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1
Yang, Min, Lin Zeng, Sheng-zhong Hou, Neng-wen Ke, Bo-le Tian, Xu-bao Liu, Bo Xiang, and Yi Zhang. "Clinical Features and Long-Term Survival of Metastatic Hepatic Neuroendocrine Neoplasms Secondary to Gastroenteropancreatic Site: An Analysis by Applying the Grading Classification." Journal of Oncology 2020 (September 15, 2020): 1–10. http://dx.doi.org/10.1155/2020/6572398.
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Background and Purpose. Neuroendocrine neoplasms occurring in the liver are very rare, in which metastatic hepatic neuroendocrine neoplasms [(MH)-NENs] secondary to gastroenteropancreatic NENs [(GEP)-NENs] account for their majority. The clinical features and long-term survival of (MH)-NENs secondary to (GEP)-NENs were not clear, especially for each grading group of G1 neuroendocrine tumors (NETs), G2 NETs, and G3 NETs and G3 neuroendocrine carcinomas (G3 NECs). Method. Data of patients who were surgically treated and clinicopathologically diagnosed as (MH)-NENs secondary to (GEP)-NENs at West China Hospital of Sichuan University from January 2006 to December 2018 were retrospectively collected and analyzed by the grading classification for (GEP)-NENs. Results. We identified 150 patients with (MH)-NENs secondary to (GEP)-NENs, including 10 patients with G1 NETs, 26 with G2 NETs, 33 with G3 NETs, and 81 with G3 NECs. There were significant differences between patients with G1/G2/G3 NETs and those with G3 NECs, such as age at diagnosis (P=0.041), synchronous liver lesion (P=0.032), incidental diagnosis (P=0.014), tumor largest diameter (P=0.047), vascular invasion (P=0.017), and extrahepatic metastatic disease (P=0.029). The estimated 3-year overall survival for patients with G1 NETs, G2 NETs, G3 NETs, and G3 NECs was 100%, 79.4%, 49.5%, and 20.7%, respectively (P<0.001). The survival of G1 NETs or G2 NETs was significantly better than that of G3 NETs (P=0.013, P=0.037, respectively) and G3 NECs (P=0.001, P<0.001; respectively). Patients with G3 NECs present notably worse survival than those with G3 NETs (P=0.012), while survival comparison between G1 NETs and G2 NETs was not statistically different (P=0.131). The grading classification for (GEP)-NENs was an effective independent predictor of survival for (MH)-NENs secondary to (GEP)-NENs (hazard ratio: 4.234; 95% confidence intervals: 1.984–6.763; P=0.003). Conclusion. Our demonstration revealed that the grading classification for (GEP)-NENs could well stratify (MH)-NENs secondary to (GEP)-NENs into prognostic groups and supported its wide use in clinical practice.
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Ramage, John K., Juan W. Valle, Els J. M. Nieveen van Dijkum, Anders Sundin, Andreas Pascher, Anne Couvelard, and Guenter Kloeppel. "Colorectal Neuroendocrine Neoplasms: Areas of Unmet Need." Neuroendocrinology 108, no. 1 (September 16, 2018): 45–53. http://dx.doi.org/10.1159/000493767.
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The subject of colorectal neuroendocrine neoplasms (NENs), subdivided into well-differentiated NENs, termed neuroendocrine tumours (NETs; grade (G) 1 and 2), and poorly differentiated NENs, termed neuroendocrine carcinomas (NECs; G3) according to the 2010 World Health Organisation (WHO) classification, has arguably not had as much attention or study as NENs occurring in other sites. Colorectal NETs and NECs are however easier to study than many others since they are usually not difficult to remove and are increasingly detected because of intensified colorectal cancer screening and surveillance programmes. Colorectal NETs and NECs show site-specific heterogeneity with variable behaviour and different therapeutic options; these various aspects provide unique challenges. Because of bowel cancer screening programmes, colorectal NENs, like conventional adenocarcinomas, may be diagnosed at a stage that is associated with improved survival. In this article we intend to describe and define areas of unmet needs relating to the epidemiology, classification, pathology, diagnosis and therapy of colorectal NETs (including NETs G3), colorectal NECs, and finally, mixed adeno-neuroendocrine carcinomas (MANECs) by reviewing and discussing the relevant literature.
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Tsang, Erica, Caroline Speers, and Hagen F. Kennecke. "Treatment and outcomes of neuroendocrine malignancies (NEMs) of the rectum." Journal of Clinical Oncology 32, no. 3_suppl (January 20, 2014): 594. http://dx.doi.org/10.1200/jco.2014.32.3_suppl.594.
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594 Background: NEMs of the rectum are rare and standard therapy is not well defined. We sought to characterize the clinicopathologic features, locoregional, and systemic management of a series of rectal NEMs and correlated these with outcomes. Methods: Patients referred to the BC Cancer Agency with rectal NEMs between 2005-2011 were included. Well-differentiated tumors with a Ki67 ≤20% and/or mitotic count ≤ 20 per high power field were classified as neuroendocrine tumors (NETs) while poorly differentiated tumors with higher Ki67 and/or mitotic count were classified as neuroendocrine carcinomas (NECs). Results: Of 28 NEMs, 18 (64%) NETs, and 9 (36%) NECs were identified with a median age of 56 and 59, respectively. Of 15 patients with stage I-III NETs, 13 underwent local excision, 2 had a surgical resection and none received pelvic radiation. Univariate analysis demonstrated an association between tumor size (< 1cm, 1-2 cm, > 2cm) and T stage (χ2 = 10.7, p = 0.03). One of 15 NETs developed distant relapse 8.9 months after surgical resection of a T1bN1 tumor. Of 9 NECs, only 2 presented with stage I-III tumors and were treated with radiation (1) or surgery (1). One patient developed distant relapse 4.8 months after radiation. Among all NEMs, liver was the most common site of metastasis (n = 10) followed by bone (n = 3). Median overall survival was 46.5 and 4.8 months for NETs and NECs (p < 0.01), respectively. Conclusions: Rectal NEMs comprise a rare subgroup of rectal tumors and may be classified as NETs or NECs. NETs generally present with early stage disease and are associated with good outcomes with local excision and without pelvic radiation. Rectal NECs frequently present with advanced disease and are associated with poor outcomes.
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Zhang, Lin, Zhenjian Cai, and Hui Zhu. "Fine-Needle Aspiration Biopsy of Neuroendocrine Neoplasms in the Liver: A 9-Year Retrospective, Single Institutional Study." American Journal of Clinical Pathology 152, Supplement_1 (September 11, 2019): S94. http://dx.doi.org/10.1093/ajcp/aqz118.005.
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Abstract Objectives Neuroendocrine neoplasms (NENs) are divided into two major categories according to the 2018 WHO expert consensus proposal: well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinoma (NECs). Primary liver NENs are very rare and majority of NENs in the liver are metastatic. In this study, we retrospectively reviewed NENs in the liver diagnosed by fine-needle aspiration biopsy (FNAB). Methods We retrospectively reviewed malignant neoplasms diagnosed by imaging-guided liver FNAB performed between 2010 and 2018 in our institution. Patients’ electronic medical records and selective slides were reviewed. Results A total of 624 liver FNAB cases with a diagnosis of positive for malignancy were identified. Among those cases, 56 cases (9%) were NENs. Poorly differentiated NECs constituted 71% (40/56) of cases, and well-differentiated NETs constituted 29% (16/56) of cases. The most common primary sites of poorly differentiated NECs were lung (35%, 13/40), followed by pancreas (20%, 8/40), GI tract (17.5%, 7/40), GU (7.5%, 3/40), breast (5%, 2/40), head and neck (2.5%, 1/40), GYN tract (2.5%, 1/40), and CNS (dedifferentiated glioblastoma, 2.5%, 1/40). The remaining three cases (7.5%, 3/40) were diagnosed as primary liver NECs based on the clinical presentation. All three patients presented with a single large liver mass with no other mass lesions identified in other organ systems. For well-differentiated NETs, majority were from the GI tract (81.3%, 13/16), followed by pancreas (6.25%, 1/16) and lung (6.25%, 1/16). One patient was diagnosed with metastatic NET of unknown primary. Conclusion NENs in liver are predominantly metastatic, and majority of them are high-grade NECs. Most of well-differentiated NETs are metastases from the GI tract, while more than one-third of poorly differentiated NECs are metastases from the lung. Primary liver NENs also occur and all three cases in this study are poorly differentiated NECs.
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La Rosa, Stefano, and Alessandro Vanoli. "Gastric neuroendocrine neoplasms and related precursor lesions." Journal of Clinical Pathology 67, no. 11 (July 22, 2014): 938–48. http://dx.doi.org/10.1136/jclinpath-2014-202515.
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Gastric neuroendocrine neoplasms (NENs) are a heterogeneous group of tumours showing different clinicopathological features and behaviour, implying a wide spectrum of therapeutic options. They are currently classified using the 2010 WHO classification of digestive neuroendocrine neoplasms into G1-neuroendocrine tumours (NETs), G2-NETs, neuroendocrine carcinomas (NECs) and mixed adenoneuroendocrine carcinomas (MANECs). However, most gastric NENs are composed of ECL-cells (ECL-cell NETs) that can be preceded by ECL-cell hyperplastic and dysplastic lesions, whose oncologic potential has not yet been completely elucidated. ECL-cell NETs differ considerably in terms of prognosis depending on the proliferative status and clinicopathological background. The integration of both aspects in the diagnostic pathway may help to better classify tumours in different prognostic categories, especially when diagnosing them in small bioptic specimens. NECs are all poorly differentiated, highly aggressive carcinomas, while MANECs can show different morphological features that are directly associated with different prognoses. Precursor lesions of such carcinomas are not entirely understood. In this review, the clinicopathological features of gastric NENs and related precursor lesions will be described to give the reader a comprehensive overview on this topic.
