Mesenteric sparing approach for advanced nodal extent in small intestinal neuroendocrine tumors. Is there a limit to the vascular resection in order to avoid creating a short small bowel syndrome? An anatomic research study.

PURPOSE: By selectively perfusing the first three jejunal arteries (JA), we aim to assess the individual perfusion length of small bowel (SB) and its impact on nodal resection in stage III-up small-intestinal neuroendocrine tumors (SI-NET). METHODS: Our anatomical research protocol implies a midline laparotomy and three measures of the SB length. We then perform a classical anterior approach of the superior mesenteric vessels. We carry on with the complete dissection and checking of the superior mesenteric artery (SMA) in order to identify the first three JA. Then we selectively perfuse each artery with colored latex solutions and measure the length of small bowel perfused respectively. RESULTS: We conducted our protocol on six cadaveric subjects. Mean(SD) SB length was 413(5.7), 535(13.2), 485(15), 353(25.1), 730(17.3) and 525(16° cm respectively from subject one to six. Most JA originated from the left side of the SMA. The first JA originated from its posterior wall in two subjects. Mean(SD) distance of origin of the first three JA was 4.6(1.3)cm, 6(1.1)cm and 7.1(0.9)cm respectively. Mean(SD) diameter of SMA was 10.8(3.3)mm. Mean diameter of the three first JA was 4(1.4)mm, 4(1.5)mm and 5(1.2)mm respectively. Mean(SD) SB length perfused by first and second JA was 224(14.9)cm, 175(8.6)cm, 238.3(7.6)cm, 84.3(5.1)cm, 233.3(5.8)cm and 218.3(10.4)cm respectively from subject one to six. CONCLUSION: We observed a trend suggesting that the first and second JA may sustain a SB length beyond the viable 1.5 m limit, implying the feasibility of stage III-up SI-NET resection with just two JA.

Ramucirumab in combination with dacarbazine in patients with progressive well-differentiated metastatic pancreatic neuroendocrine tumors (RamuNET): study protocol for a multicenter single-arm trial.

BACKGROUND: Cytotoxic chemotherapy combinations and targeted agents represent established treatment concepts in advanced pancreatic neuroendocrine tumors (PNETs). However, response rates, side effects and outcome data strongly vary among these therapeutic approaches. Head-to-head comparisons between chemo- and molecular therapies are missing and secondary resistances frequently occur. The RamuNET trial aims to identify the effectiveness of dual treatment with DTIC and ramucirumab in progressive advanced PNET patients. METHODS: The RamuNET study is an investigator-initiated multicenter prospective single-arm trial to evaluate the efficacy of ramucirumab in combination with dacarbazine (DTIC) over a period of at least 6 months. Patients with progressive well-differentiated and metastatic pancreatic neuroendocrine tumors are eligible. The study aims to include 45 patients over a period of 24 months with a minimum follow-up of 24 months. The primary endpoint is disease control after 6 months. Secondary endpoints include progression-free survival, biochemical response, overall survival, quality of life and toxicity. Based on the hypothesis that 80% of the patients can achieve a disease control after 6 months, the sample size calculation follows an exact binomial single-stage design. H0: p < =p0 = 60% versus H1: p > =p1 = 80%, alpha = 0.05, beta = 0.1. DISCUSSION: This study investigates a new therapeutic approach using the combination of cytotoxic and targeted antiangiogenic therapy in advanced PNET. If positive, this trial will be the basis for a randomized two-arm study to investigate the combination of ramucirumab and DTIC against other established therapies in PNET. TRIAL REGISTRATION: EudraCT: 2017-001207-68 . Date of registration: 2018.01.03.

The impact of SST2 trafficking and signaling in the treatment of pancreatic neuroendocrine tumors.

