Pancreatic Neuroendocrine Neoplasia Research Articles

Multiple endocrine neoplasia type 1 with MEN1 variant of unknown significance, in a patient after the diagnosed of pancreatic neuroendocrine neoplasia.

Duodenopancreatic neuroendocrine neoplasia (DP-NEN) is in approximately 10% of cases of multiple endocrine neoplasia type 1 (MEN1). We encountered a case in which the onset of NEN led to suspicion and diagnosis of MEN1. Although genetic testing showed MEN1 variant of uncertain significance (VUS), we considered it pathological from the clinical course, promoting the provision of genetic counseling and screening for relatives. MEN1 has a variety of clinical manifestations, and DP-NENs are the second-most common manifestation after primary hyperparathyroidism (pHPT). It is important to assume that MEN1 is an underlying cause of NEN.

PPY-cell hyperplasia accompanying NENs: Immunohistochemical and nuclear medicine analysis

Pancreatic polypeptide cell hyperplasia (PPY-H) is a multiplication of the neuroendocrine cells producing pancreatic polypeptide (PPY). The development and role of PPY-H and its corresponding clinical and imaging findings still need to be fully elucidated. We present 12 cases of PPY-H accompanying pancreatic neuroendocrine neoplasias (NEN). PPY-H was analyzed with the help of immunohistochemistry and confocal microscopy; preoperative clinical data and imaging studies were evaluated retrospectively. We observed PPY-H emerging from pancreatic ducts, and in some cases, we observed simultaneous NKX6.1 positivity in ducts and PPY-H. Additional clinical-pathological correlations suggests that gastrointestinal symptoms (e.g., epigastric pain and cholestasis) could be more related to PPY-H than to NEN hormonal production. In particular cases, SSTR2 expression was strong in PPY-H and correlated with distinguishable accumulation of activity next to NEN on 99 mTc EDDA/Hynic-TOC SPECT/CT. In another case, 18F-FDG-PET/CT showed increased metabolic activity in the area of PPY-H surrounding NEN. Our data suggest that PPY-H originates in the lining of pancreatic ducts. Confirmation of SSTR2 in PPY-H, using immunohistochemistry, suggests the utility of 99 mTc EDDA/Hynic-TOC or 68Ga-DOTA radiotracers in clinical diagnostics; however, studies with larger cohort are needed.

Sex Differences in Survival from Neuroendocrine Neoplasia in England 2012-2018: A Retrospective, Population-Based Study.

Pre-clinical studies have suggested sex hormone signalling pathways may influence tumorigenesis in neuroendocrine neoplasia (NEN). We conducted a retrospective, population-based study to compare overall survival (OS) between males and females with NEN. A total of 14,834 cases of NEN diagnosed between 2012 and 2018, recorded in England's National Cancer Registry and Analysis Service (NCRAS), were analysed. The primary outcome was OS with 5 years maximum follow-up. Multivariable analysis, restricted mean survival time and mediation analysis were performed. Appendiceal, pulmonary and early-stage NEN were most commonly diagnosed in females; stomach, pancreatic, small intestinal, colonic, rectal and later-stage NEN were more often diagnosed in males. Females displayed increased survival irrespective of the stage, morphology or level of deprivation. On average, they survived 3.62 (95% CI 1.73-5.90) to 10.26 (6.6-14.45) months longer than males; this was statistically significant in NEN of the lung, pancreas, rectum and stomach (p < 0.001). The stage mediated improved survival in stomach, lung, and pancreatic NEN but not in rectal NEN. The reasons underlying these differences are not yet understood. Overall, females diagnosed with NEN tend to survive longer than males, and the stage at presentation only partially explains this. Future research, as well as prognostication and treatment, should consider sex as an important factor.