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Zatelli, Maria Chiara, Elia Guadagno, Erika Messina, Fabio Lo Calzo, Antongiulio Faggiano, Annamaria Colao, and _. _. "Open issues on G3 neuroendocrine neoplasms: back to the future." Endocrine-Related Cancer 25, no. 6 (June 2018): R375—R384. http://dx.doi.org/10.1530/erc-17-0507.
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The recent recognition that grade 3 (G3) neuroendocrine neoplasms (NENs) can be divided into two different categories according to the histopathological differentiation, that is G3 neuroendocrine tumors (NETs) and G3 neuroendocrine carcinomas (NECs) has generated a lot of interest concerning not only the diagnosis, but also the differential management of such new group of NENs. However, several issues need to be fully clarified in order to put G3 NETs and G3 NECs in the right place. The aim of this review is to focus on those issues that are still undetermined starting from the current knowledge, evaluating the available evidence and the possible clinical implications.
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Thuillier, Philippe, Virginia Liberini, Osvaldo Rampado, Elena Gallio, Bruno De Santi, Francesco Ceci, Jasna Metovic, et al. "Diagnostic Value of Conventional PET Parameters and Radiomic Features Extracted from 18F-FDG-PET/CT for Histologic Subtype Classification and Characterization of Lung Neuroendocrine Neoplasms." Biomedicines 9, no. 3 (March 10, 2021): 281. http://dx.doi.org/10.3390/biomedicines9030281.
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Aim: To evaluate if conventional Positron emission tomography (PET) parameters and radiomic features (RFs) extracted by 18F-FDG-PET/CT can differentiate among different histological subtypes of lung neuroendocrine neoplasms (Lu-NENs). Methods: Forty-four naïve-treatment patients on whom 18F-FDG-PET/CT was performed for histologically confirmed Lu-NEN (n = 46) were retrospectively included. Manual segmentation was performed by two operators allowing for extraction of four conventional PET parameters (SUVmax, SUVmean, metabolic tumor volume (MTV), and total lesion glycolysis (TLG)) and 41 RFs. Lu-NENs were classified into two groups: lung neuroendocrine tumors (Lu-NETs) vs. lung neuroendocrine carcinomas (Lu-NECs). Lu-NETs were classified according to histological subtypes (typical (TC)/atypical carcinoid (AC)), Ki67-level, and TNM staging. The least absolute shrink age and selection operator (LASSO) method was used to select the most predictive RFs for classification and Pearson correlation analysis was performed between conventional PET parameters and selected RFs. Results: PET parameters, in particular, SUVmax (area under the curve (AUC) = 0.91; cut-off = 5.16) were higher in Lu-NECs vs. Lu-NETs (p < 0.001). Among RFs, HISTO_Entropy_log10 was the most predictive (AUC = 0.90), but correlated with SUVmax/SUVmean (r = 0.95/r = 0.94, respectively). No statistical differences were found between conventional PET parameters and RFs (p > 0.05) and TC vs. AC classification. Conventional PET parameters were correlated with N+ status in Lu-NETs. Conclusion: In our study, conventional PET parameters were able to distinguish Lu-NECs from Lu-NETs, but not TC from AC. RFs did not provide additional information.
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Klöppel, Günter. "Classification and pathology of gastroenteropancreatic neuroendocrine neoplasms." Endocrine-Related Cancer 18, S1 (October 2011): S1—S16. http://dx.doi.org/10.1530/erc-11-0013.
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Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are composed of cells with a neuroendocrine phenotype. The old and the new WHO classifications distinguish between well-differentiated and poorly differentiated neoplasms. All well-differentiated neoplasms, regardless of whether they behave benignly or develop metastases, will be called neuroendocrine tumours (NETs), and graded G1 (Ki67 <2%) or G2 (Ki67 2–20%). All poorly differentiated neoplasms will be termed neuroendocrine carcinomas (NECs) and graded G3 (Ki67 >20%). To stratify the GEP-NETs and GEP-NECs regarding their prognosis, they are now further classified according to TNM-stage systems that were recently proposed by the European Neuroendocrine Tumour Society (ENETS) and the AJCC/UICC. In the light of these criteria the pathology and biology of the various NETs and NECs of the gastrointestinal tract (including the oesophagus) and the pancreas are reviewed.
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Mandys, Václav, and Tomáš Jirásek. "Spectrum of Gastroenteropancreatic NENs in Routine Histological Examinations of Bioptic and Surgical Specimen: A Study of 161 Cases Collected from 17 Departments of Pathology in the Czech Republic." Gastroenterology Research and Practice 2014 (2014): 1–5. http://dx.doi.org/10.1155/2014/373828.
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Objective.To characterize GEP-NENs in routine biopsies and surgical specimen in the Czech Republic and to evaluate how WHO Classification (2010) is acceptable in diagnostic practice.Methods.Paraffin-embedded blocks and bioptic reports were collected from 17 departments of pathology. Histologic slides were stained with H&E and immunohistologically for CgA, synaptophysin, and Ki-67.Results.Out of 28 gastric NENs, there were 22 NETs, G1, 5 NETs, G2, and 1 NEC. Ten duodenal NENs were NETs, G1. Among 27 NENs of jejunum and ileum, 23 were NETs, G1, 2 NETs, G2, and 1 NEC and 1 mixed adenoneuroendocrine carcinoma (MANEC). Among 42 appendiceal “incidentalomas”, 39 were NETs G1, 2 goblet cell carcinoids, and 1 MANEC. Out of 34 large intestinal NENs, 30 were NETs, G1, 3 NETs, G2, and 1 NEC. One small intestinal and 6 large bowel neoplasms were reclassified as poorly differentiated adenocarcinomas. In 12 pancreatic NENs, there were 7 NETs, G1, 3 NETs, G2, and 2 NECs.Conclusions.Our study demonstrates differences in GEP-NENs frequency in sites of origin in our region, comparing to other countries. Regarding routine bioptic diagnostics, we gave evidence that the WHO 2010 classification of NENs is fully acceptable for exact categorisation of tumours.
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Metovic, Jasna, Marco Barella, Fabrizio Bianchi, Paul Hofman, Veronique Hofman, Myriam Remmelink, Izidor Kern, et al. "Morphologic and molecular classification of lung neuroendocrine neoplasms." Virchows Archiv 478, no. 1 (January 2021): 5–19. http://dx.doi.org/10.1007/s00428-020-03015-z.
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AbstractNeuroendocrine neoplasms (NENs) of the lung encompass neuroendocrine tumors (NETs) composed of typical (TC) and atypical (AC) carcinoids and full-fledged carcinomas (NECs) inclusive of large cell neuroendocrine carcinoma (LCNEC) and small cell carcinoma (SCLC). NETs and NECs are thought to represent distinct and separate lesions with neither molecular overlap nor common developmental continuum. Two perspectives were addressed regarding the morphologic and molecular classification of lung NENs: (i) a supervised approach by browsing the traditional classification, the relevant gene alterations, and their clinical implications; and (ii) an unsupervised approach, by reappraising neoplasms according to risk factors and natural history of disease to construct an interpretation model relied on biological data. We herein emphasize lights and shadows of the current classification of lung NENs and provide an alternative outlook on these tumors focused on what we currently know about the biological determinants and the natural history of disease.
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Kővári, Bence, Sándor Turkevi-Nagy, Ágnes Báthori, Zoltán Fekete, and László Krenács. "Syntaxin 1: A Novel Robust Immunophenotypic Marker of Neuroendocrine Tumors." International Journal of Molecular Sciences 21, no. 4 (February 12, 2020): 1213. http://dx.doi.org/10.3390/ijms21041213.
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Considering the specific clinical management of neuroendocrine (NE) neoplasms (NENs), immunohistochemistry (IHC) is required to confirm their diagnosis. Nowadays, synaptophysin (SYP), chromogranin A (CHGA), and CD56 are the most frequently used NE immunohistochemical markers; however, their sensitivity and specificity are less than optimal. Syntaxin 1 (STX1) is a member of a membrane-integrated protein family involved in neuromediator release, and its expression has been reported to be restricted to neuronal and NE tissues. In this study, we evaluated STX1 as an immunohistochemical marker of NE differentiation. STX1, SYP, CHGA, and CD56 expression was analyzed in a diverse series of NE tumors (NETs), NE carcinomas (NECs), and non-NE tumors. All but one (64/65; 98%) NETs and all (54/54; 100%) NECs revealed STX1 positivity in at least 50% of the tumor cells. STX1 showed the highest sensitivity both in NETs (99%) and NECs (100%) compared to CHGA (98% and 91%), SYP (96% and 89%), and CD56 (70% and 93%), respectively. A wide variety of non-NE tumors were tested and found to be uniformly negative, yielding a perfect specificity. We established that STX1 is a robust NE marker with an outstanding sensitivity and specificity. Its expression is independent of the site and grade of the NENs.
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Mohamed, Amr, Sylvia L. Asa, Thomas McCormick, Hilmi Al-Shakhshir, Arvind Dasari, Retuerto Mauricio, Iman Salem, et al. "The Role of the Microbiome in Gastroentero-Pancreatic Neuroendocrine Neoplasms (GEP-NENs)." Current Issues in Molecular Biology 44, no. 5 (April 30, 2022): 2015–28. http://dx.doi.org/10.3390/cimb44050136.
