Pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous population of neoplasms that arise from hormone-secreting islet cells of the pancreas and have increased markedly in incidence over the past four decades. Non-functional PanNETs, which occur more frequently than hormone-secreting tumors, are often not diagnosed until later stages of tumor development and have poorer prognoses. Development of successful therapeutics for PanNETs has been slow, partially due to a lack of diverse animal models for pre-clinical testing. Here, we report development of an inducible, conditional mouse model of PanNETs by using a bi-transgenic system for regulated expression of the aberrant activator of Cdk5, p25, specifically in β-islet cells. This model produces a heterogeneous population of PanNETs that includes a subgroup of well-differentiated, non-functional tumors. Production of these tumors demonstrates the causative potential of aberrantly active Cdk5 for generation of PanNETs. Further, we show that human PanNETs express Cdk5 pathway components, are dependent on Cdk5 for growth, and share genetic and transcriptional overlap with the INS-p25OE model. The utility of this model is enhanced by the ability to form tumor-derived allografts. This new model of PanNETs will facilitate molecular delineation of Cdk5-dependent PanNETs and the development of new targeted therapeutics.

Disparities in cancer patient responses have prompted widespread searches to identify differences in sensitive vs. nonsensitive populations and form the basis of personalized medicine. This customized approach is dependent upon the development of pathway-specific therapeutics in conjunction with biomarkers that predict patient responses. Here, we show that Cdk5 drives growth in subgroups of patients with multiple types of neuroendocrine neoplasms. Phosphoproteomics and high throughput screening identified phosphorylation sites downstream of Cdk5. These phosphorylation events serve as biomarkers and effectively pinpoint Cdk5-driven tumors. Toward achieving targeted therapy, we demonstrate that mouse models of neuroendocrine cancer are responsive to selective Cdk5 inhibitors and biomimetic nanoparticles are effective vehicles for enhanced tumor targeting and reduction of drug toxicity. Finally, we show that biomarkers of Cdk5-dependent tumors effectively predict response to anti-Cdk5 therapy in patient-derived xenografts. Thus, a phosphoprotein-based diagnostic assay combined with Cdk5-targeted therapy is a rational treatment approach for neuroendocrine malignancies.

Background Appendiceal neuroendocrine tumors (ANETs) are rare neoplasms usually discovered incidentally during appendectomy. ANETs < 2 cm were thought to have no metastatic potential, and this dogma has driven management. Our aim is to evaluate the metastatic potential of ANETs < 2 cm. Patients and Methods A retrospective review was performed in a series of patients with ANETs who presented to our tertiary referral center from 1998 to 2019. Demographics, tumor characteristics, treatment, and clinical outcomes were evaluated. Results In total, 114 patients were included. Median follow-up was 3.3 years (range, 21 days–15 years). At last follow-up, 34 (30%) patients had positive regional lymph nodes and 20 (18%) patients had metastatic disease. Of the 20 patients with metastatic disease, 11 (55%) had primary ANETs < 2 cm. Patient age > 40 years at diagnosis and ANETs with serosal invasion, lymphovascular invasion, intermediate tumor grade, or positive lymph nodes were features significantly more likely to present with metastatic disease. We found no difference in the rate of lymph node positivity, metastatic disease, or overall survival when patients were stratified by tumor size or type of resection (appendectomy vs. right hemicolectomy). On multivariate analysis, patients with metastatic disease at diagnosis had worse overall survival (HR = 24.4, p = 0.008). Conclusions In our cohort, tumor size was not a significant risk factor for metastatic disease or worse outcome as many patients with ANETs < 2 cm developed metastatic disease. Appendectomy alone was sufficient surgical management for most ANETs. Patients with risk factors for metastatic disease, regardless of primary ANET size, should be evaluated thoroughly and counseled for further management and surveillance.

