Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 57
Filtrar
1.
Mod Pathol ; 2022 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-35249100

RESUMO

Ki-67 assessment is a key step in the diagnosis of neuroendocrine neoplasms (NENs) from all anatomic locations. Several challenges exist related to quantifying the Ki-67 proliferation index due to lack of method standardization and inter-reader variability. The application of digital pathology coupled with machine learning has been shown to be highly accurate and reproducible for the evaluation of Ki-67 in NENs. We systematically reviewed all published studies on the subject of Ki-67 assessment in pancreatic NENs (PanNENs) employing digital image analysis (DIA). The most common advantages of DIA were improvement in the standardization and reliability of Ki-67 evaluation, as well as its speed and practicality, compared to the current gold standard approach of manual counts from captured images, which is cumbersome and time consuming. The main limitations were attributed to higher costs, lack of widespread availability (as of yet), operator qualification and training issues (if it is not done by pathologists), and most importantly, the drawback of image algorithms counting contaminating non-neoplastic cells and other signals like hemosiderin. However, solutions are rapidly developing for all of these challenging issues. A comparative meta-analysis for DIA versus manual counting shows very high concordance (global coefficient of concordance: 0.94, 95% CI: 0.83-0.98) between these two modalities. These findings support the widespread adoption of validated DIA methods for Ki-67 assessment in PanNENs, provided that measures are in place to ensure counting of only tumor cells either by software modifications or education of non-pathologist operators, as well as selection of standard regions of interest for analysis. NENs, being cellular and monotonous neoplasms, are naturally more amenable to Ki-67 assessment. However, lessons of this review may be applicable to other neoplasms where proliferation activity has become an integral part of theranostic evaluation including breast, brain, and hematolymphoid neoplasms.

2.
JAMA Netw Open ; 5(2): e220290, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-35201309

RESUMO

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.


Assuntos
Tumores Neuroendócrinos , Neoplasias Pancreáticas , Radioterapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/epidemiologia , Tumores Neuroendócrinos/mortalidade , Tumores Neuroendócrinos/radioterapia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/radioterapia , Intervalo Livre de Progressão , Radioterapia/efeitos adversos , Radioterapia/métodos , Radioterapia/estatística & dados numéricos , Receptores de Peptídeos , Estudos Retrospectivos
3.
Fam Cancer ; 2022 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-35075588

RESUMO

Juvenile polyposis (JP) is a rare familial syndrome characterized by the development of numerous hamartomatous polyps of the gastrointestinal tract and by an increased risk of developing gastrointestinal cancers. It follows a pattern of autosomal dominant inheritance and is associated with germline variants of SMAD4 or BMPR1A genes. Differential diagnosis may be difficult based on histology alone, due to morphological similarities to other familial syndromes. Here we report a case of familial JP diagnosed in a 50-years woman with a familial history positive for gastrointestinal cancers and other tumor types. The patient presented with severe iron deficiency anemia and showed numerous polyps in the stomach and jejunum according to endoscopy and imaging. She underwent an intra-gastric laparoscopic removal of the major gastric polyp, followed by jejunal exploration and resection of a segment with multiple neoformations. Histological examination revealed the presence of hamartomatous polyposis. Gastric and intestinal samples were analyzed with next-generation sequencing. Molecular analysis showed that the patient harbored a germline splicing site variant of SMAD4, c.1139 + 3A > G, which was complemented by different somatic variants of the same gene in the different polyps. Immunohistochemistry for SMAD4 confirmed loss of protein expression in the polyps, with regular expression in normal cells. cDNA sequencing further confirmed the findings. We thus definitively diagnosed the woman as having JP thanks to an integrated approach based on histology, immunohistochemistry and molecular analysis. The identified variants, all previously reported as variants of unknown significance, were classified as pathogenic as they complemented each other leading to SMAD4 loss.

4.
Gut ; 71(5): 961-973, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-33849943

RESUMO

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.


