Advanced Pancreatic Neuroendocrine Tumors Research Articles

Phase 3 Trial of Cabozantinib to Treat Advanced Neuroendocrine Tumors.

Treatment options for patients with advanced neuroendocrine tumors are limited. The efficacy of cabozantinib in the treatment of previously treated, progressive extrapancreatic or pancreatic neuroendocrine tumors is unclear. We enrolled two independent cohorts of patients - those with extrapancreatic neuroendocrine tumors and those with pancreatic neuroendocrine tumors - who had received peptide receptor radionuclide therapy or targeted therapy or both. Patients were randomly assigned in a 2:1 ratio to receive cabozantinib at a dose of 60 mg daily or placebo. The primary end point was progression-free survival as assessed by blinded independent central review. Key secondary end points included objective response, overall survival, and safety. In the cohort of 203 patients with extrapancreatic neuroendocrine tumors, the median progression-free survival with cabozantinib was 8.4 months, as compared with 3.9 months with placebo (stratified hazard ratio for progression or death, 0.38; 95% confidence interval [CI], 0.25 to 0.59; P<0.001). In the cohort of 95 patients with pancreatic neuroendocrine tumors, the median progression-free survival with cabozantinib was 13.8 months, as compared with 4.4 months with placebo (stratified hazard ratio, 0.23; 95% CI, 0.12 to 0.42; P<0.001). The incidence of confirmed objective response with cabozantinib was 5% and 19% among patients with extrapancreatic and pancreatic neuroendocrine tumors, respectively, as compared with 0% with placebo. Grade 3 or higher adverse events were noted in 62 to 65% of the patients treated with cabozantinib, as compared with 23 to 27% of the patients who received placebo. Common treatment-related adverse events of grade 3 or higher included hypertension, fatigue, diarrhea, and thromboembolic events. Cabozantinib, as compared with placebo, significantly improved progression-free survival in patients with previously treated, progressive advanced extrapancreatic or pancreatic neuroendocrine tumors. Adverse events were consistent with the known safety profile of cabozantinib. (Funded by the National Cancer Institute and others; CABINET ClinicalTrials.gov number, NCT03375320.).

1150P Search for biomarkers to personalize treatment with streptozotocin plus 5-fluorouracil or everolimus in patients with advanced pancreatic neuroendocrine tumors: The randomized phase III SEQTOR trial (GETNE-1206)

1150P Search for biomarkers to personalize treatment with streptozotocin plus 5-fluorouracil or everolimus in patients with advanced pancreatic neuroendocrine tumors: The randomized phase III SEQTOR trial (GETNE-1206)

A real-world pharmacovigilance study of FDA adverse event reporting system (FAERS) events for sunitinib.

Sunitinib is approved for the treatment of metastatic renal cell carcinoma (mRCC), imatinib-resistant gastrointestinal stromal tumors (GIST), and advanced pancreatic neuroendocrine tumors (PNET). This study aims to investigate the safety profiles of sunitinib through data mining of the US Food and Drug Administration Adverse Event Reporting System (FAERS). The individual case safety reports (ICSRs) on sunitinib from 2006 Q1 to 2024 Q1 were collected from the ASCII data packages in the Food and Drug Administration Adverse Event Reporting System (FAERS). After standardizing the data, a variety of disproportionality analyses, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS) were employed to identify the potential safety signals of sunitinib-associated AEs. A total of 35,923 ICSRs of sunitinib as the "primary suspected" drug were identified within the reporting period. The search detected 276 disproportionate preferred terms (PTs). The most common AEs, including diarrhea, asthenia, decreased appetite, hypertension, and dysgeusia, were consistent with the drug label and clinical trials. Unexpected significant AEs, such as uveal melanocytic proliferation, salivary gland fistula, yellow skin, eyelash discoloration, scrotal inflammation, were detected. The median onset time of sunitinib-related AEs was 57 days (interquartile range [IQR]16-170 days), with most of the ICSRs developing within the first month (n = 4,582, 39.73%) after sunitinib therapy as initiated. The results of our study were consistent with routine clinical observations, and some unexpected AEs signals were also identified for sunitinib, providing valuable evidence for the safe use of sunitinib in the real-world and contributing to the clinical monitoring and risk identification of sunitinib.