Pancreatic neuroendocrine tumors (Pan-NETs), are heterogeneous neoplasms, whose incidence and prevalence are increasing worldwide. Pan-NETs are characterized by the expression of somatostatin receptors (SSTs). In particular, SST2 is the most widely distributed SST in NETs, thus representing the main molecular target for somatostatin analogs (SSAs). SSAs are currently approved for the treatment of well-differentiated NETs, and radionuclide-labeled SSAs are used for diagnostic and treatment purposes. SSAs, by binding to SSTs, have been shown to inhibit hormone secretion and thus provide control of hypersecretion symptoms, when present, and inhibit tumor proliferation. After SSA binding to SST2, the fate of the receptor is determined by trafficking mechanisms, crucial for the response to endogenous or pharmacological ligands. Although SST2 acts mostly through G protein-dependent mechanism, receptor-ligand complex endocytosis and receptor trafficking further regulate its function. SST2 mediates the decrease of hormone secretion via a G protein-dependent mechanism, culminating with the inhibition of adenylyl cyclase and calcium channels; it also inhibits cell proliferation and increases apoptosis through the modulation of protein tyrosine phosphatases. Moreover, SST2 inhibits angiogenesis and cell migration. In this respect, the cross-talk between SST2 and its interacting proteins, including Filamin A (FLNA) and aryl hydrocarbon receptor-interacting protein (AIP), plays a crucial role for SST2 signaling and responsiveness to SSAs. This review will focus on recent studies from our and other groups that have investigated the trafficking and signaling of SST2 in Pan-NETs, in order to provide insights into the mechanisms underlying tumor responsiveness to pharmacological treatments.

The distinctive characteristics of the micro-vasculature and immune cell infiltration in cystic pancreatic neuroendocrine tumors.

PURPOSE: Hypervascularity is a main characteristic of pancreatic neuroendocrine tumors (PanNETs), and cystic PanNETs (CPanNETs) are unique type of PanNETs in which the microenvironment remains unknown. We aim to compare the micro-vasculature features and immune cell infiltration between CPanNETs and solid PanNETs (SPanNETs). METHODS: Data of 301 SPanNET and 36 CPanNET patients from a high-volume institution were evaluated. CD4, CD8, CD11c, CD15, CD20, CD68, CD34 and α-SMA expression levels were assessed by immunohistochemistry and immunofluorescent double staining. The microvessel density (MVD) and microvessel integrity (MVI) were examined. RESULTS: MVD and MVI expression levels in CPanNETs were significantly higher than those in SPanNETs (p = 0.025 and 0.0092, respectively). CPanNETs had higher proportions of T1 (p = 0.023) and G1 (p = 0.052) than SPanNETs. In SPanNETs, higher MVD occurred in stages T1, N0 and G1 than in the T2/T3, N1 and G2 subgroups. In CPanNETs, CD34-MVD was uncorrelated with the T stage or grade. Higher CD34-MVD, but not MVI, was associated with better DFS (HR 0.3209, 95% CI 0.1259-0.8176, p = 0.004). There were significantly more peritumoral infiltrating immune cells than their intratumoral counterparts (p < 0.001 for each) in CPanNETs and SPanNETs. The mean number of peritumoral CD68 + TAM in CPanNETs was significantly lower than that in SPanNETs (p = 0.008). The counts of other peritumoral immune cells did not significantly differ between CPanNETs and SPanNETs. CONCLUSIONS: CPanNETs had a microenvironment distinct from that of SPanNETs, including higher CD34-MVD, higher MVI and lower TAM. This specific microenvironment structure may partially help predicting the prognosis of patients with PanNET.

Effect of Tumor Perfusion and Receptor Density on Tumor Control Probability in 177Lu-DOTATATE Therapy: An In Silico Analysis for Standard and Optimized Treatment.

