Correlation of MR features and histogram-derived parameters with aggressiveness and outcomes after resection in pancreatic ductal adenocarcinoma.

PURPOSE: To evaluate MR-derived histogram parameters in predicting aggressiveness and surgical outcomes in patients with PDAC, by correlating them to pathological features, recurrence-free survival (RFS), and overall survival (OS). METHODS: Pre-operative MR examinations of 103 patients with PDAC between July 2014 and September 2018 were retrospectively analyzed. Morphologic features and whole-tumor histogram-derived parameters were correlated to pathological features using Fisher's exact or Mann-Whitney U tests and receiver operating characteristic (ROC) curves were constructed for significant parameters. Cox regression analysis and Kaplan-Meier curves were used to determine the association of clinical-pathological variables, morphological features, and histogram-derived parameters with RFS and OS. RESULTS: T1entropy, ADCentropy, T2kurtosis, and ADCuniformity had the highest area under the curve (AUC) for prediction of vascular infiltration, nodal metastases, microscopic vascular invasion, and peripancreatic fat invasion (.657, .742, .760, and .818, respectively). Poor tumor differentiation (P = 0.002, hazard ratio-HR = 4.08), nodal ratio (P = 0.034, HR 6.95), and ADCmaximum (P = 0.021, HR 1.01) were significant predictors of RFS. Poor tumor differentiation (P = 0.05, HR 2.82), ADCuniformity (P = 0.02, HR 3.32), and arterialentropy (P = 0.02, HR 6.84) were the only significant predictors of death; patients with higher arterialentropy had significantly shorter OS than patients who did not meet this criterion (P = 0.02; median OS 24 vs 31 months). CONCLUSION: Histogram-derived parameters may predict adverse pathological features in PDACs. High arterialentropy seems to be associated with short OS after surgery in patients with PDAC.

Intravoxel incoherent motion diffusion-weighted MR imaging of solid pancreatic masses: reliability and usefulness for characterization.

PURPOSE: IVIM-DW imaging has shown potential usefulness in the study of pancreatic lesions. Controversial results are available regarding the reliability of the measurements of IVIM-derived parameters. The aim of this study was to evaluate the reliability and the diagnostic potential of IVIM-derived parameters in differentiation among focal solid pancreatic lesions and normal pancreas (NP). METHODS: Fifty-seven patients (34 carcinomas-PDACs, 18 neuroendocrine neoplasms-panNENs, and 5 autoimmune pancreatitis-AIP) and 50 subjects with NP underwent 1.5-T MR imaging including IVIM-DWI. Images were analyzed by two independent readers. Apparent diffusion coefficient (ADC), slow component of diffusion (D), incoherent microcirculation (Dp), and perfusion fraction (f) were calculated. Interobserver reliability was assessed with intraclass correlation coefficient (ICC). A Kruskal-Wallis H test with Steel-Dwass post hoc test was used for comparison. The diagnostic performance of each parameter was evaluated through receiver operating characteristic (ROC) curve analysis. RESULTS: Overall interobserver agreement was excellent (ICC = 0.860, 0.937, 0.968, and 0.983 for ADC, D, Dp, and f). D, Dp, and f significantly differed among PDACs and panNENs (p = 0.002, < 0.001, and < 0.001), albeit without significant difference at the pairwise comparison of ROC curves (p = 0.08-0.74). Perfusion fraction was higher in AIP compared with PDACs (p = 0.024; AUC = 0.735). Dp and f were higher in panNENs compared with AIP (p = 0.029 and 0.023), without differences at ROC analysis (p = 0.07). CONCLUSIONS: IVIM-derived parameters have excellent reliability and could help in differentiation among solid pancreatic lesions and NP.

Metformin Use Is Associated With Longer Progression-Free Survival of Patients With Diabetes and Pancreatic Neuroendocrine Tumors Receiving Everolimus and/or Somatostatin Analogues.

