Localization Defines Streptozotocin/5-FU Response in Primary Pancreatic Neuroendocrine Tumours.

INTRODUCTION: Incidence of pancreatic neuroendocrine tumours (pNETs) is on the rise. The only curative treatment is surgical resection in localized or oligo-metastatic disease. However, patients may present with locally advanced or unresectable primary tumours. So far, no conversion therapy to achieve resectability has been established, which is partly due to lack of data on primary tumour response to therapies. Here, we specifically evaluate the primary tumour response to streptozocin/5-FU in a large cohort of metastatic pNET patients. METHODS: Five ENETS centres in Germany contributed 84 patients to the study cohort for retrospective analysis. RESULTS: Overall response rate (ORR) in primary tumours was 34% and disease control rate (DCR) 88%. ORR was different in metastases at 44% and DCR at 70%. Partial remission in primary tumours was more frequent among those located in pancreatic tail than that in pancreatic head (49% vs. 14%, p = 0.03). Correspondingly, metastases from tumours originating from pancreatic tail responded more frequently than metastases originating from pancreatic head (88.5% vs. 41.7%, p = 0.005). The median PFS of the primary tumours was longer than that in metastases (31 months vs. 16 months; p = 0.04). Considerable downsizing of the primary tumour was rare and occurred primarily in tumours located in the pancreatic tail. CONCLUSION: STZ/5-FU can achieve disease stabilization in a high proportion of metastatic pNET patients. In the majority of cases however it does not induce substantial downsizing of the primary tumour, thus possibly limiting its potential as conversion chemotherapy. Furthermore, the difference in response rate observed between different primary tumour locations warrants further exploration.

PuraStat in gastrointestinal bleeding: results of a prospective multicentre observational pilot study.

BACKGROUND: A recently developed haemostatic peptide gel for endoscopic application has been introduced to improve the management of gastrointestinal bleeding. The aim of this pilot study was to evaluate the feasibility, safety, efficacy and indication profiles of PuraStat in a clinical setting. METHODS: In this prospective observational multicentre pilot study, patients with acute non-variceal gastrointestinal bleeding (upper and lower) were included. Primary and secondary application of PuraStat was evaluated. Haemoglobin, prothrombin time, platelets and transfusion behaviour were documented before and after haemostasis. The efficacy of PuraStat was assessed during the procedure, at 3 days and 1 week after application. RESULTS: 111 patients with acute gastrointestinal bleeding were recruited into the study. 70 percent (78/111) of the patients had upper gastrointestinal bleeding and 30% (33/111) had lower gastrointestinal bleeding. After primary application of PuraStat, initial haemostatic success was achieved in 94% of patients (74/79, 95% CI 88-99%), and in 75% of the patients when used as a secondary haemostatic product, following failure of established techniques (24/32, 95% CI 59-91%). The therapeutic success rates (absence of rebleeding) after 3 and 7 days were 91% and 87% after primary use, and 87% and 81% in all study patients. Overall rebleeding rate at 30 day follow-up was 16% (18/111). In the 5 patients who finally required surgery (4.5%), PuraStat allowed temporary haemostasis and stabilisation. CONCLUSIONS: PuraStat expanded the therapeutic toolbox available for an effective treatment of gastrointestinal bleeding sources. It could be safely applied and administered without complications as a primary or secondary therapy. PuraStat may additionally serve as a bridge to surgery in order to achieve temporary haemostasis in case of refractory severe bleeding, possibly playing a role in preventing immediate emergency surgery.

Prognostic Significance of Somatostatin Receptor Heterogeneity in Progressive Neuroendocrine Tumor Treated with Lu-177 DOTATOC or Lu-177 DOTATATE.