Assuntos
Deficiência Intelectual , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Talassemia alfa , Proteínas Correpressoras/genética , Genes Homeobox , Proteínas de Homeodomínio , Humanos , Deficiência Intelectual/genética , Chaperonas Moleculares/genética , Recidiva Local de Neoplasia/genética , Tumores Neuroendócrinos/genética , Proteínas Nucleares/genética , Neoplasias Pancreáticas/patologia , Telômero/genética , Telômero/patologia , Fatores de Transcrição/genética , Proteína Nuclear Ligada ao X/genética , Talassemia alfa/genética
5.
Neuroendocrinology ; 112(2): 143-152, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-33508821

RESUMO

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.


Assuntos
Fluordesoxiglucose F18 , Octreotida/análogos & derivados , Compostos Organometálicos , Neoplasias Pancreáticas/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Compostos Radiofarmacêuticos , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Processos e Resultados em Cuidados de Saúde , Neoplasias Pancreáticas/cirurgia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/normas , Estudos Retrospectivos
6.
Cancers (Basel) ; 13(16)2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34439308

RESUMO

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%; p = 0.002); (2) a lower proportion of cases with a Ki-67 index of ≥55% (73.9% vs. 88.7%; p = 0.025); (3) reduced sensitivity to first-line platinum/etoposide (objective response rate: 31.6% vs. 55.1%, p = 0.015; and disease control rate; 59.7% vs. 79.6%, p = 0.027); (4) worse progression-free survival (PFS) (adjusted-HR = 1.615, p = 0.016) and overall survival (OS) (adjusted-HR = 1.640, p = 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-p = 0.021) and OS (adjusted-p = 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.

7.
Curr Oncol Rep ; 23(9): 106, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34269919

RESUMO

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.


Assuntos
Predisposição Genética para Doença/genética , Mutação , Tumores Neuroendócrinos/genética , Neoplasias Pancreáticas/genética , Homeostase do Telômero , Telômero/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proteínas Correpressoras/genética , Humanos , Hibridização in Situ Fluorescente/métodos , Chaperonas Moleculares/genética , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Proteína Nuclear Ligada ao X/genética , Proteína Nuclear Ligada ao X/metabolismo
8.
World J Surg Oncol ; 19(1): 65, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33648512

RESUMO

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.


Assuntos
Laparoscopia , Sarcoma Sinovial , Neoplasias Gástricas , Adulto , Feminino , Humanos , Hibridização in Situ Fluorescente , Prognóstico , Sarcoma Sinovial/diagnóstico por imagem , Sarcoma Sinovial/cirurgia , Neoplasias Gástricas/cirurgia
9.
Commun Biol ; 4(1): 155, 2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33536587

RESUMO

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.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Neuroendócrino/genética , Metilação de DNA , Epigênese Genética , Epigenoma , Neoplasias Pancreáticas/genética , Carcinoma Neuroendócrino/metabolismo , Epigenômica , Predisposição Genética para Doença , Humanos , Gradação de Tumores , Neoplasias Pancreáticas/patologia , Fenótipo , Carga Tumoral
10.
Pancreas ; 50(2): 138-146, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33565789

RESUMO

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.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Neuroendócrino/tratamento farmacológico , Diferenciação Celular , Neoplasias Pancreáticas/tratamento farmacológico , Compostos de Platina/uso terapêutico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Neuroendócrino/mortalidade , Carcinoma Neuroendócrino/patologia , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Compostos de Platina/efeitos adversos , Intervalo Livre de Progressão , Estudos Retrospectivos , Fatores de Tempo
11.
Gut ; 70(10): 1904-1913, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-32883872

RESUMO

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.


Assuntos
Genes Neoplásicos/imunologia , Mimetismo Molecular/imunologia , Tumores Neuroendócrinos/imunologia , Neoplasias Pancreáticas/imunologia , Microambiente Tumoral/imunologia , Progressão da Doença , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Gradação de Tumores , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/patologia , Fenótipo , Prognóstico , Carga Tumoral
12.
Ann Surg ; 274(6): 1051-1057, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31567347

RESUMO

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.