Surgical resection of double advanced pancreatic neuroendocrine tumors with multiple renal cell carcinoma associated with von Hippel-Lindau disease.

Von Hippel-Lindau (VHL) disease, an autosomal dominant genetic disorder caused by a germline mutation, is associated with non-functional and slow-growing pancreatic neuroendocrine tumor (PNET) and kidney cancer. We describe the case of a 46year-old man with a 35mm mass in the pancreatic head causing stricture of the bile duct and main pancreatic duct, a 55mm mass in the pancreatic tail causing obstruction of the splenic vein (SV), and multiple masses of > 36mm on both kidneys. We performed a two-stage resection. First, a total pancreatectomy with superior mesenteric vein (SMV) resection and reconstruction and retroperitoneoscopic right partial nephrectomy (NP) for five lesions was performed, followed by retroperitoneoscopic left partial NP of the five lesions 6months later. Postoperative histopathological examination revealed NET G2 in the pancreatic head with SMV invasion and somatostatin receptor type 2A (SSTR2A) positivity, NET G2 in the pancreatic tail showed SV invasion and negative SSTR2A, and multiple clear cell renal cell carcinomas (RCC) were also noted. Multiple liver recurrences occurred 22months after primary surgery. The patient remains alive 41months after primary surgery. Kidney cancer generally determines VHL prognosis; however, we experienced dual-advanced PNETs with a more defined prognosis than multiple RCC associated with VHL.

Abstract 4387: Interplay of Notch1 and Notch3 signaling regulates pancreatic neuroendocrine tumor proliferation

Abstract Background: The 5-year survival rate for patients with advanced pancreatic neuroendocrine tumors (pNETs) is less than 30%. Notch signaling is a transmembrane receptor pathway with four receptor isoforms and five different ligands. Binding between a receptor and ligand triggers pathway activation and is linked to cellular differentiation, cell fate, proliferation, and viability. Both Notch1 and Notch3 signaling have been shown to be dysregulated in pNETs. Notch3 activation has been shown to repress Notch1 activity in other cancers. We hypothesize that activation of Notch3 can reduce Notch1-mediated proliferation in pNETs. Methods: Genetic deletion of Notch1 (N1-KO) in a pNET cell line (BON) was achieved using CRISPR/Cas9 to create a compound heterozygous knockout at exon 3. An inducible Notch1 overexpression cell line was generated by stably transfecting BON with a plasmid construct containing the Notch1 active form (N1ICD) under a Tet-On regulator. A constitutively active Notch3 cell line was generated by lentiviral transduction of BON with a plasmid overexpressing the Notch3 active form (N3ICD). Real-time quantitative PCR was used to measure mRNA transcript levels, and western blot was used to measure protein expression. Two-dimensional (2D) viability was measured by MTT assay, and three-dimensional (3D) proliferation was measured by spheroid size. Results: Genetic knockout of Notch1 (N1-KO) reduced the expression of Notch3 at both mRNA and protein levels. N1-KO had reduced proliferation compared to (WT) BON. Increased cell density (ligand availability) or treatment with valproic acid (known Notch1 inducer) led to increased N3ICD in WT BON but not in N1-KO. Overexpression of N1ICD was associated with increased expression of a known downstream target Hes1, as well as Notch3. In contrast, forced overexpression of N3ICD led to increased Notch1 expression, but not Hes1 when compared to a BON cell line transfected with an empty vector. Functionally, N1-KO and N3ICD overexpression cells both had reduced proliferation in both 2D and 3D cell culture. Conclusions: The Notch1 and Notch3 receptors produce signaling cascades that regulate growth in pNET cells through distinct mechanisms. Reduction of Notch1 signaling suppresses growth, while the same effect can be achieved with Notch3 overexpression. Thus, specifically upregulating Notch3 may be a strategy to block Notch1-mediated proliferation in pNET cells. Citation Format: Rachael Guenter, Weisheng Chen, Yuvasri Golivi, Mario Robledo, Cole Adams, Renata Jaskula-Sztul, Herbert Chen, J. Bart Rose. Interplay of Notch1 and Notch3 signaling regulates pancreatic neuroendocrine tumor proliferation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4387.