AIM: One of the primary prerequisites for peptide receptor radionuclide therapy (PRRT) in patients with neuroendocrine tumors (NET) is the presence of somatostatin receptors (SSTR) on NET cells. NET are highly heterogeneous and an individual patient as well as separate metastases can harbor cells with different clones, which influence the SSTR expression on NET cells. With this background we looked into our institutional database to assess the prognostic significance of quality of SSTR expression on SSTR PET/CT imaging in patients treated with at least two cycles of Lu-177 DOTATOC or Lu-177 DOTATATE. METHOD: Clinical reports and images from 65 (25 females, 40 males; 65 ± 11 years old) patients with progressive grade 1 or grade 2 NET with 2-5 therapy cycles of PRRT with an average administered dose of 6.6 ± 0.97 GBq Lu-177 DOTATOC or Lu-177 DOTATATE were analyzed. All patients were examined with baseline Ga-68 DOTATATE or Ga-68 DOTATOC PET/CT (PET). Quality of SSTR expression as a measure of heterogeneity on indexed lesions was assessed visually. Patients were followed for a median duration of 25 months after the first PRRT (range 5-77 months). RESULTS: A total of 70% of the patients received three or more therapy cycles. Twenty-six patients (40%) were treated with PRRT as first or second line while 39 (60%) as third line or more. SSTR expression was heterogeneous in 28 (44.4%) and homogeneous in 35 (55.6%) patients. Disease stabilization could be achieved in 23 patients (35.4%), whereas 17 (26.1%) showed partial remission and 25 patients (38.5%) had disease progression. Median OS was not reached. The 24-month survival rate of the whole study cohort was 83%. In univariate analyses, factors influencing OS were carcinoid heart disease, carcinoid syndrome and quality of SSTR expression (p < 0.05). Patients with heterogeneous SSTR expression on target lesions had a significantly lower OS (p = 0.01). Median time to progression in total patient population was found to be 40 months. Patients with heterogeneous SSTR expression on target lesions had significantly lower TTP (26 months vs 54 months log Rank p = 0.013). By multivariate analyses, quality of SSTR was found to be the only prognostic factor for OS (p = 0.04; HR = 3.68) and also for TTP (p = 0.03; HR = 3.09). CONCLUSION: Visual assessment of SSTR heterogeneity has both predictive and prognostic value in progressive grade 1 or grade 2 NET patients undergoing PRRT.

Peritoneal Carcinomatosis in Gastro-Entero-Pancreatic Neuroendocrine Neoplasms: Clinical Impact and Effectiveness of the Available Therapeutic Options.

BACKGROUND: Peritoneal carcinomatosis (PC) can affect the quality of life of patients with gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs). Peritoneal disease control by medical therapies in these patients has been poorly investigated Objectives: To describe, in a consecutive series of GEP-NENs, the clinical impact of PC and to report the effectiveness of available treatments in PC control. METHODS: A retrospective, monocenter analysis was performed of 135 GEP-NENs (1993-2016) with at least a 12-month follow-up. Peritoneal disease progression was defined as detection of a significant increase in size or appearance of new implants by imaging. RESULTS: A total of 62.9% of cases had diffuse PC (involving at least 2 abdominal quadrants). According to WHO 2017 classification, cases were 42.3% neuroendocrine tumors NET-G1, 45.5% NET-G2, 6.5% NET-G3, 4.9% neuroendocrine carcinomas NEC-G3, and 0.8% mixed neuroendocrine-nonneuroendocrine neoplasms. Bowel obstruction occurred in 30 (22.2%) patients mainly depending on size of peritoneal implants (HR: 1.10; 95% CI: 1.02-1.20; p = 0.01). Patients with diffuse PC treated with peptide receptor radionuclide therapy (PRRT) showed peritoneal progression in 37.5% of cases, and bowel obstruction or ascites in 28.1%. Better peritoneal disease control was observed in cases receiving somatostatin analogs at first-line therapy, probably due to a less aggressive disease behavior for these patients. CONCLUSIONS: Bowel obstruction is not uncommon in GEP-NENs with PC. PRRT should be adopted with caution in GEP-NENs with diffuse PC, but larger series are needed to confirm these data.

Long-term outcome of surgical resection in patients with gastroenteropancreatic neuroendocrine neoplasia: results from a German nation-wide multi-centric registry.

