Angiogenesis represents a key event in cancer development, leading to local invasion e metastatization, and might be considered a basic feature in gastroenteropancreatic neuroendocrine neoplasms ...(GEP-NENs) with a high expression of angiogenic molecules. We aimed to analyze the prognostic and predictive role of angiogenic factors in GEP-NENs through the analysis of single nucleotide polymorphisms (SNPs) of VEGF-A, VEGFR2 and VEGFR3. The genomic DNA of 58 consecutive patients with GEP-NENs treated at our Institution was extracted from peripheral blood. Two SNPs were identified respectively in VEGF-A (rs2010963G>C, rs699947A>C), VEGFR-2 (rs2305948C>T, rs1870377T>A), and VEGFR-3 (rs307821T>C, rs307826C>A) gene. Gene polymorphisms were determined by Real-Time PCR using TaqMan assays. Median age was 57 years (range 24-79 years); 32 patients were male and 77.5% of NENs were localized in the pancreas. The allele frequency of VEGFR-2 rs2305948T and of VEGF-A rs2010963C showed a trend of higher frequency than in general population (12.1% vs. 8.0% and 34.5% vs. 31.2%, respectively). Three out SNPs (VEGF-A rs699947C, VEGF-A rs2010963GC and VEGFR-3 rs307821C) showed a correlation with an increased risk of disease relapse. Moreover median PFS changes according to the presence of 0-1 SNPs (20.7% of cases; 61.9 months), 2 SNPs (25.9%; 49.2 months) and 3 SNPs (53.4%; 27.8 months) (p = 0.034). Results suggest, for the first time, that specific SNPs in VEGF-A and VEGFR-3 correlate with poor prognosis in GEP-NENs. The identification of this new prognostic factor might be helpful in order to optimize the management of these heterogeneous neoplasms.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Medical therapy of pancreatic neuroendocrine tumors (P-NET) may take advantage of Everolimus treatment. However, the extent of therapeutic response cannot be predicted. This study was aimed to ...identify the possible predictive markers of response to Everolimus in P-NET. We found that Everolimus reduced the cell viability and induced apoptosis in primary cultures of 6 P-NET (P-NET-R), where the proliferative and antiapoptotic effects of IGF1 were blocked by Everolimus. On the contrary, 14 P-NET primary cultures (P-NET-NR) were resistant to Everolimus and IGF1, suggesting an involvement of PI3K/AKT/mTOR pathway in the mechanism of resistance. The response to Everolimus in vitro was associated with an active AKT/mTOR pathway and seemed to be associated with a greater clinical aggressiveness. In addition, a patient sensitive to Everolimus in vitro was sensitive to this drug in vivo also and showed a positive p-AKT immunohistochemistry (IHC) at tissue level. Similarly, a patient resistant to Everolimus treatment after surgery was not sensitive to the drug in vitro and had a negative p-AKT IHC staining. Therefore, present data confirm that P-NET primary cultures may be considered a model for testing medical treatment efficacy and that IHC characterization of p-AKT might help in identifying human P-NET who can benefit from Everolimus treatment. These data encourage conducting a prospective multicenter study involving different groups of P-NET patients treated with Everolimus.
Highlights • Neuroendocrine tumors of the gastro-entero-pancreatic system (GEP-NETs) are a heterogeneous group of neoplasms, with different
behavior. • A shared therapeutic sequence for GEP-NET ...treatment still does not exist. • The aim of this review is to identify the first and further better approaches among all available therapeutic options.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The incidence of neuroendocrine tumors (NETs) has increased in the last decades. Surgical treatment encompasses a panel of approaches ranging from conservative procedures to extended surgical ...resection. Tumor size and localization usually represent the main drivers in the choice of the most appropriate surgical resection. In the presence of small (<2 cm) and asymptomatic nonfunctioning NETs, a conservative treatment is usually recommended. For localized NETs measuring above 2 cm, surgical resection represents the cornerstone in the management of these tumors. As they are relatively biologically indolent, an extended resection is often justified also in the presence of advanced NETs. Surgical options for NET liver metastases range from limited resection up to liver transplantation. Surgical choices for metastatic NETs need to consider the extent of disease, the grade of tumor, and the presence of extra-abdominal disease. Any surgical procedures should always be balanced with the benefit of survival or relieving symptoms and patients' comorbidities.
The aim of this study was to evaluate the effect of combined (68)Ga and (18)F-FDG PET/CT on treatment management for patients with pancreatic neuroendocrine tumor (PNET).
Between January 2012 and ...April 2014, 49 consecutive patients with a cytologically and/or histologically proven diagnosis of PNET underwent combined (68)Ga and (18)FDG PET/CT on the same day.
The study group consisted of 21 males and 28 females with a median age of 59 years. Disease detection was achieved in 48 out of the 49 cases with (68)Ga imaging, and in 36 of the 49 cases with (18)FDG PET/CT. These results corresponded to sensitivities of 98% for (68)Ga versus 73% for (18)FDG PET/CT. Patients with NET-G1/NET-G2 had a positive (68)Ga and negative (18)FDG PET/CT in 13 cases, whereas both (68)Ga and (18)FDG PET/CT were positive in 27 cases. Patients with NEC-G3 were positive by both (68)Ga and (18)FDG PET/CT in 7 cases and positive only by (18)FDG in 1 case. Another NEC-G3 patient was only positive by (68)Ga PET/CT. The median Ki67 was 7% for (68)Ga PET/CT-positive tumors and 10% for tumors with both (68)Ga and (18)FDG PET/CT positivity (p = 0.130). Half of the patients with a prevalent uptake of (18)FDG (n = 7) had an NEC-G3 compared with 12% of patients with a prevalent uptake of (68)Ga (p = 0.012). There were no significant differences between patients with positive (68)Ga and those with positive (18)FDG with regards to treatment choice.
