Recruitment of bone marrow derived cells during anti-angiogenic therapy in GBM:The potential of combination strategies

Glioblastoma (GBM) is a highly vascular tumor characterized by rapid and invasive tumor growth, followed by oxygen depletion, hypoxia and neovascularization, which generate a network of disorganized, tortuous and permeable vessels. Recruitment of bone marrow derived cells (BMDC) is crucial for vasculogenesis. These dells may act as vascular progenitors by integrating into the newly formed blood vessels or as vascular modulators by releasing pro-angiogenic factors. In patients with recurrent GBM, anti-vascular endothelial growth factor (VEGF) therapy has been evaluated in combination with chemotherapy, yielding improvements in progression-free survival (PFS). However, benefits are temporary as vascular tumors acquire angiogenic pathways independently of VEGF. Specifically, acute hypoxia following prolonged VEGF depletion induces the recruitment of certain myeloid cell subpopulations, which highly contribute to treatment refractoriness. Here we review the molecular mechanisms of neovascularization in relation to bevacizumab therapy with special emphasis on the recruitment of BMDCs and possible combination therapies for GBM patients. (C) 2014 Elsevier Ireland Ltd. All rights reserved

At the bedside:Profiling and treating patients with CXCR4-expressing cancers

The chemokine receptor, C-X-C chemokine receptor type 4 (CXCR4) and its ligand, C-X-C motif chemokine 12, are key mediators of hematopoietic cell trafficking. Their roles in the proliferation and metastasis of tumor cells, induction of angiogenesis, and invasive tumor growth have been recognized for over 2 decades. CXCR4 is a promising target for imaging and therapy of both hematologic and solid tumors. To date, Sanofi Genzyme's plerixafor is the only marketed CXCR4 inhibitor (i.e., Food and Drug Administration-approved in 2008 for stem cell mobilization). However, several new CXCR4 inhibitors are now being investigated as potential therapies for a variety of fluid and solid tumors. These small molecules, peptides, and Abs include balixafortide (POL6326, Polyphor), mavorixafor (X4P-001, X4 Pharmaceuticals), motixafortide (BL-8040, BioLineRx), LY2510924 (Eli Lilly), and ulocuplumab (Bristol-Myers Squibb). Early clinical evidence has been encouraging, for example, with motixafortide and balixafortide, and the CXCR4 inhibitors appear to be generally safe and well tolerated. Molecular imaging is increasingly being used for effective patient selection before, or early during CXCR4 inhibitor treatment. The use of radiolabeled theranostics that combine diagnostics and therapeutics is an additional intriguing approach. The current status and future directions for radioimaging and treating patients with CXCR4-expressing hematologic and solid malignancies are reviewed. See related review - At the Bench: Pre-Clinical Evidence for Multiple Functions of CXCR4 in Cancer. J. Leukoc. Biol. xx: xx-xx; 2020

External validation of clinical decision rules for children with wrist trauma

Background: Clinical decision rules help to avoid potentially unnecessary radiographs of the wrist, reduce waiting times and save costs. Objective: The primary aim of this study was to provide an overview of all existing non-validated clinical decision rules for wrist trauma in children and to externally validate these rules in a different cohort of patients. Secondarily, we aimed to compare the performance of these rules with the validated Amsterdam Pediatric Wrist Rules. Materials and methods: We included all studies that proposed a clinical prediction or decision rule in children presenting at the emergency department with acute wrist trauma. We performed external validation within a cohort of 379 children. We also calculated the sensitivity, specificity, negative predictive value and positive predictive value of each decision rule. Results: We included three clinical decision rules. The sensitivity and specificity of all clinical decision rules after external validation were between 94% and 99%, and 11% and 26%, respectively. After external validation 7% to 17% less radiographs would be ordered and 1.4% to 5.7% of all fractures would be missed. Compared to the Amsterdam Pediatric Wrist Rules only one of the three other rules had a higher sensitivity; however both the specificity and the reduction in requested radiographs were lower in the other three rules. Conclusion: The sensitivity of the three non-validated clinical decision rules is high. However the specificity and the reduction in number of requested radiographs are low. In contrast, the validated Amsterdam Pediatric Wrist Rules has an acceptable sensitivity and the greatest reduction in radiographs, at 22%, without missing any clinically relevant fractures

