as well as measures of the neurohormonal activation.

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.

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.

Pressure pain sensitivity: a new method of stress measurement in patients with ischemic heart disease.

BACKGROUND: Chronic stress is prevalent in patients with ischemic heart disease (IHD) and worsens the long-term prognosis. Chronic stress is vaguely defined, but is associated with depressive symptoms, reduced psychological wellbeing, and reduced quality of life (QOL). Stress seems to induce hyperalgesia.The aim of the present study was to evaluate hyperalgesia by pressure pain sensitivity (PPS) in patients with IHD, and compare PPS to questionnaires measuring depressive symptoms, reduced psychological wellbeing, and QOL as markers of stress. Design. A cross-sectional study of 361 subjects with IHD. METHODS: PPS was measured on the sternum, and compared to the questionnaires: Clinical stress symptoms score (CSS), Major Depression Inventory (MDI), WHO-5 Wellbeing Index, and SF-36 QOL score. RESULTS: PPS correlated to CSS (r = 0.20, p < 0.001), MDI (r = 0.14, p = 0.02), SF-36 mental component summary score (MCS) (r = - 0.10, p = 0.049), SF-36 physical component summary score (PCS) (r = - 0.17, p = 0.001), and self-perceived stress level (r = 0.15, p = 0.006). CSS correlated similarly (r = 0.5-0.7, all p < 0.001). Comparing subjects within the lowest vs. highest tertiles of PPS and CSS, the mean MDI score was 4 vs. 15, WHO-5 was 77 vs. 53, SF-36 PCS was 53 vs. 43, and SF-36 MCS was 58 vs. 46; all p < 0.001. CONCLUSIONS: PPS reflected to a modest degree markers of chronic stress in IHD. PPS and CSS together might be useful as easy-to use tools for evaluating these markers in IHD patients.

Faster-acting insulin aspart versus insulin aspart in the treatment of type 1 or type 2 diabetes during pregnancy and post-delivery (CopenFast): an open-label, single-centre, randomised controlled trial.

BACKGROUND: Faster-acting insulin aspart (faster aspart) is considered safe for use during pregnancy and breastfeeding but has not been evaluated in this population. We aimed to evaluate the effect of faster aspart versus insulin aspart on fetal growth, in women with type 1 or type 2 diabetes during pregnancy and post-delivery. METHODS: This open-label, single-centre, superiority trial was conducted at Rigshospitalet, Copenhagen, Denmark. Participants aged 18 years or older with type 1 or type 2 diabetes were stratified by diabetes type and insulin treatment modality (multiple daily injections or insulin pump), randomly assigned 1:1 to faster aspart or insulin aspart, from 8 weeks and 0 days (8+0) of gestation to 13+6 weeks of gestation, and followed up until 3 months post-delivery. Primary outcome was infant birthweight SD score. Secondary outcomes included HbA1c as well as maternal and fetal outcomes in all participants during the trial. This trial is registered with ClinicalTrials.gov, NCT03770767. FINDINGS: Between Nov 11, 2019 and May 10, 2022, 109 participants were included in the faster aspart group and 107 in the insulin aspart group. Primary outcome data were available in 203 (94%) of 216 participants, and no participants discontinued treatment during the trial. Mean birthweight SD score was 1·0 (SD 1·4) in the faster aspart group versus 1·2 (1·3) in the insulin aspart group; estimated treatment difference -0·22 [-0·58 to 0·14]; p=0·23. At 33 weeks of gestation, mean HbA1c was 42 mmol/mol (SD 6 mmol/mol; 6·0% [SD 0·9%]) versus 43 mmol/mol (SD 7 mmol/mol; 6·1% [SD 1·2%]); estimated treatment difference -1·01 (-2·86 to 0·83), p=0·28. No additional safety issues were observed with faster aspart compared with insulin aspart. INTERPRETATION: Treatment with faster aspart resulted in similar fetal growth and HbA1c, relative to insulin aspart, in women with type 1 or type 2 diabetes. Faster aspart can be used in women with type 1 or type 2 diabetes during pregnancy and post-delivery with no additional safety issues. FUNDING: Novo Nordisk. TRANSLATION: For the Danish translation of the abstract see Supplementary Materials section.

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.

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.

Falling Insulin Requirement in Pregnant Women With Diabetes Delivering Preterm: Prevalence, Predictors, and Consequences.

