Importance Data about the optimal timing for the initiation of peptide receptor radionuclide therapy (PRRT) for advanced, well-differentiated enteropancreatic neuroendocrine tumors are lacking. Objective To evaluate the association of upfront PRRT vs upfront chemotherapy or targeted therapy with progression-free survival (PFS) among patients with advanced enteropancreatic neuroendocrine tumors who experienced disease progression after treatment with somatostatin analogues (SSAs). Design, Setting, and Participants This retrospective, multicenter cohort study analyzed the clinical records from 25 Italian oncology centers for patients aged 18 years or older who had unresectable, locally advanced or metastatic, well-differentiated, grades 1 to 3 enteropancreatic neuroendocrine tumors and received either PRRT or chemotherapy or targeted therapy after experiencing disease progression after treatment with SSAs between January 24, 2000, and July 1, 2020. Propensity score matching was done to minimize the selection bias. Exposures Upfront PRRT or upfront chemotherapy or targeted therapy. Main Outcomes and Measures The main outcome was the difference in PFS among patients who received upfront PRRT vs among those who received upfront chemotherapy or targeted therapy. A secondary outcome was the difference in overall survival between these groups. Hazard ratios (HRs) were fitted in a multivariable Cox proportional hazards regression model to adjust for relevant factors associated with PFS and were corrected for interaction with these factors. Results Of 508 evaluated patients (mean ([SD] age, 55.7 [0.5] years; 278 [54.7%] were male), 329 (64.8%) received upfront PRRT and 179 (35.2%) received upfront chemotherapy or targeted therapy. The matched group included 222 patients (124 [55.9%] male; mean [SD] age, 56.1 [0.8] years), with 111 in each treatment group. Median PFS was longer in the PRRT group than in the chemotherapy or targeted therapy group in the unmatched (2.5 years [95% CI, 2.3-3.0 years] vs 0.7 years [95% CI, 0.5-1.0 years]; HR, 0.35 [95% CI, 0.28-0.44;P < .001]) and matched (2.2 years [95% CI, 1.8-2.8 years] vs 0.6 years [95% CI, 0.4-1.0 years]; HR, 0.37 [95% CI, 0.27-0.51;P < .001]) populations. No significant differences were shown in median overall survival between the PRRT and chemotherapy or targeted therapy groups in the unmatched (12.0 years [95% CI, 10.7-14.1 years] vs 11.6 years [95% CI, 9.1-13.4 years]; HR, 0.81 [95% CI, 0.62-1.06;P = .11]) and matched (12.2 years [95% CI, 9.1-14.2 years] vs 11.5 years [95% CI, 9.2-17.9 years]; HR, 0.83 [95% CI, 0.56-1.24;P = .36]) populations. The use of upfront PRRT was independently associated with improved PFS (HR, 0.37; 95% CI, 0.26-0.51;P < .001) in multivariable analysis. After adjustment of values for interaction, upfront PRRT was associated with longer PFS regardless of tumor functional status (functioning: adjusted HR [aHR], 0.39 [95% CI, 0.27-0.57]; nonfunctioning: aHR, 0.29 [95% CI, 0.16-0.56]), grade of 1 to 2 (grade 1: aHR, 0.21 [95% CI, 0.12-0.34]; grade 2: aHR, 0.52 [95% CI, 0.29-0.73]), and site of tumor origin (pancreatic: aHR, 0.41 [95% CI, 0.24-0.61]; intestinal: aHR, 0.19 [95% CI, 0.11-0.43]) (P < .001 for all). Conversely, the advantage was not retained in grade 3 tumors (aHR, 0.31; 95% CI, 0.12-1.37;P = .13) or in tumors with a Ki-67 proliferation index greater than 10% (aHR, 0.73; 95% CI, 0.29-1.43;P = .31). Conclusions and Relevance In this cohort study, treatment with upfront PRRT in patients with enteropancreatic neuroendocrine tumors who had experienced disease progression with SSA treatment was associated with significantly improved survival outcomes compared with upfront chemotherapy or targeted therapy. Further research is needed to investigate the correct strategy, timing, and optimal specific sequence of these therapeutic options.

