Publications by authors named "Sara Cingarlini"

54 Publications

Merkel Cell Carcinoma: Evaluation of the Clinico-Pathological Characteristics, Treatment Strategies and Prognostic Factors in a Monocentric Retrospective Series (n=143).

Front Oncol 2021 17;11:737842. Epub 2021 Dec 17.

Independent Statistician, Solagna, Italy.

Background: Merkel cell carcinoma (MCC) is a rare neuroendocrine tumor of the skin. The incidence of the disease has undergone a significant increase in recent years, which is caused by an increase in the average age of the population and in the use of immunosuppressive therapies. MCC is an aggressive pathology, which metastasizes early to the lymph nodes. These characteristics impose an accurate diagnostic analysis of the regional lymph node district with radiography, clinical examination and sentinel node biopsy. In recent years, there has been a breakthrough in the treatment of the advanced pathology thanks to the introduction of monoclonal antibodies acting on the PD-1/PD-L1 axis. This study aimed to describe the clinico-pathological characteristics, treatment strategies and prognostic factors of MCC.

Methods: A retrospective cohort study was conducted involving 143 consecutive patients who were diagnosed and/or treated for MCC. These patients were referred to the Veneto Institute of Oncology IOV-IRCCS and to the University Hospital of Padua (a third-level center) in the period between December 1991 and January 2020. In the majority of cases, diagnosis took place at the IOV. However, some patients were diagnosed elsewhere and subsequently referred to the IOV for a review of the diagnosis or to begin specific therapeutic regimens.

Results: 143 patients, with an average age of 71 years, were affected mainly with autoimmune and neoplastic comorbidities. Our analysis has shown that age, autoimmune comorbidities and the use of therapy with immunomodulating drugs (which include corticosteroids, statins and beta-blockers) are associated with a negative prognosis. In this sense, male sex is also a negative prognostic factor.

Conclusions: Autoimmune and neoplastic comorbidities were frequent in the studied population. The use of drugs with immunomodulatory effects was also found to be a common feature of the population under examination. The use of this type of medication is considered a negative prognostic factor. The relevance of a multidisciplinary approach to the patient with MCC is confirmed, with the aim of assessing the risks and benefits related to the use of immunomodulating therapy in the individual patient.
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http://dx.doi.org/10.3389/fonc.2021.737842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8718393PMC
December 2021

Is the Morphological Subtype of Extra-Pulmonary Neuroendocrine Carcinoma Clinically Relevant?

Cancers (Basel) 2021 Aug 18;13(16). Epub 2021 Aug 18.

Division of Cancer Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester M13 9PL, UK.

Extra-pulmonary neuroendocrine carcinomas (EP-NECs) are lethal cancers with limited treatment options. Identification of contributing factors to the observed heterogeneity of clinical outcomes within the EP-NEC family is warranted, to enable identification of effective treatments. A multicentre retrospective study investigated potential differences in "real-world" treatment/survival outcomes between small-cell (SC) versus (vs.) non-SC EP-NECs. One-hundred and seventy patients were included: 77 (45.3%) had SC EP-NECs and 93 (54.7%) had non-SC EP-NECs. Compared to the SC subgroup, the non-SC subgroup had the following features: (1) a lower mean Ki-67 index (69.3% vs. 78.7%; = 0.002); (2) a lower proportion of cases with a Ki-67 index of ≥55% (73.9% vs. 88.7%; = 0.025); (3) reduced sensitivity to first-line platinum/etoposide (objective response rate: 31.6% vs. 55.1%, = 0.015; and disease control rate; 59.7% vs. 79.6%, = 0.027); (4) worse progression-free survival (PFS) (adjusted-HR = 1.615, = 0.016) and overall survival (OS) (adjusted-HR = 1.640, = 0.015) in the advanced setting. Within the advanced EP-NEC cohort, subgroups according to morphological subtype and Ki-67 index (<55% vs. ≥55%) had significantly different PFS (adjusted- = 0.021) and OS (adjusted- = 0.051), with the non-SC subgroup with a Ki-67 index of <55% and non-SC subgroup with a Ki-67 index of ≥55% showing the best and worst outcomes, respectively. To conclude, the morphological subtype of EP-NEC provides complementary information to the Ki-67 index and may aid identification of patients who could benefit from alternative first-line treatment strategies to platinum/etoposide.
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http://dx.doi.org/10.3390/cancers13164152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8392018PMC
August 2021

Alternative Lengthening of Telomeres (ALT) in Pancreatic Neuroendocrine Tumors: Ready for Prime-Time in Clinical Practice?

Curr Oncol Rep 2021 07 16;23(9):106. Epub 2021 Jul 16.

Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, 37134, Verona, Italy.

Purpose Of Review: Alternative lengthening of telomeres (ALT) is a telomerase-independent mechanism used by some types of malignancies, including pancreatic neuroendocrine tumors, to overcome the issue of telomere shortening, thus supporting tumor growth and cell proliferation. This review is focused on the most important achievements and opportunities deriving from ALT assessment in PanNET onco-pathology, highlighting the most promising fields in which such biomarker could be implemented in clinical practice.

Recent Findings: In pancreatic neuroendocrine tumors (PanNET), ALT is strongly correlated with the mutational status of two chromatin remodeling genes, DAXX and ATRX. Recent advances in tumor biology permitted to uncover important roles of ALT in the landscape of PanNET, potentially relevant for introducing this biomarker into clinical practice. Indeed, ALT emerged as a reliable indicator of worse prognosis for PanNET, helping in clinical stratification and identification of "high-risk" patients. Furthermore, it is a very specific marker supporting the pancreatic origin of neuroendocrine neoplasms and can be used for improving the diagnostic workflow of patients presenting with neuroendocrine metastasis from unknown primary. The activation of this process can be determined by specific FISH analysis. ALT should be introduced in clinical practice for identifying "high-risk" PanNET patients and improving their clinical management, and as a marker of pancreatic origin among neuroendocrine tumors.
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http://dx.doi.org/10.1007/s11912-021-01096-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285324PMC
July 2021

Non-functional pancreatic neuroendocrine tumours: ATRX/DAXX and alternative lengthening of telomeres (ALT) are prognostically independent from ARX/PDX1 expression and tumour size.

