Combined Large Cell Neuroendocrine Carcinomas of the Lung: Integrative Molecular Analysis Identifies Subtypes with Potential Therapeutic Implications

Combined large cell neuroendocrine carcinoma (CoLCNEC) is given by the association of LCNEC with adeno or squamous or any non-neuroendocrine carcinoma. Molecular bases of CoLCNEC pathogenesis are scant and no standardized therapies are defined

Proposal of early CT morphological criteria for response of liver metastases to systemic treatments in gastroenteropancreatic neuroendocrine tumors:Alternatives to RECIST

RECIST 1.1 criteria are commonly used with computed tomography (CT) to evaluate the efficacy of systemic treatments in patients with neuroendocrine tumors (NETs) and liver metastases (LMs), but their relevance is questioned in this setting. We aimed to explore alternative criteria using different numbers of measured LMs and thresholds of size and density variation. We retrospectively studied patients with advanced pancreatic or small intestine NETs with LMs, treated with systemic treatment in the first-and/or second-line, without early progression, in 14 European expert centers. We compared time to treatment failure (TTF) between responders and non-responders according to various criteria defined by 0%, 10%, 20% or 30% decrease in the sum of LM size, and/or by 10%, 15% or 20% decrease in LM density, measured on two, three or five LMs, on baseline (≤1 month before treatment initiation) and first revaluation (≤6 months) contrast-enhanced CT scans. Multivariable Cox proportional hazard models were performed to adjust the association between response criteria and TTF on prognostic factors. We included 129 systemic treatments (long-acting somatostatin analogs 41.9%, chemotherapy 26.4%, targeted therapies 31.8%), administered as first-line (53.5%) or second-line therapies (46.5%) in 91 patients. A decrease ≥10% in the size of three LMs was the response criterion that best predicted prolonged TTF, with significance at multivariable analysis (HR 1.90; 95% CI: 1.06–3.40; p =.03). Conversely, response defined by RECIST 1.1 did not predict prolonged TTF (p =.91), and neither did criteria based on changes in LM density. A ≥10% decrease in size of three LMs could be a more clinically relevant criterion than the current 30% threshold utilized by RECIST 1.1 for the evaluation of treatment efficacy in patients with advanced NETs. Its implementation in clinical trials is mandatory for prospective validation. Criteria based on changes in LM density were not predictive of treatment efficacy. Clinical Trial Registration: Registered at CNIL-CERB, Assistance publique hopitaux de Paris as “E-NETNET-L-E-CT” July 2018. No number was assigned. Approved by the Medical Ethics Review Board of University Medical Center Groningen.</p

Association of Upfront Peptide Receptor Radionuclide Therapy With Progression-Free Survival Among Patients With Enteropancreatic Neuroendocrine Tumors

open57noIMPORTANCE 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 &lt; .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 &lt; .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 &lt; .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 &lt; .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.openPusceddu, Sara; Prinzi, Natalie; Tafuto, Salvatore; Ibrahim, Toni; Filice, Angelina; Brizzi, Maria Pia; Panzuto, Francesco; Baldari, Sergio; Grana, Chiara M.; Campana, Davide; Davì, Maria Vittoria; Giuffrida, Dario; Zatelli, Maria Chiara; Partelli, Stefano; Razzore, Paola; Marconcini, Riccardo; Massironi, Sara; Gelsomino, Fabio; Faggiano, Antongiulio; Giannetta, Elisa; Bajetta, Emilio; Grimaldi, Franco; Cives, Mauro; Cirillo, Fernando; Perfetti, Vittorio; Corti, Francesca; Ricci, Claudio; Giacomelli, Luca; Porcu, Luca; Di Maio, Massimo; Seregni, Ettore; Maccauro, Marco; Lastoria, Secondo; Bongiovanni, Alberto; Versari, Annibale; Persano, Irene; Rinzivillo, Maria; Pignata, Salvatore Antonio; Rocca, Paola Anna; Lamberti, Giuseppe; Cingarlini, Sara; Puliafito, Ivana; Ambrosio, Maria Rosaria; Zanata, Isabella; Bracigliano, Alessandra; Severi, Stefano; Spada, Francesca; Andreasi, Valentina; Modica, Roberta; Scalorbi, Federica; Milione, Massimo; Sabella, Giovanna; Coppa, Jorgelina; Casadei, Riccardo; Di Bartolomeo, Maria; Falconi, Massimo; de Braud, FilippoPusceddu, Sara; Prinzi, Natalie; Tafuto, Salvatore; Ibrahim, Toni; Filice, Angelina; Brizzi, Maria Pia; Panzuto, Francesco; Baldari, Sergio; Grana, Chiara M.; Campana, Davide; Davì, Maria Vittoria; Giuffrida, Dario; Zatelli, Maria Chiara; Partelli, Stefano; Razzore, Paola; Marconcini, Riccardo; Massironi, Sara; Gelsomino, Fabio; Faggiano, Antongiulio; Giannetta, Elisa; Bajetta, Emilio; Grimaldi, Franco; Cives, Mauro; Cirillo, Fernando; Perfetti, Vittorio; Corti, Francesca; Ricci, Claudio; Giacomelli, Luca; Porcu, Luca; Di Maio, Massimo; Seregni, Ettore; Maccauro, Marco; Lastoria, Secondo; Bongiovanni, Alberto; Versari, Annibale; Persano, Irene; Rinzivillo, Maria; Pignata, Salvatore Antonio; Rocca, Paola Anna; Lamberti, Giuseppe; Cingarlini, Sara; Puliafito, Ivana; Ambrosio, Maria Rosaria; Zanata, Isabella; Bracigliano, Alessandra; Severi, Stefano; Spada, Francesca; Andreasi, Valentina; Modica, Roberta; Scalorbi, Federica; Milione, Massimo; Sabella, Giovanna; Coppa, Jorgelina; Casadei, Riccardo; Di Bartolomeo, Maria; Falconi, Massimo; de Braud, Filipp

