Prognostic factors of metastatic neuroendocrine carcinoma under first-line treatment with platinum etoposide with a focus on NEC score and Rb expression: Results from the multicentre RBNEC study of the Groupe d'Etude des Tumeurs Endocrines (GTE) and the ENDOCAN-RENATEN network.

INTRODUCTION AND AIM: Neuroendocrine carcinomas (NECs) are aggressive malignant diseases. Platinum-etoposide (PE) combination is the standard first-line treatment, whatever the primary location. The NEC score and also retinoblastoma protein (Rb) status have been suggested to be predictive/prognostic factors in NEC. The primary objective of our multicentric retrospective study was to evaluate the prognostic relevance of the NEC score and Rb status, assessed by immunohistochemistry in PE-treated patients with metastatic NEC. METHODS: Seven centres participated. The inclusion criteria were NEC, whatever the primary site, metastatic stage, first-line treatment with PE and tissue samples available. Rb status was determined centrally. RESULTS: We report multicentric data from 185 metastatic patients (37% women, median age 63). There were 108 small-cell NECs (SCNECs, 58.4%), 50 large-cell NECs (LCNECs, 27%) and 27 not otherwise specified NECs (nosNECs, 14.6%). The primary sites were the thorax (37%), gastroenteropancreatic sites (38%), unknown (15%) and other (9%). The mean Ki-67 index was 76% (range 20-100). Rb status was interpretable in 122 cases. Rb expression was lost in 74% of the cases: 84% of SCNEC vs. 60% and 63% of LCNEC and nosNEC, respectively (p = 0.016). Objective response was seen in 70% of SCNEC, 45% of LCNEC and 48% of nosNEC (p < 0.001) and in 62% of Rb-negative tumours vs. 46% of Rb-positive tumours (p = 0.3). There was no difference in median progression-free survival or overall survival (OS) as per Rb status. Age, NEC score and response to chemotherapy were the main factors associated with OS in our cohort. CONCLUSION: In our series, Rb status had no prognostic impact in PE-treated metastatic patients with NEC, whereas age, NEC score and response to chemotherapy were the main factors associated with OS.

Fine-needle aspiration as an alternative to core needle biopsy for tumour molecular profiling in precision oncology: prospective comparative study of next-generation sequencing in cancer patients included in the SHIVA02 trial.

High-throughput molecular profiling of solid tumours using core needle biopsies (CNB) allows the identification of actionable molecular alterations, with around 70% success rate. Although several studies have demonstrated the utility of small biopsy specimens for molecular testing, there remains debate as to the sensitivity of the less invasive fine-needle aspiration (FNA) compared to CNB to detect molecular alterations. We aimed to prospectively evaluate the potential of FNA to detect such alterations in various tumour types as compared to CNB in cancer patients included in the SHIVA02 trial. An in-house amplicon-based targeted sequencing panel (Illumina TSCA 99.3 kb panel covering 87 genes) was used to identify pathogenic variants and gene copy number variations (CNV) in concomitant CNB and FNA samples obtained from 61 patients enrolled in the SHIVA02 trial (NCT03084757). The main tumour types analysed were breast (38%), colon (15%), pancreas (11%), followed by cervix and stomach (7% each). We report 123 molecular alterations (85 variants, 23 amplifications and 15 homozygous deletions) among which 98 (80%) were concordant between CNB and FNA. The remaining discordances were mainly related to deletions status, yet undetected alterations were not exclusively specific to FNA. Comparative analysis of molecular alterations in CNB and FNA showed high concordance in terms of variants as well as CNVs identified. We conclude FNA could therefore be used in routine diagnostics workflow and clinical trials for tumour molecular profiling with the advantages of being minimally invasive and preserve tissue material needed for diagnostic, prognostic or theranostic purposes.

Effect of chronic left ventricular unloading on myocardial remodeling: Multimodal assessment of two heterotopic heart transplantation techniques.

BACKGROUND: Cardiac recovery is possible by means of mechanical unloading yet remains rare. Excessive unloading-associated myocardial atrophy and fibrosis may adversely affect the process of reverse remodeling. In this study, we sought to evaluate the effect of different intensities of chronic left ventricular (LV) unloading on myocardial remodeling. METHODS: Twenty-five isogenic Lewis rats underwent complete LV unloading (CU, n = 15) induced by heterotopic heart transplantation or partial LV unloading (PU, n = 10) by heterotopic heart-lung transplantation. Information obtained from serial echocardiography, 2-deoxy-2[(18)F]fluoro-d-glucose ((18)F-FDG)-positron emission tomography, and an LV pressure-volume catheter were used to evaluate the morphology, glucose metabolism, and hemodynamic performance of the orthotopic hearts and heterotopic transplants over 4 weeks. Cell size, collagen content, tissue cytokines (interleukin [IL]-1α, IL-2, IL-6, IL-10, tumor necrosis factor-α, and vascular endothelial growth factor), and matrix metalloproteinase-2 and -9 were also determined. The recorded parameters included LV end-systolic dimension, LV end-diastolic dimension, posterior wall thickness, diastolic interventricular septum thickness, LV fractional shortening, and LV ejection fraction. RESULTS: We demonstrated an LV load-dependent relationship using echo-based structural (left posterior wall thickness, diastolic interventricular septum thickness, and left ventricular end-diastolic dimension) and functional (LV fractional shortening and LV ejection fraction) parameters, as well as an (18)F-FDG uptake (all p < 0.05). This load-dependent relationship was also evidenced in measurements from the pressure-volume conductance catheter (stroke volume, stroke work, cardiac output, dP/dTmax, and -dP/dTmin; all p < 0.05). Significant myocardial atrophy and fibrosis were observed in unloaded hearts, whereas concentrations of cytokines and matrix metalloproteinases were comparable in both unloading conditions. CONCLUSIONS: Partial and complete unloading affected the remodeling of non-failing hearts in a rodent model to different extents on myocardial atrophy, fibrosis, glucose metabolism, and mechanical work. Cardiac atrophy is the prominent change after mechanical unloading, which exaggerates the proportion of total collagen that is responsible for diastolic dysfunction.