BACKGROUND: Neuroendocrine neoplasia (NEN) are rare and heterogenous tumours. Few data exist on the impact of surgical therapy. MATERIALS AND METHODS: This is a retrospective analysis of prospectively collected data of gastroenteropancreatic NEN in the German NET-Registry (1999-2012). It focuses on patients without distant metastases (limited disease, LD, stage I-IIIB). RESULTS: Data of 2239 patients with NEN were recorded. Median age was 59 years, the gender ratio was 1:1.3 (f:m). A total of 986 patients (44%) had LD, and the 5-year survival rate (5 years) was 77% for all and 90% for patients with LD. A total of 1635 patients (73%) received a surgical therapy (1st to 6th line); the 5 and 10 ysr were 83/65% after and 59/35% without surgery for all patients (p < .001). The resection margins in the LD patients were 76%, 16%, and 3% for R0, R1 and R2, respectively. The 10 ysr was 84%, 59% and 42% for R0, R1 and R2 resections, respectively (p = .021 R0/R1, p < .001 R0/R2). The R0 resection rate was 75% for G1/G2 NET and 67% for G3 NEC. CONCLUSION: The rate of complete tumour resection (R0) in LD is independent of tumour grading, and R0 resection is the key determinant of long-term survival, as demonstrated by the 10 ysr. of 84%. All NEN patients with limited disease should be considered for operation, if possible, as the best 10-year survival is shown after an R0 resection.

Unmet Needs in Appendiceal Neuroendocrine Neoplasms.

Appendiceal neuroendocrine neoplasms (ANEN) are mostly discovered coincidentally during appendicectomy and usually have a benign clinical course; thus, appendicectomy alone is considered curative. However, in some cases, a malignant potential is suspected, and therefore additional operations such as completion right hemicolectomy are considered. The existing European Neuroendocrine Tumour Society (ENETS) guidelines provide useful data about epidemiology and prognosis, as well as practical recommendations with regards to the risk factors for a more aggressive disease course and the indications for a secondary operation. However, these guidelines are based on heterogeneous and retrospective studies. Therefore, the evidence does not seem to be robust, and there are still unmet needs in terms of accurate epidemiology and overall prognosis, optimal diagnostic and follow-up strategy, as well as identified risk factors that would indicate a more aggressive surgical approach at the beginning and a more intense follow-up. In this review, we are adopting a critical approach of the ENETS guidelines and published series for ANEN, focusing on the above-noted "grey areas".

Competitive Testing of the WHO 2010 versus the WHO 2017 Grading of Pancreatic Neuroendocrine Neoplasms: Data from a Large International Cohort Study.

BACKGROUND: The World Health Organization (WHO) and the American Joint Cancer Committee (AJCC) modified the grading of pancreatic neuroendocrine neoplasms from a three-tier (WHO-AJCC 2010) to a four-tier system by introducing the novel category of NET G3 (WHO-AJCC 2017). OBJECTIVES: This study aims at validating the WHO-AJCC 2017 and identifying the most effective grading system. METHOD: A total of 2,102 patients were enrolled; entry criteria were: (i) patient underwent surgery; (ii) at least 2 years of follow-up; (iii) observation time up to 2015. Data from 34 variables were collected; grading was assessed and compared for efficacy by statistical means including Kaplan-Meier method, Cox regression analysis, Harrell's C statistics, and Royston's explained variation in univariable and multivariable analyses. RESULTS: In descriptive analysis, the two grading systems demonstrated statistically significant differences for the major category sex but not for age groups. In Cox regression analysis, both grading systems showed statistically significant differences between grades for OS and EFS; however, no statistically significant difference was observed between the two G3 classes of WHO-AJCC 2017. In multivariable analysis for the two models fitted to compare efficacy, the two grading systems performed equally well with substantially similar optimal discrimination and well-explained variation for both OS and EFS. The WHO-AJCC 2017 grading system retained statistically significant difference between the two G3 classes for OS but not for EFS. CONCLUSIONS: The WHO-AJCC 2017 grading system is at least equally performing as the WHO-AJCC 2010 but allows the successful identification of the most aggressive PanNET subgroup. Grading is confirmed as probably the most powerful tool for predicting patient survival.

Stage IV Gastro-Entero-Pancreatic Neuroendocrine Neoplasms: A Risk Score to Predict Clinical Outcome.