Neuroendocrine tumors (NETs) are epithelial neoplasms with predominant neuroendocrine differentiation that arise in most organs of the body. Mediastinal NETs are very rare, and account for no more than 5% of all mediastinal tumors. R0 surgery represents the milestone of treatment. Here, we describe a case of a locally advanced primary atypical carcinoid of the mediastinum. This was initially considered inoperable due to infiltration of a great vessel and was successfully resected after neoadjuvant treatment as a result of very extensive surgery. Only through an accurate preoperative diagnosis and good radiological planning is it possible to obtain satisfactory oncological results.

This study was conducted in the setting of advanced Non-small-cell lung cancer in older patients. It is a multicenter retrospective analysis on very old persons that explores the efficacy and the safety of anti-programmed cell death protein 1 therapy. Older patients seem to tolerate immunotherapy as well as younger patients with comparable efficacy. This is a relevant message for everyday clinical practice. Introduction: Non-small-cell lung cancer (NSCLC) is predominantly a disease of the elderly population. Over the past few years, immunotherapy with monoclonal antibodies named checkpoint inhibitors (ICIs) greatly improved the clinical management of a significant proportion of patients with metastatic NSCLC. However, pivotal trials excluded older patients, although, given the favorable clinical profile of ICIs, this treatment may be revealed to be a most valuable option also for these patients. To this aim, a multicenter retrospective analysis was performed on patients aged >= 75 years with NSCLC treated with anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) immunotherapy. Material and Methods: Inclusion criteria were: diagnosis of locally advanced or metastatic NSCLC (stage IIIB or IV, according to the American Joint Committee on Cancer (AJCC) classification system, version 8.0); age >= 75 years; treatment with anti-PD-1/PD-L1 monoclonal antibodies in first or subsequent lines of treatment; absence of epidermal growth factor receptor-activating mutations or anaplastic lymphoma kinase and ROS-1 rearrangements. The primary endpoints of the study were the efficacy, in terms of overall response rate, progression-free survival, and overall survival, and safety, by means of evaluations of the incidence of immune-related adverse events. Results: Eighty-six patients were considered for the final analysis; 71 (82.6%) were male. The mean age was 78.5 years (range, 75-86 years; SD, 3.12 years). Of the 86 patients, 69 (80.2%) of patients had a performance status of 0 or 1. The overall median progression-free survival was 5.6 months (range 1-36 months; SD, 7.5 months,) whereas the median overall survival was 10.1 months (range, 1.7-34.8 months; SD, 8 months). At the Cox regression analysis, the only parameter significantly associated with survival was the smoking status (P =.008). No difference in survival was found between patients younger and older than 80 years. Conclusions: In the present real-world retrospective cohort, efficacy and toxicity profiles of ICIs in older patients with advanced NSCLC were comparable with those observed in younger patients enrolled in clinical trials. (C) 2020 Elsevier Inc. All rights reserved.

Small bowel adenocarcinomas (SBAs) are often associated with poor prognosis and have limited therapeutic options. Programmed cell death protein-1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway blockade is an effective treatment in many microsatellite instability-high (MSI-H) solid tumors. We aimed at investigating PD-L1 and PD-1 expression in non-hereditary, non-ampullary SBAs, associated with celiac disease (CeD), Crohn's disease (CrD), or sporadic, recruited through the Small Bowel Cancer Italian Consortium. We assessed PD-L1 and PD-1 by immunohistochemistry in a series of 121 surgically resected SBAs, including 34 CeD-SBAs, 49 CrD-SBAs, and 38 sporadic SBAs. PD-L1 and PD-1 expression was correlated with several clinico-pathological features, such as the etiology, microsatellite instability status, and tumor-infiltrating lymphocyte (TIL) density. The prevalence of PD-L1 positivity according to combined positive score (CPS) was 26% in the whole cohort of SBAs, with significantly (p = 0.001) higher percentage (35%) in both CeD-SBAs and CrD-SBAs in comparison with sporadic SBAs (5%). CPS ≥ 1 SBAs were significantly (p = 0.013) more frequent in MSI-H cases (41%) than in non-MSI-H ones (18%); however, 15 CPS ≥ 1 microsatellite stable SBAs were also identified. CPS ≥ 1 SBAs showed higher TIL and PD-1+ immune cell density, more frequently medullary histotype, as well as a better outcome in comparison with CPS < 1 cases. This study demonstrates an increased proportion of PD-L1+ cases in both CeD-SBAs and CrD-SBAs in comparison with sporadic SBAs. In addition, the identification of a subset of PD-L1+ microsatellite stable SBAs supports the need to ascertain additional biomarkers of response to immune checkpoint inhibitors along with MSI-H.