BACKGROUND & AIMS: Metformin seems to have anticancer effects. However, it is not clear whether use of glycemia and metformin affect outcomes of patients with advanced pancreatic neuroendocrine tumors (pNETs). We investigated the association between glycemia and progression-free survival (PFS) of patients with pNETs treated with everolimus and/or somatostatin analogues, as well as the association between metformin use and PFS time. METHODS: We performed a retrospective analysis of 445 patients with advanced pNET treated at 24 medical centers in Italy from 1999 through 2015. Data on levels of glycemia were collected at time of diagnosis of pNET, before treatment initiation, and during treatment with everolimus (with or without somatostatin analogues), octreotide, or lanreotide. Diabetes was defined as prior or current use of glycemia control medication and/or fasting plasma glucose level ≥ 126 mg/dL, hemoglobin A1c ≥ 6.5% (48 mmol/L), or a random sample of plasma glucose ≥ 200 mg/dL (11.1 mmol/L), with reported classic symptoms of hyperglycemia or hyperglycemic crisis. Patients were assigned to groups based on diagnosis of diabetes before or during antitumor therapy. PFS was compared between patients with vs without diabetes. Among patients with diabetes, the association between metformin use and PFS was assessed. We performed sensitivity and landmark analyses to exclude patients who developed diabetes while receiving cancer treatment and to exclude a potential immortal time bias related to metformin intake. RESULTS: PFS was significantly longer in patients with diabetes (median, 32.0 months) than without diabetes (median, 15.1 months) (hazard ratio for patients with vs without diabetes, 0.63; 95% confidence interval, 0.50-0.80; P = .0002). PFS of patients treated with metformin was significantly longer (median PFS, 44.2 months) than for patients without diabetes (hazard ratio for survival of patients with diabetes receiving metformin vs without diabetes, 0.45; 95% confidence interval, 0.32-0.62; P < .00001) and longer than for patients with diabetes receiving other treatments (median PFS, 20.8 months; hazard ratio, 0.49; 95% confidence interval, 0.34-0.69; P < .0001). In multivariable analysis, adjusted for other factors associated with outcomes, metformin was associated with longer PFS but level of glycemia was not. Metformin was associated with increased PFS of patients receiving somatostatin analogues and in those receiving everolimus, with or without somatostatin analogues. Sensitivity and landmark analyses produced similar results. CONCLUSIONS: In a retrospective study of patients with pNETs, we found a significant association between metformin use and longer PFS.

Can histogram analysis of MR images predict aggressiveness in pancreatic neuroendocrine tumors?

OBJECTIVES: To evaluate MRI derived whole-tumour histogram analysis parameters in predicting pancreatic neuroendocrine neoplasm (panNEN) grade and aggressiveness. METHODS: Pre-operative MR of 42 consecutive patients with panNEN >1 cm were retrospectively analysed. T1-/T2-weighted images and ADC maps were analysed. Histogram-derived parameters were compared to histopathological features using the Mann-Whitney U test. Diagnostic accuracy was assessed by ROC-AUC analysis; sensitivity and specificity were assessed for each histogram parameter. RESULTS: ADCentropy was significantly higher in G2-3 tumours with ROC-AUC 0.757; sensitivity and specificity were 83.3 % (95 % CI: 61.2-94.5) and 61.1 % (95 % CI: 36.1-81.7). ADCkurtosis was higher in panNENs with vascular involvement, nodal and hepatic metastases (p= .008, .021 and .008; ROC-AUC= 0.820, 0.709 and 0.820); sensitivity and specificity were: 85.7/74.3 % (95 % CI: 42-99.2 /56.4-86.9), 36.8/96.5 % (95 % CI: 17.2-61.4 /76-99.8) and 100/62.8 % (95 % CI: 56.1-100/44.9-78.1). No significant differences between groups were found for other histogram-derived parameters (p >.05). CONCLUSIONS: Whole-tumour histogram analysis of ADC maps may be helpful in predicting tumour grade, vascular involvement, nodal and liver metastases in panNENs. ADCentropy and ADCkurtosis are the most accurate parameters for identification of panNENs with malignant behaviour. KEY POINTS: • Whole-tumour ADC histogram analysis can predict aggressiveness in pancreatic neuroendocrine neoplasms. • ADC entropy and kurtosis are higher in aggressive tumours. • ADC histogram analysis can quantify tumour diffusion heterogeneity. • Non-invasive quantification of tumour heterogeneity can provide adjunctive information for prognostication.

Tumor thrombosis: a peculiar finding associated with pancreatic neuroendocrine neoplasms. A pictorial essay.