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Gut microbiome balance plays a key role in human health and maintains gut barrier integrity. Dysbiosis, referring to impaired gut microbiome, is linked to a variety of diseases, including cancers, through modulation of the inflammatory process. Most studies concentrated on adenocarcinoma of different sites with very limited information on gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). In this study, we have analyzed the gut microbiome (both fungal and bacterial communities) in patients with metastatic GEP-NENs. Fecal samples were collected and compared with matched healthy control samples using logistic regression distances utilizing R package MatchIt (version 4.2.0, Daniel E. Ho, Stanford, California). We examined differences in microbiome profiles between GEP-NENs and control samples using small subunit (SSU) rRNA (16S), ITS1, ITS4 genomic regions for their ability to accurately characterize bacterial and fungal communities. We correlated the results with different behavioral and dietary habits, and tumor features including differentiation, grade, primary site, and therapeutic response. All tests are two-sided and p-values ≤ 0.05 were considered statistically significant. Gut samples of 34 patients (12 males, 22 females, median age 64 years) with metastatic GEP-NENs (22 small bowel, 10 pancreatic, 1 gall bladder, and 1 unknown primary) were analyzed. Twenty-nine patients had well differentiated GEP-neuroendocrine tumors (GEP-NETs), (G1 = 14, G2 = 12, G3 = 3) and five patients had poorly differentiated GEP-neuroendocrine carcinomas (GEP-NECs). Patients with GEP-NENs had significantly decreased bacterial species and increased fungi (notably Candida species, Ascomycota, and species belonging to saccharomycetes) compared to controls. Patients with GEP-NECs had significantly enriched populations of specific bacteria and fungi (such as Enterobacter hormaechei, Bacteroides fragilis and Trichosporon asahii) compared to those with GEP-NETs (p = 0.048, 0.0022 and 0.034, respectively). In addition, higher grade GEP-NETs were associated with significantly higher Bacteroides fragilis (p = 0.022), and Eggerthella lenta (p = 0.00018) species compared to lower grade tumors. There were substantial differences associated with dietary habits and therapeutic responses. This is the first study to analyze the role of the microbiome environment in patients with GEP-NENs. There were significant differences between GEP-NETs and GEP-NECs, supporting the role of the gut microbiome in the pathogenesis of these two distinct entities.
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Dinu, Alexandra, Mariana Aschie, Georgeta Camelia Cozaru, Anca Florentina Mitroi, Catalin Nicolae Grasa, Ionut Eduard Iordache, Mariana Deacu, Cristian Ionut Orasanu, Antonela-Anca Nicolau, and Gabriela Izabela Baltatescu. "NET G3 vs NEC: p53 and Rb1 Immunolabeling in High-grade Gastrointestinal Neuroendocrine Neoplasms - Is It Enough for the Differential Diagnosis?" Journal of Gastrointestinal and Liver Diseases 32, no. 2 (June 22, 2023): 162–69. http://dx.doi.org/10.15403/jgld-4654.
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Background and Aims: High-grade gastrointestinal neuroendocrine neoplasms (GI-NENs) are divided into well-differentiated G3 neuroendocrine tumors (NETs G3) and neuroendocrine carcinomas (NECs), having identical cut-offs of proliferation, but different biomolecular origins. This translates in distinct treatment choices. Our aim was to establish if p53/Rb1 immunohistochemical status in GI-NENs with Ki67 index >20% can predict the histopathological diagnosis.
Methods: p53/Rb1 immunolabelling was performed on 42 cases of high-grade GI-NENs, diagnosed as NET G3, NEC and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) with NEC component. Immunolabeled slides were digitally scanned, with automatic quantification of p53 and Rb1, blind to the diagnosis.
Results: The p53 positive percentage was stratified; two cut-offs were selected, naming the intervals as N (null, <1%), T (tumor, 1%-20%) and C (carcinoma, >20%). The Rb1 expression loss in >90% of neoplastic cells was considered mutational. NETs G3 mainly showed the T status (14/16, 87.5%), followed by N (1/16, 6.25%) and C (1/16, 6.25%); NECs and NEC components in MiNENs predominantly expressed the C status (19/26, 73.08%), followed by N (5/26, 19.23%) and T (2/26, 7.69%) (p<0.001, χ 2 =27.017). NET G3s showed positive expression for Rb1; 73.08% of NECs expressed negative Rb1 (p<0.001, χ 2 =21.351). NECs and NEC components in MiNENs showed Rb1 mutational status in 13 C cases (13/19, 68.42%), 4 N cases (4/5, 80%) and in both the T cases (p=0.002, χ 2 =11.187).
Conclusions: Our results highlight the correlations between the p53/Rb1 immunostainings and the histopathological diagnosis of high-grade GI-NENs. NECs and NEC components in MiNENs showed a p53 mutational status (0% or 21-100%) and predominantly negative Rb1 expression. NETs G3 showed a p53 wild-type status (1-20%) and retained Rb1 expression. These findings suggest that the differential diagnosis of high-grade GI-NENs may benefit from p53/Rb1 immunohistochemical tests in everyday practice.
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Kolomeytseva, A. A., V. A. Gorbunova, N. F. Orel, G. S. Emelianova, A. M. Ivanov, A. S. Odintsova, and A. A. Fedenko. "HIGH-GRADE GASTROENTEROPANCREATIC NEUROENDOCRINE NEOPLASMS. MODERN CLASSIFICATION, DIAGNOSTICS AND TREATMENT." Malignant tumours 8, no. 3 (November 13, 2018): 13–20. http://dx.doi.org/10.18027/2224-5057-2018-8-3-13-20.
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Poorly differentiated gastroenteropancreatic neuroendocrine neoplasms (GEP NENs) are rare malignancies, most of which are characterized by aggressiveness, a tendency to rapid metastasis and an unfavorable prognosis even when localized. In 2017 World Health Organization (WHO) updated classification of GEP NENs and recognized the category of well-differentiated pancreatic NET G3, associated with Ki‑67 index usually over 20%. The upper level of Ki‑67 is not defined. Usually it is 55%. Highgrade poorly differentiated pancreatic NENs are defined as pancreatic neuroendocrine carcinomas (panNECs). Although the NET G3 category is recognized for pancreatic neuroendocrine neoplasms only, many specialists consider it reasonable to apply this term to all well-differentiated GEP NETs with Ki‑67 index in the 20 to 55 percent range. Clinical behavior and therapeutic approaches for advanced GEP NECs and NETs G3 are different. Standard palliative chemotherapy for GEP NECs consists of cisplatin or carboplatin combined with etoposide. The second-line regimens include irinotecan-, oxaliplatin, fluoropyrimidine- and temozolomide-based regimens. Temozolomide-based chemotherapy regimens, as well as targeted therapy are more preferable as first line therapy for patients with NETs G3. The platinum-based chemotherapy regimens are considered at the time of disease progression. Further clinical studies with the inclusion of much more patients will determine the optimal treatment strategy for this category of patients.
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Georgescu, Tiberiu-Augustin, Roxana Elena Bohiltea, Octavian Munteanu, Florentina Furtunescu, Antonia-Carmen Lisievici, Corina Grigoriu, Florentina Gherghiceanu, et al. "Emerging Therapeutic Concepts and Latest Diagnostic Advancements Regarding Neuroendocrine Tumors of the Gynecologic Tract." Medicina 57, no. 12 (December 7, 2021): 1338. http://dx.doi.org/10.3390/medicina57121338.
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Neuroendocrine neoplasms (NENs) are particularly rare in all sites of the gynecological tract and include a variety of neoplasms with variable prognosis, dependent on histologic subtype and site of origin. Following the expert consensus proposal of the International Agency for Research on Cancer (IARC), the approach in the latest World Health Organization (WHO) Classification System of the Female Genital Tumours is to use the same terminology for NENs at all body sites. The main concept of this novel classification framework is to align it to all other body sites and make a clear distinction between well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). The previous WHO Classification System of the Female Genital Tumours featured more or less the same principle, but used the terms ‘low-grade neuroendocrine tumor’ and ‘high-grade neuroendocrine carcinoma’. Regardless of the terminology used, each of these two main categories include two distinct morphological subtypes: NETs are represented by typical and atypical carcinoid and NEC are represented by small cell neuroendocrine carcinoma (SCNEC) and large cell neuroendocrine carcinoma (LCNEC). High-grade NECs, especially small cell neuroendocrine carcinoma tends to be more frequent in the uterine cervix, followed by the endometrium, while low-grade NETs usually occur in the ovary. NENs of the vulva, vagina and fallopian tube are exceptionally rare, with scattered case reports in the scientific literature.
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Zappi, Arianna, Irene Persano, Linda Galvani, Elena Parlagreco, Elisa Andrini, Davide Campana, Maria Pia Brizzi, Giuseppe Lamberti, and Anna La Salvia. "Chemotherapy in Well Differentiated Neuroendocrine Tumors (NET) G1, G2, and G3: A Narrative Review." Journal of Clinical Medicine 12, no. 2 (January 16, 2023): 717. http://dx.doi.org/10.3390/jcm12020717.
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Neuroendocrine tumors (NETs) are rare neoplasms with a wide spectrum of clinical behavior, from the long survival of well-differentiated NETs to the dismal prognosis of high-grade neuroendocrine carcinomas (NECs), being G3 NETs a recently recognized intermediate entity. While the role of chemotherapy is well established in NECs, data on NETs mostly derives from small studies, experts’ opinions, and extrapolating results from small-cell lung cancer studies. This narrative review aims to summarize available evidence about the use of chemotherapy in the setting of G1-2 NETs and G3 NETs. We performed literature research in PubMed Library for all articles published up to September 2022 about the efficacy of chemotherapy in NETs. Treatment regimens with STZ-5FU, CAPTEM, and anti-metabolite-based treatment are the most active and tolerated in gastroenteropancreatic NETs (GEP-NETs) G1-G2, while platinum-based regimens (FOLFOX/XELOX) and TEM/CAPTEM showed the best activity in thoracic NETs. Solid evidence about chemotherapy efficacy in G3 NETs is still lacking. Literature data support the use of chemotherapy in low-intermediate grade NETs after the failure of other therapies or if tumor shrinkage is needed. Studies assessing G3 NETs independently from NECs are needed to better understand the role of chemotherapy in this setting.
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Espinosa-Olarte, Paula, Anna La Salvia, Maria C. Riesco-Martinez, Beatriz Anton-Pascual, and Rocio Garcia-Carbonero. "Chemotherapy in NEN: still has a role?" Reviews in Endocrine and Metabolic Disorders 22, no. 3 (April 11, 2021): 595–614. http://dx.doi.org/10.1007/s11154-021-09638-0.