Pancreatic neuroendocrine carcinomas (NECs) are rare and very aggressive neoplasms with dismal prognosis, especially when metastatic or with negative prognostic factors, such as vascular invasion. To the best of our knowledge, no case of pancreatic NEC with mismatch repair deficiency has been reported to date. We describe a 62-year-old patient who underwent pancreaticoduodenectomy for a NEC located in the pancreatic head, with peripancreatic lymph node metastases. Tumor necrosis was prominent and the Ki67 proliferative index was 60%. One year after the diagnosis, the patient experienced recurrence with a left supraclavicular lymph node metastasis, which was surgically removed, followed by standard cisplatin-etoposide chemotherapy. Neoplastic cells showed combined loss of expression of MLH1 and PMS2 in both primary tumor and lymph node metastasis. Microsatellite instability (MSI) test using a mononucleotide repeats pentaplex PCR (BAT-25, BAT-26, NR-21, NR-22, and NR-24) revealed minimal mononucleotide shifts showing deletion of less than 3 bp at NR-21, BAT-26, NR-24, and NR-22 loci. MLH1 methylation analysis revealed absence of the gene promoter methylation. BRAF and KRAS mutations were not detected. In gut, NECs' mismatch repair deficiency phenotype has been reported in about 10% of cases, and it represents an independent factor of more favorable outcome. Likewise, our patient is currently alive with a follow-up of more than 12 years after pancreaticoduodenectomy, by itself an unexpected finding for such an aggressive neoplasm.

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.

Gastrointestinal stromal tumors are mesenchymal tumors arising in the stomach and small bowel and more rarely in the rectum, esophagus, peritoneum and retroperitoneum. These tumors are characterized by KIT or PDGFRA mutations. KIT mutations are all in frame and lead to constitutive tyrosine kinase domain activation without ligand binding. Mutations concern four exons (9, 11, 13 and 17) but mainly exon 11. In this work we report a case of a GIST patient with wild-type PDGFRA but bearing two mutations in KIT exon 9, i.e., the insertion mutation Y503_F504insAY and the missense mutation K509N. The patient was treated with Imatinib at standard regimen dose (400 mg/day), and responded well. Accordingly, in silico experiments were performed to disclose the effects exerted by these new mutations on the protein structure, its thermodynamic stability, and the ability to promote/interfere with Imatinib binding. Direct drug binding thermodynamics and kinetics of the mutant KIT were measured using isothermal titration calorimetry. FInally, in vitro kinase assays were performed to monitor the phosphorylation status of this new mutant KIT. The prototypical KIT mutations Δ559 and T670I were also analyzed in parallel for comparison. To our knowledge, only AY 502-503 duplication/insertion and K509I substitution have been previously reported. Citation Format: Erik Laurini, Suzana Aulic, Domenico Marson, Maurizio Fermeglia, Roberta Riboni, Marco Lucioni, Elena Dellera, Mario Alessiani, Vittorio Perfetti, Sabrina Pricl. New c-KIT mutations in GISTs: Bad for good [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 812.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. GISTs express the receptor tyrosine kinase KIT, and the majority of GISTs present KIT gain-of-function mutations that cluster in the 5' end of the receptor juxtamembrane domain. On the other hand, little information is known about GISTs carrying mutations in the 3' end of the KIT juxtamembrane domain. Here we report and discuss a clinical case of localized duodenal GIST whose molecular characterization revealed the presence of a new 21 nucleotide/7 amino acid deletion in the 3' end of KIT juxtamembrane domain (Δ574-580). The patient was treated with Imatinib at standard regimen dose (400 mg/day), and responded well as the original tumor mass reduced, ultimately allowing conservative surgery. In line with these clinical evidences computer simulations, biophysical techniques and in vitro experiments demonstrated that the receptor tyrosine kinase KIT carrying the Δ574-580 mutation displays constitutive phosphorylation, which can be switched-off upon Imatinib treatment. In addition, results from this study showed that a clinical useful procedure, neoadjuvant treatment, can occasionally be of value for the understanding of the molecular pathogenesis of GIST.