Metformin and pancreatic neuroendocrine tumors: A systematic review and meta-analysis.

Most patients with advanced pancreatic neuroendocrine tumors (pNETs) die due to tumor progression. Therefore, identifying new therapies with low toxicity and good tolerability to use concomitantly with the established pNET treatment is relevant. In this perspective, metformin is emerging as a molecule of interest. Retrospective studies have described metformin, a widely used agent for the treatment of patients with type 2 diabetes mellitus (T2DM), to be effective in modulating different tumor-related events, including cancer incidence, recurrence and survival by inhibiting mTOR phosphorylation. This systematic review evaluates the role of T2DM and metformin in the insurgence and post-treatment outcomes in patients with pNET. To systematically analyze and summarize evidence related to the diagnostic and prognostic value of T2DM and metformin for predicting the insurgence and post-treatment outcomes of pNET. A systematic review of the published literature was undertaken, focusing on the role of T2DM and metformin in insurgence and prognosis of pNET, measured through outcomes of tumor-free survival (TFS), overall survival and progression-free survival. A total of 13 studies (5674 patients) were included in this review. Analysis of 809 pNET cases from five retrospective studies (low study heterogeneity with I² = 0%) confirms the correlation between T2DM and insurgence of pNET (OR = 2.13, 95%CI = 1.56-4.55; P < 0.001). The pooled data from 1174 pNET patients showed the correlation between T2DM and post-treatment TFS in pNET patients (hazard ratio = 1.84, 95%CI = 0.78-2.90; P < 0.001). The study heterogeneity was intermediate, with I² = 51%. A few studies limited the possibility of performing pooled analysis in the setting of metformin; therefore, results were heterogeneous, with no statistical relevance to the use of this drug in the diagnosis and prognosis of pNET. T2DM represents a risk factor for the insurgence of pNET and is a significant predictor of poor post-treatment TFS of pNET patients. Unfortunately, a few studies with heterogeneous results limited the possibility of exploring the effect of metformin in the diagnosis and prognosis of pNET.

Cholangitis with bacteremia due to Pseudomonas nitroreducens in a patient with pancreatic neuroendocrine tumors: a case report

BackgroundPseudomonas nitroreducens is a non-fermenting, gram-negative, rod-shaped bacterium commonly inhabiting soil, particularly soil contaminated with oil brine. To our knowledge, no cases of human infection with P. nitroreducens have been previously reported. Here, we present the first documented case of cholangitis caused by P. nitroreducens in a patient with bacteremia.Case presentationA 46-year-old Japanese man with an advanced pancreatic neuroendocrine tumor was hospitalized with fever and chills. Four days before admission, the patient developed right upper abdominal pain. Two days later, he also experienced fever and chills. Endoscopic retrograde cholangiopancreatography was performed on the day of admission, and the patient was diagnosed as having cholangitis associated with stent dysfunction. Gram-negative rods were isolated from blood cultures, but attempts to identify the bacteria using VITEK2 and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) with VITEK MS ver. 4.7.1 (bioMérieux Japan Co. Ltd., Tokyo, Japan) were unsuccessful. Finally, the organism was identified as P. nitroreducens using MALDI-TOF MS with a MALDI Biotyper (Bruker Daltonics Co., Ltd., Billerica, MA, USA) and 16 S ribosomal RNA sequencing. Despite thorough interviews with the patient, he denied any exposure to contaminated soil. The patient was treated with intravenous cefepime and oral ciprofloxacin for 16 days based on susceptibility results, achieving a good therapeutic outcome. At the outpatient follow-up on day 28, the patient was in good general condition.ConclusionsThis is the first reported human case of cholangitis with bloodstream infection caused by P. nitroreducens. This report provides clinicians with novel insights into the clinical manifestations and diagnostic methods necessary for the accurate diagnosis of P. nitroreducens, along with guidance on treatment.

Bone Metastases in Patients with Pancreatic NETs: Prevalence and Prognosis.