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AbstractNeuroendocrine neoplasms (NENs) comprise a broad spectrum of tumors with widely variable biological and clinical behavior. Primary tumor site, extent of disease, tumor differentiation and expression of so matostatin receptors, proliferation and growth rates are the major prognostic factors that determine the therapeutic strategy. Treatment options for advanced disease have considerably expanded in recent years, particularly for well differentiated tumors (NETs). Novel drugs approved over the past decade in this context include somatostatin analogues and 177Lu-oxodotreotide for somatostatin-receptor-positive gastroenteropancreatic (GEP) NETs, sunitinib for pancreatic NETs (P-NETs), and everolimus for P-NETs and non-functioning lung or gastrointestinal NETs. Nevertheless, chemotherapy remains an essential component of the treatment armamentarium of patients with NENs, particularly of patients with P-NETs or those with bulky, symptomatic or rapidly progressive tumors (generally G3 or high-G2 NENs). In this manuscript we will comprehensively review available evidence related to the use of chemotherapy in lung and GEP NENs and will critically discuss its role in the treatment algorithm of this family of neoplasms.
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Wang, Zhijie, Susheng Shi, Hongchang Ren, and Qian Liu. "Tumor Differentiation is the Dominant Prognostic Factor for Patients with Colorectal Neuroendocrine Neoplasms with Distant Metastasis." International Journal of Endocrinology 2022 (December 19, 2022): 1–10. http://dx.doi.org/10.1155/2022/1720624.
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Purpose. Colorectal neuroendocrine neoplasms (NENs) are rare tumors. The prognosis and prognostic factors of metastatic colorectal NENs have not been fully elucidated. Methods. We retrospectively enrolled 77 consecutive patients diagnosed with colorectal NENs with synchronous distant metastases between 2000 and 2021. All patients were assigned to the neuroendocrine tumor (NET) group or the neuroendocrine carcinoma (NEC) group based on histological differentiation. Propensity score matching (PSM) was performed to minimize confounding bias. The Kaplan–Meier method was used to calculate the survival rates. Univariate and multivariate logistic regression analyses were performed to identify prognostic factors. Results. In total, 35 (45.5%) and 42 (54.5%) patients had well-differentiated NETs and poorly differentiated NECs, respectively. The median overall survival (OS) was 26 months for the entire cohort, and the 1-year, 3-year, and 5-year OS rates were 69.4%, 41.4%, and 27.8%, respectively. In the subgroup analysis, the median OS was 62 and 10 months for NETs and NECs, respectively. Univariate analysis demonstrated that patients with a primary tumor located in the colon, ulcerative tumors and poorly differentiated tumors were at higher risk for poorer progression-free survival (PFS) and OS. However, only histological differentiation was identified as an independent factor affecting OS (hazard ratio (HR) = 8.28, 95% confidence interval (CI): 2.98–23.01, P < 0.001 ) in multivariate analysis. After PSM, histological differentiation was further confirmed as the dominant factor affecting OS (HR = 6.09, 95% CI: 1.96–18.95, P = 0.002 )). Conclusion. Histological differentiation was the most dominant prognostic factor in patients with metastatic colorectal NENs. Patients with well-differentiated NETs had a good chance of long-term survival.
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Tran, Catherine G., Luis C. Borbon, Jacqueline L. Mudd, Ellen Abusada, Solmaz AghaAmiri, Sukhen C. Ghosh, Servando Hernandez Vargas, et al. "Establishment of Novel Neuroendocrine Carcinoma Patient-Derived Xenograft Models for Receptor Peptide-Targeted Therapy." Cancers 14, no. 8 (April 10, 2022): 1910. http://dx.doi.org/10.3390/cancers14081910.
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Gastroenteropancreatic neuroendocrine neoplasms (GEP NENs) are rare cancers consisting of neuroendocrine carcinomas (NECs) and neuroendocrine tumors (NETs), which have been increasing in incidence in recent years. Few cell lines and pre-clinical models exist for studying GEP NECs and NETs, limiting the ability to discover novel imaging and treatment modalities. To address this gap, we isolated tumor cells from cryopreserved patient GEP NECs and NETs and injected them into the flanks of immunocompromised mice to establish patient-derived xenograft (PDX) models. Two of six mice developed tumors (NEC913 and NEC1452). Over 80% of NEC913 and NEC1452 tumor cells stained positive for Ki67. NEC913 PDX tumors expressed neuroendocrine markers such as chromogranin A (CgA), synaptophysin (SYP), and somatostatin receptor-2 (SSTR2), whereas NEC1452 PDX tumors did not express SSTR2. Exome sequencing revealed loss of TP53 and RB1 in both NEC tumors. To demonstrate an application of these novel NEC PDX models for SSTR2-targeted peptide imaging, the NEC913 and NEC1452 cells were bilaterally injected into mice. Near infrared-labelled octreotide was administered and the fluorescent signal was specifically observed for the NEC913 SSTR2 positive tumors. These 2 GEP NEC PDX models serve as a valuable resource for GEP NEN therapy testing.
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Vanoli, Alessandro, Stefano La Rosa, Emanuela Miceli, Catherine Klersy, Roberta Maragliano, Francesca Capuano, Andrea Persichella, et al. "Prognostic Evaluations Tailored to Specific Gastric Neuroendocrine Neoplasms: Analysis Of 200 Cases with Extended Follow-Up." Neuroendocrinology 107, no. 2 (2018): 114–26. http://dx.doi.org/10.1159/000489902.
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Background: Gastric neuroendocrine neoplasms (NENs) are very heterogeneous, ranging from mostly indolent, atrophic gastritis-associated, type I neuroendocrine tumors (NETs), through highly malignant, poorly differentiated neuroendocrine carcinomas (pdNECs), to sporadic type III NETs with intermediate prognosis, and various rare tumor types. Histologic differentiation, proliferative grade, size, level of gastric wall invasion, and local or distant metastases are used as prognostic markers. However, their value remains to be tailored to specific gastric NENs. Methods: Series of type I NETs (n = 123 cases), type III NETs (n = 34 cases), and pdNECs (n = 43 cases) were retrospectively collected from four pathology centers specializing in endocrine pathology. All cases were characterized clinically and histopathologically. During follow-up (median 93 months) data were recorded to assess disease-specific patient survival. Results: Type I NETs, type III NETs, and pdNECs differed markedly in terms of tumor size, grade, invasive and metastatic power, as well as patient outcome. Size was used to stratify type I NETs into subgroups with significantly different invasive and metastatic behavior. All 70 type I NETs < 0.5 cm (micro-NETs) were uneventful. Ki67-based grading proved efficient for the prognostic stratification of type III NETs; however, grade 2 (G2) was not associated with tumor behavior in type I NETs. Although G3 NETs (2 type I and 9 type III) had a very poor prognosis, it was found that patient survival was longer with type III G3 NETs compared to pdNECs. Conclusions: Given the marked, tumor type-related behavior differences, evaluation of gastric NEN prognostic parameters should be tailored to the type of neoplastic disease.
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Li, Junjie, Jing Wang, Dan Su, Xiu Nie, Yueping Liu, Lianghong Teng, Junyi Pang, Huanwen Wu, and Zhiyong Liang. "p53 Immunohistochemistry Patterns Are Surrogate Biomarkers for TP53 Mutations in Gastrointestinal Neuroendocrine Neoplasms." Gastroenterology Research and Practice 2021 (December 15, 2021): 1–9. http://dx.doi.org/10.1155/2021/2510195.
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Aims. The aim of this study was to establish p53 immunohistochemistry (IHC) patterns to predict TP53 mutations in gastrointestinal neuroendocrine neoplasms (GI-NENs) and to determine whether p53 IHC patterns could be used for the differential diagnosis of neuroendocrine neoplasms. Methods. TP53 gene sequencing and p53 IHC were performed on formalin-fixed paraffin-embedded (FFPE) tissue samples from 92 patients diagnosed with GI-NENs from five medical centers. Results. The cohort included 35 well-differentiated neuroendocrine tumors and 57 poorly differentiated neuroendocrine carcinomas. Gene sequencing revealed 38 wild-type TP53 and 54 TP53 mutations. p53 expression was interpreted as follows: pattern A, p53 was absent from all tumor cells; pattern B, scattered and weak p53 expression in 1-20% of tumor cells; and pattern C was subclassified as pattern C1: variable p53 staining intensity in 21-60% of tumor cells and tumor cell nests with focal strong positive p53 staining and pattern C2: strong p53 staining in more than 60% of tumor cells. p53 IHC patterns were evaluated as a binary classifier where pattern B predicted wild-type TP53, and patterns A and C predicted TP53 mutations. The sensitivity, specificity, and overall accuracy of this binary classification to predict TP53 status were 0.963, 0.868, and 0.924, respectively. p53 IHC patterns were also correlated with TP53 mutation types. Most cases with pattern A harboured loss-of-function (LOF) mutations, whereas patterns B and C tended to indicate wild-type TP53 and gain-of-function (GOF) mutations, respectively. Furthermore, most of the well-differentiated NETs showed pattern B, whereas pattern C2 was more common in poorly differentiated NECs. Finally, staining interpretation between different observers also yielded high reproducibility. Conclusions. p53 IHC patterns may be used as predictors of TP53 gene mutations and therefore could be potential surrogate markers for TP53 mutations in GI-NENs and could distinguish between well-differentiated NETs and poorly differentiated NECs.
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Evdokimova, E. V., E. V. Artamonova, V. V. Delectorskaya, G. Yu Chemeris, G. S. Emelyanova, S. G. Bagrova, and A. A. Markovich. "Treatment tactics of new NET G3 subgroup in first line of therapy." Medical alphabet, no. 37 (January 2, 2022): 20–24. http://dx.doi.org/10.33667/2078-5631-2021-37-20-24.