Gut 2021 Apr 13. Epub 2021 Apr 13.

Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

Objective: Recent studies have found aristaless-related homeobox gene (ARX)/pancreatic and duodenal homeobox 1 (PDX1), alpha-thalassemia/mental retardation X-linked (ATRX)/death domain-associated protein (DAXX) and alternative lengthening of telomeres (ALT) to be promising prognostic biomarkers for non-functional pancreatic neuroendocrine tumours (NF-PanNETs). However, they have not been comprehensively evaluated, especially among small NF-PanNETs (≤2.0 cm). Moreover, their status in neuroendocrine tumours (NETs) from other sites remains unknown.

Design: An international cohort of 1322 NETs was evaluated by immunolabelling for ARX/PDX1 and ATRX/DAXX, and telomere-specific fluorescence in situ hybridisation for ALT. This cohort included 561 primary NF-PanNETs, 107 NF-PanNET metastases and 654 primary, non-pancreatic non-functional NETs and NET metastases. The results were correlated with numerous clinicopathological features including relapse-free survival (RFS).

Results: ATRX/DAXX loss and ALT were associated with several adverse prognostic findings and distant metastasis/recurrence (p<0.001). The 5-year RFS rates for patients with ATRX/DAXX-negative and ALT-positive NF-PanNETs were 40% and 42% as compared with 85% and 86% for wild-type NF-PanNETs (p<0.001 and p<0.001). Shorter 5-year RFS rates for ≤2.0 cm NF-PanNETs patients were also seen with ATRX/DAXX loss (65% vs 92%, p=0.003) and ALT (60% vs 93%, p<0.001). By multivariate analysis, ATRX/DAXX and ALT status were independent prognostic factors for RFS. Conversely, classifying NF-PanNETs by ARX/PDX1 expression did not independently correlate with RFS. Except for 4% of pulmonary carcinoids, ATRX/DAXX loss and ALT were only identified in primary (25% and 29%) and NF-PanNET metastases (62% and 71%).

Conclusions: ATRX/DAXX and ALT should be considered in the prognostic evaluation of NF-PanNETs including ≤2.0 cm tumours, and are highly specific for pancreatic origin among NET metastases of unknown primary.
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http://dx.doi.org/10.1136/gutjnl-2020-322595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511349PMC
April 2021

Laparoscopic intragastric resection of gastric synovial sarcoma: report of the first ever case with video demonstration.

World J Surg Oncol 2021 Mar 1;19(1):65. Epub 2021 Mar 1.

Unit of General and Hepatobiliary Surgery, Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, Verona University, Verona, Italy.

Background: Synovial sarcoma (SS) is a rare soft tissue tumor. Among different anatomical locations where it can be found, gastric localization is a very uncommon one. Based on soft tissue sarcoma guidelines, complete tumor excision is considered the main treatment approach. Depending on size and localization of the tumor, both wedge and major gastric resections have been performed in the past for the treatment of this condition.

Case Presentation: We present the case of a 43-year-old woman who underwent a laparoscopic intragastric excision of a gastric 10-mm SS located nearby the esophagogastric junction. Pathology examination confirmed the presence of a SS. The resected specimen confirmed margin-free excision of a monophasic spindle cell neoplasm invading the submucosa and presenting the rearrangement of SS18 gene at fluorescence in situ hybridization (FISH). No adjuvant treatment was offered, and 18 months after surgery, the patient was alive and disease free.

Conclusions: This represents the first case reported in literature of a laparoscopic intragastric resection for a gastric SS. This approach allowed to obtain a full thickness radical tumor resection with the advantages of minimally invasive and organ preserving surgery.
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http://dx.doi.org/10.1186/s12957-021-02172-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923835PMC
March 2021

Platinum-Based Treatment for Well- and Poorly Differentiated Pancreatic Neuroendocrine Neoplasms.

Pancreas 2021 02;50(2):138-146

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.

Objectives: Pancreatic neuroendocrine neoplasms include well-differentiated tumors (PanNETs) and poorly differentiated carcinomas (PanNECs). Previous reports suggested a role for platinum-based therapy largely in PanNEC. We sought to investigate the role of platinum-based therapy in pancreatic neuroendocrine neoplasms regardless of tumor grade and differentiation.

Methods: Patients with pancreatic neuroendocrine neoplasms treated with platinum-based therapy at Memorial Sloan Kettering (1994-2016) and Verona University Hospital (2008-2016) were retrospectively identified. Response to treatment by RECIST v1.1, overall survival, and progression-free survival were defined. Among patients with available tissue, DAXX, ATRX, Rb, and p53 expression was evaluated to support the histologic grade of differentiation.

Results: Fifty PanNETs, 29 PanNECs, and 22 high-grade tumors with undeterminable differentiation were included. No patients achieved complete response. Overall rate of partial response was 31%, 41% for PanNEC, and 20% for PanNETs. Among PanNETs, partial response was achieved in 33% of G1 (2/6), 10% of G2 (2/19), and 24% of G3 (6/25) tumors. Median overall survival was 29.3 months for PanNETs and 10.9 months for PanNEC (P < 0.001). There was no significant difference in median progression-free survival (P = 0.2).

Conclusions: Platinum-based therapies demonstrated increased activity in PanNEC; however, promising efficacy was also observed in PanNETs, irrespective of grade.
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http://dx.doi.org/10.1097/MPA.0000000000001740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880539PMC
February 2021

DNA methylation patterns identify subgroups of pancreatic neuroendocrine tumors with clinical association.

Commun Biol 2021 02 3;4(1):155. Epub 2021 Feb 3.

University of Sydney, Sydney, New South Wales, 2006, Australia.