The aim of this work was to determine a minimal tumor perfusion and receptor density for 177Lu-DOTATATE therapy using physiologically based pharmacokinetic (PBPK) modeling considering, first, a desired tumor control probability (TCP) of 99% and, second, a maximal tolerated biologically effective dose (BEDmax) for organs at risk (OARs) in the treatment of neuroendocrine tumors and meningioma. Methods: A recently developed PBPK model was used. Nine virtual patients (i.e., individualized PBPK models) were used to perform simulations of pharmacokinetics for different combinations of perfusion (0.001-0.1 mL/g/min) and receptor density (1-100 nmol/L). The TCP for each combination was determined for 3 different treatment strategies: a standard treatment (4 cycles of 7.4 GBq and 105 nmol), a treatment maximizing the number of cycles based on BEDmax for red marrow and kidneys, and a treatment having 4 cycles with optimized ligand amount and activity. The red marrow and the kidneys (BEDmax of 2 Gy15 and 40 Gy2.5, respectively) were assumed to be OARs. Additionally, the influence of varying glomerular filtration rates, kidney somatostatin receptor densities, tumor volumes, and release rates was investigated. Results: To achieve a TCP of at least 99% in the standard treatment, a minimal tumor perfusion of 0.036 ± 0.023 mL/g/min and receptor density of 34 ± 20 nmol/L were determined for the 9 virtual patients. With optimization of the number of cycles, the minimum values for perfusion and receptor density were considerably lower, at 0.022 ± 0.012 mL/g/min and 21 ± 11 nmol/L, respectively. However, even better results (perfusion, 0.018 ± 0.009 mL/g/min; receptor density, 18 ± 10 nmol/L) were obtained for strategy 3. The release rate of 177Lu (or labeled metabolites) from tumor cells had the strongest effect on the minimal perfusion and receptor density for standard and optimized treatments. Conclusion: PBPK modeling and simulations represent an elegant approach to individually determine the minimal tumor perfusion and minimal receptor density required to achieve an adequate TCP. This computational method can be used in the radiopharmaceutical development process for ligand and target selection for specific types of tumors. In addition, this method could be used to optimize clinical trials.

Application of low dose pancreas perfusion CT combined with enhancement scanning in diagnosis of pancreatic neuroendocrine tumors.

PURPOSE: To explore the diagnostic value of pancreatic perfusion CT combined with contrast-enhanced CT in one-time scanning (PCECT) in pancreatic neuroendocrine tumors (PNETs) and to evaluate the difference of perfusion parameters between different grades of PNETs. MATERIALS AND METHODS: From October 2016 to December 2018, forty consecutive patients with histopathological-proven PNETs were identified retrospectively that received PCECT for the preoperative PNETs evaluation. Two board certified radiologists who were blinded to the clinical data evaluated the images independently. The image characters of PNETs vs. tumor-free pancreatic parenchymal and different grades of PNETs were analyzed. RESULTS: One-time PCECT scanning had a detection rate of 89.1% for PNETs, which was higher than the detection accuracy of the perfusion CT only (83.6%). The perfusion parameters of PNETs including blood volume (BV), blood flow (BF), mean slope of increase (MSI), and capillary surface permeability (PS) were significantly increased than those of tumor-free pancreatic parenchyma (p < 0.05, respectively). For differential comparison between grade I (G1) and grade II (G2) tumors, the parameters of BF and impulse residue function (IRF) of tumor tissue were significantly higher in the G2 tumors (p < 0.05, for both). In this study, the total radiation dose of the whole PCECT scan was 16.241 ± 2.289 mSv. CONCLUSION: The one-time PCECT scan may improve the detection of PNETs according to morphological features and perfusion parameters with a relative small radiation dose. The perfusion parameters of BF and IRF may be used to help distinguish G1 and G2 tumors in the preoperative evaluation.

Time to peak enhancement of malignant hypervascular hepatic tumors versus that of the aorta evaluating by test bolus sequence of magnetic resonance imaging.

PURPOSE: To determine the relationship between time to peak enhancement (TPE) of malignant hypervascular hepatic tumors and that of the aorta. METHOD: Sixty patients with malignant hypervascular hepatic tumors (48 with hepatocellular carcinoma and 12 with metastatic neuroendocrine tumor) who received abdominal MRI with test bolus sequence between January 2015 and May 2019 were enrolled. The test bolus images were monitored every 3 s after the injection of 2 mL gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) and 10 mL saline flush, to evaluate the TPE of the tumors and aorta. We used linear regression with a least squares approach to show the relationship between TPE of the malignant hypervascular hepatic tumors and that of the aorta. RESULTS: TPE of malignant hypervascular hepatic tumors and abdominal aorta were 43.4 ±â€¯12.9 and 23.3 ±â€¯7.4 s, respectively (mean ±â€¯standard deviation). In univariate regression analysis, the TPE of malignant hypervascular hepatic tumors have a positively linear correlation with that of the aorta by the following equation: (TPE of malignant hypervascular hepatic tumor) = 1.4 X (TPE of the aorta) + 10.6 s (r = 0.65, p < 0.005). CONCLUSIONS: TPE of malignant hypervascular hepatic tumors can be predicted by a simple linear transformation from that of the aorta.