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Considering the fact that the group of neuroendocrine carcinomas (NECs) grade 3 is heterogenous, in the year of 2017 a new subgroup of welldifferentiated neuroendocrine tumors grade 3 (NETs G3) was described. NETs G3 are tumors with more favorable prognosis and less sensitive to platinum-based chemotherapy regimens than NECs, they also have peculiar morphogenetical qualities: lower ki‑67 index (mean 35.0 %), higher somatostatin receptors expression, absence of DAXX/ATRX/MEN 1 genes mutation, p53 expression in the absence of TP53 mutation. Nowadays treatment standard for NETs G3 subgroup is still remain unclear due to lack of prospective clinical trials. At the same time taking in note historical retrospective data, NETs G3 should be treated in line with NETs G1/G2 and only patients with higher ki‑67 index can be treated as NECs with platinum-based chemotherapy. In our non-randomised phase II prospective trial, we accessed the efficacy of different chemotherapy regimens in combination with somatostatin analogues in new NETs G3 subgroup. 153 patients with IHC-confirmed neuroendocrine neoplasm diagnose were included: NETs G3 n = 53 mean ki‑67 36.4 % [21.0–60.0 %], NETs G2 n = 50 mean ki‑67 15.7 % [2.1–20.0 %], NECs n = 50 mean ki‑67 69.0 % [38.0–96.0 %]). Patients from NETs G3 subgroup received 4 chemotherapy regimens: Aranose (n = 19), Aranose (arabinopiranosilmethyl nitrosocarbamide, ALK, – cytostatic drug with a chemical structure similar to Streptozotocin and Nitrosomethylurea, approved in Russian Federation for melanoma and welldifferentiated neuroendocrine tumors treatment), XELOX (n = 8), TemCAP (n = 11), EP/EC (n = 10). mPFS in Aranose-subgroup was 19.3 ± 5.9 months (95 % CI: 7.7–30.8), in XELOX – 10.8 ± 3.6 months (3.7–17.8), in TemCAP – 14.8 ± 4.2 months (6.6–23.1) and in platinum-based regimens – 4.4 ± 1.9 months (0.6–8.2) (p = 0.01). DCR in Aranose subgroup was 73.6 % and ORR – 36.8 %, PDR – 21.1 %, in XELOX subgroup ORR was 62.5 %, SDR was 50.0 % and PDR – 25.0 %, in TemCAP subgroup DCR was 63.6 %, ORR – 9.1 %, PDR – 18.2 % and in platinum-based regimens SDR was 40.0 %, PDR – 50.0 % (p = 0.05).
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Shogbesan, Oluwaseun, Abdullateef Abdulkareem, Binu Pappachen, and John Altomare. "Primary Mesenteric Carcinoid Tumor Presenting with Carcinoid Syndrome." Case Reports in Gastroenterology 12, no. 2 (August 21, 2018): 396–401. http://dx.doi.org/10.1159/000490522.
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Neuroendocrine neoplasms (NENs) are a diverse group of tumors arising throughout the body with a common origin from neuroendocrine cells. Well-differentiated NENs, also known as neuroendocrine tumors (NETs), are generally indolent and are often found incidentally, while poorly differentiated tumors are more aggressive. Carcinoid tumors are NETs arising from the gastrointestinal tract and less commonly from the lungs, thymus, and kidneys. NETs in the mesentery arise from metastasis from primary tumor, and carcinoid syndrome in this setting results from concomitant metastasis to the liver. Primary mesenteric carcinoid tumors are very rare. We present a 64-year-old man with carcinoid syndrome from a mesenteric carcinoid tumor without evidence of liver metastasis or other primary tumor sites.
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Marchese, Ugo, Martin Gaillard, Anna Pellat, Stylianos Tzedakis, Einas Abou Ali, Anthony Dohan, Maxime Barat, Philippe Soyer, David Fuks, and Romain Coriat. "Multimodal Management of Grade 1 and 2 Pancreatic Neuroendocrine Tumors." Cancers 14, no. 2 (January 15, 2022): 433. http://dx.doi.org/10.3390/cancers14020433.
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Pancreatic neuroendocrine tumors (p-NETs) are rare tumors with a recent growing incidence. In the 2017 WHO classification, p-NETs are classified into well-differentiated (i.e., p-NETs grade 1 to 3) and poorly differentiated neuroendocrine carcinomas (i.e., p-NECs). P-NETs G1 and G2 are often non-functioning tumors, of which the prognosis depends on the metastatic status. In the localized setting, p-NETs should be surgically managed, as no benefit for adjuvant chemotherapy has been demonstrated. Parenchymal sparing resection, including both duodenum and pancreas, are safe procedures in selected patients with reduced endocrine and exocrine long-term dysfunction. When the p-NET is benign or borderline malignant, this surgical option is associated with low rates of severe postoperative morbidity and in-hospital mortality. This narrative review offers comments, tips, and tricks from reviewing the available literature on these different options in order to clarify their indications. We also sum up the overall current data on p-NETs G1 and G2 management.
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Das, Satya, Taymeyah Al-Toubah, and Jonathan Strosberg. "Chemotherapy in Neuroendocrine Tumors." Cancers 13, no. 19 (September 29, 2021): 4872. http://dx.doi.org/10.3390/cancers13194872.
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The role for cytotoxic chemotherapy in patients with well-differentiated neuroendocrine tumors (NETs) remains debated. Compared to patients with poorly differentiated neuroendocrine carcinomas (NECs) where chemotherapy is utilized ubiquitously, chemotherapy may play a more select role in patients with certain types of NETs (e.g., pancreatic tumors, higher grade tumors, and tumors possessing DNA damage repair defects). The primary types of chemotherapy that have been tested in patients with NETs include alkylating agent- and platinum agent-based combinations. Across regimens, chemotherapy appears to elicit greater antitumor activity in patients with pancreatic or grade 3 NETs. The role for chemotherapy in lower grade extra-pancreatic NETs remains undefined. Furthermore, while chemotherapy has demonstrated clinically meaningful benefit for patients in the systemic setting, its role in the adjuvant or neoadjuvant setting is as-of-yet undetermined. Finally, efforts to combine chemotherapy with targeted therapy and peptide receptor radionuclide therapy are ongoing, in hopes of improving the cytoreductive treatment options for patients with NETs.
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Pantelis, Athanasios G., Panagiota A. Panagopoulou, and Dimitris P. Lapatsanis. "Artificial Intelligence and Machine Learning in the Diagnosis and Management of Gastroenteropancreatic Neuroendocrine Neoplasms—A Scoping Review." Diagnostics 12, no. 4 (March 31, 2022): 874. http://dx.doi.org/10.3390/diagnostics12040874.
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Neuroendocrine neoplasms (NENs) and tumors (NETs) are rare neoplasms that may affect any part of the gastrointestinal system. In this scoping review, we attempt to map existing evidence on the role of artificial intelligence, machine learning and deep learning in the diagnosis and management of NENs of the gastrointestinal system. After implementation of inclusion and exclusion criteria, we retrieved 44 studies with 53 outcome analyses. We then classified the papers according to the type of studied NET (26 Pan-NETs, 59.1%; 3 metastatic liver NETs (6.8%), 2 small intestinal NETs, 4.5%; colorectal, rectal, non-specified gastroenteropancreatic and non-specified gastrointestinal NETs had from 1 study each, 2.3%). The most frequently used AI algorithms were Supporting Vector Classification/Machine (14 analyses, 29.8%), Convolutional Neural Network and Random Forest (10 analyses each, 21.3%), Random Forest (9 analyses, 19.1%), Logistic Regression (8 analyses, 17.0%), and Decision Tree (6 analyses, 12.8%). There was high heterogeneity on the description of the prediction model, structure of datasets, and performance metrics, whereas the majority of studies did not report any external validation set. Future studies should aim at incorporating a uniform structure in accordance with existing guidelines for purposes of reproducibility and research quality, which are prerequisites for integration into clinical practice.
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Chmiel, Paulina, Paulina Rychcik-Pazyrska, and Rafał Stec. "Defining Tumor Microenvironment as a Possible Target for Effective GEP-NENs Immunotherapy—A Systematic Review." Cancers 15, no. 21 (October 31, 2023): 5232. http://dx.doi.org/10.3390/cancers15215232.
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Neuroendocrine neoplasms (NENs) are a heterogenous and recurrent group of malignancies originating from neuroendocrine secretory cells diffused on all parts of the human body. Gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) account for most NENs. Considering the abundance of possible origins, locations, and tumor specifications, there is still no consensus about optimal treatment options for these neoplasms. In light of the escalating immunotherapeutic approaches, it is crucial to define indications for such therapy in GEP-NETs. Bearing in mind the significance of pathophysiological mechanisms and tumor microenvironment (TME) impact on carcinogenesis, defining TME structure and correlation with the immune system in GEP-NETs appears essential. This paper aimed to assess the characterization of the tumor immune microenvironment for a better understanding of the possible therapeutic options in GEP-NETS. The authors performed a systematic review, extracting papers from the PubMed, Web of Science, and Scopus databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Among 3800 articles identified through database searching, 292 were assessed for eligibility. Ultimately, 28 articles were included in the qualitative synthesis. This paper sums up the research on the immune cell infiltrates, immune checkpoint expression, cytokine profile, neoangiogenesis, and microbiome in the TME of GEP-NETs.
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Oka, Naomi, Atsuko Kasajima, Björn Konukiewitz, Akira Sakurada, Yoshinori Okada, Toru Kameya, Wilko Weichert, et al. "Classification and Prognostic Stratification of Bronchopulmonary Neuroendocrine Neoplasms." Neuroendocrinology 110, no. 5 (August 19, 2019): 393–403. http://dx.doi.org/10.1159/000502776.
