A phase II study to evaluate the efficacy and safety of camrelizumab plus famitinib in advanced or metastatic thyroid cancer.

6085 Background: Many studies have confirmed that the combination with anti-vascular drugs can significantly improve the efficacy of anti-PD-1/PD-L1 inhibitor in a variety of tumors. Camrelizumab is a humanized anti-programmed cell death receptor 1 (PD-1) antibody. Famitinib is a tyrosine kinase inhibitor which exhibits anti-angiogenesis and antiproliferative effects via targeting VEGFR-2, c-Kit and PDGFR-β. Herein, we aimed to evaluate the efficacy and safety of camrelizumab plus famitinib in the treatment of advanced or metastatic thyroid cancer. Methods: A single-arm, open-label phase II study was conducted, patients (pts) with advanced or metastatic thyroid cancer were recruited, including radioiodine-refractory differentiated thyroid cancer (group 1), differentiated thyroid cancer ineligible for 131I treatment (group 2), medullary thyroid cancer (group 3) and anaplastic thyroid cancer (group 4). Pts received camrelizumab 200mg i.v. on day 1 of each 21-day cycle and oral famitinib 20mg po qd in 21-day cycles until progressive disease or drug intolerance. The primary endpoint was objective response rate (ORR). The secondary endpoints were safety, adverse events (AEs), duration of response (DoR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Results: Between Jan 14, 2020 and Feb 9, 2022, 74 pts were enrolled. There were 12/26/5/31 pts in group 1/2/3/4 respectively. Median follow-up time was 11.4 months. In group 1, of 12 evaluable pts, confirmed ORR, ORR and DCR accounted for 33.3%, 41.7% and 100.0%, respectively. In group 2, of 25 evaluable pts, the confirmed ORR and DCR were 44.0% and 96.0%, respectively. In group 3, of 5 evaluable pts, the confirmed ORR and DCR were 40.0% and 100.0%, respectively. In group 4, of 24 evaluable pts, the confirmed ORR, ORR and DCR were 62.5%, 75% and 95.8%, respectively. PFS and OS were not yet mature for group 1-3, and in group 4, of all enrolled pts, estimated median PFS was 8.4 months and estimated median OS was 13.6 months. 73 pts were included in safety set. The most common treatment related AEs were diarrhea (37.0%), palmoplantiplanar swelling syndrome (34.2%), hypertension (31.5%) and fatigue (31.5%). Conclusions: Camrelizumab plus famitinib demonstrated promising anti-tumor efficacy with acceptable toxicity in pts with advcanced or metastatic thyroid cancer. Clinical trial information: NCT04521348. </jats:p

ALCAM+ stromal cells: role in giant cell tumor of bone progression

Abstract Giant cell tumor of bone(GCTB) is a special benign tumor with variable aggressiveness and recurrence rate. Increasing evidences suggest that a subset of cells called cancer stem cells (CSCs) are present as cancer-initiating cells in a range of malignant tumors. However, the role of CSCs in benign tumor such as GCTB remains unknown, and the connection between the presence of CSCs and biological characteristics of GCTB is unclear. To investigate this issue, we screened a panel of markers of normal stem cells and CSCs and found ALCAM+ stromal cells possessed characteristics of stem-like cells. Subsequently a series of experiments such cell proliferation, migration and invasion assays were performed to investigate the biological characteristics of ALCAM+ stromal cells in vivo and in vitro. The clinical significance of ALCAM expression were further evaluated using Kaplan-Meier analyses. The ALCAM+ GCTB cells showed the stem cell properties of self renewal and had the capacity to differentiate in vitro. The ALCAM+ GCTB cells showed increased resistance for chemotherapy- or radiation-induced cell death. ALCAM knockdown reduced stem/progenitor characteristics in GCTB Cells. Furthermore, ALCAM expression was associated with outcome in GCTB patients. Our work demonstrates for the first time ALCAM+ tumorigenic sub-population within stromal GCTB cells and may represent a potential therapeutic target in aggressive and recurrent GCTBs