BACKGROUND: Several risk factors predict clinical outcome in gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs); however, the impact of their combination has not been investigated so far. PATIENTS AND METHODS: A retrospective analysis of stage IV GEP-NENs was performed. Multivariate analysis for progression of disease (PD) was performed by Cox proportional hazards method to obtain a risk score. Area under the curve obtained by receiver operating characteristic analysis was used to assess the score performance. Progression-free survival analysis was performed by Kaplan-Meier method. RESULTS: Two hundred eighty-three stage IV GEP-NENs were evaluated, including 93 grade 1 neuroendocrine tumors (32.9%), 153 grade 2 neuroendocrine tumors (54%), and 37 grade 3 neuroendocrine carcinomas (13.1%). Independent risk factors for PD were Ki67, proportion of metastatic liver involvement, and presence of extra-abdominal metastases. The risk score was calculated as follows: (0.025 × Ki67) + [(0 if no liver metastases or liver involvement <25%) OR (0.405 if liver involvement 25%-50%) OR (0.462 if liver involvement >50%)] + [(0 if no extra-abdominal metastases) OR (0.528 if extra-abdominal metastases present)]. The risk score accuracy to predict PD was superior compared with the G grading system (area under the curve: 0.705 and 0.622, respectively). Three subgroups of patients with low, intermediate, and high risk of PD according to risk score were identified, median progression-free survival being 26 months, 19 months, and 12 months, respectively. CONCLUSION: In stage IV GEP-NENs, a risk score able to predict PD was obtained by combining Ki67, proportion of metastatic liver involvement, and presence of extra-abdominal metastases. The score may help to discriminate patients with different progression risk level to plan tailored therapeutic approaches and follow-up programs. The Oncologist 2017;22:409-415Implications for Practice: Clinical outcome of patients with advanced gastro-entero-pancreatic neuroendocrine neoplasms is affected by several risk factors, including the proliferative index Ki67, extension of liver metastases, and the presence of distant extra-abdominal lesions. A risk score that combines these variables may help physicians dealing with these diseases to plan the optimal therapeutic approach and follow-up program.

Increased Activity of the Immunoregulatory Enzyme Indoleamine-2,3-Dioxygenase with Consecutive Tryptophan Depletion Predicts Death in Patients with Neuroendocrine Neoplasia.

BACKGROUND/AIMS: Data from a considerable number of malignancies demonstrate that depletion of the essential amino acid tryptophan via induction of the immunoregulatory enzyme indoleamine-2,3-dioxygenase (IDO) serves as an important tumour escape strategy and is of prognostic importance. Here we investigate the predictive value of the activity of IDO as well as levels of tryptophan and respective downstream catabolites in a large cohort of patients with neuroendocrine neoplasms (NEN). METHODS: 142 consecutive Caucasian patients (62 male, aged 60.3 ± 11.9 years) with histologically confirmed NEN were systematically analysed in a retrospective blinded end point analysis. Patients were followed up for a mean period of about 3.9 ± 1.9 years. Clinical outcome, levels of established biomarkers, and tryptophan degradation markers (assessed using tandem mass spectrometry) including estimated IDO activity were recorded. Cox proportional hazards regression models were performed for the assessment of prognostic power. RESULTS: We found that baseline tryptophan levels were significantly lower and IDO activity was significantly increased in non-survivors. The risk for death inclined stepwise and was highest in patients in the upper tertile of IDO activity. Cox proportional regression models identified IDO activity as an independent predictor of death. CONCLUSIONS: In this retrospective analysis, we observed that baseline activity of the immunoregulatory enzyme IDO was significantly increased in non-survivors. IDO activity was identified as an independent predictor of death in this cohort of NEN patients. Whether IDO activity or tryptophan depletion serves to guide future therapeutic interventions in NEN remains to be established.

Malnutrition Predicts Clinical Outcome in Patients with Neuroendocrine Neoplasia.

Malnutrition is a common problem in oncological diseases, influencing treatment outcomes, treatment complications, quality of life and survival. The potential role of malnutrition has not yet been studied systematically in neuroendocrine neoplasms (NEN), which, due to their growing prevalence and additional therapeutic options, provide an increasing clinical challenge to diagnosis and management. The aim of this cross-sectional observational study, which included a long-term follow-up, was therefore to define the prevalence of malnutrition in 203 patients with NEN using various methodological approaches, and to analyse the short- and long-term outcome of malnourished patients. A detailed subgroup analysis was also performed to define risk factors for poorer outcome. When applying malnutrition screening scores, 21-25% of the NEN patients were at risk of or demonstrated manifest malnutrition. This was confirmed by anthropometric measurements, by determination of serum surrogate parameters such as albumin as well as by bioelectrical impedance analysis (BIA), particularly phase angle α. The length of hospital stay was significantly longer in malnourished NEN patients, while long-term overall survival was highly significantly reduced. Patients with high-grade (G3) neuroendocrine carcinomas, progressive disease and undergoing chemotherapy were at particular risk of malnutrition associated with a poorer outcome. Multivariate analysis confirmed the important and highly significant role of malnutrition as an independent prognostic factor for NEN besides proliferative capacity (G3 NEC). Malnutrition is therefore an underrecognized problem in NEN patients which should systematically be diagnosed by widely available standard methods such as Nutritional Risk Screening (NRS), serum albumin assessment and BIA, and treated to improve both short- and long-term outcomes.