While abutment, encasement or vessel occlusion are identified in most patients with a pancreatic tumor, tumor thrombosis is an uncommon finding. In particular, there are no description in the literature of tumor thrombosis associated with ductal adenocarcinoma, the most common pancreatic tumor. On the other hand, surgical series reveal that tumor thrombosis is associated with about 5% of pancreatic neuroendocrine neoplasms (PanNENs), and literature data suggest that this finding is frequently underreported on pre-operative imaging examinations. Tumor thrombosis may be clinically relevant, causing splenoportomesenteric hypertension, possibly responsible for life-threatening upper gastrointestinal bleeding. Bland thrombosis caused by direct infiltration of peri-pancreatic vessels frequently determines surgical unresectability, even in neuroendocrine tumors; on the opposite, tumor thrombosis associated with PanNENs do not exclude surgery per se, even though both morbidity and mortality can be increased by such condition. Considering the favorable prognosis of PanNENs and the frequent need to treat tumor thrombosis in order to prevent complications or to relieve symptoms, it is of paramount importance for radiologists the knowledge of the variety of findings associated with tumor thrombosis in PanNENs.

Perfusion CT Changes in Liver Metastases from Pancreatic Neuroendocrine Tumors During Everolimus Treatment.

AIM: To evaluate modifications of perfusional parameters assessed by perfusion computed tomography (P-CT) of liver metastases (LM) from pancreatic neuroendocrine tumors (PanNETs) during everolimus treatment. PATIENTS AND METHODS: All patients with LMs from G1-2 PanNETs undergoing everolimus treatment between January 2013 and January 2015 were prospectively evaluated with P-CT at baseline, and after 2 and 4 months of therapy. Size, perfusion, blood volume (BV), peak enhancement intensity (PEI) and time to peak for each lesion were calculated. RESULTS: A total of 33 LMs in nine patients with G1-2 PanNETs were prospectively evaluated: 23/33 (69.7%) were responders, 10/33 (30.3%) were non-responders. Among perfusional parameters, only numerical peak enhancement intensity values significantly differed between the two groups at baseline (p=0.043). BV increase was the most significant perfusional modification identifying responding lesions, even at an early stage of treatment, with a high positive predictive value (89.47%). CONCLUSION: P-CT seems to be useful for prediction of response to everolimus of LMs from PanNETs.

Pancreatic neuroendocrine neoplasms: Magnetic resonance imaging features according to grade and stage.

AIM: To describe magnetic resonance (MR) imaging features of pancreatic neuroendocrine neoplasms (PanNENs) according to their grade and tumor-nodes-metastases stage by comparing them to histopathology and to determine the accuracy of MR imaging features in predicting their biological behavior. METHODS: This study was approved by our institutional review board; requirement for informed patient consent was waived due to the retrospective nature of the study. Preoperative MR examinations of 55 PanNEN patients (29 men, 26 women; mean age of 57.6 years, range 21-83 years) performed between June 2013 and December 2015 were reviewed. Qualitative and quantitative features were compared between tumor grades and stages determined by histopathological analysis. RESULTS: Ill defined margins were more common in G2-3 and stage III-IV PanNENs than in G1 and low-stage tumors (P < 0.001); this feature had high specificity in the identification of G2-3 and stage III-IV tumors (90.3% and 96%, 95%CI: 73.1-97.5 and 77.7-99.8). The mean apparent diffusion coefficient value was significantly lower in G2-3 and stage III-IV lesions compared to well differentiated and low-stage tumors (1.09 × 10-3 mm2/s vs 1.45 × 10-3 mm2/s and 1.10 × 10-3 mm2/s vs 1.53 × 10-3 mm2/s, P = 0.003 and 0.001). Receiving operator characteristic analysis determined optimal cut-offs of 1.21 and 1.28 × 10-3 mm2/s for the identification of G2-3 and stage III-IV tumors, with sensitivity and specificity values of 70.8/80.7% and 64.5/64% (95%CI: 48.7-86.6/60-92.7 and 45.4-80.2/42.6-81.3). CONCLUSION: MR features of PanNENs vary according to their grade of differentiation and their stage at diagnosis and could predict the biological behavior of these tumors.

Role of Combined 68Ga-DOTATOC and 18F-FDG Positron Emission Tomography/Computed Tomography in the Diagnostic Workup of Pancreas Neuroendocrine Tumors: Implications for Managing Surgical Decisions.

