The Value of Somatostatin Receptor Scintigraphy (SRS) in Patients with NETG1/G2 Pancreatic Neuroendocrine Neoplasms (p-NENs).

Background: Neuroendocrine neoplasms of the pancreas (p-NEN) are common gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs). The aim of this retrospective study was to review the of value of Somatostatin Receptor Scintigraphy (SRS) in initial detection of p-NEN, evaluation of tumour extent and as imaging follow-up after radical surgery in patients with confirmed well (NETG1) or moderate (NETG2) differentiated p-NEN based on pathological WHO 2017 classification. Material and methods: Overall 281 patients with confirmed p-NEN were enrolled. The SRS was performed to evaluation of primary p-NEN, also to assess clinical stage of disease, based on current World Health Organization (WHO) classification and during clinical follow-up. A total of 829 examinations were performed over time in these 281 patients using 99mTc HYNICTOC. Images were acquired between 1 – 3 h after i.v. injection of radiotracer. Initially whole body WB-SPECT and then WB-SPECT/CT, with standard iterative reconstruction were used. Results: There were 159 patients with NETG1 (57%) and 122 subjects with NETG2 (43%). The female to male ratio was 1.1:1. In 68 patients (22%) with NETG1/G2 eight-seven SRS (10%) were performed to confirm initial diagnosis. SRS results were as follow: true positive (TP) = 84 (97%), false negative (FN) = 3 (3%), no true negative (TN) or false positive (FP) results of SRS examination (sensitivity of SRS per patient was 96%). In 198 subjects (66%) SRS was used in evaluation and re-evaluation of the clinical stage, A total of 661 (80%) examinations were carried out in these patients. There were TP=514 (77%), TN=136 (21%), FN=7 (1%) and FP=4 (1%) results. The sensitivity and specificity per patient were: 96% and 95%. The sensitivity and specificity per study: 98% and 97%. In 35 patients (12%) SRS was used as imaging follow-up after radical surgery, there were overall 81 examination (10%) which were performed. There were 76 (91%) TN results of examinations of SRS and in 4 patients we identified recurrence (TP). In total, which consists of initial diagnosis/staging and follow-up patients, the sensitivity of SRS was 96% and specificity 97% per patient and per study sensitivity and specificity was 98%. Conclusions: SRS using 99mTc HYNICTOC acquired in WB-SPECT or WB-SPECT/CT techniques is an excellent imaging modality in detection of primary NETG1/G2 p-NEN. Our study confirms that SRS has high sensitivity and specificity, as a result has tremendous value as an examination method to assess clinical stage of disease and as an imaging follow-up after radical treatment

Anti-tumour effects of lanreotide for pancreatic and intestinal neuroendocrine tumours: The CLARINET open-label extension study

In the CLARINET study, lanreotide Autogel (depot in USA) significantly prolonged progression-free survival (PFS) in patients with metastatic pancreatic/intestinal neuroendocrine tumours (NETs). We report long-term safety and additional efficacy data from the open-label extension (OLE). Patients with metastatic grade 1/2 (Ki-67 %) nonfunctioning NET and documented baseline tumour-progression status received lanreotide Autogel 120 mg (n=101) or placebo (n=103) for 96 weeks or until death/progressive disease (PD) in CLARINET study. Patients with stable disease (SD) at core study end (lanreotide/placebo) or PD (placebo only) continued or switched to lanreotide in the OLE. In total, 88 patients (previously: lanreotide, n=41; placebo, n=47) participated: 38% had pancreatic, 39% midgut and 23% other/unknown primary tumours. Patients continuing lanreotide reported fewer adverse events (AEs) (all and treatment-related) during OLE than core study. Placebo-to-lanreotide switch patients reported similar AE rates in OLE and core studies, except more diarrhoea was considered treatment-related in OLE (overall diarrhoea unchanged). Median lanreotide PFS (core study randomisation to PD in core/OLE; n=101) was 32.8 months (95% CI: 30.9, 68.0). A sensitivity analysis, addressing potential selection

Targeted Inactivation of p12Cdk2ap1, CDK2 Associating Protein 1, Leads to Early Embryonic Lethality

Targeted disruption of murine Cdk2ap1, an inhibitor of CDK2 function and hence G1/S transition, results in the embryonic lethality with a high penetration rate. Detailed timed pregnancy analysis of embryos showed that the lethality occurred between embryonic day 3.5 pc and 5.5 pc, a period of implantation and early development of implanted embryos. Two homozygous knockout mice that survived to term showed identical craniofacial defect, including a short snout and a round forehead. Examination of craniofacial morphology by measuring Snout Length (SL) vs. Face Width (FW) showed that the Cdk2ap1+/− mice were born with a reduced SL/FW ratio compared to the Cdk2ap1+/+ and the reduction was more pronounced in Cdk2ap1−/− mice. A transgenic rescue of the lethality was attempted by crossing Cdk2ap1+/− animals with K14-Cdk2ap1 transgenic mice. Resulting Cdk2ap1+/−:K14-Cdk2ap1 transgenic mice showed an improved incidence of full term animals (16.7% from 0.5%) on a Cdk2ap1−/− background. Transgenic expression of Cdk2ap1 in Cdk2ap1−/−:K14-Cdk2ap1 animals restored SL/FW ratio to the level of Cdk2ap1+/−:K14-Cdk2ap1 mice, but not to that of the Cdk2ap1+/+:K14-Cdk2ap1 mice. Teratoma formation analysis using mESCs showed an abrogated in vivo pluripotency of Cdk2ap1−/− mESCs towards a restricted mesoderm lineage specification. This study demonstrates that Cdk2ap1 plays an essential role in the early stage of embryogenesis and has a potential role during craniofacial morphogenesis

