Citations

AbstractBlastic plasmacytoid dendritic cell neoplasm (BPDCN) is recurrently mutated in epigenetic pathway genes. We studied the myeloid‐related genetic mutations in a cohort of five patients with BPDCN and one paired relapse case at our institution and identified a high frequency of biallelic TET2 and canonical ASXL1 (c.1934dupG) mutations. The number of cases is small, but the variant allele fraction (VAF) sums of the TET2 mutations, as well as the persistence of TET2 mutations in a case of relapsed BPDCN, suggest an ancestral/founder nature of TET2 clones in the cases. Further literature review shows a high frequency of biallelic TET2 mutations in reported cases of BPDCN.

Abstract Glioblastoma is the most common and lethal primary brain tumor in adults, with a median survival less than 15 months despite current standard of care. Oncolytic immunovirotherapies (OVs) have shown promise in early clinical trials. OVs are engineered to specifically target cancer cells, trigger autophagic programmed cell death, and release tumor antigens in the context of T-cell activating cytokines. Cellular communication network factor 1 (CCN1) is an extracellular matrix protein expressed in 70% of glioblastomas that has been shown to drastically reduce OV efficacy, particularly herpes simplex virus type 1 (HSV-1). Our objectives were to decode protein-protein interaction (PPI) networks activated by CCN1, identify critical nodes in resistance networks, and use this analysis to design OVs that overcome CCN1-mediated resistance. We used NetDecoder to elucidate phenotype-specific PPI subnetworks in LN229 human glioblastoma cells with tetracycline-inducible CCN1 expression. Publicly available microarray data on CCN1-induced and control samples established differentially expressed genes, which served as sources in our PPI network to derive prioritized context-specific subnetworks. We found that 11 source genes collaborate via 39 deep nodes to confer OV resistance to CCN1-expressing glioblastomas. Of these, a router (IKBKE) and a sink (YBX1) have been previously implicated in glioblastoma pathogenesis. We conclude that autophagy regulator HSP90AA1, a critical node, may be targeted to improve OV efficacy in CCN1-expressing glioblastomas. Furthermore, WebGestalt overrepresentation analysis of subnetwork nodes suggests that oncolytic adenovirus may be more effective than HSV-1 as a synthetic biology chassis.

Abstract Folate receptor (FR) expressing macrophages have been shown to play an integral role in a number of inflammatory diseases. (1) In this report, we characterize these FR+ macrophages and further investigate whether monocytes, the precursors to these macrophages, also express FR. We demonstrate that FR expression is observed on a subset of highly activated peritoneal and synovial macrophages, but not on other infiltrating immune cells or resident macrophages. We further find that a subset of human peripheral blood monocytes also expresses FR, albeit at a lower level than activated macrophages. Surface antigen characterization of the FR+ monocytes suggests markers characteristic of an inflammatory phenotype (CD14hiCD16), while the resident monocytes (CD14loCD16+) express few or no FR. Preliminary clinical data also suggest that the numbers of peripheral FR+ monocytes can be reduced by a folate-targeted immunotherapy. These results suggest that activated macrophages and inflammatory monocytes express a FR that can be targeted with folate-linked drugs without promoting drug uptake by non-activated macrophages and resident monocytes. 1. Xia W, Hilgenbrink AR, et al. Blood. 2008 Oct 24. [Epub ahead of print] This work was supported in part by a grant from Endocyte, Inc.

Abstract We have introduced HLA-DQ8 (HLADQB*0302 and HLA-DQA*0301) genes into A β 0 knockout mice. Transgenic animals were immunized with a whole body extract of Dermatophagoides pteronyssinus (Der p), one of the causative agents of house dust mite allergy. Transgenic mice expressing HLA-DQ8 genes elicited HLA-DQ8-restricted responses driven by CD4+ T cells. Synthetic-overlapping peptides representing a major allergen of house dust mite (Der p 2) were synthesized and used as immunogens. HLA-DQ8+ mice responded to three peptides: 8 (residues 61-80), 11 (residues 91-110), and 13 (residues 111-129). The mice produced IL-2, IL-4, and IL-6 response to Der p challenge, suggesting a mixed Th1/Th2 response. These mice represent a new model for studies of the immune basis of allergy.

AbstractBackgroundCyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo‐ovarian high‐grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large‐scale, histotype‐specific validation has been performed. The hypothesis was that high‐level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC.MethodsWithin the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated.ResultsHigh‐level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high‐level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08‐1.47, p = .034, and HR, 1.18; 95% CI, 1.05‐1.32, p = .015, respectively). This was also true for cases with combined high‐level amplification/overexpression (HR, 1.26; 95% CI, 1.09‐1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1‐SD increase; 95% CI, 0.94‐1.06; p = .58). CCNE1 high‐level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss.ConclusionThis study provides large‐scale validation that CCNE1 high‐level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.