Assuntos
Tumores Neuroendócrinos/cirurgia , Neoplasias Pancreáticas/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Bases de Dados Factuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Tumores Neuroendócrinos/mortalidade , Tumores Neuroendócrinos/patologia , Nomogramas , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Valor Preditivo dos Testes , Taxa de Sobrevida
13.
Front Oncol ; 11: 737842, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34976795

RESUMO

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.

14.
Surgery ; 168(5): 816-824, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32778411

RESUMO

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.


Assuntos
Recidiva Local de Neoplasia/terapia , Neoplasias Pancreáticas/cirurgia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Estudos Retrospectivos
15.
Endoscopy ; 52(11): 988-994, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32498099

RESUMO

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.


Assuntos
Tumores Neuroendócrinos , Neoplasias Pancreáticas , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Humanos , Antígeno Ki-67 , Gradação de Tumores , Tumores Neuroendócrinos/diagnóstico por imagem , Neoplasias Pancreáticas/diagnóstico por imagem , Reprodutibilidade dos Testes , Estudos Retrospectivos
16.
Cancers (Basel) ; 12(6)2020 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-32517291

RESUMO

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 18F-fluorodeoxyglucose (18F-FDG) standardized uptake value (SUV). Arterial relative enhancement was inversely related with G (-0.37, p = 0.006). Different metastatic spread patterns of LTB were not associated with histological grade. Arterialentropy was significantly correlated to G (-0.368, p = 0.038) and to Ki67 percentage (-0.421, p = 0.018). The ROC curve for the Arterialentropy reported an area under the curve (AUC) of 0.736 (95% confidence interval 0.545-0.928, p = 0.035) in the identification of G1-2 tumors. Arterialuniformity values were correlated to G (0.346, p = 0.005) and Ki67 levels (0.383, p = 0.033). Arterialentropy values were directly correlated with the SUV (0.449, p = 0.047) which was inversely correlated with Arterialuniformity (-0.499, p = 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.

17.
Eur J Cancer ; 135: 159-169, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32580131

RESUMO

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.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/prevenção & controle , Controle de Infecções/organização & administração , Oncologia/organização & administração , Neoplasias/terapia , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , COVID-19 , Teste para COVID-19 , Técnicas de Laboratório Clínico/normas , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/transmissão , Infecções por Coronavirus/virologia , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Pessoal de Saúde/psicologia , Humanos , Controle de Infecções/normas , Transmissão de Doença Infecciosa do Paciente para o Profissional/prevenção & controle , Transmissão de Doença Infecciosa do Profissional para o Paciente/prevenção & controle , Itália/epidemiologia , Masculino , Programas de Rastreamento/normas , Oncologia/métodos , Neoplasias/psicologia , Admissão do Paciente/normas , Pneumonia Viral/epidemiologia , Pneumonia Viral/transmissão , Pneumonia Viral/virologia , Sistemas de Apoio Psicossocial , Estudos Retrospectivos , Fatores de Risco , SARS-CoV-2
18.
Cancers (Basel) ; 11(9)2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31480372

RESUMO

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

19.
Sci Rep ; 9(1): 2176, 2019 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-30778137

RESUMO

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.


Assuntos
Tumores Neuroendócrinos/diagnóstico por imagem , Neoplasias Pancreáticas/diagnóstico por imagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imageamento Tridimensional , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Intensificação de Imagem Radiográfica , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Adulto Jovem
20.
Ann Surg ; 269(4): 725-732, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-29189384

RESUMO

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.


Assuntos
Tumores Neuroendócrinos/cirurgia , Pancreatectomia/métodos , Pancreatectomia/tendências , Neoplasias Pancreáticas/cirurgia , Feminino , Hospitais com Alto Volume de Atendimentos , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...