OBJECTIVES: Ga-DOTATOC (Ga) positron emission tomography (PET)/computed tomography (CT) is recommended in the workup of pancreas neuroendocrine tumors (PanNETs); evidence suggests that F-FDG (F) PET/CT can also provide prognostic information. Aims of this study were to assess the role of combined Ga- and F-PET/CT in the evaluation of grade (G) 1-2 PanNETs and to test the correlation between F-PET/CT positivity and tumor grade. METHODS: Preoperative Ga- and F-PET/CT of 35 patients with surgically resected G1-2 PanNETs were evaluated. For grading, the 2010 World Health Organization Classification was used; an ancillary analysis with Ki67 cutoffs at 5% to 20% was conducted. Correlation between F-PET/CT positivity (SUVmax > 3.5) and grade was assessed. RESULTS: Of 35 PanNETs, 28.6% and 71.4% were G1 and G2 as per World Health Organization. Ga-PET/CT showed high sensitivity (94.3%) in detecting G1-2 PanNETs. F-PET/CT was positive in 20% and 76% G1 and G2 tumors (P = 0.002). F-PET/CT identified G2 PanNETs with high positive predictive value (PPV, 90.5%). F-PET/CT correlated with tumor grade also in the ancillary analysis (P = 0.009). CONCLUSIONS: The high sensitivity of Ga-PET/CT in NET detection is known. The high PPV of F-PET/CT in the identification of G2 forms suggests its potential role in PanNETs prognostication and risk stratification.

Digital Subtraction of Magnetic Resonance Images Improves Detection and Characterization of Pancreatic Neuroendocrine Neoplasms.

OBJECTIVE: The aim of this study was to evaluate the usefulness of digital image subtraction of contrast-enhanced magnetic resonance (MR) images for detection and characterization of pancreatic neuroendocrine neoplasms (PanNENs). METHODS: Magnetic resonance examinations of 50 histologically verified PanNENs were retrospectively evaluated by 2 radiologists; 50 ductal adenocarcinomas were included as a control group. Late arterial phase images and correspondent subtracted images were analyzed. Tumor detectability on a subjective 3-point scale and contrast-to-noise ratios were compared across sequences using paired Student t tests. Tumor signal intensity was compared between sequences using χ or Fisher exact tests. RESULTS: Subjective conspicuity and contrast-to-noise ratios of PanNENs were significantly higher on subtracted images compared with correspondent late arterial phase images (P < 0.001 and P = 0.002). The rate of clearly hyperenhancing PanNENs was higher on subtracted images compared with arterial phase images (76% vs 36%). CONCLUSIONS: Digital image subtraction improves tumor conspicuity and allows better characterization of PanNENs compared with late arterial phase images.

Update on medical treatment of small intestinal neuroendocrine tumors.

INTRODUCTION: Small intestinal (SI) neuroendocrine tumors (NETs) are relatively rare tumors. Due to the lack of symptom or specific symptoms, SI-NETs are often diagnosed at an advanced stage, making therapy challenging. The management of patients with advanced stage SI-NETS requires a multidisciplinary approach that combines surgical and medical treatment including novel targeted molecular therapies. AREAS COVERED: This article summarizes current strategies for the medical treatment of SI-NETS. Expert commentary: The treatment plan of advanced-stage SI-NETs should be tailored in a case-by-case manner with the adoption of a multidisciplinary approach that combines different treatment options, including biological targeted therapies. In particular, we believe that the identification of the optimal treatment sequence(s), correct treatment timing and the selection of patients eligible to different treatments need specific investigation in controlled clinical trials.

Pancreatic Neuroendocrine Neoplasms: Clinical Value of Diffusion-Weighted Imaging.