Background: An increased risk for small bowel carcinoma (SBC) has been reported in Crohn's disease (CrD). We aimed to explore clinical, histopathologic, molecular and prognostic features of CrD-associated SBC (CrD-SBC) in comparison to both coeliac disease (CD)-associated SBC (CD-SBC) and sporadic SBC (spo-SBC). Methods: Seventy-six patients, who underwent surgical resection for non-familial SBC (25 CrD-SBC26, CD-SBC and 25 spo-SBC), were retrospectively recorded to investigate survival together with histological and molecular features detected by immunohistochemistry, multiplex PCR and sequencing. Results: CD-SBC showed a significantly (p=0.004) better sex-, age- and stage-adjusted overall and cancer-specific survival in comparison to CrD-SBC, while no significant difference was found between spo-SBC and either CD-SBC or CrD-SBC. CD-SBC exhibited a significantly (p=0.001) higher rate of microsatellite instability (MSI, 65%) compared to both CrD-SBC (16%) and Spo-SBC (16%). The median number of tumor-infiltrating lymphocytes (TIL) correlated with MSI status and was significantly higher in CD-SBC than in both CrD-SBC (p<0.001) and spo-SBC (p=0.002). Among CD-SBC, MSI allowed to separate two subgroups with different outcome, stage and TP53 mutation rate. MSI was the result of MLH1 methylation in all cases (with the exception of one case of CrD-SBC). No BRAF mutation was observed in any SBC. Mutations in KRAS, NRAS, and PIK3CA were detected in 30%, 4% and 13% of cases, respectively. HER2 gene amplification was identified in two CD-SBC, two CrD-SBC and one spo-SBC. Conclusions: In comparison to CrD-SBC, CD-SBC harbor much more frequently MSI and show a more favorable prognosis, likely related to their high density of TILs, which have independent prognostic value in SBC. MSI status, KRAS/NRAS mutations and HER2 amplifications might contribute to stratify patients for targeted anti-cancer therapy.

AIMS:The knowledge of the mechanism underlying the cardiac damage in immunoglobulin light chain (LC) amyloidosis (AL) is essential to develop novel therapies and improve patients' outcome. Although an active role of reactive oxygen species (ROS) in LC-induced cardiotoxicity has already been envisaged, the actual mechanisms behind their generation remain elusive. This study was aimed at further dissecting the action of ROS generated by cardiotoxic LC in vivo and investigating whether transition metal ions are involved in this process. In the absence of reliable vertebrate model of AL, we used the nematode Caenorhabditis elegans, whose pharynx is an "ancestral heart."RESULTS:LC purified from patients with severe cardiac involvement intrinsically generated high levels of ROS and when administered to C. elegans induced ROS production, activation of the DAF-16/forkhead transcription factor (FOXO) pathway, and expression of proteins involved in stress resistance and survival. Profound functional and structural ROS-mediated mitochondrial damage, similar to that observed in amyloid-affected hearts from AL patients, was observed. All these effects were entirely dependent on the presence of metal ions since addition of metal chelator or metal-binding 8-hydroxyquinoline compounds (chelex, PBT2, and clioquinol) permanently blocked the ROS production and prevented the cardiotoxic effects of amyloid LC. Innovation and Conclusion: Our findings identify the key role of metal ions in driving the ROS-mediated toxic effects of LC. This is a novel conceptual advance that paves the way for new pharmacological strategies aimed at not only counteracting but also totally inhibiting the vicious cycle of redox damage. Antioxid. Redox Signal. 27, 567-582.

Background and AimsAn increased risk of small bowel carcinoma [SBC] has been reported in coeliac disease [CD] and Crohn's disease [CrD]. We explored clinico-pathological, molecular, and prognostic features of CD-associated SBC [CD-SBC] and CrD-associated SBC [CrD-SBC] in comparison with sporadic SBC [spo-SBC].MethodsA total of 76 patients undergoing surgical resection for non-familial SBC [26 CD-SBC, 25 CrD-SBC, 25 spo-SBC] were retrospectively enrolled to investigate patients' survival and histological and molecular features including microsatellite instability [MSI] and KRAS/NRAS, BRAF, PIK3CA, TP53, HER2 gene alterations.ResultsCD-SBC showed a significantly better sex-, age-, and stage-adjusted overall and cancer-specific survival than CrD-SBC, whereas no significant difference was found between spo-SBC and either CD-SBC or CrD-SBC. CD-SBC exhibited a significantly higher rate of MSI and median tumour-infiltrating lymphocytes [TIL] than CrD-SBC and spo-SBC. Among the whole SBC series, both MSI─which was the result of MLH1 promoter methylation in all but one cases─and high TIL density were associated with improved survival at univariable and stage-inclusive multivariable analysis. However, only TILs retained prognostic power when clinical subgroups were added to the multivariable model. KRAS mutation and HER2 amplification were detected in 30% and 7% of cases, respectively, without prognostic implications.ConclusionsIn comparison with CrD-SBC, CD-SBC patients harbour MSI and high TILs more frequently and show better outcome. This seems mainly due to their higher TIL density, which at multivariable analysis showed an independent prognostic value. MSI/TIL status, KRAS mutations and HER2 amplification might help in stratifying patients for targeted anti-cancer therapy.