Proteomic analysis of plasma exosomes to differentiate malignant from benign pulmonary nodules

Abstract Background It is difficult to distinguish benign pulmonary nodules (PNs) from malignant PNs by conventional examination. Therefore, novel biomarkers that can identify the nature of PNs are needed. Exosomes have recently been identified as an attractive alternative approach since tumor-specific molecules can be found in exosomes isolated from biological fluids. Methods Plasma exosomes were extracted via the exoEasy reagent method. The major proteins from plasma exosomes in patients with PNs were identified via labelfree analysis and screened for differentially expressed proteins. A GO classification analysis and KEGG pathway analysis were performed on plasma exosomal protein from patients with benign and malignant PNs. Results Western blot confirmed that protein expression of CD63 and CD9 could be detected in the exosome extract. Via a search of the human Uniprot database, 736 plasma exosome proteins from patients with PNs were detected using high-confidence peptides. There were 33 differentially expressed proteins in the benign and malignant PNs. Of these, 12 proteins were only expressed in the benign PNs group, while 9 proteins were only expressed in the malignant PNs group. We further obtained important information on signaling pathways and nodal proteins related to differential benign and malignant PNs via bioinformatic analysis methods such as GO, KEGG, and String. Conclusions This study provides a new perspective on the identification of novel detection strategies for benign and malignant PNs. We hope our findings can provide clues for the identification of benign and malignant PNs

A systematic dissection of the epigenomic heterogeneity of lung adenocarcinoma reveals two different subclasses with distinct prognosis and core regulatory networks

AbstractBackgroundLung adenocarcinoma (LUAD) is a highly malignant and heterogeneous tumor that involves various oncogenic genetic alterations. Epigenetic processes play important roles in lung cancer development. However, the variation in enhancer and super-enhancer landscapes of LUAD patients remains largely unknown. To provide an in-depth understanding of the epigenomic heterogeneity of LUAD, we investigate the H3K27ac histone modification profiles of tumors and adjacent normal lung tissues from 42 LUAD patients and explore the role of epigenetic alterations in LUAD progression.ResultsA high intertumoral epigenetic heterogeneity is observed across the LUAD H3K27ac profiles. We quantitatively model the intertumoral variability of H3K27ac levels at proximal gene promoters and distal enhancers and propose a new epigenetic classification of LUAD patients. Our classification defines two LUAD subgroups which are highly related to histological subtypes. Group II patients have significantly worse prognosis than group I, which is further confirmed in the public TCGA-LUAD cohort. Differential RNA-seq analysis between group I and group II groups reveals that those genes upregulated in group II group tend to promote cell proliferation and induce cell de-differentiation. We construct the gene co-expression networks and identify group-specific core regulators. Most of these core regulators are linked with group-specific regulatory elements, such as super-enhancers. We further show that CLU is regulated by 3 group I-specific core regulators and works as a novel tumor suppressor in LUAD.ConclusionsOur study systematically characterizes the epigenetic alterations during LUAD progression and provides a new classification model that is helpful for predicting patient prognosis.</jats:sec

Genomic and immune profiling of pre-invasive lung adenocarcinoma

AbstractAdenocarcinoma in situ and minimally invasive adenocarcinoma are the pre-invasive forms of lung adenocarcinoma. The genomic and immune profiles of these lesions are poorly understood. Here we report exome and transcriptome sequencing of 98 lung adenocarcinoma precursor lesions and 99 invasive adenocarcinomas. We have identified EGFR, RBM10, BRAF, ERBB2, TP53, KRAS, MAP2K1 and MET as significantly mutated genes in the pre/minimally invasive group. Classes of genome alterations that increase in frequency during the progression to malignancy are revealed. These include mutations in TP53, arm-level copy number alterations, and HLA loss of heterozygosity. Immune infiltration is correlated with copy number alterations of chromosome arm 6p, suggesting a link between arm-level events and the tumor immune environment.</jats:p