The clinical relevance of bone metastases (BM) in advanced pancreatic neuroendocrine tumors (PanNETs) is poorly described. We analyzed 314 consecutive PanNET patients treated at the European Neuroendocrine Tumour Society (ENETS) Center Essen between 2009 and 2021 in terms of the occurrence and clinical and prognostic impact of BM using hybrid imaging with 68Ga-DOTATOC PET/CT. According to UICC staging, 171/314 (54.5%) patients had stage IV PanNETs. BM was diagnosed in 62/171 (36.3%) patients. Initially, 35% of BMs were visible by pathological tracer uptake only. Skeletal-related events (SREs) were detected in 11 of the 62 patients (17.7%). Patients with antiresorptive therapy had a significantly lower rate of SRE (2/36, 5.6%) than individuals without bone-specific therapy (9/26, 34.6%) (odds ratio 9.0, p=0.0054, Fisher's exact test). The median overall survival (OS) was 82 months (53.6-110.4, 95% CI) in the stage IV PanNET cohort. The median OS was significantly lower for patients with BM (63 months; 49.9-76.0, 95% CI) than for patients with distant metastases other than BM (116 months; 87.6-144.3, 95% CI) (p=0.016, log-rank test). BM occurs in more than one-third of advanced PanNETs and is associated with an unfavorable prognosis. One in five patients experiences a persistent quality-of-life-lowering SRE. Antiresorptive therapy is associated with a more favorable risk of SREs and should be offered to all patients with BM in PanNETs.

Efficacy of temozolomide-capecitabine finally demonstrated in advanced pancreatic neuroendocrine tumours, and predictable by the MGMT biomarker

Efficacy of temozolomide-capecitabine finally demonstrated in advanced pancreatic neuroendocrine tumours, and predictable by the MGMT biomarker

SEOM-GETNE clinical guidelines for the diagnosis and treatment of gastroenteropancreatic and bronchial neuroendocrine neoplasms (NENs) (2022).

Neuroendocrine neoplasms (NENs) are a heterogeneous family of tumors of challenging diagnosis and clinical management. Their incidence and prevalence continue to rise mainly due to an improvement on diagnostic techniques and awareness. Earlier detection, along with steadfast improvements in therapy, has led to better prognosis over time for advanced gastrointestinal and pancreatic neuroendocrine tumors. The aim of this guideline is to update evidence-based recommendations for the diagnosis and treatment of gastroenteropancreatic and lung NENs. Diagnostic procedures, histological classification, and therapeutic options, including surgery, liver-directed therapy, peptide receptor radionuclide therapy, and systemic hormonal, cytotoxic or targeted therapy, are reviewed and discussed, and treatment algorithms to guide therapeutic decisions are provided.

Surufatinib-induced renal thrombotic microangiopathy: first case report and review of literature

Angiogenesis inhibitors such as tyrosine kinase inhibitors (TKIs) are common therapeutics currently used to treat oncologic disease. Surufatinib is a novel, small-molecule multiple receptor TKI approved by the National Medical Products Administration (NMPA) for the treatment of progressive, advanced, and well-differentiated pancreatic and extrapancreatic neuroendocrine tumours (NETs). Thrombotic microangiopathy (TMA) is a well-documented complication of TKIs targeting the VEGF-A/VEGFR2 signalling pathway. Here, we describe a 43-year-old female patient with biopsy-proven TMA and nephrotic syndrome due to surufatinib treatment for adenoid cystic carcinoma. Histological lesions included glomerular endothelial swelling, widening of subendothelial spaces, mesangiolysis, and double contour, which caused nephrotic proteinuria. Effective management was achieved by drug withdrawal and oral anti-hypertensive regents. The management of surufatinib-related nephrotoxicity without compromising its anticancer effects is challenging. Hypertension and proteinuria must be closely monitored during drug use to reduce or stop the dose in a timely manner before severe nephrotoxicity occurs.

Multivisceral Surgical Resection of Locally Advanced Pancreatic Neuroendocrine Tumor is Associated with a Survival Benefit

Multivisceral Surgical Resection of Locally Advanced Pancreatic Neuroendocrine Tumor is Associated with a Survival Benefit

Evaluation of the Efficacy of a Combined Treatment Using the mTOR-Inhibitor Everolimus and [177Lu]Lu-DOTA-TATE in Nude CD1 Mice with SSTR-Expressing Pancreatic AR42J Xenograft Tumors.