Diagnosis and prognostic significance of extramural venous invasion in neuroendocrine tumors of the small intestine.

Extramural venous invasion (EMVI) is an established independent prognostic factor in colorectal carcinoma where it is linked to hematogenous spread (i.e., liver metastases), influencing the decision for adjuvant chemotherapy. However, its prognostic significance in small intestinal neuroendocrine tumors (NETs) has not been studied, nor is it routinely assessed or reported. We reviewed primary small bowel NETs (14 jejunum, 82 ileum, 8 not specified) from 104 patients (52 women; median age 60.5, range: 24-84). EMVI was identified in 58 cases (55.8%), including in 13 of 21 equivocal cases using an elastin stain. In univariate analysis, EMVI was associated with lymphovascular and perineural invasion, tumor stage, and lymph node and distant metastases, whereas in multivariate analysis, only distant metastases remained significant (p < 0.001). Liver metastases were present in 55 cases (52.9%) and were significantly associated in univariate analysis with lymphovascular and perineural invasion, tumor stage, lymph node metastases, and EMVI, whereas in multivariate analysis, only EMVI remained significant (p < 0.001; odds ratio (OR) = 59.42). Eight patients developed metachronous liver metastases during follow-up (mean 22.9 ± 22.0 months, range: 4.7-73.2) and all (100%) were positive for EMVI. In contrast, of 49 patients who never developed liver metastases over significantly longer follow-up (mean 71.0 ± 32.4 months, range: 6.6-150.4; p < 0.001), only 7 (14.3%) had EMVI (p < 0.001). In Kaplan-Meier analysis, 8 of 15 patients with EMVI (53.3%) developed metachronous liver metastases, compared with 0 of 42 patients without EMVI (p < 0.001). In contrast, nonhepatic distant metastases, seen in 26 (25.0%) patients, were not associated with EMVI in multivariate or Kaplan-Meier analyses. Our data demonstrate that EMVI is common in small bowel NETs and strongly correlates with development of liver metastases. Therefore, its evaluation is critical and should be assessed in combination with adjuvant techniques such as elastin staining, if necessary. Moreover, inclusion of EMVI in pathology reporting guidelines should be considered.

Differentiation of solid-pseudopapillary tumors of the pancreas from pancreatic neuroendocrine tumors by using endoscopic ultrasound.

BACKGROUND AND AIM: To differentiate solid-pseudopapillary tumors (SPTs) of the pancreas from pancreatic neuroendocrine tumors (pNETs) by endoscopic ultrasound. METHODS: We retrospectively reviewed all patients with SPTs and pNETs who underwent endoscopic ultrasound (EUS) from May 2012 to August 2018 at the Fudan University Shanghai Cancer Center. We included patients confirmed pathologically with a surgical biopsy or with endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). The demographic data of the patients, characteristics of the lesions and overall survival data of patients with these two diseases were further compared. RESULTS: A total of 147 pNET patients and 21 SPT patients were included in our study. The mean ages of the patients in the SPT and pNET groups were 35.95years and 54.30years, respectively. There were more females in the SPT group than in the pNET group (71.43% vs. 40.82%). The patients in the pNET group had significantly more lymphatic metastases and visceral organ metastases than the patients in the SPT group. A larger proportion of pNET lesions than SPT lesions had homogeneous echo patterns and were hypervascular. Cystic components and calcification components were more often observed in the SPT lesions than in the pNET lesions. In the multivariate logistic regression analysis, the hypervascularization (OR: 6.528, 95% CI: 1.562-27.285, P=0.010) and cystic component (OR: 0.106, 95% CI: 0.019-0.597, P=0.011) variables resulted in the best discrimination of patients with SPTs from patients with pNETs. Survival among patients with SPTs was higher than that among patients with pNETs at all points in the follow-up period. CONCLUSIONS: SPTs tended to occur in younger people and were more common in women. Pancreatic neuroendocrine tumors tended to form metastases more often than SPTs. The blood supply and cystic components of the lesions may have novel potential diagnostic utility for differentiating SPTs from pNETs.

Targeting cellular heterogeneity with CXCR2 blockade for the treatment of therapy-resistant prostate cancer.