Comparison of [18F]DOPA and [68Ga]DOTA-TOC as a PET imaging tracer before peptide receptor radionuclide therapy

BACKGROUND: In treatment of neuroendocrine neoplasms (NENs), confirmation of somatostatin receptor expression with 68Ga-DOTA somatostatin analogues is mandatory to determine eligibility for peptide receptor radionuclide therapy (PRRT). [18F]DOPA can detect additional lesions compared to [68Ga]DOTA-TOC. The aim of this study was to explore differences in tumour detection of both tracers and their relevance for selecting patients for PRRT. We retrospectively studied eight patients with NENs who underwent both [68Ga]DOTA-TOC and carbidopa-enhanced [18F]DOPA PET/CT, before first-time PRRT with [177Lu]DOTA-TATE. Tracer order was influenced due to stock availability or to detect suspected metastases with a second tracer. On CT, disease control was defined as a lesion showing complete response, partial response, or stable disease, according to RECIST 1.1. CRITERIA: RESULTS: Seven patients with in total 89 lesions completed four infusions of 7.4 GBq [177Lu]DOTA-TATE, one patient received only two cycles. Before treatment, [18F]DOPA PET/CT detected significantly more lesions than [68Ga]DOTA-TOC PET/CT (79 vs. 62, p < .001). After treatment, no difference in number of lesions with disease control was found for [18F]DOPA-only (5/27) and [68Ga]DOTA-TOC-only lesions (4/10, p = .25). [18F]DOPA detected more liver metastases (24/27) compared to [68Ga]DOTA-TOC (7/10, p = .006). Six patients showed inpatient heterogeneity in treatment response between [18F]DOPA-only and [68Ga]DOTA-TOC-only lesions. CONCLUSIONS: Response to PRRT with [177Lu]DOTA-TATE was comparable for both [68Ga]DOTA-TOC- and [18F]DOPA-only NEN lesions. [18F]DOPA may be capable of predicting response to PRRT while finding more lesions compared to [68Ga]DOTA-TOC, although these additional lesions are often small of size and undetected by diagnostic CT

Web-based personalised information and support for patients with a neuroendocrine tumour:randomised controlled trial

BackgroundPatients with a neuroendocrine tumour (NET) frequently have physical and psychosocial complaints. Aim of this study is to determine whether a web-based, personalised information and support system (WINS) reduces distress and/or improves patients' perception of and satisfaction with information received.MethodsPatients with NET, stratified for those newly diagnosed (</p

Serotonin and Dopamine Receptor Expression in Solid Tumours Including Rare Cancers

In preclinical studies serotonin stimulates and dopamine inhibits tumour growth and angiogenesis. Information regarding serotonin and dopamine receptor (5-HTR and DRD) expression in human cancers is limited. Therefore, we screened a large tumour set for receptor mRNA overexpression using functional genomic mRNA (FGmRNA) profiling, and we analysed protein expression and location of 5-HTR1B, 5-HTR2B, DRD1, and DRD2 with immunohistochemistry in different tumour types. With FGmRNA profiling 11,756 samples representing 43 tumour types were compared to 3,520 normal tissue samples to analyse receptor overexpression. 5-HTR2B overexpression was present in many tumour types, most frequently in uveal melanomas (56%). Receptor overexpression in rare cancers included 5-HTR1B in nasopharyngeal carcinoma (17%), DRD1 in ependymoma (30%) and synovial sarcoma (21%), and DRD2 in astrocytoma (13%). Immunohistochemistry demonstrated high 5-HTR2B protein expression on melanoma and gastro-intestinal stromal tumour cells and endothelial cells of colon, ovarian, breast, renal and pancreatic tumours. 5-HTR1B expression was predominantly low. High DRD2 protein expression on tumour cells was observed in 48% of pheochromocytomas, and DRD1 expression ranged from 14% in melanoma to 57% in renal cell carcinoma. In conclusion, 5-HTR1B, 5-HTR2B, DRD1, and DRD2 show mRNA overexpression in a broad spectrum of common and rare cancers. 5-HTR2B protein is frequently highly expressed in human cancers, especially on endothelial cells. These findings support further investigation of especially 5HTR2B as a potential treatment target