Role of (68)Ga somatostatin receptor PET/CT in the detection of endogenous hyperinsulinaemic focus: an explorative study.

PURPOSE: To explore the role of (68)Ga-DOTATATE/DOTATOC PET/CT (SR PET/CT) in patients with suspicion of or histopathologically proven pancreatogenic hyperinsulinaemic hypoglycaemia. METHODS: We included 13 patients with histopathologically proven or a high clinical suspicion of pancreatogenic hyperinsulinaemia. All the patients underwent a SR PET/CT scan. The results were correlated with histopathological findings. Normalization of blood glucose levels after resection of the pancreatic lesion, as well as a cytological and/or pathological diagnosis of insulinoma, was considered the diagnostic gold standard for insulinoma. The diagnosis of nesidioblastosis was based on exclusion of an insulinoma and conclusive pathological examination of a segment of the pancreas. Malignant insulinoma was defined as the presence of locoregional or distant metastases. RESULTS: Based on histopathology, 13 patients were found to have pancreatic hyperinsulinaemia: two patients had malignant insulinoma, eight had nonmetastasized insulinoma, and three had nesidioblastosis. SR PET was positive in 11 of the 13 patients (84.6 %) with a final diagnosis of endogenous pancreatic hypoglycaemia. Histopathological staining confirmed 16 foci of hyperinsulinism (insulin positivity). SR PET detected 14 of the 16 lesions, resulting in a sensitivity of 87 %. One intrapancreatic spleen was falsely diagnosed as insulinoma focus on SR PET, resulting in positive predictive value of 93.3 %. Immunohistochemical staining of somatostatin receptor (SSR) subtype 2a was available in ten specimens: two nesidioblastosis, and seven benign and one malignant insulinoma. Eight out of the ten specimens (80 %) stained strongly to moderately positive. Seven of the eight SSR2a-positive lesions were picked up on SR PET. Based on the results of SR PET/CT, nine patients achieved complete remission of the hypoglycaemic events during follow-up. CONCLUSION: This explorative study suggests that SR PET in combination with CT may play a significant role in the detection and management of patients with pancreatogenic hyperinsulinaemic hypoglycaemia. A large proportion of insulinomas express SSR2a, and a larger study is needed to fully assess the diagnostic accuracy of SR PET in patients with insulinoma and nesidioblastosis compared with current localizing studies used in clinical practice.

Staged Catheter-Based Valve Treatment of Severe Carcinoid Heart Disease.

PURPOSE: Carcinoid heart disease (CHD) with severe valve destruction represents the major cause of high morbidity and mortality in patients with carcinoid syndrome. In this paper, we present a novel interventional treatment approach and report the first clinical result achieved in a patient with extensive CHD. METHODS AND RESULTS: A woman with an ileal neuroendocrine tumour (G2, Ki67: 5%) presented with severe CHD (NYHA IV) affecting both the pulmonary and the tricuspid valve. First, a balloon-expandable 23-mm Edwards SAPIEN™ was successfully implanted percutaneously into the pulmonary valve. Since no catheter-based techniques were available for the replacement of the native tricuspid valve, we implanted an Edwards SAPIEN 26-mm valve into the vena cava inferior between the right atrium and the ostium of the hepatic veins to reduce abdominal congestion. The implantation was technically successful and completely prevented regurgitation into the vena cava inferior and abdominal veins. After this procedure, the patient's clinical condition improved significantly, and she achieved near-normal exercise tolerance (VO2 max: 24.4 ml O2/kg/min, NYHA II). CONCLUSION: We demonstrated that percutaneous valve implantation may offer a novel, minimally invasive option in high-risk patients with severe CHD.

Pharmacological strategies to enhance adaptation in intestinal failure.