Here we report the DNA methylation profile of 84 sporadic pancreatic neuroendocrine tumors (PanNETs) with associated clinical and genomic information. We identified three subgroups of PanNETs, termed T1, T2 and T3, with distinct patterns of methylation. The T1 subgroup was enriched for functional tumors and ATRX, DAXX and MEN1 wild-type genotypes. The T2 subgroup contained tumors with mutations in ATRX, DAXX and MEN1 and recurrent patterns of chromosomal losses in half of the genome with no association between regions with recurrent loss and methylation levels. T2 tumors were larger and had lower methylation in the MGMT gene body, which showed positive correlation with gene expression. The T3 subgroup harboured mutations in MEN1 with recurrent loss of chromosome 11, was enriched for grade G1 tumors and showed histological parameters associated with better prognosis. Our results suggest a role for methylation in both driving tumorigenesis and potentially stratifying prognosis in PanNETs.
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http://dx.doi.org/10.1038/s42003-020-01469-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859232PMC
February 2021

Dual-Tracer (68Ga-DOTATOC and 18F-FDG-)-PET/CT Scan and G1-G2 Nonfunctioning Pancreatic Neuroendocrine Tumors: A Single-Center Retrospective Evaluation of 124 Nonmetastatic Resected Cases.

Neuroendocrinology 2021 Jan 28. Epub 2021 Jan 28.

Pancreas Institute, General and Pancreatic Surgery Unit, University of Verona Hospital Trust, Verona, Italy.

Introduction: The combined use of 68gallium (68Ga)-DOTA-peptides and 18fluorine-fluoro-2-deoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) scans in the workup of pancreatic neuroendocrine tumors (PanNETs) is controversial. This study aimed at assessing both tracers' capability to identify tumors and to assess its association with pathological predictors of recurrence.

Methods: Prospectively collected, preoperative, dual-tracer PET/CT scan data of G1-G2, nonmetastatic, PanNETs that underwent surgery between January 2013 and October 2019 were retrospectively analyzed.

Results: The final cohort consisted of 124 cases. There was an approximately equal distribution of males and females (50.8%/49.2%) and G1 and G2 tumors (49.2%/50.8%). The disease was detected in 122 (98.4%) and 64 (51.6%) cases by 68Ga-DOTATOC and by 18F-FDG PET/CT scans, respectively, with a combined sensitivity of 99.2%. 18F-FDG-positive examinations found G2 tumors more often than G1 (59.4 vs. 40.6%; p = 0.036), and 18F-FDG-positive PanNETs were larger than negative ones (median tumor size 32 mm, interquartile range [IQR] 21 vs. 26 mm, IQR 20; p = 0.019). The median Ki67 for 18F-FDG-positive and -negative examinations was 3 (IQR 4) and 2 (IQR 4), respectively (p = 0.029). At least 1 pathological predictor of recurrence was present in 74.6% of 18F-FDG-positive cases (vs. 56.7%; p = 0.039), whereas this was not found when dichotomizing the PanNETs by their dimensions (≤/>20 mm). None of the 2 tracers predicted nodal metastasis. The receiver operating characteristic curve analysis showed that 18F-FDG uptake higher than 4.2 had a sensitivity of 49.2% and specificity of 73.3% for differentiating G1 from G2 (AUC = 0.624, p = 0.009).

Conclusion: The complementary adoption of 68Ga-DOTATOC and 18F-FDG tracers may be valuable in the diagnostic workup of PanNETs despite not being a game-changer for the management of PanNETs ≤20 mm.
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http://dx.doi.org/10.1159/000514809DOI Listing
January 2021

Immune landscape, evolution, hypoxia-mediated viral mimicry pathways and therapeutic potential in molecular subtypes of pancreatic neuroendocrine tumours.

Gut 2021 10 3;70(10):1904-1913. Epub 2020 Sep 3.

Division of Molecular Pathology, Institute of Cancer Research, London, UK

Objective: A comprehensive analysis of the immune landscape of pancreatic neuroendocrine tumours (PanNETs) was performed according to clinicopathological parameters and previously defined molecular subtypes to identify potential therapeutic vulnerabilities in this disease.

Design: Differential expression analysis of 600 immune-related genes was performed on 207 PanNET samples, comprising a training cohort (n=72) and two validation cohorts (n=135) from multiple transcriptome profiling platforms. Different immune-related and subtype-related phenotypes, cell types and pathways were investigated using different in silico methods and were further validated using spatial multiplex immunofluorescence.

Results: The study identified an immune signature of 132 genes segregating PanNETs (n=207) according to four previously defined molecular subtypes: metastasis-like primary (MLP)-1 and MLP-2, insulinoma-like and intermediate. The MLP-1 subtype (26%-31% samples across three cohorts) was strongly associated with elevated levels of immune-related genes, poor prognosis and a cascade of tumour evolutionary events: larger hypoxic and necroptotic tumours leading to increased damage-associated molecular patterns (viral mimicry), stimulator of interferon gene pathway, T cell-inflamed genes, immune checkpoint targets, and T cell-mediated and M1 macrophage-mediated immune escape mechanisms. Multiplex spatial profiling validated significantly increased macrophages in the MLP-1 subtype.

Conclusion: This study provides novel data on the immune microenvironment of PanNETs and identifies MLP-1 subtype as an immune-high phenotype featuring a broad and robust activation of immune-related genes. This study, with further refinement, paves the way for future precision immunotherapy studies in PanNETs to potentially select a subset of MLP-1 patients who may be more likely to respond.
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http://dx.doi.org/10.1136/gutjnl-2020-321016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8458094PMC
October 2021

Pattern of disease recurrence and treatment after surgery for nonfunctioning well-differentiated pancreatic neuroendocrine tumors.

Surgery 2020 Nov 8;168(5):816-824. Epub 2020 Aug 8.

Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, San Raffaele Hospital Neuroendocrine Tumor Group (ENETS Center of Excellence), IRCCS San Raffaele Scientific Institute, "Vita-Salute San Raffaele" University, Milan, Italy. Electronic address:

Background: The risk of recurrence after curative surgery for pancreatic neuroendocrine tumors is reported to be between 10% and 30%. Among the available locoregional and systemic treatments, there are no specific recommendations regarding the best option for treating recurrent disease. The aims of this study were to evaluate the pattern of recurrence after surgery performed with curative intent for nonfunctioning pancreatic neuroendocrine tumors and to analyze the impact of treatment on disease progression.