The association of (18)FDG slightly increases sensitivity of (68)Ga PET/CT alone in the diagnosis of PNET. A combined dual tracer PET/CT does not influence the choice of treatment strategy.
Angiogenesis represents a key event in cancer development, leading to local invasion e metastatization, and might be considered a basic feature in gastroenteropancreatic neuroendocrine neoplasms ...(GEP-NENs) with a high expression of angiogenic molecules. We aimed to analyze the prognostic and predictive role of angiogenic factors in GEP-NENs through the analysis of single nucleotide polymorphisms (SNPs) of VEGF-A, VEGFR2 and VEGFR3. The genomic DNA of 58 consecutive patients with GEP-NENs treated at our Institution was extracted from peripheral blood. Two SNPs were identified respectively in VEGF-A (rs2010963G>C, rs699947A>C), VEGFR-2 (rs2305948C>T, rs1870377T>A), and VEGFR-3 (rs307821T>C, rs307826C>A) gene. Gene polymorphisms were determined by Real-Time PCR using TaqMan assays. Median age was 57 years (range 24-79 years); 32 patients were male and 77.5% of NENs were localized in the pancreas. The allele frequency of VEGFR-2 rs2305948T and of VEGF-A rs2010963C showed a trend of higher frequency than in general population (12.1% vs. 8.0% and 34.5% vs. 31.2%, respectively). Three out SNPs (VEGF-A rs699947C, VEGF-A rs2010963GC and VEGFR-3 rs307821C) showed a correlation with an increased risk of disease relapse. Moreover median PFS changes according to the presence of 0-1 SNPs (20.7% of cases; 61.9 months), 2 SNPs (25.9%; 49.2 months) and 3 SNPs (53.4%; 27.8 months) (p = 0.034). Results suggest, for the first time, that specific SNPs in VEGF-A and VEGFR-3 correlate with poor prognosis in GEP-NENs. The identification of this new prognostic factor might be helpful in order to optimize the management of these heterogeneous neoplasms.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Introduction: Gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) are uncommon neoplasms including a wide range of anatomical, clinical, histological and molecular malignant entities. ...Improving our understanding of the molecular biology of GEP-NETs represents a key challenge in the treatment of these rare tumors. Therefore we aimed to analyze genotypes of VEGF-A, VEGFR2 and Flt4 in GEP-NETs and their potential correlation with the risk of these tumors and/or with the outcome.
Methods: The genomic DNA of 28 consecutive patients with GEP-NETs treated at our Institution was extracted from paraffinembedded tissue. We selected polymorphisms in the following genes: VEGF-A (rs2010963G>C, rs699947A>C), VEGFR-2 (rs2305948C>T, rs1870377T>A) and VEGFR-3 (rs307826T>C, rs307821C>A). Gene polymorphisms were determined by Real-Time PCR using TaqMan assays.
Results: Median age was 58 (range 33-78) and M/F ratio was 1/1. Twenty-one out of the 28 patients had NETs of the pancreas. The allele frequency of VEGFR2 rs2305948C and of VEGFA rs2010963G showed a trend of lower frequency than in general population (82% vs. 92% and 60.3% vs. 68.8%, respectively, p<0.001). The following factors significantly correlated with a poorer overall survival (p<0.05): VEGFA rs699947C, VEGFA rs2010963A, VEGFR-2 rs1870377T/A, VEGFR-2 rs2305948C/T, VEGFR-3 rs307821C and VEGFR-3 rs307826T.
Conclusion: Our results suggest, for the first time, that inherited abnormalities in VEGF pathway influence the risk and aggressiveness of GEP-NETs. Within March 2016 final data about all the enrolled 64 patients will be also available. These results should be validated prospectively in order to optimize the diagnosis and treatment of these patients.
Citation Format: Rossana Berardi, Mariangela Torniai, Silvia Pagliaretta, Silvia Rinaldi, Francesca Morgese, Stefano Partelli, Miriam Caramanti, Azzurra Onofri, Vanessa Polenta, Sonia Pasquini, Massimo Falconi, Stefano Cascinu. Impact of VEGF and VEGFR polymorphisms on neuroendocrine tumors of the gastro-entero-pancreatic system (GEPNETs) outcome. abstract. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3401.
AIM:Aim of this study is to evaluate the results of 20-year single-center laparoscopic adrenalectomy (LA), with different transperitoneal techniques.
MATERIALS AND METHODS:Three hundred twenty-six ...adrenalectomies were performed from 1993 to 2013 using a transperitoneal approach through anterior access, flank access, and anterior submesocolic access (adopted by the author for left LA since 2004).
RESULTS:Overall 142 men and 184 women (mean age 59.3 y) underwent 196 right, 113 left, and 17 bilateral adrenalectomies. There was 1 fatal outcome (0.30%) due to sepsis. Conversion to open surgery was required in 7 patients (2.14%) for intraoperative bleeding (n=5), paroxysmal hypertension during pheochromocytoma removal (n=1), and tearing of the colon during bilateral adrenalectomy in a patient with Cushing hyperplasia (n=1).There were 15 postoperative complications (4.60%) managed conservatively.
CONCLUSIONS:Transperitoneal LA is a safe, minimally invasive procedure ensuring early recovery. The submesocolic access is faster and minimizes surgical dissection.
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