NETest Liquid Biopsy Is Diagnostic of Lung Neuroendocrine Tumors and Identifies Progressive Disease

Background: There are no effective biomarkers for the management of bronchopulmonary carcinoids (BPC). We examined the utility of a neuroendocrine multigene transcript "liquid biopsy" (NETest) in BPC for diagnosis and monitoring of the disease status. Aim: To independently validate the utility of the NETest in diagnosis and management of BPC in a multicenter, multinational, blinded study. Material and Methods: The study cohorts assessed were BPC (n = 99), healthy controls (n = 102), other lung neoplasia (n = 101) including adenocarcinomas (ACC) (n = 41), squamous cell carcinomas (SCC) (n = 37), small-cell lung cancer (SCLC) (n = 16), large-cell neuroendocrine carcinoma (LCNEC) (n = 7), and idiopathic pulmonary fibrosis (IPF) (n = 50). BPC were histologically classified as typical (TC) (n = 62) and atypical carcinoids (AC) (n = 37). BPC disease status determination was based on imaging and RECIST 1.1. NETest diagnostic metrics and disease status accuracy were evaluated. The upper limit of normal (NETest) was 20. Twenty matched tissue-blood pairs were also evaluated. Data are means ± SD. Results: NETest levels were significantly increased in BPC (45 ± 25) versus controls (9 ± 8; p < 0.0001). The area under the ROC curve was 0.96 ± 0.01. Accuracy, sensitivity, and specificity were: 92, 84, and 100%. NETest was also elevated in SCLC (42 ± 32) and LCNEC (28 ± 7). NETest accurately distinguished progressive (61 ± 26) from stable disease (35.5 ± 18; p < 0.0001). In BPC, NETest levels were elevated in metastatic disease irrespective of histology (AC: p < 0.02; TC: p = 0.0006). In nonendocrine lung cancers, ACC (18 ± 21) and SCC (12 ± 11) and benign disease (IPF) (18 ± 25) levels were significantly lower compared to BPC level (p < 0.001). Significant correlations were evident between paired tumor and blood. samples for BPC (R: 0.83, p < 0.0001) and SCLC (R: 0.68) but not for SCC and ACC (R: 0.25-0.31). Conclusions: Elevated NETest levels are indicative of lung neuroendocrine neoplasia. NETest levels correlate with tumor tissue and imaging and accurately define clinical progression

ENETS Consensus Guidelines for High-Grade Gastroenteropancreatic Neuroendocrine Tumors and Neuroendocrine Carcinomas.

Consensus Guidelines for High Grade Gastro-Entero Pancreatic (GEP) Neuroendocrine Tumours and Neuroendocrine Carcinomas (NEC)

Efficacy and safety of high-dose lanreotide autogel in patients with progressive pancreatic or midgut neuroendocrine tumours. CLARINET FORTE phase 2 study results

Introduction: This prospective, single-arm, phase 2 study assessed the efficacy and safety of lanreotide autogel (LAN) administered at a reduced dosing interval in patients with progressive neuroendocrine tumours (NETs) after LAN standard regimen. Methods: Patients had metastatic or locally advanced, grade 1 or 2 midgut NETs or pancreatic NETs (panNETs) and centrally assessed disease progression on LAN 120 mg every 28 days. They were treated with LAN 120 mg every 14 days for up to 96 weeks (midgut cohort) or 48 weeks (panNET cohort). The primary end-point was centrally assessed progression-free survival (PFS). PFS by Ki-67 categories was analysed post hoc. Secondary end-points included quality of life (QoL) and safety. Results: Ninety-nine patients were enrolled (midgut, N = 51; panNET, N = 48). Median (95% CI) PFS was 8.3 (5.6–11.1) and 5.6 (5.5–8.3) months, respectively. In patients with Ki-67 ≤ 10%, median (95% CI) PFS was 8.6 (5.6–13.8) and 8.0 (5.6–8.3) months in the midgut and panNET cohorts, respectively. Patients’ QoL did not deteriorate during the study. There were no treatment-related serious adverse events and only two withdrawals for treatment-related adverse events (both in the panNET cohort). Conclusions: In patients with progressive NETs following standard-regimen LAN, reducing the dosing interval to every 14 days provided encouraging PFS, particularly in patients with a Ki-67 ≤ 10% (post hoc); no safety concerns and no deterioration in QoL were observed. Increasing LAN dosing frequency could therefore be considered before escalation to less well-tolerated therapies

Unmet medical needs in pulmonary neuroendocrine (carcinoid) neoplasms

Pulmonary carcinoids (PCs) display the common features of all well-differentiated neuroendocrine neoplasms (NEN) and are classified as low- and intermediate-grade malignant tumours (i.e. typical (TC) and atypical carcinoid (AC), respectively). There is a paucity of randomised studies dedicated to advanced PCs and management principles are drawn from the larger gastroenteropancreatic (GEP) NEN experience. There is growing evidence that NEN anatomic subgroups have different biology and different responses to treatment and, therefore, should be investigated as separate entities in clinical trials. In this review, we discuss the existing evidence and limitations of tumour classification, diagnostics and staging, prognostication and treatment in the setting of PC with focus on unmet medical needs and directions for the future