Clinical characteristics of 662 patients with pancreatic neuroendocrine tumors receiving antitumoral therapy

Pancreatic neuroendocrine neoplasia constitute an important subentity of the gastroenteropancreatic neuroendocrine neoplasms accounting for up to 15% of all neuroendocrine neoplasm. Prognosis and oncological behavior of pancreatic neuroendocrine tumors (pNETs) is extremely heterogenous and dependent on the specific tumor stage and differentiation. However, systematic data on the specific epidemiology of pNET are scarce. We identified 662 patients with pNET within the Oncology Dynamics database (IQVIA). Patients were derived from 4 European countries (Germany, France, UK, Spain), 3 Asian countries (Japan, China, South Korea) and 2 South American countries (Mexico and Brazil) and with regard to major patient and tumor related characteristics including patients' age, sex, tumor stage, tumor grading, and differentiation. The mean age of the study cohort was 62 years (SD 12 years) with 53.9.1% of all patients being male. The majority of patients had an Eastern co-operative of Oncology Group 1 performance status (63.3%). The most common Union international contre le cancer tumor stage was stage IV (85%) with liver metastases (89.0%) representing the most common site of extra-pancreatic tumor manifestation. The majority of all patients displayed well or moderate tumor differentiation (9.6% of patients had a Ki-67 expression below 2%. 67.6% of pNET patients had a Ki-67 expression between 2 and 20% and 22.8% of patients showed an expression above 20%). At time point of diagnoses, 93.1% of patients were classified as inoperable. Of note, 93.9 % of patients received systemic anti-tumoral therapy in palliative intention, while treatment was administered in 1.4 % of cases in neoadjuvant and in 4.7% of cases in in an adjuvant setting. Biological therapy was applied to 39.4% of patients, followed by targeted therapies (31.4%) and chemotherapy. Pancreatic neuroendocrine neoplasia are diagnosed in advanced tumor stages, globally. Systemic treatment was the most commonly used treatment modality. Such data may help to better understand the specific epidemiology of pNET worldwide.

Regional Growth Velocity and Incidence of Pancreatic Neuroendocrine Neoplasias in Multiple Endocrine Neoplasia Type 1.

Pancreatic neuroendocrine neoplasias (pNENs) in multiple endocrine neoplasia type 1 are predominantly found in the dorsal anlage. Whether their growth velocity and incidence might be related to their location in the pancreas has not been investigated yet. We studied 117 patients using endoscopic ultrasound. Growth velocity could be calculated for 389 pNENs. Increase of largest tumor diameter (% per month) was 0.67 (standard deviation [SD], 2.04) in the pancreatic tail (n = 138), 1.12 (SD, 3.00) in the pancreatic body (n = 100), 0.58 (SD, 1.19) in the pancreatic head/uncinate process-dorsal anlage (n = 130), and 0.68 (SD, 0.77) in the pancreatic head/uncinate process-ventral anlage (n = 12). Comparing growth velocity of all pNENs in the dorsal (n = 368, 0.76 [SD, 2.13]) versus ventral anlage, no significant difference was detected. Annual tumor incidence rate was 0.21 in the pancreatic tail, 0.13 in the pancreatic body, 0.17 in the pancreatic head/uncinate process-dorsal anlage, 0.51 dorsal anlage together, and 0.02 in the pancreatic head/uncinate process-ventral anlage. Multiple endocrine neoplasia type 1 pNENs are unequally distributed between ventral (low prevalence and incidence) and dorsal anlage. However, there are no regional differences in growth behavior.

