Silvia Ortolani

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.

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 68Ga-DOTATOC (Ga) positron emission tomography (PET)/computed tomography (CT) is recommended in the workup of pancreas neuroendocrine tumors (PanNETs); evidence suggests that 18F-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.

Update on medical treatment of small intestinal neuroendocrine tumors

ABSTRACT 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.

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

ObjectivesTo evaluate MRI derived whole-tumour histogram analysis parameters in predicting pancreatic neuroendocrine neoplasm (panNEN) grade and aggressiveness.MethodsPre-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.ResultsADCentropy 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).ConclusionsWhole-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.

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 &khgr;2 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.

Orbital lesions, an exceedingly rare site of neuroendocrine tumor metastasis

Orbital lesions, an exceedingly rare site of neuroendocrine tumor metastasis Sara Pusceddu1, Massimo Milione2, Silvia Ortolani3, Alessio Pellegrinelli2, Marco Brugia4, Filippo de Braud1, Lorenzo Antonuzzo4,5 1Department of Medical Oncology, Fondazione IRCCS “Istituto Nazionale dei Tumori”, 20133 Milan, Italy. 2Department of Phatology, Fondazione IRCCS “Istituto Nazionale dei Tumori”, 20133 Milan, Italy. 3Department of Medical Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, 37134 Verona, Italy. 4Department of Medical Oncology, Azienda Ospedaliera Universitaria Careggi, 50134 Firenze, Italy. 5Medical Genetics, University of Siena, 53100 Siena, Italy. Correspondence to: Dr. Sara Pusceddu, Department of Medical Oncology, Fondazione IRCCS “Istituto Nazionale dei Tumori”, Via G. Venezian 1, 20133 Milan, Italy. E-mail: sara.pusceddu@istitutotumori.mi.it Neuroendocrine tumors are rare neoplasms arising primarily in the gastrointestinal tract and lung. The liver is the most common site of metastases, but these tumors can rarely metastasize to atypical sites. Surgery is the only curative approach while the optimal medical treatment is debated. From this perspective, a multidisciplinary approach for each single case becomes very important. In this report we describe the case of a male affected by a single intraorbital metastasis from a midgut well differentiated neuroendocrine tumor. The patient refused surgical removal and therefore he was at first treated with stereotactic radiotherapy and systemic treatment with a somatostatin analog (SSA). After achieving a stable disease for four months he underwent primary tumor resection. Six years after the initial diagnosis, the patient is currently stable and receiving SSA at standard dose.

Double tracer PET/CT: what is it and what does it mean?

Double tracer PET/CT: what is it and what does it mean? Mattia Pellicciari, Silvia Ortolani, Elisabetta Grego, Giampaolo Tortora, Sara Cingarlini Department of Clinical Oncology, Comprehensive Cancer Network, G. B. Rossi University Hospital, University of Verona, 37134 Verona, Italy. Corresponding Author: Dr. Sara Cingarlini, Department of Clinical Oncology, Comprehensive Cancer Network, G. B. Rossi University Hospital, University of Verona, Piazzale L. A. Scuro 10, 37134 Verona, Italy. E-mail: sara.cingarlini@ospedaleuniverona.it 68Ga-DOTA-peptide PET/CT is a recommended imaging modality in the workup of neuroendocrine neoplasms (NENs), which shows high diagnostic sensitivity and is a strong predictor of successful somatostatin receptor directed treatments. Although not routinely recommended, reliable evidences show that 18F-FDG PET/CT can provide complementary information in this setting with the ability to discriminate slow-proliferating tumors from aggressive, rapidly-proliferating tumors. Further, it has been proposed as an independent prognostic factor for the prediction of either overall survival or progression free survival. In this review, we provide insight into the biologic significance of 68Ga-DOTA-peptides and 18F-FDG uptake, and of the use of double tracer (68Ga-DOTA-peptides plus 18F-FDG) PET/CT in the clinical evaluation of patients affected by NENs.

Perfusion Changes in Liver Metastases (LM) from Pancreatic Neuroendocrine Tumors (PanNETs) during Everolimus (E) Treatment: Update of Perfusion CT (P-CT) Study

Multidisciplinary Team (MDT) in Neuroendocrine Tumor (NET) Management : Results from the First Global NET Patient (pt) Survey - A Collaboration between the International Neuroendocrine Cancer Alliance (INCA) and Novartis PharmaceuticalsRadioembolization with 90Y-Labelled Resin Microspheres in Patients with Liver Metastases from Neuroendocrine TumorsIncremental Benefit of Preoperative Endoscopic Ultrasound for the Detection of Pancreatic Neuroendocrine Tumors : A Meta-AnalysisSmall intestinal neuroendocrine tumors (SI-NETs) originate from serotonin-producing enterochromaffin (EC) cells in the intestinal mucosa. Somatostatin analogs (SSAs) are mainly used to control hormonal secretion and tumor growth. However, the molecular mechanisms leading to the control of SI-NETs are unknown. Although microRNAs (miRNAs) are post transcriptional regulators deeply studied in many cancers, are not well-defined in SI-NETs. We adopted a two-pronged strategy to investigate SSAs and miRNAs: first, to provide novel insights into how SSAs control NET cells, and second, to identify an exclusive SI-NET miRNA expression, and investigate the biological functions of miRNA targets.To accomplish the first aim, we treated CNDT2.5 cells with octreotide for 16 months. Affymetrix microarray was performed to study gene variation of CNDT2.5 cells in the presence or absence of octreotide. The study revealed that octreotide induces six genes, ANXA1, ARHGAP18, EMP1, GDF15, TGFBR2 and TNFSF15.To accomplish the second aim, SI-NET tissue specimens were used to run genome-wide Affymetrix miRNA arrays. The expression of five miRNAs (miR-96, -182, -183, -196a and -200a) was significantly upregulated in laser capture microdissected (LCM) tumor cells versus LCM normal EC cells, whereas the expression of four miRNAs (miR-31, -129-5p, -133a and -215) was significantly downregulated in LCM tumor cells. We also detected nine tissue miRNAs in serum samples, showing that the expression of five miRNAs is significantly increased in SSA treated patients versus untreated patients. Conversely, SSAs do not change miRNA expression of four low expressed miRNAs. Silencing miR-196a expression was used to investigate functional activities in NET cells. This experimental approach showed that four miR-196a target genes, HOXA9, HOXB7, LRP4 and RSPO2, are significantly upregulated in silenced miR-196a NET cells.In conclusion, ANXA1, ARHGAP18, EMP1, GDF15, TGFBR2 and TNFSF15 genes might regulate cell growth and differentiation in NET cells, and play a role in an innovative octreotide signaling pathway. The global SI-NET miRNA profiling revealed that nine selected miRNAs might be involved in tumorigenesis, and play a potential role as novel markers for follow-up. Indeed, silencing miR-196a demonstrated that HOXA9, HOXB7, LRP4 and RSPO2 genes are upregulated at both transcriptional and translational levels.