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The accuracy and reproducibility of the World Health Organization (WHO) 2015 classification of bronchopulmonary neuroendocrine neoplasms (BP-NENs) is disputed. The aim of this study is to classify and grade BP-NENs using the WHO 2019 classification of digestive system NENs (DiS-NEN-WHO 2019), and to analyze its accuracy and prognostic impact. Two BP-NEN cohorts from Japan and Germany, 393 tumors (88% surgically resected), were reviewed and the clinicopathological data of the resected tumors (n = 301) correlated to patients’ disease-free survival (DFS). The DiS-NEN-WHO 2019 stratified the 350 tumors into 91 (26%) neuroendocrine tumors (NET) G1, 52 (15%) NET G2, 15 (4%) NET G3, and 192 (55%) neuroendocrine carcinomas (NEC). NECs, but not NETs, were immunohistochemically characterized by abnormal p53 (100%) and retinoblastoma 1 (83%) expression. The Ki67 index, which was on average 4 times higher than mitotic count (p < 0.0001), was prognostically more accurate than the mitotic count. NET G3 patients had a worse outcome than NET G1 (p < 0.01) and NET G2 patients (p = 0.02), respectively. No prognostic difference was detected between NET G3 and NEC patients after 5 year DFS. It is concluded that stratifying BP-NEN patients according to the DiS-NEN-WHO 2019 classification results in 3 prognostically well-defined NET groups, if grading is solely based on Ki67 index. Mitotic count alone may underestimate malignant potential of NETs.
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Klimstra, David S., Himisha Beltran, Rogerio Lilenbaum, and Emily Bergsland. "The Spectrum of Neuroendocrine Tumors: Histologic Classification, Unique Features and Areas of Overlap." American Society of Clinical Oncology Educational Book, no. 35 (May 2015): 92–103. http://dx.doi.org/10.14694/edbook_am.2015.35.92.
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Neuroendocrine neoplasms are diverse in terms of sites of origin, functional status, and degrees of aggressiveness. This review will introduce some of the common features of neuroendocrine neoplasms and will explore the differences in pathology, classification, biology, and clinical management between tumors of different anatomic sites, specifically, the lung, pancreas, and prostate. Despite sharing neuroendocrine differentiation and histologic evidence of the neuroendocrine phenotype in most organs, well-differentiated neuroendocrine tumors (WD-NETs) and poorly differentiated neuroendocrine carcinomas (PD-NECs) are two very different families of neoplasms. WD-NETs (grade 1 and 2) are relatively indolent (with a natural history that can evolve over many years or decades), closely resemble non-neoplastic neuroendocrine cells, and demonstrate production of neurosecretory proteins, such as chromogranin A. They arise in the lungs and throughout the gastrointestinal tract and pancreas, but WD-NETs of the prostate gland are uncommon. Surgical resection is the mainstay of therapy, but treatment of unresectable disease depends on the site of origin. In contrast, PD-NECs (grade 3, small cell or large cell) of all sites often demonstrate alterations in P53 and Rb, exhibit an aggressive clinical course, and are treated with platinum-based chemotherapy. Only WD-NETs arise in patients with inherited neuroendocrine neoplasia syndromes (e.g., multiple endocrine neoplasia type 1), and some common genetic alterations are site-specific (e.g., TMPRSS2-ERG gene rearrangement in PD-NECs arising in the prostate gland). Advances in our understanding of the molecular basis of NETs should lead to new diagnostic and therapeutic strategies and is an area of active investigation.
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Maryański, Jan, Agata Cyran-Chlebicka, Benedykt Szczepankiewicz, Włodzimierz Cebulski, Maciej Słodkowski, and Marek Wroński. "Surgical treatment of extra-appendiceal colorectal neuroendocrine tumors." Polish Journal of Surgery 90, no. 3 (May 16, 2018): 7–12. http://dx.doi.org/10.5604/01.3001.0011.8164.
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Background: Extra-appendiceal colorectal neuroendocrine tumors are rare neoplasms with a variable biological behavior. Materials and Methods: The study group consisted of 15 patients with an extra-appendiceal colorectal neuroendocrine tumor who underwent surgical resection (M/F=3:12, mean age=62.9 years). Lower-grade neuroendocrine tumors and neuroendocrine carcinomas were recognized in 5 and 10 patients, respectively. Data were evaluated retrospectively with regard to clinical and pathologic characteristics and outcomes. Results: The median age of the patients with lower-grade NETs was significantly lower than that in patients with NECs (53 yr vs. 68 yr, p=0.03). NETs G1-G2 were significantly smaller than neuroendocrine carcinomas (4.0 cm vs. 6.4 cm, p=0.02). There were no differences between lower-grade NETs and NECs with regard to tumor location, rate of nodal involvement and distant metastases. All the patients underwent open segmental resection of the colon or rectum. Complete resection was achieved in 3 of 5 patients from the lower-grade NET group, and in 5 of 10 patients in the NEC group. Overall survival was significantly better for lower-grade NETs tumors (p=0.005). The median survival was 4.8 months in the NEC group. The median survival in the lower-grade NET group was not achieved after a median follow-up of 69 months. Three-year overall survival was 100% for lower-grade NETs, and only 27% for NECs. Conclusion: Lower-grade neuroendocrine tumors seem to exhibit comparable potential for dissemination as neuroendocrine carcinomas, but prognostic implications of metastases are distinct.
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Peregorodiev, I. N., S. V. Vinokurova, V. Yu Bohyan, V. V. Delektorskaya, O. A. Malikhova, V. A. Gorbunova, B. I. Sakibov, D. S. Elkin, and I. S. Stilidi. "Role of microRNAs in neuroendocrine neoplasms of the stomach." Advances in Molecular Oncology 7, no. 3 (November 24, 2020): 19–26. http://dx.doi.org/10.17650/2313-805x-2020-7-3-19-26.
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Neuroendocrine neoplasms (NENs) are a heterogeneous group of rare epithelial tumors that arise from cells with a neuroendocrine phenotype. NENs are found in the gastrointestinal tract and pancreas – 60 % of all localities. The incidence of gastric NENs is about 9 % of all neuroendocrine tumors of the gastrointestinal tract and 0.3 % of all stomach tumors. Stomach neuroendocrine tumors (NETs) are classified into three clinico-pathological types, based on etiology, pathogenesis and morphology. There are also separate neuroendocrine cancers: small- and large-cell. The prognosis and approach to treatment of various types of gastric NENs differs significantly. Modern methods of instrumental diagnostics, immunohistochemical methods of morphological research, along with light microscopy, do not always allow us to accurately assess the malignant potential of a tumor and individualize the treatment process. One of the promising directions in the study of NETs is to determine the molecular mechanism underlying their development, in particular the role of microRNAs. This direction can open a new vector of understanding the pathogenesis, determining the prognosis of the disease, as well as finding new application points for the drug treatment of NETs. MicroRNAs are a class of short non-coding RNA molecules (18–25 nucleotides). MicroRNAs can be involved in the regulation of all major cellular processes, including proliferation and differentiation, metabolism, signaling pathways, and apoptosis. A study of microRNA expression in tissues revealed tumor-specific microRNAs. In contrast to a number of other malignant tumors, microRNA expression in patients diagnosed with NENs is poorly understood. MicroRNA-222 and microRNA-202 are among the few microRNAs that have been demonstrated in the NETs of the stomach.
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Mandair, Dalvinder, Leonidas-Nikolaos Diamantopoulos, George Demetriou, Faidon Laskaratos, Christos Toumpanakis, and Martyn E. Caplin. "Typical bronchial NETs as a misleading biology." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 8528. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.8528.
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8528 Background: Bronchial Neuroendocrine tumours (NETs) are rare with an incidence of between 0.2 – 2 per 100,000 population. There has been an increase in prevalence due to increased awareness, enhanced immunohistochemistry and greater use of Computed tomography (CT). Bronchial NETs are classified according to the WHO guidelines developed in 2004 where they are graded by histological classification into ‘typical’, ‘atypical’ NETs or small and large neuroendocrine carcinoma’s (NECs). Typical NETs are regarded as being low-grade malignant however metastatic disease can still develop. Aims: We sought to determine the incidence of metastatic typical bronchial NETs, their survival and investigate the imaging and treatment used in their management. Methods: We performed a retrospective analysis of all bronchial NETs managed at our centre from 2001 to 2016. From those identified as typical NETs, we analysed clinical records in those with advanced disease (Stage IV). Results: From a total of 251 bronchial NETs, there were 147 ‘Typical’ NETs, 30(20%) of whom had advanced disease compared to 82 'Atypical' bronchial NETs of whom 55 had advanced disease (67%). The median age at diagnosis was 58 (range 24-77). In the 'Typical' NETs, 24/30 had liver metastases, 19/30 skeletal metastases, and 16 had carcinoid syndrome (CS). Functional imaging with FDG PET scan was positive in 7/10 patients and somatostatin receptor scintigraphy (SRS) positive in 16/20 and in 4/11 there was avidity with both. 20 patients were treated with somatostatin analogues predominantly for CS symptoms. 11 patients treated with peptide radiolabelled receptor targeted therapy (PRRT) with a median Time-To-Progression (TTP) of 27 months. 11 patients received chemotherapy with median TTP of 16 months with 4 patients demonstrating partial response. Conclusions: Typical bronchial NETs can lead to advanced disease in up to 20% of patients. Their behavior can be aggressive and is not predictable by histology alone. Functional imaging with both FDG and SRS may help determine the most appropriate treatment. Both PRRT and chemotherapy can be considered in progressive disease.
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Yoon, Susik, Jae-Gil Lee, and Byung Suk Lee. "NETS." Proceedings of the VLDB Endowment 12, no. 11 (July 2019): 1303–15. http://dx.doi.org/10.14778/3342263.3342269.
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Abe, Jonathan D., Lawrence R. Alexander, Christopher F. Clark, and Richard A. Rosen. "NETS." Electricity Journal 12, no. 4 (May 1999): 46–54. http://dx.doi.org/10.1016/s1040-6190(99)00026-3.