Refractory celiac disease is characterized by mucosal damage in patients with celiac disease despite a gluten-free diet. Little is known about the mechanisms that cause persistent intestinal inflammation in these patients. We performed a case-control study of 17 consecutive patients diagnosed with refractory celiac disease from 2001 through 2014 (median age, 51 y; 10 women) and 24 patients with uncomplicated celiac disease (controls) to determine whether refractory disease is associated with infection by lymphotropic oncogenic viruses. We performed real-time PCR analyses of duodenal biopsy samples from all patients to detect Epstein-Barr virus (EBV), human herpesvirus-8, and human T-cell lymphotropic virus-I, -II, or -III. We used in situ hybridization and immunohistochemical analyses to identify infected cells and viral proteins. We did not detect human herpesvirus-8 or human T-cell lymphotropic viruses in any of the biopsy specimens. However, 12 of 17 (70.5%) biopsy specimens from patients with refractory celiac disease were positive for EBV, compared with 4 of 24 (16.6%) biopsy specimens from controls (P<.001). EBV was detected in inflammatory cells and enterocytes. An analysis of latency- and replication-associated proteins confirmed active infection. Further studies are needed to determine whether EBV infection contributes to the pathogenesis of refractory celiac disease and enteropathy-associated T-cell lymphoma.