Therapy options for advanced pancreatic neuroendocrine tumors (pNETs) include the mTOR inhibitor everolimus and peptide receptor radionuclide therapy (PRRT) with [177Lu]Lu-DOTA-TATE, however further optimization in the therapeutic landscape is required as response rates are still low. In this study, we investigated the synergistic and potentially enhanced efficacy of a combined treatment with everolimus and [177Lu]Lu-DOTA-TATE in a mouse model. Baseline [68Ga]Ga-DOTA-TATE PET scans were obtained five days after athymic CD1 mice were inoculated with AR42J tumor cells, before separating the animals into four groups. Group 1 received a placebo, group 2 everolimus, group 3 a placebo and PRRT, and group 4 everolimus and PRRT. The treatment response was monitored by manually measuring the tumor volumes (manual tumor volume, MTV) and conducting sequential [68Ga]Ga-DOTA-TATE PET scans at one, two, and four weeks after treatment induction. The biological tumor volume (BTV) was derived from PET scans using threshold-based volume of interest (VOI) measurements. Tracer uptake was measured semi-quantitatively as a tumor to background ratio (TBR). Mice were euthanized due to excessive tumor growth according to the ethics protocol; blood samples were drawn for the preparation of full blood counts and kidneys were obtained for histological analysis. For the histological assessment, a standardized score (renal damage score, RDS) was used. Full blood counts showed significantly increased numbers of neutrophils and lymphocytes in the groups receiving PRRT. All other parameters did not differ relevantly. In the histological analysis, groups receiving PRRT had a significantly higher RDS, whereas everolimus only tended to cause an increase in the RDS. Mice in groups 1 and 2 had to be euthanized due to excessive tumor growth two weeks after the start of the therapy, whereas follow-up in groups 3 and 4 comprised four weeks. PRRT significantly inhibited tumor growth; the administration of everolimus did not induce an additional effect. A good correlation existed between MTV and BTV. PRRT significantly reduced the TBR. [68Ga]Ga-DOTA-TATE PET is suitable for monitoring tumor growth in the applied model. The high efficacy of [177Lu]Lu-DOTA-TATE is not enhanced by the combination with everolimus.

Evaluation of survival outcomes in patients with sporadic, advanced, unresectable well-differentiated pancreatic neuroendocrine tumors treated initially with octreotide LAR and subsequent therapeutical approaches on relapse. A real-world data set

Introduction. Somatostatin analogs (SSA) are widely used in the treatment of patients with well-differentiated neuroendocrine tumors (NET). There are limited reports about the role of octreotide LAR in first-line therapy of advanced pancreatic NET (pan-NET). This study aimed to evaluate the antiproliferative effect of octreotide LAR in patients with sporadic, advanced, unresectable pan-NET, based on progression-free survival (PFS). Material and methods. This was a retrospective analysis of 374 patients with pan-NET; 41 treated subjects were included. The primary endpoint was PFS defined as the time to disease progression (Response Evaluation Criteria in Solid Tumors: RECIST). Univariate and multivariate analyses were used to identify predictors of PFS. Secondary endpoints included overall survival (OS) and second-line therapies after progression. Results. There were 13 (32%) patients with G1 pan-NET and 28 (68%) with pan-NET G2, 21 female and 20 male, with mean age 55.4 (range 29–87). Median PFS was 9.0 months (95% CI 4.7–24.0). Subgroup analysis revealed that G1 and no-bulky liver disease ( &lt; 25% liver volume) were associated with significantly longer PFS. Univariate analysis confirmed a correlation between G1 [0.34 hazard rate (HR) of progression or death (95% CI 0.16–0.72)] and no-bulky liver disease HR = 0.31 (95% CI 0.13–0.71). Multivariable analysis demonstrated that only functional (secretory) pan-NET was associated as an independent factor with shorter PFS HR = 2.97 (95% CI 1.0–8.74). Median OS was 105.4 months (95% CI 40.0–172.0). After relapse following initial systemic therapy, the second line was used in 34 subjects, 3rd line in 18th, and 4th line in 9 subjects. Conclusions. Octreotide LAR shows moderate antiproliferative activity in pan-NET. Prolonged PFS may be associated with G1 and low-volume metastatic liver disease. In patients with progressive disease, various treatment options were used, which resulted in median OS of 105.4 months.