Hormonal therapy targeting androgen receptor (AR) is initially effective to treat prostate cancer (PCa), but it eventually fails. It has been hypothesized that cellular heterogeneity of PCa, consisting of AR+ luminal tumor cells and AR- neuroendocrine (NE) tumor cells, may contribute to therapy failure. Here, we describe the successful purification of NE cells from primary fresh human prostate adenocarcinoma based on the cell surface receptor C-X-C motif chemokine receptor 2 (CXCR2). Functional studies revealed CXCR2 to be a driver of the NE phenotype, including loss of AR expression, lineage plasticity, and resistance to hormonal therapy. CXCR2-driven NE cells were critical for the tumor microenvironment by providing a survival niche for the AR+ luminal cells. We demonstrate that the combination of CXCR2 inhibition and AR targeting is an effective treatment strategy in mouse xenograft models. Such a strategy has the potential to overcome therapy resistance caused by tumor cell heterogeneity.

The Tumor Microenvironment in Neuroendocrine Tumors: Biology and Therapeutic Implications.

Neuroendocrine tumors (NETs) include a heterogeneous group of malignancies arising in the diffuse neuroendocrine system and characterized by indolent growth. Complex interactions take place among the cellular components of the microenvironment of these tumors, and the recognition of the molecular mediators of their interplay and cross talk is crucial to discover novel therapeutic targets. NET cells overexpress a plethora of proangiogenic molecules including vascular endothelial growth factor, platelet-derived growth factor, fibroblast growth factor, semaphorins, and angiopoietins that promote both recruitment and proliferation of endothelial cell precursors, thus resulting among the most vascularized cancers with a microvessel density 10-fold higher than epithelial tumors. Also, NETs operate multifaceted interactions with stromal cells, both at local and distant sites, and whether their paracrine secretion of serotonin, connective tissue growth factor, and transforming growth factor ß primarily drives the fibroblast activation to enhance the tumor proliferation, on the other side NET-derived profibrotic factors accelerate the extracellular matrix remodeling and contribute to heart valves and/or mesenteric fibrosis development, namely, major complications of functioning NETs. However, at present, little is known on the immune landscape of NETs, but accumulating evidence shows that tumor-infiltrating neutrophils, mast cells, and/or macrophages concur to promote the neoangiogenic switch of these tumors by either direct or indirect mechanisms. On the other hand, immune checkpoint molecules are heterogeneously expressed in NETs' surrounding cells, and it is unclear whether or not tumor-infiltrating lymphocytes are antitumor armed within the microenvironment, given their low mutational load. Here, we review the current knowledge on both gastroenteropancreatic and pulmonary NETs' microenvironment as well as both established and innovative treatments aimed at targeting the tumor-host interplay.

STEMI: rare initial presentation of a mediastinal mass supplied by the RCA.

In the setting of severe septic shock, a 70-year-old woman had an ST segment myocardial infarction with ST elevations in the inferolateral leads. On cardiac catheterisation, no obstructive pathology was noted. Chest imaging revealed a large mediastinal mass measuring 8.5×6.5×7.5 cm in the visceral compartment of the mediastinum, with contrast enhancement from the right coronary artery (RCA). A biopsy was preformed and cytology was consistent with a well-differentiated neuroendocrine neoplasm. On review of the cardiac catherisation, it was noted that the mass was deriving blood supply from the RCA. Myocardial infarction with non-obstructive coronary arteries (MINOCA) is a rare but well-documented phenomenon. In this case, MINOCA was caused by coronary steal syndrome in the setting of profound hypotension. Immediate management is with haemodynamic support; there is no role for coronary intervention.

Hypervascular lesions of the pancreas: Think before you act.