Introduction: Abnormal PI3K–Akt–mTOR pathway, mediated through insulin-like growth factor 1 (IGF1), is involved in the proliferation of pNET cells. In phase III trials, both everolimus (EVE), an inhibitor of mTOR pathway, and somatostatin analogues (SA) have shown antitumor efficacy in pNETs. Several studies have identified diabetic patients (pts) as having increased risk for the development of cancer and have associated metformin (MET) treatment with a decrease of cancer risk. MET may have anti-proliferative activity due to its ability to decrease insulin and IGF1 levels; in addition, it promotes AMPK activation and TSC1-2/mTOR inhibition. This multicentric, retrospective study evaluates the impact of glycemic status (hyper vs normoglycemic pts) on progression-free survival (PFS); the impact of concomitant MET administered during EVE and/or SA therapy in diabetic pNETs is also assessed.Methods: In order to obtain a 90% statistical power, with a error 0.05, and to detect an Hazard Ratio of progression (PD) of 0.67 for hyperglycemic vs normoglycemic pts, 267 events (PD or deaths without PD) were needed, 445 pts were planned. With these numbers, 77% power was anticipated to detect HR 0.67 in each subgroup analysis (hyperglycemic pts on MET vs normoglycemic and hyperglycemic pts on INS vs normoglycemic pts).Results: Between 1999 and 2016, 445 pts (median age 59, range 49-69; 53.5% males), were treated with EVE and/or SA in 24 Italian Centers. In total, 112 (25.2%) diabetic pts received MET, 91 (20.4%) received INS and 33 (7.7%) received dietetic counseling; 209 (46.7%) pts were normoglycemic. In the overall population, median PFS was 23.4 months (mo) (95%CI 19.1–27.9); mPFS was 32.0 mo in diabetic pts and 15.1 mo in normoglycemic pts (HR 0.63, 95%CI 0.50-0.80; p = 0.0002). Median PFS was 20.8 mo (95%CI 15.6-36.3) in pts receving INS (HR vs normoglycemic pts 0.81, 95%CI 0.60-1.1, p = 0.18) and 44.2 mo (95%CI 36.4-61.9) in pts on MET (HR vs normoglycemic pts 0.45, 95%CI 0.32-0.62, p < 0.0001).Conclusions: With the limitations of any retrospective analysis, the results of this large study may suggest that the addition of MET to EVE and/or SA can provide clinical benefits in advanced diabetic pNETs pts. Prospective evaluations are required to either confirm or discard these preliminary findings. Introduction: Abnormal PI3K–Akt–mTOR pathway, mediated through insulin-like growth factor 1 (IGF1), is involved in the proliferation of pNET cells. In phase III trials, both everolimus (EVE), an inhibitor of mTOR pathway, and somatostatin analogues (SA) have shown antitumor efficacy in pNETs. Several studies have identified diabetic patients (pts) as having increased risk for the development of cancer and have associated metformin (MET) treatment with a decrease of cancer risk. MET may have anti-proliferative activity due to its ability to decrease insulin and IGF1 levels; in addition, it promotes AMPK activation and TSC1-2/mTOR inhibition. This multicentric, retrospective study evaluates the impact of glycemic status (hyper vs normoglycemic pts) on progression-free survival (PFS); the impact of concomitant MET administered during EVE and/or SA therapy in diabetic pNETs is also assessed. Methods: In order to obtain a 90% statistical power, with a error 0.05, and to detect an Hazard Ratio of progression (PD) of 0.67 for hyperglycemic vs normoglycemic pts, 267 events (PD or deaths without PD) were needed, 445 pts were planned. With these numbers, 77% power was anticipated to detect HR 0.67 in each subgroup analysis (hyperglycemic pts on MET vs normoglycemic and hyperglycemic pts on INS vs normoglycemic pts). Results: Between 1999 and 2016, 445 pts (median age 59, range 49-69; 53.5% males), were treated with EVE and/or SA in 24 Italian Centers. In total, 112 (25.2%) diabetic pts received MET, 91 (20.4%) received INS and 33 (7.7%) received dietetic counseling; 209 (46.7%) pts were normoglycemic. In the overall population, median PFS was 23.4 months (mo) (95%CI 19.1–27.9); mPFS was 32.0 mo in diabetic pts and 15.1 mo in normoglycemic pts (HR 0.63, 95%CI 0.50-0.80; p = 0.0002). Median PFS was 20.8 mo (95%CI 15.6-36.3) in pts receving INS (HR vs normoglycemic pts 0.81, 95%CI 0.60-1.1, p = 0.18) and 44.2 mo (95%CI 36.4-61.9) in pts on MET (HR vs normoglycemic pts 0.45, 95%CI 0.32-0.62, p < 0.0001). Conclusions: With the limitations of any retrospective analysis, the results of this large study may suggest that the addition of MET to EVE and/or SA can provide clinical benefits in advanced diabetic pNETs pts. Prospective evaluations are required to either confirm or discard these preliminary findings.

Background: GISTs are rare mesenchymal tumors of the GI tract. Surgery is of choice in localized disease, and neoadjuvant treatment with imatinib (a tyrosine kinase inhibitor, TKI) is increasingly applied. Indeed, 90% of GISTs have a gain-of-function somatic alteration in the proto oncogene KIT. Exon 11 is the most frequently involved. Detection of mutations in GIST is critical for targeted therapy since patients respond differently to TKI, depending on the specific mutations displayed by their tumors. We report a new imatinib-sensitive mutation in exon 11 in a duodenal GIST who underwent neoadjuvant treatment. Case description, c-KIT sequencing: a 35-y old male presented with melena and an ulcerated GIST (fine needle biopsy, 3.4x2.2x3.1 cm) at the II duodenal tract (medial aspect of the duodenal wall, immediately distal to the papilla and exteding to nearby pancreas). The lesion was amenable with pancreaticoduodenectomy and displayed contact with cava inferior. Neoadjuvant treatment was started with complete metabolic response (PET-FDG negative at + 30d). Segmental duodenal resection distally to the papilla was performed 6 months later when NMR showed substantial size reduction and no blood vessel contacts. Molecular studies revealed a new exon 11 deletion (p.T574_H580delTQLPYDH) in the functional domain of c-KIT. Conclusions: Neoadjuvant treatment allowed conservative surgery as well as to demonstrate imatinib sensitivity of a new exon 11 c-Kit-deletion. This case underlies the clinical and scientific relevance of this procedure and of the molecular characterization of GIST.