CONTEXT: Falling insulin requirements often lead to considerations of whether a pregnancy can continue safely or if delivery is indicated. OBJECTIVE: To evaluate prevalence and predictors of falling insulin requirements in pregnant women with preexisting diabetes delivering preterm and to explore the relationship to fetal asphyxia and neonatal morbidity. METHODS: A prospective cohort study of 101 consecutive singleton pregnant women with preexisting diabetes delivering preterm < 37 weeks (68 type 1 and 33 type 2 diabetes) where the prevalence of falling insulin requirements (≥20%) before delivery was recorded. RESULTS: In total, 27% (27/101) experienced falling insulin requirements of median 30% (interquartile range 24-40) before delivery. In all women with type 1 diabetes, the prevalence was 37% (25/68), whereas it was 43% (24/56) in those with indicated preterm delivery and 6% (2/33) among women with type 2 diabetes. In women with type 1 diabetes and indicated preterm delivery, falling insulin requirements were first identified at 34 + 5 (33 + 6-35 + 4) weeks + days and delivery occurred 3 (1-9) days later. Gestational age at delivery, prevalence of suspected fetal asphyxia, and neonatal morbidity were similar in women with and without falling insulin requirements. Neither glycemic control, nausea, or preeclampsia was associated with falling insulin requirement. CONCLUSION: Falling insulin requirements often preceded preterm delivery in women with type 1 diabetes, foremost when preterm delivery was indicated, but was not related to fetal asphyxia or neonatal morbidity. Whether falling insulin requirements in late pregnancy are a warning sign of placental insufficiency or mainly reflects variations in normal physiology needs further investigation.

[Pseudohyperaldosteronism with severe hypokalaemia and focal paresis triggered by licorice tea].

An excessive consumption of licorice can cause pseudohyperaldosteronism, which can lead to severe hypokalaemia and hypertension. Glycyrrhizin in licorice root activates the renal mineralocorticoid receptor increasing sodium reabsorption and potassium excretion. In this case report, an otherwise healthy 43-year-old woman presented with severe hypokalaemia, rhabdomyolysis, electrocardiogram changes and focal paresis after having consumed 2-2,5 litres of licorice tea daily for approximately eight weeks.

Incidence, Clinical Presentation and Trends in Indication for Diagnostic Work-Up of Small Intestinal and Pancreatic Neuroendocrine Tumors.

BACKGROUND: The incidence of small intestinal (SI) and pancreatic neuroendocrine tumors (siNETs and pNETs) seems to have increased. The increased frequency of incidental findings might be a possible explanation. The study aimed to examine (1) changes in incidence and the stage at diagnosis (2010-2011 vs. 2019-2020), (2) changes in the initial indication for diagnostic workup and 3) the differences in stage between incidentally discovered vs. symptomatic disease during the entire study period. METHODS: We performed a retrospective study, that includes consecutive siNET and pNET patients referred to the Copenhagen ENETS center of excellence in 2010-2011 and 2019-2020. RESULTS: The annual incidence of siNET per 100,000 increased from 1.39 to 1.84, (p = 0.05). There was no change in the stage at diagnosis, and in both periods approximately 30% of patients were incidentally diagnosed (p = 0.62). Dissemination was found in 72/121 (60%) of symptomatic vs. 22/50 (44%) of incidentally discovered SI tumors in the entire cohort, (p = 0.06). The annual incidence of pNET increased from 0.42 to 1.39 per 100,000, (p < 0.001). The proportion of patients with disseminated disease decreased from 8/21 (38%) to 12/75 (16%), (p = 0.02) and the number of incidental findings increased from 4/21 (19%) to 43/75 (57%), (p = 0.002). More symptomatic patients had disseminated disease compared to patients with incidentally discovered tumors (15/49 (31%) vs. 5/47 (11%), (p = 0.01)). CONCLUSION: The incidence of siNET and pNETs increased over the past decade. For siNETs, the stage of disease and the distribution of symptomatic vs. incidentally discovered tumors were unchanged between the two periods. Patients with pNETs presented with more local and incidentally discovered tumors in the latter period. Patients with incidentally discovered siNETs had disseminated disease in 44% of the overall cases. The vast majority of incidentally found pNETs were localized.

Increase of Ki-67 index and influence on mortality in patients with neuroendocrine neoplasms.