BACKGROUND: The "classic" CT appearance of pancreatic neuroendocrine tumors (PNETs) is a solid, hypervascular lesion; however, non-PNET diagnoses may appear similar. In addition, some PNETs have a "non-classic" appearance. METHODS: Demographic, imaging, endoscopic ultrasound-fine needle aspiration (EUS/FNA) results, and pathology data were analyzed for patients who underwent pancreatectomy for suspected or confirmed diagnosis of PNET from our institutional database. RESULTS: Forty-three patients with a hypervascular lesion on CT had pancreatectomy for a pre-operative diagnosis of PNET. Final pathology revealed PNET in 30 (70%) and non-PNET diagnoses in 13 (30%). EUS/FNA had a sensitivity of 82% for the pre-operative diagnosis of PNET in patients with "classic" CT. Of 13 non-PNET diagnoses, 7 were benign. Among a total of 41 patients with a final diagnosis of PNET, 11 (27%) had "non-classic" CT (5 hypodense solid lesions, 3 isodense solid lesions, and 3 cystic lesions). Among these patients, EUS/FNA had a sensitivity of 100% in diagnosing PNET. CONCLUSIONS: Consideration of non-PNET diagnoses is important for patients with hypervascular lesions on CT. Appropriate pre-operative evaluation will optimize treatment plans.

Usefulness of indocyanine green-fluorescence imaging for real-time visualization of pancreas neuroendocrine tumor and cystic neoplasm.

We evaluated the usefulness of fluorescence imaging using indocyanine green to identify pancreas tumors in 23 patients undergoing pancreas resection. This technique was useful in visualizing pancreas lesions during surgery, specifically, neuroendocrine tumors as fluorescence and cystic neoplasms as a fluorescence defect.

Simple Vascular Architecture Classification in Predicting Pancreatic Neuroendocrine Tumor Grade and Prognosis.

BACKGROUND AND AIM: Vascularity is a critical feature in the evaluation of pancreatic neuroendocrine tumor (PNET). When done by EUS, contrast agents are recommended. However, vascular architecture (VA) can also be evaluated by routine Doppler flow in EUS without contrast agents. Our aim was to provide a simple VA classification in EUS for PNET grade and prognosis. METHODS: All pathologically proven PNET cases with EUS between 2012 and 2018 were retrospectively analyzed. The Doppler imaging was retrieved for VA classification. Predictive model construction was performed by machine learning algorithms. RESULTS: A total of 112 PNET cases were evaluated, among which 93 cases were subjected to VA classification. The VA was classified into type A (peritumoral with or without intratumoral vessels [A1 or A2]); type B (only intratumoral vessels); and type C (flow was absent). The VA classification was significantly correlated with tumor grades: 74% type A1 was G1, 73% type B was G2, and 58% type C was G3. Multivariate analysis indicated that elevated serum CA19-9 and type C classification were the independent predictors of G3 tumor. Five machine learning models were constructed, among which random forest was the best one with an AUC of 0.9972. Low-risk patients classified by this model exhibited better prognosis than high-risk patients (p = 0.0087). CONCLUSIONS: In the novel simple VA classification, peritumoral, intratumoral, and absent vessels are prone to be G1, G2, and G3, respectively. Combined with serum CA19-9 and lesion size, the VA classification could predict tumor grade and prognosis in PNET.

An update on the management of pancreatic neuroendocrine tumors.

Pancreatic neuroendocrine tumors (PNETs) are a rare and heterogeneous group of neoplasia and differ in their clinical presentation, behavior, and prognosis based on both histological features and cancer stage at the time of diagnosis. Although small-sized tumors can be surgically resected, locally advanced and metastatic tumors confer a poor prognosis. In addition, only limited treatment options are available to the latter group of patients with PNETs, such as hormonal analogs, cytotoxic agents, and targeted therapy. In selected patients, liver-directed therapies are also used. As expected, clinicians taking care of these patients are challenged to develop an effective and comprehensive treatment strategy for their patients amid a wide variety of treatment modalities. Targeted therapy for PNETs is limited to sunitinib and everolimus. Presently, a number of clinical studies are ongoing to assess the efficacy of newer targeted agents alone and in combination with previous agents for the treatment of advanced PNETs. The authors reviewed the current treatment and also discussed the emerging agents and emphasized the need to identify biomarkers.

New insights into hypoxia-related mechanisms involved in different microvascular patterns of bronchopulmonary carcinoids and poorly differentiated neuroendocrine carcinomas. Role of ribonuclease T2 (RNASET2) and HIF-1α.