LBODP065 Rare Cause Of Bone Pain In MEN Syndrome

Abstract Introduction: MEN 1 syndrome is a rare disease in children and young adults, with prevalence reported as 2 per 100,000. MEN 1 caused by mutations in the MEN1 tumor suppressor gene, characterized by 2 or more MEN1 tumors: parathyroid, anterior pituitary, pancreatic islet tumors. To the best of our knowledge, osteomyelitis of the pelvis has not been reported as a complication in the literature in patients who were diagnosed with MEN1Case21 yo male from Honduras with PMHx of remote asthma presented with a common complaint of abdomen pain but found to have a rare diagnosis. He had 2 days of lower abdomen pain associated with non-bilious non bloody vomiting. Initial were significant for calcium 12.9, phosphorus 1.5 magnesium 1.8 and PTH 360. 4 mm renal stone 4 mm was detected on CT abdomen/pelvis. The initial EKG demonstrated J point elevation due to the hypercalcemia. He was admitted to the PICU for continuous telemetry monitoring due to the abnormal EKG related to electrolyte abnormalities. Hypercalcemia treatment was initiated with aggressive hydration, calcitonin administration as well as zoledronic acid administration. The patient's calcium levels improved as well as EKG. The parathyroid scan was positive for a right-sided parathyroid adenoma. He underwent right Inferior Parathyroidectomy, Intraoperative Nerve Monitoring, Cryopreservation of Parathyroid Tissue. As part of his diagnostic work-up for hyperparathyroidism, he was screened for MEN. His pituitary function was abnormal: ACTH and cortisol levels were high, his testosterone and gonadotropins were inappropriately low as well as TSH and T4. A microadenoma was present on brain MRI. No Pancreatic Neuroendocrine Neoplasia was found. The diagnosis of MEN 1 was made. Despite the improvements in his endocrinopathies, he continued to have lower abdomen pain associated with intermittent fevers. He was seen by urology and orthopedics. Initially MRI demonstrated bone erosion thought to be secondary to hypercalcemia but repeat MRI imaging of the pelvis was suspicious for phlegmon vs. developing abscess secondary to osteitis pubis. His blood cultures were positive for MSSA. He was started on antibiotics with continued clinical improvementThis patient presented with one of the most common complaints in the ED, abdomen pain and was found to have two rare and potentially fatal diagnosis which was identified and treated with a good clinical outcome Discussion: This case highlights a rare disease in the setting of osteomyelitis which could easily be missed as a manifestation of bone pain from hypercalcemia. The patient did experience fevers and malaise that was initially attributed to zoledronic acid administration. When his pain did not resolve MRI found osteomyelitis, allowing early antibiotic administration and prevention of sepsis. Presentation: No date and time listed

Pancreatic neuroendocrine neoplasms: survival trend analysis of a comprehensive center.

Therapeutic options for pancreatic neuroendocrine neoplasia (Pan-NEN) have increased over the last decade. We aim to understand the evolution of the prognosis of patients with diagnosis of Pan-NEN within a 12-year period, considering the implementation of new treatments. This study is a retrospective cohort study of patients diagnosed with Pan-NENs between 2006 and 2017. Survival outcome estimates were calculated by Kaplan-Meier method. The impact of baseline clinicopathological characteristics on survival was explored with the use of Cox proportional hazard model. Of the 97 patients, 77 (79.9%) had well-differentiated neuroendocrine tumor (NET) according to WHO 2010 classification, and 52 (53.6%) had localized or locoregional disease. There were no differences between clinicopathological characteristics and survival outcomes when comparing patients diagnosed between 2006-2011 and 2012-2017. Neuroendocrine carcinoma - HR 2.76, 95% CI 1.17-6.55 - and stages III and IV at diagnosis were independent poor prognostic factors - HR 6.02, 95% CI 2.22-16.33 and HR 6.93, 95% CI 2.94-16.32, respectively. The new therapeutic approaches did not induce better survival outcomes on Pan-NEN in recent years. This is possibly due to the indolent nature of NET grades 1 and 2, even metastatic, allowing patients to be submitted to new target therapies along their disease course.

Exploring the MEN1 dependent modulation of caspase 8 and caspase 3 in human pancreatic and murine embryo fibroblast cells

MEN1 mutation causes pancreatic neuroendocrine neoplasia and benign malignancies of the parathyroid, the adrenal cortex and pituitary gland. The transcriptional activity of its product menin promotes the expression of genes deputed to several cellular mechanism including cell death. Here, we focused on its implication in the activation of the initiator and executioner caspases after staurosporine mediated cell death in 2D and 3D human and murine cell models. The administration of staurosporine, a well-known inducer of apoptotic cell death, caused a significant reduction of BON1, QGP1 and HPSC2.2 cell viability. The transient knockdown of MEN1, performed by using a specific siRNA, caused a significant down-regulation of CDKN1A and TP53 transcripts. The treatment with 1 µM of staurosporine caused also a significant down-regulation of MEN1 and was able to restore the basal expression of TP53 only in QGP1 cells. Transient or permanent MEN1 inactivation caused a decrease of caspase 8 activity in BON1, HPSC2.2 cells and MEN1−/− MEFs treated with staurosporine. Caspase 3/7 activity was suppressed after administration of staurosporine in MEN1 knocked down HPSC2.2 and MEN1−/− MEFs as well. The cleaved caspase 8 and caspase 3 decreased in human cells after MEN1 knockdown and in MEN1−/− MEFs. The treatment with staurosporine caused a reduction of the size of MEN1+/+ MEFs spheroids. Instead, MEN1−/− MEFs spheroids did not show any significant reduction of their size. In conclusion, MEN1 controls the activity of the initiator caspase 8 and the executioner caspase 3 in human and murine cells. Restoring of a functional MEN1 and interfering with the apoptotic mechanism could represent a future strategy for the treatment of MEN1-related malignancies.