Special issue "The advance of solid tumor research in China": Prediction of Sunitinib efficacy using computed tomography in patients with pancreatic neuroendocrine tumors.

Clinically effective methods to predict the efficacy of sunitinib, for patients with metastatic or locally advanced pancreatic neuroendocrine tumors (panNET) are scarce, making precision treatment difficult. This study aimed to develop and validate a computed tomography (CT)-based method to predict the efficacy of sunitinib in patients with panNET. Pretreatment CT images of 171 lesions from 38 patients with panNET were included. CT value ratio (CT value of tumor/CT value of abdominal aorta from the same patient) and radiomics features were extracted for model development. Receiver operating curve (ROC) with area under the curve (AUC) and decision curve analysis (DCA) were used to evaluate the proposed model. Tumor shrinkage of >10% at first follow-up after sunitinib treatment was significantly associated with longer progression-free survival (PFS; P < .001) and was used as the major treatment outcome. The CT value ratio could predict tumor shrinkage with AUC of 0.759 (95% confidence interval [CI], 0.685-0.833). We then developed a radiomics signature, which showed significantly higher AUC in training (0.915; 95% CI, 0.866-0.964) and validation (0.770; 95% CI, 0.584-0.956) sets than CT value ratio. DCA also confirmed the clinical utility of the model. Subgroup analysis showed that this radiomics signature had a high accuracy in predicting tumor shrinkage both for primary and metastatic tumors, and for treatment-naive and pretreated tumors. Survival analysis showed that radiomics signature correlated with PFS (P=.020). The proposed radiomics-based model accurately predicted tumor shrinkage and PFS in patients with panNET receiving sunitinib and may help select patients suitable for sunitinib treatment.

Addressing the Role of Angiogenesis in Patients with Advanced Pancreatic Neuroendocrine Tumors Treated with Everolimus: A Biological Prospective Analysis of Soluble Biomarkers and Clinical Outcomes.

Simple SummaryDespite the approval of new targeted therapies for pancreatic neuroendocrine tumors (PanNETs) over the past decades, the early identification of resistant tumors remains the major challenge, mainly because clear signs of tumor shrinkage are rarely achieved by imaging assessment. Starting from the hypothesis that angiogenesis can be implicated in the resistance to mTOR inhibitors, we evaluated a specific angiogenesis panel (through the measurement of soluble biomarkers for angiogenesis turnover, circulating endothelial cells, and circulating progenitors) as possible predictors of resistance to everolimus or everolimus efficacy in PanNETs. Our study showed that none of the investigated categories of biomarkers had a predictive value for everolimus resistance or efficacy. However, we suggest that circulating endothelial progenitors might be surrogate biomarkers for angiogenesis activity in PanNETs during everolimus treatment, and their baseline levels might correlate with survival outcomes. These data have never been reported before for NETs.Background: The success of targeted therapies in the treatment of pancreatic neuroendocrine tumors has emphasized the strategy of targeting angiogenesis and the PI3K/AKT/mTOR pathway. However, the major challenge in the targeted era remains the early identification of resistant tumors especially when the efficacy is rarely associated to a clear tumor shrinkage at by imaging assessment. Methods: In this prospective study (NCT02305810) we investigated the predictive and prognostic role of soluble biomarkers of angiogenesis turnover (VEGF, bFGF, VEGFR2, TSP-1) circulating endothelial cells and progenitors, in 43 patients with metastatic panNET receiving everolimus. Results: Among all tested biomarkers, we found a specific subpopulation of circulating cells, CD31+CD140b-, with a significantly increased tumor progression hazard for values less or equal to the first quartile. Conclusion: Our study suggested the evidence that circulating cells might be surrogate biomarkers of angiogenesis activity in patients treated with everolimus and their baseline levels can be correlated with survival. However, further studies are now needed to validate the role of these cells as surrogate markers for the selection of patients to be candidates for antiangiogenic treatments.