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Kotsiopoulos, Dorian. "Nets." JAMA 312, no. 18 (November 12, 2014): 1933. http://dx.doi.org/10.1001/jama.2014.8866.
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Bartels, Arthur, Christopher L. Douglas, and André Henriques. "Conformal Nets I: Coordinate-Free Nets." International Mathematics Research Notices 2015, no. 13 (June 6, 2014): 4975–5052. http://dx.doi.org/10.1093/imrn/rnu080.
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Bonazzi, Norma, Emilia Fortunati, Lucia Zanoni, Giulia Argalia, Diletta Calabrò, Elena Tabacchi, Vincenzo Allegri, et al. "Real-Life Use of [68Ga]Ga-DOTANOC PET/CT in Confirmed and Suspected NETs from a Prospective 5-Year Electronic Archive at an ENETS Center of Excellence: More Than 2000 Scans in More Than 1500 Patients." Cancers 16, no. 4 (February 7, 2024): 701. http://dx.doi.org/10.3390/cancers16040701.
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The recent introduction of novel treatments for advanced neuroendocrine tumors (NETs) and the well-established impact of clinical case discussion within dedicated multidisciplinary teams indicates the need to promote the centralization of rare diseases, such as NENs (neuroendocrine neoplasms). Data on the real-life use of and indications for [68Ga]Ga-DOTANOC PET/CT were collected from a prospective monocentric 5-year electronic archive including consecutive patients with confirmed and suspected NETs (September 2017 to May 2022). Overall, 2082 [68Ga]Ga-DOTANOC PET/CT scans (1685 confirmed NETs, 397 suspected NETs) were performed in 1537 patients. A high positivity rate was observed across different clinical settings (approximately 70%). Approximately 910/2082 scans were requested by the local oncology ward (851 confirmed NETs, 59 suspected NETs). The following observations were found: (i) the detection rate across all indications was 73.2% (higher for staging, peptide receptor radioligand therapy (PRRT) selection, and treatment response assessment); (ii) in suspected NETs, PET was more often positive when based on radiological findings. This systematic data collection in a high-volume diagnostic center represents a reliable cohort reflecting the global trends in the use of [68Ga]Ga-DOTANOC PET/CT for different clinical indications and primary tumor sites, but prompts the need for further multicenter data sharing in such a rare and slowly progressive disease setting.
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M. Pandian. "Habitats of House Sparrow Passer domesticus (Linnaeus, 1758) in Rameswaram Island, Tamil Nadu, India." Journal of Threatened Taxa 15, no. 2 (February 26, 2023): 22586–96. http://dx.doi.org/10.11609/jott.7879.15.2.22586-22596.
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This paper pertains to the nesting habitats of House Sparrow Passer domesticus with specific reference to population dynamics, nesting-related habits, nests, behaviours and other threats faced by these birds in Rameswaram Island. A total of 2,988 adult House Sparrows and 407 active nests were counted during the study. Of nests counted, 19% (n = 77) were solitary. The highest number of nests observed in a cluster was 9 (2 clusters). 60% of nests (n = 244) were found in concrete buildings, 39% (n = 159) in artificial nest-boxes, and 35% (n = 144) in cavities/crevices within buildings. House Sparrow population exhibited nesting plasticity, and 2% of nests were found constructed on vegetation. A wide variety of locally available materials, such as pieces of synthetic fishing nets, nylon ropes, and polythene papers were used for construction of nests. Sand and water bathing by birds were observed. Accidental fall of eggs and chicks, predation of nests by House Crows Corvus splendens, and unsuccessful attempts to predate adult birds by Black Kite Milvus migrans were observed, as well as opportunistic sightings of Shikra Accipiter badius.
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Memmi, G., and A. Finkel. "An introduction to FIFO nets— monogeneous nets: A subclass of FIFO nets." Theoretical Computer Science 35 (1985): 191–214. http://dx.doi.org/10.1016/0304-3975(85)90014-3.
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Tran, Catherine G., Luis C. Borbon, Dane H. Tow, Jonathan Shilyansky, Guiying Li, James Egan, Scott K. Sherman, et al. "Abstract 3578: A systematic NEN spheroid drug screen reveals a novel drug resistance mechanism in small bowel NETs." Cancer Research 84, no. 6_Supplement (March 22, 2024): 3578. http://dx.doi.org/10.1158/1538-7445.am2024-3578.
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Abstract Neuroendocrine neoplasms (NENs) are rare cancers that arise from neuroendocrine cells. NENs are classified as well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Small bowel NETs (SBNETs) and pancreatic NETs (PNETs) are generally slow growing but they commonly metastasize to the liver and can become aggressive cancers. NECs are rapidly growing, and patients have poor prognosis. Little is known about the drug sensitivity profile of SBNETs, PNETs and NECs due to a paucity of cellular and animal models of these malignancies. We have successfully cultured NEN cells from clinical samples as patient-derived spheroids (PDS) and showed that they express appropriate tumor markers. We systematically screened 20 NEN (12 SBNET, 5 PNET, and 3 NEC) spheroid cultures against a library of 175 compounds (147 FDA-approved anti-cancer drugs, 8 lab selected compounds, and 20 structurally diverse molecules) and compared their drug sensitivity profiles to identify the most effective drug classes and to better understand the biology of each NEN subtype. Top drug hits were validated for their anti-tumor properties in NEN PDS and patient-derived xenograft (PDX) mouse models. Our NEN PDS cultures identified common and unique drug sensitivity profiles for each type of NEN. SBNET spheroids were more resistant to many classes of anti-cancer drugs, which was due to overexpression of cytochrome P450 genes. Consistent with clinical findings, PNET spheroids showed increased sensitivity to tyrosine kinase and mTOR/PI3K inhibitors compared to SBNET & NEC spheroids. NEC spheroids showed the broadest sensitivity to many anti-neoplastic compounds. The top candidate drug identified from our screen was romidepsin, a histone deacetylase inhibitor. Romidepsin displayed anti-tumor properties in vitro and in vivo for all 3 NEN models and was highly synergistic with rapamycin, an mTOR inhibitor similar to the SBNET approved drug everolimus. Excitingly, low-dose romidepsin effectively inhibited tumor growth when combined with low-dose rapamycin in an SBNET PDX mouse model. These NEN PDS drug screens enabled direct drug testing in primary tumor cultures to identify promising drugs that could be used alone or in combination with currently approved-NEN therapies. Histone deacetylase inhibitors, such as romidepsin, may be effective against SBNETs. NEN PDS models also serve as a valuable resource for understanding the unique biology and mechanisms of drug resistance for specific NEN subtypes. Citation Format: Catherine G. Tran, Luis C. Borbon, Dane H. Tow, Jonathan Shilyansky, Guiying Li, James Egan, Scott K. Sherman, Ellen Abusada, Jing Tang, Ramaswamy govindan, Ryan C. Fields, Terry A. Braun, Carlos HF Chan, Chandrikha Chandrasekharan, Douglas Spitz, Dawn E. Quelle, Andrew M. Bellizzi, James R. Howe, Po Hien Ear. A systematic NEN spheroid drug screen reveals a novel drug resistance mechanism in small bowel NETs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3578.
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Hinterleitner, Martina, Bence Sipos, Verena Wagner, Julia M. Grottenthaler, Ulrich M. Lauer, Lars Zender, and Clemens Hinterleitner. "Platelet-Expressed Synaptophysin (pSyn) as Novel Biomarker in Neuroendocrine Malignancies." Cancers 13, no. 10 (May 11, 2021): 2286. http://dx.doi.org/10.3390/cancers13102286.
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Neuroendocrine neoplasms (NENs) encompass a heterogeneous group of tumors. Whereas low-grade neuroendocrine tumors (NETs) are histologically well-differentiated, highly aggressive neuroendocrine carcinomas (NECs) are characterized by a high proliferation rate and a worse clinical outcome. Since most NEN patients need monitoring of tumor progress and response to treatment for a long period of time, especially in metastatic disease, reliable, dynamic, and easy-to-assess biomarkers are needed. In this prospective study, we identified platelet-expressed synaptophysin (pSyn) as a novel biomarker in NENs. The level of pSyn in NENs was significantly upregulated compared to healthy donors. pSyn was positively correlated with higher tumor stages, the occurrence of metastasis, histological grading, and higher tumor proliferation (Ki67). Most importantly, high pSyn expression in our NEN cohort was shown to predict shorter progression-free survival (PFS). In conclusion, our data highlight the potential of pSyn as a novel biomarker in NENs reflecting tumor stages, grading, and prognosis.
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Lettrich, Jaroslav. "Anti-nets. II. (Collineations of anti-nets)." Časopis pro pěstování matematiky 112, no. 1 (1987): 32–57. http://dx.doi.org/10.21136/cpm.1987.118293.
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Hobart, S. A., and D. R. Hughes. "Extended Partial Geometries: Nets and Dual Nets." European Journal of Combinatorics 11, no. 4 (July 1990): 357–72. http://dx.doi.org/10.1016/s0195-6698(13)80138-2.
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Delgado Friedrichs, Olaf, Michael O'Keeffe, and Omar M. Yaghi. "Three-periodic nets and tilings: semiregular nets." Acta Crystallographica Section A Foundations of Crystallography 59, no. 6 (October 28, 2003): 515–25. http://dx.doi.org/10.1107/s0108767303017100.
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Bonneau, Charlotte, Olaf Delgado-Friedrichs, Michael O'Keeffe, and Omar M. Yaghi. "Three-periodic nets and tilings: minimal nets." Acta Crystallographica Section A Foundations of Crystallography 60, no. 6 (October 26, 2004): 517–20. http://dx.doi.org/10.1107/s0108767304015442.