Biomarker Landscape in Neuroendocrine Tumors With High-Grade Features: Current Knowledge and Future Perspective

19noNeuroendocrine tumors (NETs) are classified based on morphology and are graded based on their proliferation rate as either well-differentiated low-grade (G1) to intermediate (G2-G3) or poorly differentiated high-grade neuroendocrine carcinomas (NEC G3). Recently, in gastroenteropancreatic (GEP) NETs, a new subgroup of well-differentiated high-grade tumors (NET G3) has been divided from NEC by WHO due to its different clinical-pathologic features. Although several mutational analyses have been performed, a molecular classification of NET is an unmet need in particular for G3, which tends to be more aggressive and have less benefit to the available therapies. Specifically, new possible prognostic and, above all, predictive factors are highly awaited, giving the basis for new treatments. Alteration of KRAS, TP53, and RB1 is mainly reported, but also druggable alterations, including BRAF and high microsatellite instability (MSI-H), have been documented in subsets of patients. In addition, PD-L1 demonstrated to be highly expressed in G3 NETs, probably becoming a new biomarker for G3 neuroendocrine neoplasm (NEN) discrimination and a predictive one for immunotherapy response. In this review, we describe the current knowledge available on a high-grade NET molecular landscape with a specific focus on those harboring potentially therapeutic targets in the advanced setting.openopenMichele Prisciandaro, Maria Antista, Alessandra Raimondi, Francesca Corti, Federica Morano, Giovanni Centonze, Giovanna Sabella, Alessandro Mangogna, Giovanni Randon, Filippo Pagani, Natalie Prinzi, Monica Niger, Salvatore Corallo, Erica Castiglioni di Caronno, Marco Massafra, Maria Di Bartolomeo, Filippo de Braud, Massimo Milione, Sara PuscedduPrisciandaro, Michele; Antista, Maria; Raimondi, Alessandra; Corti, Francesca; Morano, Federica; Centonze, Giovanni; Sabella, Giovanna; Mangogna, Alessandro; Randon, Giovanni; Pagani, Filippo; Prinzi, Natalie; Niger, Monica; Corallo, Salvatore; Castiglioni di Caronno, Erica; Massafra, Marco; Di Bartolomeo, Maria; de Braud, Filippo; Milione, Massimo; Pusceddu, Sar

Nutritional status and follicular-derived thyroid cancer: An update

The incidence of differentiated thyroid cancer has been increasing in the last decades all over the world. Such a steady growth cannot be entirely attributable to more intensive thyroid nodule screening and more sensitive diagnostic procedures. Several environmental factors have changed with sufficient rapidity in the same time frame and may represent credible candidates for this increase. They include modified iodine intake, lifestyle-associated risk factors, exposure to various toxic compounds, pollutants and xenobiotics, nutritional deficiencies, eating habits and comorbidities. Foremost, nutritional patterns have gained high interest as possible promoters and modifiable risk factors for thyroid cancer in recent years. The aim of this narrative review is to focus on the relationship between thyroid cancer and nutritional factors, dietary habits and obesity. Low iodine intake has been associated to increased risk of thyroid cancer, favoring the development of more aggressive histotypes. Moreover, correction of iodine deficiency can shift thyroid cancer subtypes toward less aggressive forms, without affecting the overall risk for cancer. Actually, evidence regarding the association between selenium and vitamin D deficiency and thyroid cancer is very limited, despite their well-known anti-cancer potentials, and the clinical usefulness of their supplementation is still uncertain in this setting. Albeit the relationship between single foods and thyroid cancer is difficult to examine, fish and iodine-rich foods, vegetables, and fruits might exert protective effects on thyroid cancer risk. Conversely, no clear association has been found for other foods to date. Lastly, a clear association between obesity and the risk of thyroid cancer, with more aggressive behavior, seems to emerge from most studies, likely involving variations in thyroid function and chronic inflammation mediated by cytokines, insulin, leptin and adiponectins. Although no definite association between dietary factors and thyroid cancer has been firmly established so far, some nutritional patterns, together with excessive weight, seem to play a relevant role in thyroid cancer carcinogenesis as well as in its severity and aggressiveness. These effects may play an additive role to the well-established one exerted by environmental carcinogens, such as pollutants and radiation exposure