P7.01: Selecting Candidates for Multi-Visceral Transplantation in Neuroendocrine Tumors (NET) of the Gastrointestinal Tract: A Review of Two Cases

Introduction: Neuroendocrine tumors (NETs) are rare neoplasms arising neurologic or endocrine tissues. These tumors can be seen in nearly any organ system, though they mostly would be present in the gastrointestinal and respiratory systems. In this study, we report two cases of multi-visceral transplantations (MVT) in NET and discuss our indications for MVT among NET patients. Methods and Results: Case 1: A 44-year-old lady referred with a complaint of acute abdominal pain and small bowel obstruction symptoms in June 2018. In laparotomy, an obstructive jejunal mass, a huge retroperitoneal lesion involving the mesentery and liver, was found. A partial resection of the jejunal mass and palliative anastomosis of the bowel was performed. Histopathologic examinations revealed a well-differentiated NET [G1 (ki67:1%)]. The patient underwent MVT. She developed an entero-cutaneous fistula ten days after the surgery which was managed. After which the patient was relatively well till February 2021, when she was admitted with severe watery diarrhea. Severe mucosal ulcerations were seen in endoscopy, and rejection was confirmed through pathologic assessments. The patient died despite our efforts. Case 2: A 46-year-old man who had been suffering from vague abdominal pain and dyspepsia was referred to our clinic in February 2021. He gave a history of 5 kilograms weight loss in the preceding six months. Computed tomography (CT) showed a large lobulated heterogeneously enhancing mass about 150*90 mm in the pancreas with extension to the liver hilum and involvement of spleen and stomach, and signs of partial port vein thrombosis. The pathologist reported a well-differentiated NET (G2, ki67<15%, mitosis 1-2/10 HPF). Exploratory laparotomy, performed in May 2021, showed locally advanced pancreatic NET with celiac encasement and involvement of stomach and colon and portal vein thrombosis with varicose veins and portal hypertension, but no evidence of hepatic metastases. MVT was performed in June 2021. The grafts, including stomach, duodenum, liver, pancreas, and small bowel, were implanted. One month later, the patient complained of diarrhea, 3rd-grade acute T-cell rejection, in a small bowl biopsy was reported. However, the liver biopsy was insignificant. Favorably the patient responded well to the treatment, and after six months, closure of ostomy was performed. The patient is alive and well to this day. Conclusion: We propose the following criteria for MVTx in NETs: Well-differentiated NETs; absence of progression in the last six months; extensive porto-mesenteric thrombosis; intestinal failure with liver metastases; Both superior mesenteric artery and celiac trunk involvement; absence of extra-abdominal involvement that is confirmed by Ga-68 dotatate scan. We should note that this was a case report and larger series are required to support our conclusion.

Highlights of pancreatic surgery: extended indications in pancreatic neuroendocrine tumors

Advanced pancreatic neuroendocrine tumors (paNET) are mostly characterized by infiltration of vascular structures and/or neighboring organs. The indications for resection in these cases should be measured based on the possibility of an R0 resection. Although the data situation for this rare entity is limited, small case series have shown asignificant survival advantage in patients who underwent a radical resection in locally advanced stages of paNET. Both vascular reconstruction and multivisceral resection, when performed at experienced centers, should be considered as curative treatment options. The very special biological behavior of the paNET and the often young patient age justify amuch more aggressive approach compared to the pancreatic ductal adenocarcinoma.

A randomized study of temozolomide or temozolomide and capecitabine in patients with advanced pancreatic neuroendocrine tumors: Final analysis of efficacy and evaluation of MGMT (ECOG-ACRIN E2211).