Pancreatic Neuroendocrine Neoplasias in Multiple Endocrine Neoplasia Type 1 Are Predominantly Located in the Dorsal Anlage: An Endoscopic Ultrasound Study.

Pancreatic neuroendocrine neoplasias (pNENs) frequently occur in multiple endocrine neoplasia type 1 (MEN1). Their distribution referring to embryology, that is, the pancreatic anlagen, has not been investigated yet. In the time between 1998 and 2019, we studied the distribution of pNENs in MEN1 concerning the embryologic origin of the pancreas, that is, the dorsal versus ventral anlage using endoscopic ultrasound in 117 MEN1 patients: 56 women, 61 men; aged 40 years (standard deviation, 14 years) at first endoscopic ultrasound. In 105 patients, a total of 628 pNENs were detected. They were located in the pancreatic tail: 231; pancreatic body: 177; pancreatic head/uncinate process: 220. Of the latter, 22 were located in the ventral anlage, 176 in the dorsal anlage, and 22 remained undefined. In summary, just 3.5% of all detected pNENs were located in the ventral anlage, 93.0% in the dorsal anlage, and 3.5% could not be assigned. Our study indicates that the vast majority of pNENs in MEN1 is located in the dorsal anlage, whereas the ventral anlage of the pancreas seems to be to a large extend spared from pNENs. Implications for new surgical strategies might be considered.

P-208 Pancreatic neuroendocrine neoplasia: Experience of a comprehensive cancer center

Pancreatic neuroendocrine neoplasia (Pan-NEN) are rare tumors in which therapeutic options have been increasing over the last decade. However, the effect of implementing these therapies in the real world is poorly understood. We aim to characterize the clinical features and therapeutic strategies of patients with Pan-NEN within a 12-year period in a cohort of patients followed at IPOFG-Porto. We performed a retrospective cohort study of patients diagnosed with Pan-NEN between 2006 and 2017 at the largest NEN reference Portuguese Center. Progression-free (PFS) and overall survival (OS) time estimates were calculated by Kaplan-Meier method. To assess the impact of baseline clinicopathological characteristics on survival, we used univariate and multivariate Cox proportional hazard models. Ninety-seven patients were included. Mean patient age was 59.5±13.55 years-old, with 55 (56.7%) being male. Forty-five patients (48.5%) had an Adjusted Charlson Comorbidity Index >3. Most patients were symptomatic at diagnosis, mainly due to tumor location-related symptoms (n=55, 69.6%), and 12 (15.0%) hormone secretion-related symptoms. Most tumors were well differentiated neuroendocrine tumors (NET) (n=77, 79.9%) according with WHO 2010 classification. NET G1 and NET G2 constituted the majority of cases (n=72, 75.8%). Predominant pancreatic topography was body and tail (n=43, 44.3%) followed by head (n=28, 28.9%). Fifty-two (53.6%) had localized/locoregional disease while 46.4% (n=45) had metastatic disease. Liver was the most frequent site of synchronous metastasis at diagnosis (n=42, 93.3%), followed by non-regional nodal (n=11, 24.4%) and bone (n=11, 24.4%). Globally, 60 (61.9%) surgical procedures were performed, 22 (22.9%) transarterial embolization, 5 (5.2%) other locoregional therapies, 56 (57.7%) somatostatin analogues, 23 (23.7%) Peptide Receptor Radionuclide Therapy, 11 (11.3%) everolimus and 32 (33.0%) chemotherapy. Forty-six patients (47.4%) had potentially curative disease, of which 43 (93.5%) had surgery as primary treatment. Eighteen patients (45.0%) had disease recurrence after surgery. Five-year Disease-free Survival was 61.9%. Seventy-two patients received antineoplastic palliative treatments (51 patients with metastatic/irresectable disease at diagnosis, 18 with disease recurrence and 3 refused curative intention therapy). Of those, twenty-six (36.1%) received 2 lines and 20 (27.8%) ≥3 lines of treatment. Median PFS after first line treatment was 25.0 months (95%CI 18.0-32.0) and median OS was 58 months (95%CI 30.0-86.0). Patients with localized/locoregional disease had a median OS of 160 months and patients with metastatic disease of 29 months, HR 4.55 (95%CI 2.58-8.02), p On univariate analysis, the risk of death was increased in those patients with NEC, metastatic disease at diagnosis, and primary location of the tumor not in the pancreatic body or tail. On multivariate analysis, NEC (HR 2.46 95%CI 1.28-4.73) and metastatic disease (HR 3.44 95%CI 1.85-6.37) were independent prognostic factors. Patients with PAN-NENs analyzed in this study present similar characteristics to other cohorts described in the literature. Therapeutic strategies in PAN-NENs are highly diversified and adapted to histological differentiation, stage, hormone hypersecretory-related symptoms and patients characteristics and preferences. NEC and metastatic disease were associated with a significant increase risk of death.

