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

Insulinoma Manifesting Early Postpartum:Case Report and Review of the Literature

Objective: Insulinomas are insulin-producing neuroendocrine tumors. Insulinomas presenting during pregnancy and the early postpartum period are very rare. Methods: A 33-year-old woman with hypoglycemia early postpartum is described. Abdominal computed tomography and endoscopic ultrasound showed 2 lesions of the pancreas. An 11C-5-hydroxy-L-tryptophan (11CHTP) positron emission tomography-computed tomography (PET-CT) scan demonstrated additional uptake in lymph nodes and liver, suggesting malignant insulinoma. Six months after pylorus-preserving pancreatoduodenectomy and excision of liver and lymph node metastases, tumor progression was noted on repeated 11C-HTP PET-CT scans without recurrent hypoglycemia. She was enrolled in a clinical trial and was randomized for dual pan-class I phosphoinositide 3-kinase inhibitor and mammalian target of rapamycin inhibitor treatment, on which there was no tumor progression during 21 months follow-up. A systematic search of PubMed and Medline with the search strategy ‘insulinoma AND pregnancy’ OR ‘insulinoma AND postpartum’ was performed to identify English-, Dutch-, and German-language publications. All publications about (malignant) insulinoma during pregnancy and in the early postpartum period (≤3 months postpartum) were reviewed in addition to the described case report. Results: Insulinoma manifesting during pregnancy or early after delivery has been described in 31 cases, including only 3 cases of malignant insulinoma. Management of malignant insulinoma requires an individualized approach; optimal medical treatment is evolving. Conclusion: The usefulness of 11C-HTP PET-CT in the diagnosis of malignant insulinoma was demonstrated in the present case. Hypoglycemia may particularly become manifest in the postpartum period when insulin action increases consequent to decreased levels of placenta-derived counterregulatory hormones after delivery.</p

Home-based Physical Activity to Alleviate Fatigue in Cancer Survivors:A Systematic Review and Meta-analysis

PURPOSE: Physical activity (PA) affects fatigue and mental health in cancer survivors favorably, but participation in PA interventions tends to be low. More participants may be reached by home-based PA due to greater accessibility and self-monitoring. This systematic review therefore evaluated the effects of home-based PA of low to moderate intensity on symptoms of fatigue, depression, and anxiety among cancer survivors.METHODS: PubMed, CINAHL, PsycINFO, and Web of Science were systematically searched for randomized controlled trials. We included investigations of home-based PA interventions in adults treated curatively for cancer and evaluating fatigue, depression, or anxiety as outcomes. We performed a random-effect meta-analysis for the effects of PA interventions on fatigue in the short and long term. Sub-group analyses were performed for the frequency of counseling. Standardized mean differences (SMD) and 95% confidence intervals are reported.RESULTS: Eleven articles comprising 1066 participants were included: 77% had a history of breast cancer, 14% of ovarian cancer, 4% of colorectal cancer, 4% of prostate cancer and 1% of "other" cancer (not specified). Concerning the outcomes, nine articles reported on fatigue and two reported on depression or anxiety. Meta-analyses showed a significant effect of home-based PA on fatigue immediately post-intervention (SMD = 0.22 [0.06-0.37]), at 3 months' follow-up (SMD = 0.27 [0.04-0.51]), and at 6-9 months' follow-up (SMD = 0.31 [0.08-0.55]). PA interventions that used frequent counseling were associated with larger improvements in fatigue than those using no or infrequent counseling.CONCLUSION: Home-based PA interventions can reduce fatigue among adult cancer survivors for up to 9 months, and frequent counseling may improve the benefits of these interventions.</p

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

Novel insights into vascularization patterns and angiogenic factors in glioblastoma subclasses

Glioblastoma (GBM) is a highly vascularized and aggressive type of primary brain tumor in adults with dismal survival. Molecular subtypes of GBM have been identified that are related to clinical outcome and response to therapy. Although the mesenchymal type has been ascribed higher angiogenic activity, extensive characterization of the vascular component in GBM subtypes has not been performed. Therefore, we aimed to investigate the differential vascular status and angiogenic signaling levels in molecular subtypes. GBM tissue samples representing proneural IDH1 mutant, classical-like and mesenchymal-like subtypes were analyzed by morphometry for the number of vessels, vessel size and vessel maturity. Also the expression levels of factors from multiple angiogenic signaling pathways were determined. We found that necrotic and hypoxic areas were relatively larger in mesenchymal-like tumors and these tumors also had larger vessels. However, the number of vessels, basement membrane deposition and pericyte coverage did not vary between the subtypes. Regarding signaling patterns the majority of factors were expressed at similar levels in the subtypes, and only ANGPT2, MMP2, TIMP1, VEGFA and MMP9/TIMP2 were higher expressed in GBMs of the classical-like subtype. In conclusion, although morphological differences were observed between the subtypes, the angiogenic signaling status of GBM subtypes seemed to be rather similar. These results challenge the concept of mesenchymal GBMs being more angiogenic than other subclasses

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

Implementation and evaluation of a physical activity counselling programme in primary care among cancer survivors:SoDA study protocol

INTRODUCTION: Physical activity (PA) favourably affects various health outcomes in cancer survivors, but little is known about how to implement a PA programme in primary care. We therefore aim to implement and evaluate such a programme for cancer survivors in general practice. METHODS AND ANALYSES: The Stimulation of Daily Activity study is an implementation study with a single-arm longitudinal design in 15 Dutch general practices. Patients aged ≥18 years who finished cancer treatment more than 6 months ago will be eligible for inclusion. The intervention will comprise six coaching sessions with the practice nurse in 9 months, seeking to increase PA in daily activities and using an activity tracker for goal setting and feedback. The Reach, Effectiveness, Adoption, Implementation and Maintenance framework will be used to evaluate implementation in terms of the health outcomes, extent of implementation and barriers and facilitators to implementation, using a mixed methods approach. Descriptive analyses and linear mixed model analyses will be performed on the quantitative data, while qualitative data from focus groups and interviews will be analysed by thematic analyses. ETHICS AND DISSEMINATION: The Medical Research Ethics Committee of the University Medical Centre Groningen, the Netherlands, concluded that this study was not subject to the Dutch Medical Research Involving Human Subjects Act (registration number: 201900586). The study results will be made available to patients and general practitioners via (inter)national publications and conferences, newsletters, public summaries and via (social) media