Jace P. Landry1*, Yvette B. Mattison1,2,3, Robert A. Ramirez2,3, J. Philip Boudreaux1,2,3, Eugene A. Woltering1,2,3, Mary A. Maluccio1,2,3, Ramcharan Thiagarajan1,2,3 1Louisiana State University Health Sciences Center – Department of Surgery, New Orleans, LA, USA 2The New Orleans Louisiana Neuroendocrine Tumor Specialists, New Orleans, LA, USA 3Ochsner Medical Center, Neuroendocrine Tumor Clinic, Kenner, LA , USA *Correspondence should be addressed to Jace Philip Landry; jlan10@lsuhsc.edu

Capecitabine and temozolomide (CAPTEM) have shown promising results in the treatment of neuroendocrine neoplasms (NEN). The aim of this study was to evaluate the outcome and role for CAPTEM in malignant neuroendocrine neoplasms. Data were obtained from NEN patients who received at least one cycle of CAPTEM between November 2010 and June 2018. The average number of cycles was 9.5. For analysis, 116 patients were included, of which 105 patients (91%) underwent prior treatment. Median progression free survival (PFS) and overall survival (OS) were 13 and 38 months, respectively. Overall response rate (ORR) was 21%. Disease control rate (DCR) was 73% in all patients. PFS, median OS, ORR, and DCR for pancreatic NENs (pNEN) vs. non-pNEN was 29 vs. 11 months, 35 vs. 38 months, 38% vs. 9%, and 77% vs. 71%, respectively. Patients with pNEN had a 50% lower hazard of disease progression compared to those with non-pNEN (adjusted Hazard Ratio: 0.498, p = 0.0100). A significant difference in PFS was found between Ki-67 < 3%, Ki-67 3–20%, Ki-67 > 20–54%, and Ki-67 ≥ 55% (29 vs. 12 vs. 7 vs. 5 months; p = 0.0287). Adverse events occurred in 74 patients (64%). Our results indicate that CAPTEM is associated with encouraging PFS, OS, and ORR data in patients with NENs.

Neuroendocrine tumors (NETs) are a heterogeneous group of malignancies with limited systemic treatment options. Preclinical evidence has shown that the PI3K/AKT/mTOR signaling pathway plays a central role in the pathogenesis and progression of NETs. Clinical studies with the mTOR inhibitor, everolimus, demonstrated its safety and efficacy in the treatment of NET, however, patients will ultimately progress. A novel mTOR inhibitor, ABI-009 (albumin-bound rapamycin nanoparticles, nab-rapamycin), has a favorable safety profile and evidence of efficacy in patients with solid tumors and offers promise for NETs. A preclinical study showed significantly greater antitumor activity and prolonged survival with ABI-009 compared with equal weekly dosing of oral rapamycin and oral everolimus. This preclinical study demonstrated superior efficacy of ABI-009 to oral mTOR inhibitors and suggest that ABI-009 may result in disease control after everolimus failure. The goal of this phase II pilot study is to evaluate the utility of ABI-009 in NETs to warrant a full phase II clinical study. This pilot phase II trial is a prospective, open-label, single arm, single center trial evaluating the efficacy and safety of ABI-009 in patients with gastroenteropancreatic or lung NETs who have undergone prior treatment with everolimus. Patients with unresectable, metastatic grade 1 and 2 NETs of the gastroenteropancreatic system or lung who have progressed or have been intolerant to everolimus will be eligible for inclusion in this study. The study will enroll 10 patients with Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. ABI-009 will be administered intravenously at 100 mg/m2 on days 1 and 8 of a 21-day cycle. Patients will be treated until disease progression. Tumor response will be assessed by computerized tomography scan at baseline then every 9 weeks for 1 year, then every 12 weeks thereafter until progression. The primary endpoint is disease control rate at 6 months measured by RECIST 1.1. Currently, 3 of the planned 10 patients have been enrolled. ClinicalTrials.gov Identifier: NCT03670030. Section not applicable Section not applicable

Poorly differentiated gastroenteropancreatic neuroendocrine carcinomas (GEPNECs) are a rare neoplasm with a bleak prognosis. Currently there are little prospective data available for optimal treatment. This review discusses the current available regimens and the future direction for the treatment of GEPNECs. Treatment plans for GEPNECs are often adapted from those devised for small cell lung cancer; however, differences in these malignancies exist, and GEPNECs require their own treatment paradigms. As such, current first-line treatment for GEPNECs is platinum-based chemotherapy with etoposide. Studies show that response rate and overall survival remain comparable between cisplatin and carboplatin versus etoposide and irinotecan; however, prognosis remains poor, and more efficacious therapy is needed to treat this malignancy. Additional first-line and second-line treatment options beyond platinum-based chemotherapy have also been investigated and may offer further treatment options, but again with suboptimal outcomes. Recent U.S. Food and Drug Administration approval of peptide receptor radionuclide therapy in low- and intermediate-grade neuroendocrine tumors may open the door for further research in its usefulness in GEPNECs. Additionally, the availability of checkpoint inhibitors lends promise to the treatment of GEPNECs. This review highlights the lack of large, prospective studies that focus on the treatment of GEPNECs. There is a need for randomized control trials to elucidate optimal treatment regimens specific to this malignancy. Implications for Practice There are limited data available for the treatment of poorly differentiated gastroenteropancreatic neuroendocrine carcinomas (GEPNECs) because of the rarity of this malignancy. Much of the treatment regimens used in practice today come from research in small cell lung cancer. Given the poor prognosis of GEPNECs, it is necessary to have treatment paradigms specific to this malignancy. The aim of this literature review is to summarize the available first- and second-line GEPNEC therapy, outline future treatments, and highlight the vast gap in the literature.