Characterizing Canine Hepatobiliary Neuroendocrine Neoplasia: A Proteomic Approach

Hepatobiliary neuroendocrine neoplasia is an extremely rare cancer in humans and other species. In humans, neuroendocrine neoplasia of the liver and gallbladder represents less than 2% of all gastroenteropancreatic neuroendocrine neoplasia. In the veterinary literature, there is a paucity of information on hepatobiliary neuroendocrine cancer with only a small number of published studies. Improved characterization of these tumors is needed to identify additional biomarkers for diagnosis and generate informed treatment protocols for human and veterinary patients. Here, we applied a proteomics strategy to identify differentially expressed proteins in canine hepatobiliary neoplasia as compared to normal canine adrenal and liver tissue from formalin-fixed paraffin-embedded samples. Our objective was to identify unique protein biomarkers and possible chemotherapeutic targets. Thirty-four up-regulated, differentially expressed proteins were identified in the hepatobiliary neuroendocrine neoplasia samples. Galectin-1, a multivalent carbohydrate binding protein known to play a role in lung and pancreatic neuroendocrine neoplasia development and progression, was among them. Drugs targeting the galectin family have shown promise as anticancer therapeutics in cervical cancer, prostate cancer, lung and pancreatic neuroendocrine neoplasia. Galectin-1 may represent a novel treatment target in hepatobiliary neuroendocrine neoplasia in both humans and dogs.

Approach to the Diagnosis of Hepatocutaneous Syndrome in Dogs: A Retrospective Study and Literature Review.

Superficial necrolytic dermatitis (SND) is a rare and often fatal disease in dogs that has been associated with pancreatic neuroendocrine neoplasia (SND/EN) and hepatocutaneous syndrome (SND/HCS). Although various combinations of diagnostics have been used to differentiate these two causes of SND, there are currently no data on which combination would enable the most timely and noninvasive way to diagnose HCS. Medical records were reviewed retrospectively (2004-2018) for dogs with SND/HCS (n = 24) and SND/EN (n = 1). These data were compared with cases found by review of the literature of dogs with SND/HCS (n = 105) and SND/EN (n = 13). The most consistent findings with SND were dermatological lesions affecting paw pads or mucocutaneous junctions (143/143, 100%) and marked plasma hypoaminoacidemia (58/58, 100%). On ultrasound, a honeycomb liver was seen in 62/63 (98%) dogs with SND/HCS but none with SND/EN. Six out of 23 (26%) dogs in the retrospective study with SND/HCS had marked keratinocyte apoptosis, a finding that was associated with diabetes mellitus. This study suggests that in dogs with characteristic skin lesions, an amino acid profile permits a noninvasive diagnosis of SND. An abdominal ultrasound can then assist in the differentiation of SND/HCS and SND/EN.