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Sinaga, Meiana Olivia, Irawadi Gunawan, Ricky Djauhari, Maryani Maryani, and Murrod C. Wirabakti. "Kinerja Pertumbuhan Benih Ikan Lele (Clarian gariepinus) Yang Diberi Prebiotik Ekstrak Umbi Sarang Semut (Myrmecodia pendans) dan Probiotik Lacticaseibacillus paracasei." Jurnal Akuakultur Sungai dan Danau 7, no. 2 (October 28, 2022): 68. http://dx.doi.org/10.33087/akuakultur.v7i2.131.
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This study aimed to evaluated the growth performance of dumbo catfish (Clarias gariepinus). In this study, ant nest tuber extract and probiotic Lacticaseibacillus paracasei were mixed into feed with the coated method without the addition of ant nest tuber extract and probiotic Lacticaseibacillus paracasei (A), 1% ant nest tuber extract (B), probiotic Lacticaseibacillus paracasei 1% (C). and a combination of ant nest tuber extract and probiotic Lacticaseibacillus paracasei each 1% (D). Fish with an initial body weight of 1.5 - 2 g were kept in 3 ponds (15x10x1.5) m3 with a total of 12 hapa nets measuring 1x1x1 (m3) (45 fish / hapa nets). Fish were fed treatment with three replications for 35 days. The best feed efficiency, feed conversion ratio, daily growth rate and absolute weight growth were found in the African catfish fry group that consumed a combination of feed supplementation with 1% dose of ant nest tuber extract and 1% dose of probiotic Lacticaseibacillus paracasei, each of 185.47%. , 0,55,7,79%, and 20,80 gr
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Wang, Jian, Xiangling Wang, Yunxia Chu, Shuguang Li, and Jing Hao. "Oxaliplatin based chemotherapy for advanced well-differentiated neuroendocrine tumors: A systematic review and meta-analysis." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): e16240-e16240. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.e16240.
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e16240 Background: Currently, chemotherapy is predominantly considered in advanced well-differentiated neuroendocrine tumors (NENs) with high ki67 proliferation index and tumor burden. So far, no standard regimen is available and alkylating agents alone, such as temozolomide or in combination with 5-fluorouracil or capecitabine are widely used. Besides, oxaliplatin based chemotherapy has shown promising antitumor activity without being influenced by the MGMT status. In the current SRMA, we aim to address the efficacy of oxaliplatin based chemotherapy in advanced well differentiated NENs. Methods: We conducted a systematic database search using PubMed/MEDLINE and EMBASE. Eligible studies included randomized and single-arm trials, prospective observational and retrospective studies documenting the clinical efficacy of oxaliplatin based chemotherapy for advanced well-differentiated NENs. The pooled overall response rate (ORR), median progression-free survival (PFS), and median overall survival (OS) were calculated and weighted using generic inverse variance in a random-effects model, as well as subgroup analysis for pts with pancreatic NETs (pNETs) and extra-pancreatic NETs (epNETs), G1-2 and G3 NETs. Results: 14 of 24 identified publications were included with a combined total of 865 patients in 3 phase II trial and 11 retrospective studies. 495 pts received FOLFOX, 155 pts XELOX, 130 pts GEMOX and 138 pts plus bevacizumab. 48.4% (419/865) patients were pNETs, and G3 NETs accounted for 21.7% (188/865). The pooled ORR was 27.9% (237/865, 95% CI: 23.2-32.5). pNETs showed much higher ORRs (37.7%,114/303, 95% CI: 31.1-44.3) than epNETs (14.9%, 40/251, 95% CI: 10.5-19.2), χ2 = 32.17, p < 0.001. ORRs in G1-2 NETs was 23.1% (66/273, 95% CI: 18.2-28.1), while in G3 NETs was 45.7% (42/85, 95% CI: 29.7-61.6), χ2 = 19.60, p < 0.001. FOLFOX plus bevacizumab showed a higher ORR (38.3%, 38/98, 95% CI: 28.8-47.9) than the oxaliplatin based regimens without bevacizumab (26.9%, 166/594, 95% CI: 23.4-30.4), χ2 = 4.745, p = 0.029. The median PFS in pNETs was 8.1 months (n = 247, 95% CI: 6.3-9.9), similar to 8.4 months in epNETs (n = 211, 95% CI 5.7-11.2). The median PFS in G1-G2 and G3 NET was 13.4 months (95% CI 9.1-17.6) and 7.1 months (95% CI 4.1-9.6) respectively. Besides, FOLFOX plus bevacizumab also showed a trend of a longer PFS (12.4months, 95% CI 9.5-15.2) than those without bevacizumab (7.6months, 95% CI 6.8-8.3). The pooled median overall survival was 28.8months (95% CI 26.7-30.9). Conclusions: Among the advanced well-differentiated neuroendocrine tumors, oxaliplatin based chemotherapy alone or plus bevacizumab could be a good alternative regimen, especially in pts with pNETs and G3 NETs.
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Alexandraki, Krystallenia I., Aggeliki Karapanagioti, Ioannis Karoumpalis, Georgios Boutzios, and Gregory A. Kaltsas. "Advances and Current Concepts in the Medical Management of Gastroenteropancreatic Neuroendocrine Neoplasms." BioMed Research International 2017 (2017): 1–12. http://dx.doi.org/10.1155/2017/9856140.
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Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are rare and heterogeneous group of tumors presenting as localised or metastatic disease and in a subset with distinct clinical syndromes. Treatment is aimed at controlling the functional syndrome, eradicating the tumor, and/or preventing further tumor growth. Surgery is the treatment of choice in removing the primary tumor and/or reducing tumor burden but cannot be applied to all patients. Somatostatin analogs (SS-analogs) obtain control of functional syndromes in the majority of GEP-neuroendocrine tumors (NETs); phase III trials have shown that SS-analogs can be used as first-line antiproliferative treatment in patients with slow-growing GEP-NETs. The role of the recently approved serotonin inhibitor, telotristat ethyl, and gastrin receptor antagonist, netazepide, is evolving. Streptozotocin-based chemotherapy has been used for inoperable or progressing pancreatic NENs but the orally administered combination of capecitabine/temozolomide is becoming more popular due to its better tolerability and potential effect in other GEP-NENs. Phase III trials have shown efficacy of molecular targeted therapies in GEP-NETs and of radionuclide treatment in patients with midgut carcinoid tumors expressing somatostatin receptors. Most patients will develop disease progression necessitating further therapeutic options. A combination of currently available treatments along with the molecular signature of each tumor will guide future treatment.
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Abdelmalak, Rebecca, Mark P. Lythgoe, Joanne Evans, Michael Flynn, Justin Waters, Andy Webb, David J. Pinato, and Rohini Sharma. "Exploration of Novel Prognostic Markers in Grade 3 Neuroendocrine Neoplasia." Cancers 13, no. 16 (August 23, 2021): 4232. http://dx.doi.org/10.3390/cancers13164232.
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Background: High-grade neuroendocrine tumours and carcinomas (NET/NECs) behave aggressively, typically presenting at an advanced stage. Prognosis is poor, with median survival between 5 and 34 months. The mainstay of treatment is palliative systemic therapy. However, therapy carries a risk of toxicity, which can reduce quality of life. Therefore, accurate prognostic scores for risk stratification of patients with high-grade NET/NECs are needed to help guide patient management to decide whether active treatment is likely to improve overall survival (OS). We aimed to compare the prognostic ability of published prognostic scores to predict OS in a cohort of patients with high-grade NET/NECs of any primary site. Methods: Treatment, biochemical and clinicopathological data were collected retrospectively from 77 patients with high-grade NET/NECs across three hospitals between 2016 and 2020. Variables including performance status (PS), Ki-67, age at diagnosis, previous treatment and presence of liver metastases were recorded. Pre-treatment neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio, modified Glasgow prognostic score (mGPS), and gastrointestinal neuroendocrine carcinoma (GI-NEC) score were derived. Univariable and multivariable survival analyses were used to assess prognostic ability. Results: The median age of the cohort was 63 years (range: 31–85); 53% of subjects were female. Grade 3 NETs (G3-NETs) were identified in 32 patients and NECs in 45 patients. The median OS was 13.45 months (range: 0.87–65.37) with no difference observed between G3-NETs and NECs. Univariable analysis revealed that NLR (n = 72, p = 0.049), mGPS (n = 56, p = 0.003), GI-NEC score (n = 27, p = 0.0007) and Ki-67 (n = 66, p = 0.007) were significantly associated with OS. Multivariable analysis confirmed that elevated mGPS (p = 0.046), GI-NEC score (p = 0.036), and Ki-67 (p = 0.02) were independently prognostic for reduced OS across the entire cohort. mGPS was identified as an independent prognostic factor in G3-NETs. Independent predictors of OS in NECs were PS and Ki-67. Conclusions: mGPS, PS and Ki-67 are independent prognostic markers in high-grade NET/NEC patients. Our study supports the use of these prognostic scores for risk stratification of patients with high grade cancers and as useful tools to guide treatment decisions.
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Castle, Jennifer T., Brittany E. Levy, and Aman Chauhan. "Pediatric Neuroendocrine Neoplasms: Rare Malignancies with Incredible Variability." Cancers 14, no. 20 (October 15, 2022): 5049. http://dx.doi.org/10.3390/cancers14205049.
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Neuroendocrine neoplasms (NENs) encompass a variety of neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs) which can arise anywhere in the body. While relatively rare in the pediatric population, the incidence of NENs has increased in the past few decades. These neoplasms can be devastating if not diagnosed and treated early, however, symptoms are variable and can be indolent for many years. There is a reported median of 10 years from the appearance of the first symptoms to time of diagnosis. Considering some of these neoplasms have a mortality rate as high as 90%, it is crucial healthcare providers are aware of NENs and remain vigilant. With better provider education and easily accessible resources for information about these neoplasms, awareness can be improved leading to earlier disease recognition and diagnosis. This manuscript aims to provide an overview of both the most common NENs as well as the rarer NENs with high lethality in the pediatric population. This review provides up to date evidence and recommendations, encompassing recent changes in classification and advances in treatment modalities, including recently completed and ongoing clinical trials.