PURPOSE OF REVIEW: Intestinal failure because of more or less extensive resection of parts of the small and large intestine (short bowel syndrome) results from the reduction of absorptive surface of the remaining intestine and frequently results in dependence on parenteral nutrition. Parenteral nutrition, although lifesaving, is associated with short and long-term complications as well as with reduced quality of life and overall survival. RECENT FINDINGS: Pharmacological enhancement of the physiological intestinal adaptive response by subcutaneous application of the glucagon-like peptide 2 analogue teduglutide results in an improved, hyperadaptive response. This is reflected by decreased parenteral calorie and fluid requirements, decreased parenteral nutrition infusion days per week including complete weaning off parenteral nutrition with complete oral autonomy, improved quality of life, and metabolic and nutritional stability. SUMMARY: The advent of teduglutide as an authority-approved specific medication for intestinal failure in parenteral nutrition-dependent short bowel syndrome offers an effective and beneficial treatment for these patients. As a result, patients are more stable whether for medical or further surgical management including intestinal transplantation. Long-term efficacy and safety still have to be proven.

Glucocorticoids regulate barrier function and claudin expression in intestinal epithelial cells via MKP-1.

Barrier dysfunction is pivotal to the pathogenesis of inflammatory bowel diseases (IBD) and collagenous colitis. Glucocorticoids restore barrier function in Crohn's disease, but whether this reflects attenuated inflammation or an epithelial-specific action has not yet been addressed. Using filter-grown Caco-2 monolayers as an in vitro model of the intestinal epithelial barrier, we observed that glucocorticoids induced a time- and dose-dependent increase in transepithelial electrical resistance (TEER) in a glucocorticoid receptor-dependent manner without altering flux of larger solutes or changing principal tight junction architecture. This was accompanied by reduced paracellular cation flux, reduced expression of the pore-forming tight junction component claudin-2, and upregulation of the sealing tight junction protein claudin-4. In contrast, expression of occludin, claudin-1, -7, or -8 was not altered. Dexamethasone increased expression and activity of MAPK phosphatase-1 and inhibition of this phosphatase prevented the glucocorticoid-induced changes in TEER and claudin expression, whereas inhibiting p38 or MEK1/2 was not sufficient to replicate the glucocorticoid effects. Upon exposure to IFN-γ, TNF-α, or IL-1ß, TEERs declined in dexamethasone-treated cells but remained consistently higher than in cells not receiving glucocorticoids. Treatment with IFN/TNF resulted in an upregulation of claudin-2 that was significantly attenuated by dexamethasone, whereas increased claudin-2 expression upon IL-1ß stimulation was not affected by glucocorticoids. Taken together, barrier augmentation might represent a previously unrecognized mechanism of action, potentially contributing to the therapeutic efficacy of glucocorticoids in IBD and collagenous colitis.

Accurate assessment of long-term nephrotoxicity after peptide receptor radionuclide therapy with (177)Lu-octreotate.

PURPOSE: Renal radiation during peptide receptor radionuclide therapy (PRRT) may result in glomerular damage, a potential reduction of glomerular filtration rate (GFR) and ultimately lead to renal failure. While reported PRRT nephrotoxicity is limited to data derived from serum creatinine-allowing only approximate estimates of GFR-the aim of this study is to accurately determine PRRT-induced long-term changes of renal function and associated risk factors according to state-of-the-art GFR measurement. METHODS: Nephrotoxicity was analysed using (99m)Tc-diethylenetriaminepentaacetic acid (DTPA) clearance data of 74 consecutive patients with gastroenteropancreatic neuroendocrine tumours (GEP NET) undergoing PRRT with (177)Lu-octreotate. The mean follow-up period was 21 months (range 12-50) with a median of five GFR measurements per patient. The change of GFR was analysed by linear curve fit. Potential risk factors including diabetes mellitus, arterial hypertension, previous chemotherapy, renal impairment at baseline and cumulative administered activity were analysed regarding potential impact on renal function loss. In addition, Common Terminology Criteria for Adverse Events (CTCAE) v3.0 were used to compare nephrotoxicity determined by (99m)Tc-DTPA clearance versus serum creatinine. RESULTS: The alteration in GFR differed widely among the patients (mean -2.1 ± 13.1 ml/min/m(2) per year, relative yearly reduction -1.8 ± 18.9%). Fifteen patients (21%) experienced a mild (2-10 ml/min/m(2) per year) and 16 patients (22%) a significant (>10 ml/min/m(2) per year) decline of GFR following PRRT. However, 11 patients (15%) showed an increase of >10 ml/min/m(2) per year. Relevant nephrotoxicity according to CTCAE (grade ≥3) was observed in one patient (1.3%) with arterial hypertension and history of chemotherapy. Nephrotoxicity according to serum creatinine was discordant to that defined by GFR in 15% of the assessments and led to underestimation in 12% of patients. None of the investigated factors including cumulative administered activity contributed to the decline of renal function. CONCLUSION: Serious nephrotoxicity after PRRT with (177)Lu-octreotate is rare (1.3%). However, slight renal impairment (GFR loss >2 ml/min/m(2) per year) can frequently (43%) be detected by (99m)Tc-DTPA clearance assessments. Cumulative administered activity of (177)Lu-octreotate is not a major determinant of renal impairment in our study.