An increase in the Ki-67 index in neuroendocrine neoplasms over time in relation to prognosis has scarcely been investigated. We aimed to assess whether the Ki-67 index changed over time and also whether a change influenced prognosis. Second, we investigated the difference in the Ki-67 index between primary tumour and metastases. From 1 January 1995 to 31 December 2019, 108 consecutive patients with gastroenteropancreatic tumours were included. Patients were followed with regard to an increase in the Ki-67 index and all-cause mortality. Ki-67 determination of the primary tumour at diagnosis and at the time of radiological progression, including developed metastases, was performed. A significant increase in the Ki-67 index was defined as a doubling of the value at disease progression compared to the value at diagnosis. In addition, in 14 patients, the Ki-67 index of the primary tumour and present metastases at the time of diagnosis was investigated. At diagnosis, there were no differences in the Ki-67 index between primary tumours and metastases (P = .41). Sixty-five patients had a doubling of the Ki-67 index. The median Ki-67 index at the time of progression 17% (1%-90%) vs 5% (1%-60%) at the time of diagnosis (P = .006). A doubling of the Ki-67 index was independently associated with all-cause mortality (hazard ratio = 2.7 [1.3-6.3], P = 0.02), after adjustment for relevant co-variables including the Ki-67 index at baseline. Doubling of the Ki-67 index at the time of disease progression was associated with a significantly higher risk of all-cause mortality. We recommend that a Ki-67 index is obtained whenever disease progression is recorded by demonstrated progression because it may have impact on the choice of treatment.

Neuroendocrine neoplasms of the appendix: Characterization of 335 patients referred to the Copenhagen NET Center of Excellence.

INTRODUCTION: Neuroendocrine neoplasms (NEN) of the appendix are often incidentally discovered after appendectomy. Appropriate management is debated. The purpose was to characterize a cohort of 335 appendix NEN and evaluate the risk of recurrence. METHODS: Retrospective collection of data from 335 patients referred to the Neuroendocrine Tumor Center at Rigshospitalet 2000-2019. Appendix goblet cell carcinoids and mixed neuroendocrine non-neuroendocrine neoplasms were excluded. Patients were followed until December 31st, 2019. No patients were lost to follow-up. RESULTS: Sixty-three percent of the patients were female. The median (range) age at diagnosis was 34 (9-92) years. Median follow-up was 66 (1-250) months. Median tumor size was 7 (1-45) mm with 10 (3%) tumors >20 mm. In 18 specimens (5%) resection margins were positive. Mesoappendiceal invasion was found in 113 (35%). Sixty-three (19%) patients underwent right-sided completion hemicolectomy (RHC) after appendectomy according to ENETS guidelines. Among these, 11 (17%) had lymph node metastases in the resected tissue. Further, one patient who underwent initial RHC due to colonic adenocarcinoma had lymph node metastases. All lymph node metastases were detected in patients with serotonin positive tumors. No patients with glucagon positive tumors (n = 85) had lymph node metastases. Mesoappendiceal invasion >3 mm and positive resection margins were associated with presence of lymph node metastases. No recurrences were recorded. CONCLUSION: Following ENETS guidelines may lead to overtreatment of patients with respect to completion RHC. The risk of over- and undertreatment needs to be further evaluated.

Limited Diagnostic Utility of Chromogranin A Measurements in Workup of Neuroendocrine Tumors.

BACKGROUND: Plasma chromogranin A (CgA) is related to tumor burden and recommended in the follow-up of patients diagnosed with neuroendocrine tumors (NETs). The use of CgA in the workup of a suspected NET is more questionable. OBJECTIVE: To assess the positive predictive value (PPV) of CgA plasma concentrations above the upper reference limit (URL) in patients with suspected NET. METHOD: Patients referred to the NET Centre, Rigshospitalet, Copenhagen from 2015 to 2019 with clinically suspected NET were included if a CgA measurement was performed prior to referral. The utility of CgA was assessed by comparing pre-referral CgA concentrations to the outcome of a thorough workup. In 47 selected cases with continuously unexplained elevated CgA concentrations, a processing-independent analysis (PIA) for CgA was performed. RESULTS: A total of 197 patients were included. NET was ultimately diagnosed in 25 patients. CgA plasma concentrations were above the URL (elevated) in 19/25 patients diagnosed with NET. In total, 167/197 had elevated CgA concentrations at referral. The positive predictive value (PPV) of elevated CgA concentration was 11% (19/167). Proton pump inhibitor (PPI) treatment was identified as the possible cause of CgA elevation in 55/148 patients with falsely elevated CgA. CgA concentration was normal in 28/47 patients when using PIA. CONCLUSION: Our data do not support using measurement of CgA for screening when NET is suspected since the PPV was rather low. PPI treatment is a common cause of increased CgA concentrations and should always be discontinued before CgA measurement. PIA of CgA could be a way of excluding NET when suspicion is based primarily on elevated CgA.