Methods: All patients submitted to curative surgery for sporadic, well-differentiated, nonfunctioning pancreatic neuroendocrine tumors at 2 Italian centers between 2001 and 2018, with evidence of disease recurrence during follow-up, were included (n = 46).

Results: The most frequent type of recurrence was distant metastases (n = 38, 83%), located in the liver in 100% of cases, whereas 8 patients (17%) had an isolated local recurrence. Therapy for first disease recurrence included both locoregional (n = 14) and systemic treatments (n = 32). A second disease recurrence/progression occurred in 28 patients (61%). Patients who underwent systemic treatment after the first disease recurrence had better progression-free survival (1-year progression-free survival 78%) compared with those submitted to a locoregional procedure (1-year progression-free survival 50%; P = .007). Independent predictors of shortened progression-free survival after the first disease recurrence were the type of treatment (locoregional, hazard ratio 4.452, P = .001), the presence of necrosis (hazard ratio 2.732, P = .022) and age (>60 year, hazard ratio 2.494, P = .040).

Conclusion: Upfront locoregional treatment of the first recurrence of nonfunctioning pancreatic neuroendocrine tumors after curative surgery should be avoided in favor of systemic therapy.
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http://dx.doi.org/10.1016/j.surg.2020.06.034DOI Listing
November 2020

Organisational challenges, volumes of oncological activity and patients' perception during the severe acute respiratory syndrome coronavirus 2 epidemic.

Eur J Cancer 2020 08 11;135:159-169. Epub 2020 Jun 11.

Section of Oncology, Department of Medicine, University of Verona School of Medicine and Verona University Hospital Trust, Verona, Italy. Electronic address:

Background: On February 23rd, the 1st case of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was diagnosed at the University Hospital Trust of Verona, Italy. On March 13th, the Oncology Section was converted into a 22-inpatient bed coronavirus disease (COVID) Unit, and we reshaped our organisation to face the SARS-CoV-2 epidemic, while maintaining oncological activities.

Methods: We tracked down (i) volumes of oncological activities (January 1st - March 31st, 2020 versus the same period of 2019), (ii) patients' and caregivers' perception and (iii) SARS-CoV-2 infection rate in oncology health professionals and SARS-CoV-2 infection-related hospital admissions of "active"' oncological patients.

Results: As compared with the same trimester in 2019, the overall reduction in total numbers of inpatient admissions, chemotherapy administrations and specialist visits in January-March 2020 was 8%, 6% and 3%, respectively; based on the weekly average of daily accesses, reduction in some of the oncological activities became statistically significant from week 11. The overall acceptance of adopted measures, as measured by targeted questionnaires administered to a sample of 241 outpatients, was high (>70%). Overall, 8 of 85 oncology health professionals tested positive for SARS-CoV-2 infection (all but one employed in the COVID Unit, no hospital admissions and no treatment required); among 471 patients admitted for SARS-CoV-2 infection, 7 had an "active"' oncological disease (2 died of infection-related complications).

Conclusions: A slight, but statistically significant reduction in oncology activity was registered during the SARS-CoV-2 epidemic peak in Verona, Italy. Organisational and protective measures adopted appear to have contributed to keep infections in both oncological patients and health professionals to a minimum.
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http://dx.doi.org/10.1016/j.ejca.2020.05.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287451PMC
August 2020

Liver Tumor Burden in Pancreatic Neuroendocrine Tumors: CT Features and Texture Analysis in the Prediction of Tumor Grade and F-FDG Uptake.

Cancers (Basel) 2020 Jun 7;12(6). Epub 2020 Jun 7.

Department of Radiology, G.B. Rossi Hospital, University of Verona, 37134 Verona, Italy.

Pancreatic neuroendocrine tumors (p-NETs) are a rare group of neoplasms that often present with liver metastases. Histological characteristics, metabolic behavior, and liver tumor burden (LTB) are important prognostic factors. In this study, the usefulness of texture analysis of liver metastases in evaluating the biological aggressiveness of p-NETs was assessed. Fifty-six patients with liver metastases from p-NET were retrospectively enrolled. Qualitative and quantitative CT features of LTB were evaluated. Histogram-derived parameters of liver metastases were calculated and correlated with the tumor grade (G) and F-fluorodeoxyglucose (F-FDG) standardized uptake value (SUV). Arterial relative enhancement was inversely related with G (-0.37, = 0.006). Different metastatic spread patterns of LTB were not associated with histological grade. Arterial was significantly correlated to G (-0.368, = 0.038) and to Ki67 percentage (-0.421, = 0.018). The ROC curve for the Arterial reported an area under the curve (AUC) of 0.736 (95% confidence interval 0.545-0.928, = 0.035) in the identification of G1-2 tumors. Arterial values were correlated to G (0.346, = 0.005) and Ki67 levels (0.383, = 0.033). Arterial values were directly correlated with the SUV (0.449, = 0.047) which was inversely correlated with Arterial (-0.499, = 0.025). Skewness and kurtosis reported no significant correlations. In conclusion, histogram-derived parameters may predict adverse histological features and metabolic behavior of p-NET liver metastases.
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http://dx.doi.org/10.3390/cancers12061486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352332PMC
June 2020

Endoscopic ultrasound-guided fine-needle aspiration for the diagnosis and grading of pancreatic neuroendocrine tumors: a retrospective analysis of 110 cases.

Endoscopy 2020 11 4;52(11):988-994. Epub 2020 Jun 4.

General and Pancreatic Surgery Unit, Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy.

Background: Data on the reliability of the Ki-67 index and grading calculations from endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) of pancreatic neuroendocrine tumors (PanNETs) are controversial. We aimed to assess the accuracy of these data compared with histology.

Methods: Cytological analysis from EUS-FNA in patients with suspected PanNETs (n = 110) were compared with resection samples at a single institution. A minimum of 2000 cells were considered to be adequate for grading. Correlation and agreement between cytology and histology in grading and Ki-67 values, respectively, were investigated. Secondary outcomes included the diagnostic performance of EUS-FNA.