BACKGROUND/AIMS: Diffusion-weighted imaging (DWI) can depict random motions of water molecules in biological tissues during magnetic resonance (MR) examinations. Few papers have tested its application to pancreatic neuroendocrine neoplasms (PanNENs). The aim of this paper is to assess the clinical value of DWI regarding the identification and characterization of PanNENs and diagnosis of liver metastases. METHODS: Preoperative MR examinations of 30 PanNEN patients were retrospectively reviewed; 30 patients with pathologically proven pancreatic ductal adenocarcinoma (PDAC) were included to compare the imaging features. Qualitative and quantitative MR features were compared between histotypes. A blinded-reader comparison of diagnostic confidence for PanNENs and liver metastases was conducted on randomized image sets. All results were compared with pathological data. RESULTS: PanNEN conspicuity was higher on DW images compared to conventional MR sequences. DWI had higher detection rates for PanNENs than had conventional sequences (93.3 vs. 71.1%). Sharp margins and absence of main pancreatic duct/common bile duct dilation and chronic pancreatitis were more common among PanNENs as compared to PDACs. Arterial iso- or hyperenhancement and portal hyperenhancement were more frequent within PanNENs as compared to PDACs. No differences between histotypes were found for quantitative features. Arterial-phase images had the highest interobserver agreement for the diagnosis of PanNEN (Cohen's κ = 0.667). DWI provided the highest detection rate for liver metastases as well as excellent interobserver agreement for the diagnosis of liver metastases (κ = 0.932), with good accuracy (AUC = 0.879-0.869). CONCLUSION: DWI has clinical value regarding the identification of PanNENs and the diagnosis of liver metastases, while conventional MR sequences are fundamental for their characterization.

Prognostication and response assessment in liver and pancreatic tumors: The new imaging.

Diffusion-weighted imaging (DWI), dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and perfusion computed tomography (CT) are technical improvements of morphologic imaging that can evaluate functional properties of hepato-bilio-pancreatic tumors during conventional MRI or CT examinations. Nevertheless, the term "functional imaging" is commonly used to describe molecular imaging techniques, as positron emission tomography (PET) CT/MRI, which still represent the most widely used methods for the evaluation of functional properties of solid neoplasms; unlike PET or single photon emission computed tomography, functional imaging techniques applied to conventional MRI/CT examinations do not require the administration of radiolabeled drugs or specific equipments. Moreover, DWI and DCE-MRI can be performed during the same session, thus providing a comprehensive "one-step" morphological and functional evaluation of hepato-bilio-pancreatic tumors. Literature data reveal that functional imaging techniques could be proposed for the evaluation of these tumors before treatment, given that they may improve staging and predict prognosis or clinical outcome. Microscopic changes within neoplastic tissues induced by treatments can be detected and quantified with functional imaging, therefore these techniques could be used also for post-treatment assessment, even at an early stage. The aim of this editorial is to describe possible applications of new functional imaging techniques apart from molecular imaging to hepatic and pancreatic tumors through a review of up-to-date literature data, with a particular emphasis on pathological correlations, prognostic stratification and post-treatment monitoring.

Suppression of mTOR pathway in solid tumors: lessons learned from clinical experience in renal cell carcinoma and neuroendocrine tumors and new perspectives.

The PI3K-AKT-mTOR pathway plays role in the regulation of many cellular processes. Hyperactivation of mTOR signaling has been implicated in human carcinogenesis, representing an attractive target for cancer therapy. Among other cancer subtypes, renal cell carcinoma (RCC) and neuroendocrine tumors are relevant settings in which the deregulation of mTOR pathway is of crucial importance. Different mTOR-inhibitory agents have been developed in recent years. Temsirolimus is approved for advanced RCC; everolimus is registered for the treatment of advanced RCC, pancreatic neuroendocrine tumors and postmenopausal, hormone receptor-positive/HER2-negative, advanced breast cancer. This review is focused on the description of the clinical experience with mTOR-inhibitor agents for the treatment of advanced RCC and neuroendocrine tumors, followed by an excursus on the landscape of the ongoing research in this field.

Acquired hemophagocytic syndrome in a patient with synovial sarcoma: a case report.

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome characterized by severe hyperinflammation due to an overwhelming ineffective immune response to different triggers. Most important symptoms are fever, hepatosplenomegaly and cytopenias. Biochemical signs include elevated ferritin, hypertriglyceridemia and low fibrinogen. Hemophagocytosis in the bone marrow is a hallmark of this syndrome. Based on the pathogenetic mechanism, it can be classified into primary (inherited) or secondary (acquired) HLH. We report, to our knowledge, the first case of acquired hemophagocytic syndrome that arose in a 20-year-old man affected by synovial sarcoma as a complication during chemotherapy.