Is splenectomy really necessary in left pancreatectomy for pancreatic neoplasia? A bicentric retrospective analysis of surgical specimens

Background: Although left pancreatectomy with splenectomy (LPS) is considered as the gold standard for the treatment of neoplasia from the pancreatic body and tail, the oncological benefit of spleen removal has never been demonstrated. This study aimed to assess the involvement of the spleen, the splenic hilum and lymph nodes (LN) on pathological specimens of LPS for neoplasia. Methods: All patients undergoing LPS for pancreatic carcinoma or neuroendocrine neoplasia in 2 tertiary centers were retrospectively reviewed. Pathological analysis of the splenic parenchyma, the hilar tissue and the peripancreatic and splenic hilar lymph nodes (LN) was reviewed, such as the pancreatic tumor location on preoperative imaging. Results: Between 2004 and 2018, 161 patients had a LPS for pancreatic neoplasia, including 114 adenocarcinoma, 38 neuroendocrine neoplasia and 9 other rare carcinoma. Tumor was located into the pancreatic body without infiltrating the tail in 81 patients (group Body), and involved the tail with or without the body in 80 patients (group Tail). The median number of LN found on specimens was 15 (± 16). Positive LN were present in 48% (39/81) and 45% (36/81) of patients from groups Body and Tail, respectively. Splenic hilar LN were not frequent, and were positive in only 1 patient from group Tail (1%) and no patient from group Body. Direct involvement of the splenic parenchyma and/or hilum was observed in 9 patients from group Tail (11%) and absent in group Body. Conclusions: According to the Results of the present study, the value of performing a splenectomy in patients with a neoplasia located into the pancreatic body should be questioned. Resection of the splenic vessels remains essential for regional lymphadenectomy, so the splenic preservation using the Warshaw technique could be a good option.

The prognostic value of C-reactive protein in a new preoperative clinical risk score for survival after surgery for sporadic, non-functioning pancreatic neuroendocrine neoplasia: An international multicentre study

The prognostic value of C-reactive protein in a new preoperative clinical risk score for survival after surgery for sporadic, non-functioning pancreatic neuroendocrine neoplasia: An international multicentre study

Characteristics and outcomes of therapy-related myeloid neoplasms after peptide receptor radionuclide/chemoradionuclide therapy (PRRT/PRCRT) for metastatic neuroendocrine neoplasia: a single-institution series.

Peptide receptor radionuclide/chemoradionuclide therapy (PRRT/PRCRT) is an effective therapy for metastatic neuroendocrine neoplasia (NEN), but therapy-related myeloid neoplasms (t-MN) remain of concern. The study reviewed the clinicopathological features and outcomes of patients who developed t-MN. Retrospective analysis of all patients diagnosed with t-MN by 2016 WHO classification, from a cohort of 521 patients who received PRRT/PRCRT over a 12-year period. Molecular next-generation sequencing using an in-house 26-gene panel was performed. Twenty-five of 521 (4.8%) patients were diagnosed with t-MN, including six acute myeloid leukaemia (AML) and 19 myelodysplastic syndrome (MDS). The median time from first cycle PRRT/PRCRT to diagnosis of t-MN was 26months (range 4-91). Twenty-two of 25 (88%) patients had grade 1-2 pancreatic or small bowel NEN with moderate metastatic liver burden. Six patients (24%) had prior chemotherapy. Median number of PRRT cycles = 5 (22/25 (88%) with concomitant radiosensitising chemotherapy). All 25 patients achieved disease stabilisation (68%) or partial response (32%) on RECIST 1.1 at 3months post-PRRT. At t-MN diagnosis, all patients presented with thrombocytopenia (median nadir 33 × 109/L, range 3-75) and 17 (68%) remained NEN progression-free. Marrow genetic analysis revealed unfavourable karyotype in 16/25 (66%) patients with tumour protein 53 (TP53) mutation in nine (36%). Azacitidine therapy was utilised in ten eligible patients, while four received induction chemotherapy for AML. The median overall survival from first PRRT was 62months (19-94), but from t-MN diagnosis was only 13months (1-56), with death due primarily to haematological disease progression. The diagnosis of t-MN after PRRT/PRCRT is an infrequent but serious complication with poor overall survival. Most patients present with thrombocytopenia; unfavourable genetic mutations have a poor response to t-MN treatment. Prospective data are needed to explore potential pre-existing genetic factors and predictive biomarkers to minimise the risk of t-MN.