Results: EUS-FNA samples were adequate for PanNET diagnosis and PanNET grading in 98/110 (89.1 %) and 77/110 (70.0 %) patients, respectively; thus, 77 samples were adequate for comparing cytology vs. histology. There were 67 (62.0 %), 40 (36.4 %), and 1 (0.9 %) patients with a final diagnosis of G1, G2, and G3 tumors, respectively. EUS-FNA grading was concordant with surgical pathology in 81.8 % of patients; under- and overgrading occurred in 15.6 % and 2.6 %, respectively. The overall level of agreement for grading was moderate (Cohen's κ = 0.59, 95 % confidence interval [CI] 0.34 - 0.78). Spearman's rho for Ki-67 in tumors ≤ 20 mm and > 20 mm was strong and moderate, respectively (rho = 0.68, 95 %CI 0.47 - 0.83; rho = 0.59, 95 %CI 0.35 - 0.75). The Bland - Altman plot showed that the Ki-67 values were comparable and reproducible between the two measurements.

Conclusions: Although they were not available for a significant number of patients, grading and Ki-67 values from cytology correlated with histology moderately to strongly.
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http://dx.doi.org/10.1055/a-1180-8614DOI Listing
November 2020

Multi-institutional Development and External Validation of a Nomogram to Predict Recurrence After Curative Resection of Pancreatic Neuroendocrine Tumors.

Ann Surg 2021 12;274(6):1051-1057

Unit of General and Pancreatic Surgery, University and Hospital Trust of Verona, Italy.

Objective: To develop a nomogram estimating the probability of recurrence free at 5 years after resection for localized grade 1 (G1)/ grade 2 (G2) pancreatic neuroendocrine tumors (PanNETs).

Background: Among patients undergoing resection of PanNETs, approximately 17% experience recurrence. It is not established which patients are at risk, with no consensus on optimal follow-up.

Method: A multi-institutional database of patients with G1/G2 PanNETs treated at 2 institutions was used to develop a nomogram estimating the rate of freedom from recurrence at 5 years after curative resection. A second cohort of patients from 3 additional institutions was used to validate the nomogram. Prognostic factors were assessed by univariate analysis using Cox regression model. The nomogram was internally validated using bootstrap resampling method and on the external cohort. Performance was assessed by concordance index (c-index) and a calibration curve.

Results: The nomogram was constructed using a cohort of 632 patients. Overall, 68% of PanNETs were G1, the median follow-up was 51 months, and we observed 74 recurrences. Variables included in the nomogram were the number of positive nodes, tumor diameter, Ki-67, and vascular/perineural invasion. The model bias-corrected c-index from the internal validation was 0.85, which was higher than European Neuroendocrine Tumors Society/ American Joint Committee on Cancer 8th staging scheme (c-index 0.76, P = <0.001). On the external cohort of 328 patients, the nomogram c-index was 0.84 (95% confidence interval 0.79-0.88).

Conclusion: Our externally validated nomogram predicts the probability of recurrence-free survival at 5 years after PanNETs curative resection, with improved accuracy over current staging systems. Estimating individual recurrence risk will guide the development of personalized surveillance programs after surgery.
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http://dx.doi.org/10.1097/SLA.0000000000003579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8557638PMC
December 2021

Ultra-Mutation in Wild-Type Glioblastomas of Patients Younger than 55 Years is Associated with Defective Mismatch Repair, Microsatellite Instability, and Giant Cell Enrichment.

Cancers (Basel) 2019 Aug 30;11(9). Epub 2019 Aug 30.

Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy.

Background: Glioblastomas (GBMs) are classified into isocitrate dehydrogenase () mutants and IDH wild-types (-wt). This study aimed at identifying the mutational assets of -wt GBMs in patients aged 18-54 years for which limited data are available.

Methods: Sixteen -wt GBMs from adults < 55 years old were explored for mutations, copy number variations, tumour mutational load (TML), and mutational spectrum by a 409 genes TML panel.

Results: Eight (50%) -wt GBMs were hypermutated (TML > 9 mutations/Mb) and two (12.5%) were ultra-mutated (TML > 100 mutations/Mb). One ultra-mutated GBM had microsatellite instability (MSI), a somatic MSH6 mutation, and a germline POLE mutation. The other ultra-mutated GBMs had MSI and two somatic mutations in MSH2. Both ultra-mutated GBMs featured at least 25% giant cells. The overall survival of eight patients with hypermutated GBMs was significantly longer than that of patients with non-hypermutated GBMs ( = 0.04).

Conclusions: We identified a hyper-mutated subgroup among IDH-wt GBMs in adults < 55 years that had improved prognosis. Two cases were ultra-mutated and characterized by the presence of at least 25% giant cells, MMR mutations, and MSI. Since high TML has been associated with response to immune checkpoint inhibition in paediatric gliomas, the identification of a subtype of ultra-mutated IDH-wt GBM may have implications for immunotherapy.
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http://dx.doi.org/10.3390/cancers11091279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770353PMC
August 2019

CT Enhancement and 3D Texture Analysis of Pancreatic Neuroendocrine Neoplasms.

Sci Rep 2019 02 18;9(1):2176. Epub 2019 Feb 18.

Department of Pathology, Pancreas Institute, G.B. Rossi Hospital - University of Verona, Verona, Italy.

To evaluate pancreatic neuroendocrine neoplasms (panNENs) grade prediction by means of qualitative and quantitative CT evaluation, and 3D CT-texture analysis. Patients with histopathologically-proven panNEN, availability of Ki67% values and pre-treatment CT were included. CT images were retrospectively reviewed, and qualitative and quantitative images analysis were done; for quantitative analysis four enhancement-ratios and three permeability-ratios were created. 3D CT-texture imaging analysis was done (Mean Value; Variance; Skewness; Kurtosis; Entropy). Subsequently, these features were compared among the three grading (G) groups. 304 patients affected by panNENs were considered, and 100 patients were included. At qualitative evaluation, frequency of irregular margins was significantly different between tumor G groups. At quantitative evaluation, for all ratios, comparisons resulted statistical significant different between G1 and G3 groups and between G2 and G3 groups. At 3D CT-texture analysis, Kurtosis resulted statistical significant different among three G groups and Entropy resulted statistical significant different between G1 and G3 and between G2 and G3 groups. Quantitative CT evaluation of panNENs can predict tumor grade, discerning G1 from G3 and G2 from G3 tumors. CT-texture analysis can predict panNENs tumor grade, distinguishing G1 from G3 and G2 from G3, and G1 from G2 tumors.
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http://dx.doi.org/10.1038/s41598-018-38459-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6379382PMC
February 2019

Patterns of Recurrence after Resection for Pancreatic Neuroendocrine Tumors: Who, When, and Where?