Outcome and toxicity of salvage therapy with 177Lu-octreotate in patients with metastatic gastroenteropancreatic neuroendocrine tumours.

PURPOSE: We assessed the outcome and toxicity of salvage therapy (repeat treatment) with (177)Lu-octreotate and high cumulative activities in patients with metastatic gastroenteropancreatic neuroendocrine tumours (GEP-NET). METHODS: We retrospectively analysed a consecutive cohort of 33 patients with metastatic GEP-NET who underwent salvage peptide receptor radionuclide therapy (PRRT) in our institution. All patients had progressive NET prior to salvage treatment and had shown an initial response to PRRT. The mean cumulative activity was 44.3 GBq (30.0-83.7 GBq). Radiographic response was assessed using CT and/or MRI according to modified SWOG criteria. Toxicity was evaluated using laboratory data, including complete blood counts and renal function tests using CTCAE 3.0. Survival analysis was performed with the Kaplan-Meier curve method and a significance level at p < 0.05. RESULTS: Radiographic responses consisted of complete response in 1 patient (3.0%), partial response in 6 patients (18.2%), minor response in 1 patient (3.0%), stable disease in 14 patients (42.4%), and progressive disease in 11 patients (33.3%). Median progression-free survival (PFS) from the start of salvage therapy was 13 months (95% CI 9-18) and patients with a history of a durable PFS after initial PRRT tended to have long-lasting PFS after salvage treatment (p = 0.04). None of the patients developed severe nephrotoxicity (grade 3/4) or a myelodysplastic syndrome during follow-up. Relevant albeit reversible haematotoxicity (grade 3/4) occurred in 7 patients (21.2%). The cumulative administered activity was not associated with an increased incidence of haematotoxicity. CONCLUSION: PRRT with (177)Lu-octreotate in the re-treatment setting is safe and effective in patients with metastatic GEP-NET.

Detection of neuroendocrine tumours in the small intestines using contrast-enhanced multiphase Ga-68 DOTATOC PET/CT: the potential role of arterial hyperperfusion.

BACKGROUND: Interpretation of small intestinal neuroendocrine tumours (NETs) by Ga-68 DOTATOC PET/CT can be difficult. The potential benefit of arterial hyperperfusion for the detection of NETs was evaluated. METHODS: Between 2006 and 2009, 320 consecutive Ga-68 DOTATOC PET/CT examinations, performed for NETs, revealed 40 lesions suggesting intestinal NETs in 25 patients. Two groups of lesions were distinguished: epigastric lesions evaluable in the arterial and venous CT scan (Group 1) and hypogastrial lesions evaluable in the venous CT scan only (Group 2). Lesions were jointly rated by two radiologists and a nuclear medicine physician. Maximum standard uptake values (SUVmax) of lesions and background were assessed. The reference standard was histology (available for 28 lesions) or follow-up (for a mean of 22.9 months). RESULTS: PET detected all suspicious lesions but was false positive in 3 lesions. In Group 1 the arterial scan performed significantly better than the venous scan (p = 0.008). Diagnostic performance was better in Group 1 than in Group 2 (p < 0.001). SUVmax of true positive lesions were significantly higher than background SUVmax (p < 0.001) and SUVmax of false positive lesions (p = 0.005). CONCLUSIONS: The arterial phase of multiphase Ga-68 DOTATOC PET/CT might improve the localization of intestinal NETs and, thereby, improve the overall diagnostic accuracy of this modality in the assessment of intestinal NETs by adding information about lesion perfusion not available when only venous CT is performed.