Intertumor heterogeneity in 60 pancreatic neuroendocrine tumors associated with multiple endocrine neoplasia type 1

BackgroundPatients with multiple endocrine neoplasia type 1 (MEN-1) develop multiple pancreatic neuroendocrine neoplasias (PNENs). Size at diagnosis and growth during follow-up are crucial parameters. According to the WHO 2017, grading is another important parameter. The impact of grading compared to size (WHO 2000) on the clinical course needs to be evaluated.MethodsSixty PNENs of six patients with MEN-1 were retrospectively evaluated.ResultsFifty-one tumors with a diameter of < 20 mm were graded as G1. Two of 9 tumors with diameters of ≥20 mm were graded as G2. Tumor size of ≥20 mm correlated significantly with higher proliferation (p = 0.000617). Lymph node metastases were documented in two patients with a total of 19 tumors. In one patient, all 13 tumors (diameter: 0.4 to 100 mm) were classified as G1. However, metastases were documented in 9/29 lymph nodes. In the other patient, 5 tumors (3.5 to 20 mm) were classified as G1. The sixth tumor (30 mm) was classified as G2 (Ki-67: 8%). Metastases were revealed in 2/20 lymph nodes.ConclusionsTumor size of ≥20 mm seems to correlate with more aggressive MEN-1 related pancreatic disease, regardless of individual proliferation. Tumors ≥20 mm and tumors graded as G2 should be treated surgically regardless of their size.

Characteristics and Outcomes of Therapy-Related Myeloid Neoplasms after Peptide Receptor Radionuclide/Chemoradionuclide Therapy (PRRT/PRCRT) for Metastatic Neuroendocrine Neoplasia: A Single Institutional Series

Background: Peptide receptor radionuclide/chemoradionuclide therapy(PRRT/PRCRT) is an emerging therapy in patients with metastatic neuroendocrine neoplasia (NEN). However, therapy-related myeloid neoplasms (t-MN) remain a potential complication with substantial adverse outcomes. The study reviewed our PRRT/PRCRT patients who developed t-MN, with regard to their clinicopathological features and outcomes. Methods: Retrospective analysis of all patients diagnosed with t-MN, defined as per revised 2016 WHO classification, from this single centre cohort of 521 patients who received PRRT/PRCRT over a 12-year period. Molecular next generation sequencing using an in-house 26 gene panel were performed. Findings: Twenty-five (4.8%) patients were diagnosed with t-MN, including six acute myeloid leukaemia (AML) and 19 myelodysplastic syndrome (MDS). The median time from first cycle PRRT/PRCRT to diagnosis of t-MN was 26 months (range 4 - 91). Twenty-two of 25 (88%) patients had Grade 1-2 pancreatic or small bowel NEN with moderate metastatic liver burden. The majority, 22 of 25 (88%) received concomitant radiosensitising chemotherapy. All 25 patients achieved disease stabilisation (68%) or at least a partial response (32%) on RECIST 1.1 assessment at 3 months post-PRRT. At t-MN diagnosis, all patients presented with thrombocytopenia (median nadir 33 x 109/L, range 3 - 75) and 17 (68%) were NEN progression free. Marrow genetic analysis revealed unfavourable karyotype in 16/25 (66%) patients and tumour protein 53 (TP53) mutations in nine (36%). Azacitidine therapy was utilised in ten eligible patients, while four received induction chemotherapy for AML. The median overall survival from the time of t-MN diagnosis was 13 months (range 1 - 56), with cause of death due largely to haematological disease progression. Interpretation: The diagnosis of t-MN after PRRT/PRCRT is uncommon but a serious complication with poor overall survival. Most patients present with thrombocytopenia, unfavourable genetic mutations and poor response to t-MN treatment. Funding: No funding source involved. Declaration of Interest: RJH holds shares in Telix Pharmaceuticals on behalf of the Peter MacCallum Cancer Centre. MSH reports personal fees and non-financial support from Ipsen and Sanofi Genzyme, personal fees and other from Endocyte, outside the submitted work. All remaining authors declare no competing interests. Ethical Approval: The study was approved by the hospital’s medical ethics committee as a retrospective audit with approval of waiver for patient consent (HREC Project number 18/61R). All patients had provided written, informed consent for PRRT/PRCRT.