Neuroendocrinology 2019 27;108(3):161-171. Epub 2018 Nov 27.

Department of General and Pancreatic Surgery, The Pancreas Institute, University of Verona Hospital Trust, Verona, Italy.

Background/aims: Pancreatic neuroendocrine tumors (pan-NENs) represent an increasingly common indication for pancreatic resection, but there are few data regarding possible recurrence after surgery. The aim of the study was to describe the frequency, timing, and patterns of recurrence after resection for pan-NENs with consequent implications for postoperative follow-up.

Methods: We performed a retrospective analysis of pan-NENs resected between 1990 and 2015 at The Pancreas Institute, University of Verona Hospital Trust. Predictors of recurrence were assessed. Survival analysis was conducted using the Kaplan-Meier and conditional survival (CS) methods.

Results: The cohort consisted of 487 patients with a median follow-up of 71 months. Recurrence developed in 12.3%: 54 (11.1%) liver metastases, 11 (2.3%) local recurrence, 10 (2.1%) nodal recurrence, and 8 (1.6%) metastases in other organs. Thirty-one (6.4%) died due to disease recurrence. Size > 21 mm, G3 grade, nodal metastasis, and vascular infiltration were independent predictors of overall recurrence. Recurrence occurred either during the first year of follow-up (n = 9), or after 10 years (n = 4). CS analysis revealed that nonfunctioning G1 pan-NEN ≤20 mm without nodal metastasis or vascular invasion had a negligible risk of developing recurrence. In the present series, after 5 years of follow-up without developing recurrence, tumor recurrence occurred only in the form of liver metastases.

Conclusions: Recurrence of pan-NENs is rare and is predicted by tumor size, nodal metastasis, grading, and vascular invasion. Patients with G1 pan-NEN without nodal metastasis and vascular invasion may be considered cured by surgery. After 5 years without recurrence, follow-up should focus on excluding the development of liver metastases.
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http://dx.doi.org/10.1159/000495774DOI Listing
December 2019

Imaging presentation of pancreatic neuroendocrine neoplasms.

Insights Imaging 2018 Dec 9;9(6):943-953. Epub 2018 Oct 9.

Department of Radiology, University Hospital G.B. Rossi, University of Verona, Verona, Italy.

Pancreatic neuroendocrine neoplasms (P-NENs) are the second most common solid pancreatic neoplasms. P-NENs have a wide range of imaging features presentations and they can be detected with typical and atypical imaging presentations. Typical and atypical appearances can be explained by pathologic correlations. P-NENs are generally hypervascular lesions, showing a typical enhancement behavior after contrast media injection during imaging methods, but they could also have different imaging features, creating some difficulty in differential diagnosis. For this reason, radiologists should be aware of different imaging presentations of these neoplasms. Radiological evaluation has a critical role in P-NENs identification, characterization, and staging of these neoplasms, especially in those cases in which surgery is the treatment of choice. The present paper shows, indicating the underlying pathologic correlations, typical and atypical presentations of NENs. KEY POINTS: • P-NENs have a wide range of imaging features presentations, typical and atypical. • Pathology could help in better understanding the typical P-NENs appearance at imaging. • P-NENs are generally hypervascular lesions. • Radiological evaluation has a critical role in P-NENs identification and management. • Radiologists should know every type of different imaging presentation of P-NENs to better diagnose these kinds of lesions.
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http://dx.doi.org/10.1007/s13244-018-0658-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269331PMC
December 2018

Mutational and copy number asset of primary sporadic neuroendocrine tumors of the small intestine.

Virchows Arch 2018 Dec 16;473(6):709-717. Epub 2018 Sep 16.

ARC-Net Research Centre, University and Hospital Trust of Verona, Policlinico GB Rossi, Piazzale L.A. Scuro, 10, Piastra Odontoiatrica (II floor), Verona, Italy.

Small intestine neuroendocrine tumors (SI-NETs) represent the most common histotype among small intestine neoplasms, and metastatic disease is usually present at diagnosis. A retrospective series of 52 sporadic primary surgically resected SI-NETs, which were metastatic at diagnosis, was analyzed by high-coverage target sequencing (HCTS) for the mutational status of 57 genes and copy number status of 40 genes selected from recently published genome sequencing data. Seven genes were found to be recurrently mutated: CDKN1B (9.6%), APC and CDKN2C (each 7.7%), BRAF, KRAS, PIK3CA, and TP53 (each 3.8%). Copy number analysis showed frequent allelic loss of 4 genes located on chromosome 18 (BCL2, CDH19, DCC, and SMAD4) in 23/52 (44.2%) and losses on chromosomes 11 (38%) and 16 (15%). Other recurrent copy number variations were gains for genes located on chromosomes 4 (31%), 5 (27%), 14 (36%), and 20 (20%). Univariate survival analysis showed that SRC gene copy number gains were associated with a poorer prognosis (p = 0.047). Recurrent copy number variations are important events in SI-NET and SRC may represent a novel prognostic biomarker for this tumor type.
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http://dx.doi.org/10.1007/s00428-018-2450-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6267237PMC
December 2018

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

Gastroenterology 2018 08 13;155(2):479-489.e7. Epub 2018 Apr 13.

Centro di Osteoncologia e Tumori Rari, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.

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.
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http://dx.doi.org/10.1053/j.gastro.2018.04.010DOI Listing
August 2018

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

Eur Radiol 2018 Jun 19;28(6):2582-2591. Epub 2018 Jan 19.

Department of Radiology, G.B. Rossi Hospital - University of Verona, Piazzale L.A. Scuro 10, 37134, Verona, Italy.