Searching for primaries in patients with neuroendocrine tumors (NET) of unknown primary and clinically suspected NET: Evaluation of Ga-68 DOTATOC PET/CT and In-111 DTPA octreotide SPECT/CT.

BACKGROUND: To evaluate the clinical efficacy of In-111 DTPA octreotide SPECT/CT and Ga-68 DOTATOC PET/CT for detection of primary tumors in patients with either neuroendocrine tumor of unknown primary (NETUP) or clinically suspected primary NET (SNET). PATIENTS AND METHODS: A total of 123 patients were included from 2006 to 2009, 52 received Ga-68 DOTATOC PET/CT (NETUP, 33; SNET, 19) and 71 underwent In-111 DTPA octreotide SPECT/CT (50; 21). The standard of reference included histopathology or clinical verification based on follow-up examinations. RESULTS: In the NETUP group Ga-68 DOTATOC detected primaries in 15 patients (45.5%) and In-111 DTPA octreotide in 4 patients (8%) (p < 0.001); in the SNET group, only 2 primaries could be detected, all by Ga-68 DOTATOC. In patients with NETUP, primary tumors could be found significantly more often than in patients with SNET (p = 0.01). Out of these 21 patients 14 patients were operated. CONCLUSION: Ga-68 DOTATOC PET/CT is preferable to In-111 DTPA octreotide SPECT/CT when searching for primary NETs in patients with NETUP but should be used with caution in patients with SNET.

Use of teduglutide in adults with short bowel syndrome-associated intestinal failure.

Short bowel syndrome (SBS) is a rare gastrointestinal disorder associated with intestinal failure (SBS-IF) and poor health-related outcomes. Patients with SBS-IF are unable to absorb sufficient nutrients or fluids to maintain significantly metabolic homeostasis via oral or enteral intake alone and require long-term intravenous supplementation (IVS), consisting of partial or total parenteral nutrition, fluids, electrolytes, or a combination of these. The goal of medical and surgical treatment for patients with SBS-IF is to maximize intestinal remnant absorptive capacity so that the need for IVS support may eventually be reduced or eliminated. Daily subcutaneous administration of the glucagon-like peptide 2 analog, teduglutide, has been shown to be clinically effective in reducing IVS dependence and potentially improving the health-related quality of life of patients with SBS-IF. The management of patients with SBS-IF is complex and requires close monitoring. This narrative review discusses the use of teduglutide for patients with SBS-IF in clinical practice. The screening of patient eligibility for teduglutide treatment, initiation, monitoring of efficacy and safety of treatment, adapting or weaning off IVS, and the healthcare setting needed for SBS-IF management are described, taking into consideration data from clinical trials, observational studies, and clinical experience.

Lymph node metastases are more frequent in paediatric appendiceal NET ≥1.5 cm but without impact on outcome - Data from the German MET studies.

BACKGROUND: Paediatric appendiceal neuroendocrine tumours (appNET) are very rare tumours, mostly detected incidentally by histopathological evaluation after appendectomy. Treatment recommendations are based on adult data considering high-risk NET as defined by European Neuroendocrine Tumour Society (ENETS) guidelines for completion right-sided hemicolectomy (RHC). Recent data suggest that less aggressive therapy may be justified. PROCEDURE: Analysis of children and adolescents with appNET prospectively registered with the German Malignant Endocrine Tumour (MET) studies between 1997 and 2022. RESULTS: By December 2022, 662 patients (64.7% females, 35.3% male) had been reported. Median age was 13.3 years [4.5-17.9], median duration of follow-up 2.2 years [0-10.9]. No distant metastases were reported. Tumour size was <1 cm in 63.5%, 1-2 cm in 33.2%, and >2 cm in 3.2% of patients. WHO grade 1 and 2 tumours were diagnosed in 76.9% and 23.1% of patients, respectively. Lymphovascular invasion and lymph node metastases were associated with tumour size ≥1.5 cm. 27.0% of patients presented with high-risk NET according to ENETS criteria. Of those, only 55.9% underwent secondary oncological right hemicolectomy. Neither distant metastases, nor recurrences or disease-related deaths occurred in patients with appendectomy only as well as in patients with completion RHC. Overall and event-free survival were both 100%. CONCLUSIONS: Internationally harmonized consensus recommendations on treatment of children and adolescents with appendiceal NET are urgently needed to avoid completion RHC in high-risk patients.