Ribonuclease T2 (RNASET2) is a pleiotropic and polyfunctional protein, which exerts several different activities in neoplastic cells since the early steps of tumor development. Besides having an antitumorigenic activity, RNASET2 inhibits both bFGF-induced and VEGF-induced angiogenesis and has a role as a stress-response, alarmin-like, protein. In this study, we investigated RNASET2 expression in well-differentiated and poorly differentiated neuroendocrine neoplasms of the lung (Lu-NENs), which are known to show clear-cut differences in morphology, biology and clinical behavior. In addition, we explored possible relationships between RNASET2 expression and a series of immunohistochemical markers related to hypoxic stress, apoptosis, proliferation and angiogenesis. Our results showed a significantly higher expression of RNASET2, HIF-1α, and its target CA IX in poorly differentiated than in well-differentiated Lu-NENs, the former also showing higher proliferation and apoptotic rates, as well as a lower microvessel density (MVD) than the latter. Moreover, we were able to demonstrate in vitro an overexpression of RNASET2 in consequence of the activation of HIF-1α. In conclusion, we suggest that in poorly differentiated Lu-NENs, RNASET2 expression may be induced by HIF-1α, behaving as an alarmin-like molecule. In this aggressive group of cancers, which have highly deregulated proliferation pathways, RNASET2 fails to exert the growth-inhibiting effects described in other types of neoplasms. Its increased expression, however, may contribute to the typical phenotypic alterations seen in poorly differentiated Lu-NENs, such as the high apoptotic rate and the extensive necrosis, and may also enhance the low MVD observed in these neoplasms.

Periostin Limits Tumor Response to VEGFA Inhibition.

Resistance to antiangiogenic drugs limits their applicability in cancer therapy. Here, we show that revascularization and progression of pancreatic neuroendocrine tumors (PNETs) under extended vascular-endothelial growth factor A (VEGFA) blockade are dependent on periostin (POSTN), a matricellular protein expressed by stromal cells. Genetic deletion of Postn in RIP1-Tag2 mice blunted tumor rebounds of M2-like macrophages and αSMA+ stromal cells in response to prolonged VEGFA inhibition and suppressed PNET revascularization and progression on therapy. POSTN deficiency also impeded the upregulation of basic fibroblast growth factor (FGF2), an adaptive mechanism previously implicated in PNET evasion from antiangiogenic therapy. Higher POSTN expression correlated with markers of M2-like macrophages in human PNETs, and depleting macrophages with a colony-stimulating factor 1 receptor (CSF1R) antibody inhibited PNET revascularization and progression under VEGFA blockade despite continued POSTN production. These findings suggest a role for POSTN in orchestrating resistance to anti-VEGFA therapy in PNETs.

Vascularity and Tumor Size are Significant Predictors for Recurrence after Resection of a Pancreatic Neuroendocrine Tumor.

BACKGROUND: It is difficult to identify patients at high risk of recurrence after pancreatectomy for pancreatic neuroendocrine tumor (PNET) using only the grading classification, especially the G2 category, which includes both benign and low- and high-grade malignant tumors. METHODS: Forty-one patients with PNET who underwent pancreatectomy were enrolled in this study. We defined the computed tomography (CT) ratio as the CT value of the tumor divided by that of non-tumorous pancreatic parenchyma using the late arterial phase dynamic CT. The optimal cut-off values for CT ratio and tumor size were determined using p-values that were calculated using the log-rank test. RESULTS: The optimal cut-off values of CT ratio and tumor size for dividing patients into groups according to the greatest difference in disease-free survival (DFS) were 0.85 (p < 0.001) and 3.0 cm (p < 0.001), respectively. In analysis using Spearman's correlation coefficient, CT ratio (p = 0.007) and tumor size (p = 0.003) were individually associated with the Ki-67 proliferative index. Cox proportional hazard analysis identified that a CT ratio <0.85 (n = 10, p = 0.006) and tumor size ≥3.0 cm (n = 13, p = 0.023) were independent prognostic factors associated with DFS. All patients in the CT ratio ≥0.85 and tumor size <3.0 cm group (n = 23, including seven patients with G2 disease) did not develop recurrence after surgery. On the other hand, 5-year DFS in the CT ratio <0.85 and tumor size ≥3.0 cm group (n = 5, including three patients with G2 disease) was zero. CONCLUSIONS: PNETs with a CT ratio <0.85 and tumor size ≥3.0 cm should be considered as having a high risk of recurrence after pancreatectomy.