Prognostic Value of C-Reactive Protein in a New Preoperative Clinical Risk Score for Survival after Surgery for Sporadic, Non-Functioning Pancreatic Neuroendocrine Neoplasia

Background: Pancreatic neuroendocrine neoplasia (pNEN) represents a rare entity compared to pancreatic adenocarcinoma. Treatment and associated prognosis varies significantly depending on many clinical, endocrine and pathological features. Several risk scores have been proposed for pNENs, relying mostly on postoperatively available factors. Increased preoperative C-Reactive Protein (CRP) has recently been proposed as an independent risk factor in several cancer types and has also been shown to predict overall survival in a single centre study on pNENs. The present study validates these findings in a national multicentre environment and aims to present a risk score derived from purely preoperatively available factors.

Neuroendocrine Neoplasia within the German NET Registry

Neuroendocrine neoplasias (NEN) comprise a rare tumor entity with heterogeneous biology, prognosis and therapeutic options. Together with the recent publication of the first German guidelines on diagnostics and therapy of NEN, an analysis of the German NET-registry cohort of the German Society of Endocrinology (DGE) was performed. For this purpose, 2686 cases were extracted and their patient characteristics (e. g., age, sex, histopathological characterization, grading and staging) were displayed and outcomes were calculated. Additionally, the systemic treatment reality in the two largest subgroups, small intestinal and pancreatic NEN, was analyzed within metastatic patients.Distribution of primary tumor localization, histopathological classification, disease stage and overall survival was comparable with results from international registry studies. In concordance with current guidelines, somatostatin analogues (SSA) and peptide-receptor-radionuclide-therapy (PRRT) were the most common therapeutic modalities in small intestinal NEN. In pancreatic NEN, chemotherapy was used in first line as often as SSA. In second line, chemotherapy was used as often as PRRT. WHO-classification of 2010 and TNM staging proved to be of prognostic relevance.The current analysis of the German NET-registry characterizes a multicentric, interdisciplinary cohort of NEN patients throughout Germany and it describes the applied systemic treatment modalities and overall outcome as well as the prognostic value of the WHO classification of 2010 and TNM staging.

Exploring the surgical landscape of pancreatic neuroendocrine neoplasia in Austria: Results from the ASSO pNEN study group

IntroductionPancreatic neuroendocrine neoplasia (pNEN) show increasing incidence and management is complex due to biological heterogeneity. Most publications report isolated high-volume single-centre data. This Austrian multi-centre study on surgical management of pNENs provides a comprehensive real-life picture of quality indicators, recurrence-patterns, survival factors and systemic treatments. MethodsRetrospective, national cohort-study from 7 medium-/high-volume centres in Austria, coordinated under the auspices of the Austrian Society of Surgical Oncology (ASSO). ResultsTwo-hundred patients underwent resection for pNEN, 177 had non-functioning tumours and 31 showed stage 4 disease. Participating centres were responsible for 2/3 of pNEN resections in Austria within the last years. The mean rate of completeness of variables was 98.6%. Ninety-days mortality was 3.5%, overall rate of complications was 42.5%. Morbidity did not influence long-term survival. The 5-year overall-survival (OS) was 81.3%, 10-year-OS 52.5% and 5-year recurrence-free-survival (RFS) 69.8%. Recurrence was most common in the liver (68.1%). Four out of five patients with recurrence underwent further treatment, most commonly with medical therapy or chemotherapy. Multivariable analysis revealed grading (HR:2.7) and metastasis (HR:2.5) as significant factors for relapse. Tumours-size ≥2 cm (HR:5.9), age ≥60 years (HR:3.1), metastasis (HR:2.3) and grading (HR:2.0) were associated with OS. Tumours <2 cm showed 93.9% 10-year-OS, but 33% had G2/G3 grading, 12.5% positive lymph-nodes and 4.7% metastasis at diagnosis, each associated with significant worse survival. ConclusionResection of pNENs in Austria is performed with internationally comparable safety. Analysed factors allow for risk-stratification in clinical treatment and future prospective trials. A watch-and-wait strategy purely based on tumour-size cannot be recommended.