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: ADC 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). ADC 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. ADC and ADC 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.
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http://dx.doi.org/10.1007/s00330-017-5236-7DOI Listing
June 2018

The development of PARP as a successful target for cancer therapy.

Expert Rev Anticancer Ther 2018 02 26;18(2):161-175. Epub 2017 Dec 26.

a Section of Oncology, Department of Medicine , Università degli Studi di Verona , Verona , Italy.

Introduction: PARP1 and BRCA genes are essential genome caretakers and their interaction has been the first example of synthetic lethality, a genetic concept proposed in the early 20th century, but deeply explored in cancer patients only in the last decade. Areas covered: This review describes PARP1 and BRCA main functions and different roles in genome protection. Furthermore, an overview of the principle mechanisms of action and resistance to PARP inhibitors (PARPi) is presented. This review illustrates the concept of BRCAness, and how this discovery has broadened the routes of PARPi to several different malignancies such as ovarian, breast and prostate cancer. Finally, an insight is provided into the key data of PARPi in these distinctive clinical settings. Expert commentary: PARP inhibition could be a new therapeutic option for a number of tumors in the near future. However, several aspects will be of paramount interest for future investigations, including the molecular bases for PARPi synthetic lethality, the DNA repair independent functions of PARP and BRCA genes, the resistance and biomarkers of response to PARP inhibition, and the mechanisms of interaction between PARPi and antiangiogenic or immunotherapeutic agents.
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http://dx.doi.org/10.1080/14737140.2018.1419870DOI Listing
February 2018

The Evolution of Surgical Strategies for Pancreatic Neuroendocrine Tumors (Pan-NENs): Time-trend and Outcome Analysis From 587 Consecutive Resections at a High-volume Institution.

Ann Surg 2019 04;269(4):725-732

General and Pancreatic Surgery Department, The Pancreas Institute-University of Verona Hospital Trust, Verona, Italy.

Objective: The objective of the present analysis is 2-fold: first, to define the evolution of time trends on the surgical approach to pancreatic neuroendocrine neoplasms (Pan-NENs); second, to perform a complete analysis of the predictors of oncologic outcome.

Background: Reflecting their rarity and heterogeneity, Pan-NENs represent a clinical dilemma. In particular, there is a scarcity of data regarding their long-term follow-up after surgical resection.

Methods: From the Institutional Pan-NEN database, 587 resected cases from 1990 to 2015 were extracted. The time span was arbitrarily divided into 3 discrete clusters enabling a balanced comparison between patient groups. Analyses for predictors of recurrence and survival were performed, together with conditional survival analyses.

Results: Among the 587 resected Pan-NENs, 75% were nonfunctioning tumors, and 5% were syndrome-associated tumors. The mean age was 54 years (±14 years), and 51% of the patients were female. The median tumor size was 20 mm (range 4 to 140), 62% were G1, 32% were G2, and 4% were G3 tumors. Time trends analysis revealed that the number of resected Pan-NENs constantly increased, while the size (from 25 to 20 mm) and G1 proportion (from 65% to 49%) decreased during the study period. After a mean follow-up of 75 months, recurrence analysis revealed that nonfunctioning tumors, tumor grade, N1 status, and vascular invasion were all independent predictors of recurrence. Regardless of size, G1 nonfunctioning tumors with no nodal involvement and vascular invasion had a negligible risk of recurrence at 5 years.

Conclusions: Pan-NENs have been increasingly diagnosed and resected during the last 3 decades, revealing reliable predictors of outcome. Functioning and nodal status, tumor grade, and vascular invasion accurately predict survival and recurrence with resulting implications for patient follow-up.
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http://dx.doi.org/10.1097/SLA.0000000000002594DOI Listing
April 2019

Solid non-functioning endocrine tumors of the pancreas: correlating computed tomography and pathology.

HPB (Oxford) 2017 11 4;19(11):986-991. Epub 2017 Aug 4.

Istituto di Radiologia, DAI Patologia e Diagnostica, Policlinico GB Rossi, AOUI Verona, Verona, Italy.

Background: Since prognosis and treatment of pancreatic endocrine tumors (pNET) are based on tumor grade, contrast-enhanced multidetector computed tomography (MDCT) features of solid non-functioning pNETs were studied and correlated with pathology tumor grading.

Methods: MDCTs of diagnosed pNETs were reviewed retrospectively. Each tumor was analyzed for location, size, homogeneity, margins, arterial and venous phase enhancement, main pancreatic duct diameter, calcifications, vascular invasion, lymph-nodes enlargement, and liver metastases.

Results: Of 154 pNETs presenting between January 2000 and May 2016 with available histology from resected specimen or biopsy, there were 65 G1, 72 G2 and 17 G3 pNETs. Tumor diameter varied significantly between the three groups. Tumors >20 mm were more frequently malignant and non-homogeneous than smaller tumors. G1 tumors were more commonly hypervascular and G3 tumors more often non-hypervascular in the arterial phase. Arterial phase non-hyperdensity and tumor non-homogeneity had a higher rate of metastatic lesions. Vascular invasion correlated with presence of metastases and histological grade. G3 tumors were all >20 mm (p = 0.007), more often non-hypervascular in the arterial phase (p = 0.0025), and non-hyperdense in the venous phase (p = 0.009), and showed more often vascular invasion (p = 0.0198).

Conclusion: CT correlated with tumor grade; differentiating low-grade and high-grade pNETs through routine CT imaging might improve patient management.
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http://dx.doi.org/10.1016/j.hpb.2017.06.013DOI Listing
November 2017

Are Cystic Pancreatic Neuroendocrine Tumors an Indolent Entity Results from a Single-Center Surgical Series.

Neuroendocrinology 2018 7;106(3):234-241. Epub 2017 Jun 7.

Introduction: Cystic pancreatic neuroendocrine tumors (CPanNETs) represent an uncommon variant of pancreatic neuroendocrine tumors (PanNETs). Due to their rarity, there is a lack of knowledge with regard to clinical features and postoperative outcome.

Methods: The prospectively maintained surgical database of a high-volume institution was queried, and 46 resected CPanNETs were detected from 1988 to 2015. Clinical, demographic, and pathological features and survival outcomes of CPanNETs were described and matched with a population of 92 solid PanNETs (SPanNETs) for comparison.