Myeloid and T-Cell Microenvironment Immune Features Identify Two Prognostic Sub-Groups in High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms

High-grade Gastroenteropancreatic Neuroendocrine neoplasms (H-NENs) comprehend well-differentiated tumors (NET G3) and poorly differentiated carcinomas (NEC) with proliferative activity indexes as mitotic count (MC) &gt;20 mitoses/10 HPF and Ki-67 &gt;20%. At present, no specific therapy for H-NENs exists and the several evidences of microenvironment involvement in their pathogenesis pave the way for tailored therapies. Forty-five consecutive cases, with available information about T-cell, immune, and non-immune markers, from surgical pathology and clinical databases of 2 Italian institutions were immunostained for Arginase, CD33, CD163 and CD66 myeloid markers. The association between features was assessed by Spearman's correlation coefficient. A unsupervised K-means algorithm was used to identify clusters of patients according to inputs of microenvironment features and the relationship between clusters and clinicopathological features, including cancer-specific survival (CSS), was analyzed. The H-NEN population was composed of 6 (13.3%) NET G3 and 39 (86.7%) NEC. Overall, significant positive associations were found between myeloid (CD33, CD163 and Arginase) and T/immune markers (CD3, CD4, CD8, PD-1 and HLA-I). Myeloid and T-cell markers CD3 and CD8 identified two clusters of patients from unsupervised K-means analysis. Cases grouped in cluster 1 with more myeloid infiltrates, T cell, HLA and expression of inhibitory receptors and ligands in the stroma (PD-1, PD-L1) had significantly better CSS than patients in cluster 2. Multivariable analysis showed that Ki-67 (&gt;55 vs. &lt;55, HR 8.60, CI 95% 2.61-28.33, p &lt; 0.0001) and cluster (1 vs. 2, HR 0.43, CI 95% 0.20-0.93, p = 0.03) were significantly associated with survival. High grade gastroenteropancreatic neuroendocrine neoplasms can be further classified into two prognostic sub-populations of tumors driven by different tumor microenvironments and immune features able to generate the framework for evaluating new therapeutic strategies

Machine Learning for Predicting Survival in Poorly Differentiated Neuroendocrine Carcinoma: Pooled Analysis of Four Retrospective Studies

Background: Lung and Digestive system represent the most frequent occurrence sites for neuroendocrine neoplasms (NENs). NEN clinical outcome can be predicted by the integrated evaluation of morphology and proliferation index, allowing NENs distinction into well differentiated neuroendocrine tumors (WD-NET) and poorly differentiated neuroendocrine carcinoma (PD-NEC). We recently published four studies addressed to PD-NECs in order to identify PD-NECs subgroups with better prognosis and/or to predict their therapy outcome. Design: A pooled analysis of our four retrospective studies (3 on digestive [PMID: 26943788; 29592868; 31557757] and 1 on lung NENs [PMID: 32365350]) was performed to evaluate for PD-NEC: i) Best Ki-67 cut-off in predicting Overall Survival (OS); ii) OS according to cancer primary site iii) best common predictive model using different variable selection methods in Cox proportional hazards model (Cox) and machine learning Random Survival Forest (RSF). Results: Overall, 422 PDNECs were analyzed distributed in colorectal (n = 156, 37%), lung (n = 111, 26.3%), gastroesophageal (n = 83, 19.7%), pancreas (n = 42, 10%), ileum-cecum-duodenum (n = 18, 4.2%) and gallbladder/biliary (n = 12, 2.8%). Pure neuroendocrine morphology (n = 227, 53.8%) was slightly more represented than combined (n = 195, 46.2%) although is more frequent in colorectal (59%), gastroesophageal (53%) and gallbladder/biliary (83.3%) compared to lung (31.5%) and pancreas (33.3%). Interestingly, all PDNEC in ileum- cecum-duodenum had pure morphology. Ki-67 at 55% was confirmed as the best value in predicting OS. Colorectal and gastroesophageal PD-NEC showed worse OS than pancreatic and lung. The most predictive Cox model included Ki67 (HR 1.03 - CI95% 1.03-1.04), Morphology (Pure vs Combined - HR 1.44 - CI95% 1.16-1.78), Stage III-IV (HR 1.47 - CI 95% 1.06-2.04) and Age (HR 1.01 - CI 95% 1.00-1.02). In Pancreas PD-NEC HR decreased by 0.58 (CI 95% 0.40-0.83) if compared to colorectal PD-NEC. RSF, which is dependent on the complete combination of all risk factors, confirmed that Ki-67 was the most relevant predictor followed by morphology, stage and site. The predicted response for survival at 1 or 3 years of the forest showed decreasing survival with increasing Ki-67, pure morphology, stage III-IV, and colorectal and gastroesophageal NEC disease. Furthermore, patients with Ki-67&lt;55% and combined morphology had better survival than those with pure morphology. Morphology became irrelevant in NENs when Ki-67 resulted ≥ 55%. RSF had the best predictive accuracy (AUC &gt; 80) compare to other models computed at 6, 12, 24 and 36 months specific time points. Conclusions: The present pooled analysis showed that most predictive parameters to predict OS for PD-NEC patients included Ki67, Morphology, Stage and Site. RSF outperformed all other models in OS prediction performance