Methods In this study, we reviewed patients with a metastatic NET of unknown primary site who were evaluated with a 92-gene panel assay (CancerTYPE ID, Biotheranostics, Inc., San Diego, CA) as part of routine care. Demographics, pathology, and treatment data were collected. Based on the assay prediction, patients were further evaluated with surgical exploration, endoscopic procedures, and/or imaging. Predictions were classified as “correct” if confirmed on further evaluation or “incorrect” if the primary site was identified in a different location or could not be found where predicted.

Objectives Elevated pancreastatin (PST) levels have been shown to be associated with poor prognosis in small bowel neuroendocrine tumors (NETs). We hypothesized that plasma PST levels that remain elevated following surgical cytoreduction portend a poor prognosis in well-differentiated small bowel NETs. Methods Patients diagnosed with small bowel NETs who underwent surgical cytoreduction at our institution were identified. Demographics, histopathologic characteristics, and biochemical data were collected. Only patients who had serial preoperative PST (PreopPST) and postoperative PST (PostopPST) levels were included in this study. Patients were sorted into groups by PST level to assess their response to surgical cytoreduction (group 1, PreopPST/PostopPST normal; group 2, PreopPST elevated/PostopPST normal; group 3, PreopPST/PostopPST elevated). Survival rates were calculated from the date of surgery. Results PreopPST and PostopPST levels were collected from 300 patients. Patients in groups 1 (n = 74) and 2 (n = 81) had a significant survival advantage compared with patients in group 3 (n = 145) (P < 0.0001). Kaplan-Meier 5- and 10-year survival rates were as follows: group 1: 93% and 82%; group 2: 91% and 65%; and group 3: 58% and 34%, respectively. Conclusions Serial monitoring of plasma PST is useful in predicting long-term survival following surgical cytoreduction and can be helpful to identify patients who have a poor prognosis.

METHODS: Data were analyzed from patients who underwent surgical cytoreduction for NETs of the small bowel, ileum, or jejunum. All patients received standard of care following surgical cytoreduction. Only patients who had serial preoperative PST (PreopPST) and postoperative PST (PostopPST) levels were included in this study (Normal <135 pg/ml, InterScience Institute, Inglewood, Calif). Patients were sorted into groups to assess the response of their PST level to surgery. Overall survival (OS) was calculated from date of surgery to date of death or end of study (December 31, 2017).

Objectives Elevated neurokinin A (NKA) levels are associated with poor prognosis in patients with small bowel neuroendocrine tumors. We hypothesized that patients with NKA levels that remain elevated despite treatment with surgical cytoreduction have a poor prognosis. Methods Patients diagnosed with small bowel neuroendocrine tumors who underwent surgical cytoreduction at our institution were identified. Demographics, histopathologic characteristics, and biochemical data were collected. Patients were grouped by the trend of their NKA levels (group 1, continuously normal; group 2, transiently elevated but normalized after therapy; group 3, remained elevated despite therapy). Survival rates were calculated from the date of the patient's first NKA level. Results Serial NKA values after surgical cytoreduction were monitored in 267 patients. Kaplan-Meier 2-year, 5-year, and 10-year survival rates were as follows: group 1 (n = 157), 97%, 89%, and 62%; group 2 (n = 78), 99%, 90%, and 78%; and group 3 (n = 32), 88%, 69%, and 0%. Survival rates were statistically significant between groups 1 and 3 and between groups 2 and 3 (P < 0.01). Conclusions Serial monitoring of plasma NKA levels is useful in identifying patients who have a poor prognosis. Elevated NKA levels can indicate the need for immediate therapeutic intervention.