Results: CPanNETs accounted for 7.8% of the overall number of resected PanNETs (46/587). CPanNETs were mostly sporadic (n = 42, 91%) and nonfunctioning (39%). Two functioning CPanNETs were detected (4.3%), and they were 2 gastrinomas. The median tumor diameter was 30 mm (range 10-120). All tumors were well differentiated, with 38 (82.6%) G1 and 8 (17.4%) G2 tumors. Overall, no CPanNET showed a Ki-67 >5%. A correct preoperative diagnosis of a CPanNET was made in half of the cases. After a median follow-up of >70 months, the 5- and 10-year overall survival of resected CPanNETs was 93.8 and 62.5%, respectively, compared to 92.7 and 84.6% for SPanNETs (p > 0.05). The 5- and 10-year disease-free survival rates were 94.5 and 88.2% for CPanNETs and 81.8 and 78.9% for SPanNETs, respectively (p > 0.05).

Conclusion: In the setting of a surgical cohort, CPanNETs are rare, nonfunctional, and well-differentiated neoplasms. After surgical resection, they share the excellent outcome of their well-differentiated solid counterparts for both survival and recurrence.
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http://dx.doi.org/10.1159/000477849DOI Listing
January 2019

Comparison of imaging-based and pathological dimensions in pancreatic neuroendocrine tumors.

World J Gastroenterol 2017 May;23(17):3092-3098

Salvatore Paiella, Harmony Impellizzeri, Giovanni Marchegiani, Marco Miotto, Anna Malpaga, Claudio Bassi, Roberto Salvia, Luca Landoni, General and Pancreatic Surgery Department, Pancreas Institute, University and Hospital Trust of Verona, 37134 Verona, Italy.

Aim: To establish the ability of magnetic resonance (MR) and computer tomography (CT) to predict pathologic dimensions of pancreatic neuroendocrine tumors (PanNET) in a caseload of a tertiary referral center.

Methods: Patients submitted to surgery for PanNET at the Surgical Unit of the Pancreas Institute with at least 1 preoperative imaging examination (MR or CT scan) from January 2005 to December 2015 were included and data retrospectively collected. Exclusion criteria were: multifocal lesions, genetic syndromes, microadenomas or mixed tumors, metastatic disease and neoadjuvant therapy. Bland-Altman (BA) and Mountain-Plot (MP) statistics were used to compare size measured by each modality with the pathology size. Passing-Bablok (PB) regression analysis was used to check the agreement between MR and CT.

Results: Our study population consisted of 292 patients. Seventy-nine (27.1%) were functioning PanNET. The mean biases were 0.17 ± 7.99 mm, 1 ± 8.51 mm and 0.23 ± 9 mm, 1.2 ± 9.8 mm for MR and CT, considering the overall population and the subgroup of non-functioning- PanNET, respectively. Limits of agreement (LOA) included the vast majority of observations, indicating a good agreement between imaging and pathology. The MP further confirmed this finding and showed that the two methods are unbiased with respect to each other. Considering ≤ 2 cm non-functioning-PanNET, no statistical significance was found in the size estimation rate of MR and CT ( = 0.433). PBR analysis did not reveal significant differences between MR, CT and pathology.

Conclusion: MR and CT scan are accurate and interchangeable imaging techniques in predicting pathologic dimensions of PanNET.
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http://dx.doi.org/10.3748/wjg.v23.i17.3092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5423046PMC
May 2017

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

Anticancer Res 2017 03;37(3):1305-1311

Department of Oncology, G.B. Rossi Hospital, University of Verona, Verona, Italy.

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.
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http://dx.doi.org/10.21873/anticanres.11448DOI Listing
March 2017

Whole-genome landscape of pancreatic neuroendocrine tumours.

Nature 2017 03 15;543(7643):65-71. Epub 2017 Feb 15.

QIMR Berghofer Medical Research Institute, Herston Road, Brisbane 4006, Australia.

The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.
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http://dx.doi.org/10.1038/nature21063DOI Listing
March 2017

Prognostic factors in ectopic Cushing's syndrome due to neuroendocrine tumors: a multicenter study.

Eur J Endocrinol 2017 Apr;176(4):453-461

Section of EndocrinologyDepartment of Medicine, University of Verona, Verona, Italy.

Objective: Evidence is limited regarding outcome of patients with ectopic Cushing's syndrome (ECS) due to neuroendocrine tumors (NETs).

Design: We assessed the prognostic factors affecting the survival of patients with NETs and ECS.

Methods: Retrospective analysis of clinicopathological features, severity of hormonal syndrome, treatments from a large cohort of patients with NETs and ECS collected from 17 Italian centers.

Results: Our series included 110 patients, 58.2% female, with mean (±s.d.) age at diagnosis of 49.5 ± 15.9 years. The main sources of ectopic ACTH were bronchial carcinoids (BC) (40.9%), occult tumors (22.7%) and pancreatic (p)NETs (15.5%). Curative surgery was performed in 56.7% (70.2% of BC, 11% of pNETs). Overall survival was significantly higher in BC compared with pNETs and occult tumors ( = 0.033) and in G1-NETs compared with G2 and G3 ( = 0.007). Negative predictive factors for survival were severity of hypercortisolism ( < 0.02), hypokalemia ( = 0.001), diabetes mellitus ( = 0.0146) and distant metastases ( < 0.001). Improved survival was observed in patients who underwent NET removal ( < 0.001). Adrenalectomy improved short-term survival.

Conclusions: Multiple factors affect prognosis of ECS patients: type of NET, grading, distant metastases, severity of hypercortisolism, hypokalemia and diabetes mellitus. BCs have the highest curative surgical rate and better survival compared with occult tumors and pNETs. Hypercortisolism plays a primary role in affecting outcome and quality of life; therefore, prompt and vigorous treatment of hormonal excess by NET surgery and medical therapy should be a key therapeutic goal. In refractory cases, adrenalectomy should be considered as it affects outcome positively at least in the first 2 years.
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http://dx.doi.org/10.1530/EJE-16-0809DOI Listing
April 2017
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