Lung Carcinoid Tumors: Histology and Ki-67, The Eternal Rivalry

WHO classification of Thoracic Tumors defines lung carcinoid tumors (LCTs) as well-differentiated neuroendocrine neoplasms (NENs) classified in low grade typical (TC) and intermediate grade atypical carcinoids (AC). Limited data exist concerning protein expression and morphologic factors able to predict disease aggressiveness. Though Ki-67 has proved to be a powerful diagnostic and prognostic factor for Gastro-entero-pancreatic NENs, its role in lung NENs is still debated

Pan-Lung Cancer: Integrative Genomic and Transcriptomic Analysis Suggest Novel Therapeutic Approach

Background: The World Health Organization (WHO) identifies six major histotypes of Lung Neoplasms dividing them according to two main, pure or combined, lineages: neuroendocrine – typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), small cell lung cancer (SCLC), and non-neuroendocrine – adenocarcinoma (ADC), squamous cell carcinoma (SQC). High-throughput molecular analysis, on a histologically re-evaluated large multicenter series of lung cancers, may be able to provide a more personalized characterization beyond histopathology and develop patient-tailored therapeutic approaches. Design: Six-hundred patients with primary neuroendocrine lung neoplasms were retrieved from 5 Italian Centers, creating a retrospective cohort spanning 40 years (1978-2019), with follow up information. Pathological central revision on surgical specimens, both in terms of morphology and immunohistochemical features, enabled reclassification according to WHO 2021 criteria. Specific WHO categories were deeply characterized by means of wide genomic (409 genes) and transcriptomic (20.815 genes) analyses. Results: Overall, 100 non-neuroendocrine lung neoplasms (40 ADC, 60 SQC), 114 lung neuroendocrine tumors (23 TC, 25 AC, 43 LCNEC, 23 SCLC) and 54 combined-lung tumors (41 co-LCNECs and 13 co-SCLCs) were identified as suitable for genomic and expression NGS analysis. Genomic screening of pure tumours (n=214) showed highly specific genomic alterations for each histotype. Transcriptomic analysis identified two molecular subgroups in each pure histotype, except for SQCs. In more details: two molecular clusters of ADCs were identified, linked both to different outcomes and to the association with the PD-1 blockade pathway, while an SCLC ATR positive and SCLC ATR negative were detected, highlighting new therapeutic possibilities. Deconvolution analysis also divided lung cancers in two major groups: “cold” and “hot” showing LCNECs as potential candidates for immunotherapy. Molecular characterization of combined-lung tumours identified potentially targetable alterations while transcriptomic analysis showed at least 3 distinct and standalone profiles compared to pure histotypes. Conclusions: Our study detailed the molecular landscape of major histotypes of lung neoplasms, highlighting differences and links between various histotypes, and providing indications for a better molecular stratification for the purpose of an increasingly personalized therapeutic managemen

Lung Carcinoid Tumors: Histology and Ki-67, The Eternal Rivalry

WHO classification of Thoracic Tumors defines lung carcinoid tumors (LCTs) as well-differentiated neuroendocrine neoplasms (NENs) classified in low grade typical (TC) and intermediate grade atypical carcinoids (AC). Limited data exist concerning protein expression and morphologic factors able to predict disease aggressiveness. Though Ki-67 has proved to be a powerful diagnostic and prognostic factor for Gastro-entero-pancreatic NENs, its role in lung NENs is still debated