Abstract Bone marrow (BM) niche plays critical roles in promoting progression and chemoresistance of multiple myeloma (MM), but the iron metabolism bridging the malignant plasma cells and BM stromal cells (BMSCs) has not been well elucidated. Using in vitro and in vivo models of interaction of MM and BMSCs, we identified that iron level was augmented due to the elevated expression of transferrin in MM cells, and the accumulation of iron desensitized MM cells to proteasome inhibitors (PIs) treatment and promoted productions of cholesterol and lanosterol. Simultaneously, direct contact with BMSCs remarkably upregulated the protein level of GPX4, a ROS eraser, to obviate ferroptosis in MM cells. Mechanistic studies revealed that CD40/CD40 ligand (CD40L) signaling promoted the expressions of transferrin and SUMO-specific protease 3 (SENP3), and SENP3 stabilized GPX4 protein via deSUMOylation modification. GPX4 inhibitor induced ferroptosis was cell-cell contact dependent, since blocking CD40/CD40L interaction, or depletion of Cd40l in BMSCs from Cd40lfl/fl;Prx1Cre/+ mice, eliminated the anti-MM efficacy of RSL3 in the Vk*MYC mouse model of myeloma, but not in the patient-derived xenografts (PDX) model. Our study deciphers mechanism of iron metabolism in regulating MM chemoresistance, and clarifies the therapeutic potential of non-apoptosis strategies in managing refractory or relapsed MM patients.

PURPOSE This randomized, open-label trial compared the efficacy and safety of adjuvant nab-paclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430 ). METHODS We assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m 2 ) + gemcitabine (1,000 mg/m 2 ) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28-day cycles. The primary end point was independently assessed disease-free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety. RESULTS Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nab-paclitaxel + gemcitabine and gemcitabine treatment, respectively. At primary data cutoff (December 31, 2018; median follow-up, 38.5 [interquartile range [IQR], 33.8-43 months), the median independently assessed DFS was 19.4 ( nab-paclitaxel + gemcitabine) versus 18.8 months (gemcitabine; hazard ratio [HR], 0.88; 95% CI, 0.729 to 1.063; P = .18). The median investigator-assessed DFS was 16.6 (IQR, 8.4-47.0) and 13.7 (IQR, 8.3-44.1) months, respectively (HR, 0.82; 95% CI, 0.694 to 0.965; P = .02). The median OS (427 events; 68% mature) was 40.5 (IQR, 20.7 to not reached) and 36.2 (IQR, 17.7-53.3) months, respectively (HR, 0.82; 95% CI, 0.680 to 0.996; P = .045). At a 16-month follow-up (cutoff, April 3, 2020; median follow-up, 51.4 months [IQR, 47.0-57.0]), the median OS (511 events; 81% mature) was 41.8 ( nab-paclitaxel + gemcitabine) versus 37.7 months (gemcitabine; HR, 0.82; 95% CI, 0.687 to 0.973; P = .0232). At the 5-year follow-up (cutoff, April 9, 2021; median follow-up, 63.2 months [IQR, 60.1-68.7]), the median OS (555 events; 88% mature) was 41.8 versus 37.7 months, respectively (HR, 0.80; 95% CI, 0.678 to 0.947; P = .0091). Eighty-six percent ( nab-paclitaxel + gemcitabine) and 68% (gemcitabine) of patients experienced grade ≥ 3 treatment-emergent adverse events. Two patients per study arm died of treatment-emergent adverse events. CONCLUSION The primary end point (independently assessed DFS) was not met despite favorable OS seen with nab-paclitaxel + gemcitabine.

BACKGROUND: Intraventricular metastases (IVMs) are uncommon, and their optimal management remains debatable. OBJECTIVE: To define the safety and efficacy of stereotactic radiosurgery (SRS) in the treatment of IVMs. METHODS: This retrospective, multicenter study included patients managed with SRS for IVMs. SRS-induced adverse events, local tumor or intracranial progression, and the frequency of new-onset hydrocephalus or leptomeningeal spread were documented. Analyses of variables related to patient neuroimaging or clinical outcomes were also performed. RESULTS: The cohort included 160 patients from 11 centers who underwent SRS for treatment of 1045 intracranial metastases, of which 196 were IVMs. The median survival from SRS was 10 months. Of the 154 patients and 190 IVMs with imaging follow-up, 94 patients (61%) experienced distant intracranial disease progression and 16 IVMs (8.4%) progressed locally. The 12- and 24-month local IVM control rates were 91.4% and 86.1%, respectively. Sixteen (10%) and 27 (17.5%) patients developed hydrocephalus and leptomeningeal dissemination post-SRS, respectively. Adverse radiation effects were documented in 24 patients (15%). Eleven patients (6.9%) died because of intracranial disease progression. CONCLUSION: SRS is an effective treatment option for IVMs, with a local IVM control rate comparable with SRS for parenchymal brain metastases. Leptomeningeal spread and hydrocephalus in patients with IVM occur in a minority of patients, but these patients warrant careful follow-up to detect these changes.