4004 Background: Patients with advanced pancreatic neuroendocrine tumors (NETs) have few treatment options that yield objective tumor response. Retrospective and small, prospective studies suggest that the combination of capecitabine and temozolomide is associated with high response rates (RR) and relative long progression-free survival (PFS). This trial was conducted to establish a role for the combination of capecitabine and temozolomide. Methods: E2211 was a multicenter, randomized, phase II trial comparing temozolomide (200 mg/m2 PO QD days 1-5) vs. capecitabine/temozolomide (capecitabine 750 mg/m2 PO BID days 1-14; temozolomide 200 mg/m2 PO QD days 10-14) in patients with advanced pancreatic NETs. Eligibility criteria included: metastatic or unresectable, low or intermediate grade pancreatic NETs, progression within preceding 12 months, and no prior temozolomide, DTIC, capecitabine or 5-fluorouracil. The primary endpoint was PFS; secondary endpoints were Overall Survival (OS), RR, safety, and MGMT as evaluated by immunohistochemistry (IHC) and promoter methylation. Allowing for 5% ineligibility, 145 randomized patients were required to obtain 138 eligible patients to detect a difference in median PFS of 9 versus 14 months (hazard ratio of 0.64) using a two-sided log-rank test at the overall 0.20 significance level with 81% power. Results: 144 patients were enrolled between 4/2013 to 3/2016 to temozolomide (n = 72) or capecitabine/temozolomide (n = 72); the efficacy analysis population included 133 eligible patients. At the scheduled interim analysis in January 2018, median PFS was 14.4 months for temozolomide vs. 22.7 months for capecitabine/temozolomide (HR = 0.58), which was sufficient to reject the null hypothesis for this final primary endpoint (stratified log rank p = 0.022. In the final analysis (5/2021), median OS was 53.8 months for temozolomide and 58.7 months for capecitabine/temozolomide (HR = 0.82, p = 0.42) and RR was 34% for temozolomide and 40% for capecitabine/temozolomide (p = 0.59). Capecitabine/temozolomide was associated with higher rates of grade 3-4 AEs (45% vs. 22%, p = 0.005). MGMT deficiency, defined as either low IHC or positive promoter methylation, was associated with greater odds of response (OR [95% CI] = 6.38 [2.19, 18.60] and 9.79 [1.09, 87.71], respectively). Conclusions: E2211 is the first prospective randomized trial of capecitabine/temozolomide and shows the longest PFS and highest RR reported for patients with pancreatic NETs in a prospective randomized study. MGMT deficiency was associated with greater odds of objective response. Clinical trial information: NCT01824875.

Predicting Novel Drug Candidates for Pancreatic Neuroendocrine Tumors via Gene Signature Comparison and Connectivity Mapping

IntroductionThere is a paucity of effective treatment options for advanced pancreatic neuroendocrine tumors (pNETs). Genome-wide analyses may allow for potential drugs to be identified based on differentially expressed genes (DEGs). MethodsOligo microarray data of RNA expression profiling of pNETs and normal pancreas tissues were downloaded from the Gene Expression Omnibus. Functional and pathway enrichment information of the DEGs was obtained using the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases. Corresponding homologous proteins were analyzed and potential therapeutic drugs for pNETs were identified using the Connectivity Map and Drug-Gene Interaction Database. ResultsAssessment of raw data from 12,610 pNET genes demonstrated that 1082 and 380 genes were upregulated and downregulated, respectively, compared with normal pancreas tissue. Upregulated pathways were associated with nitrogen metabolism (i.e., GABAergic synapse, and graft-versus-host disease), whereas downregulated pathways included C-type leptin receptor signaling pathway, pertussis and AMPK signaling pathway. In particular, the protein–protein interaction analysis revealed 10 upregulated hub genes (DYNLL1, GNB5, GNB2, GNG4, GNAI2, GNAI1, HIST2H2BE, NUP107, NUP133, and SNAP25) and 10 downregulated hub genes (CXCL8, F2, CXCL2, GCG, SST, INS, GALR3, CCL20, ADRA2B, and CXCL6). Using the Drug-Gene Interaction Database, candidate drugs for pNETs treatment included 3 EGFR inhibitors (canertinib, erlotinib, WZ-4–145), as well as other cell-signaling pathway inhibitors such as AG-592, acarbose, lonidamine, azacytidine, rottlerin, and HU-211. ConclusionUsing available genetic atlas data, potential drug candidates for treatment of pNETs were identified based on differentially expressed genes. These results may help focus efforts on identifying targeted agents with therapeutic efficacy to treat patients with pNETs.