Cancer therapy has developed around the concept of killing, or stopping the growth of, the cancer cells. Molecularly targeted therapy is the modern expression of this paradigm. Increasingly, however, ...the realization that the cancer has co-opted the normal cells of the stroma for its own survival has led to the concept that the tumor microenvironment (TME) could be targeted for effective therapy. In this review, we outline the importance of tumor-associated macrophages (TAM), a major component of the TME, in the response of tumors to cancer therapy. We discuss the normal role of macrophages in wound healing, the major phenotypes of TAMs, and their role in blunting the efficacy of cancer treatment by radiation and anticancer drugs, both by promoting tumor angiogenesis and by suppressing antitumor immunity. Finally, we review the many preclinical studies that have shown that the response of tumors to irradiation and anticancer drugs can be improved, sometimes markedly so, by depleting TAMs from tumors or by suppressing their polarization from an M1 to an M2 phenotype. The data clearly support the validity of clinical testing of combining targeting TAMs with conventional therapy.
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ABSTRACT
A novel cubic Pade approximation of sin(e sin E) is used to solve Kepler’s equation and compute the eccentric anomaly with high accuracy without requiring iteration. It requires computation ...of sin, cos, atan, sqrt, and a cube root. A refinement of the higher order difference methods is described that is faster and gives improved numerical accuracy.
Stereotactic radiosurgery (SRS) and stereotactic body radiation therapy (SBRT), also known as stereotactic ablative radiation therapy (SABR), are rapidly becoming accepted practice for the radiation ...therapy of certain tumors. Typically, SRS and SBRT involve the delivery of 1 or a few large-dose fractions of 8 to 30 Gy per fraction: a major paradigm shift from radiation therapy practice over the past 90 years, when, with relatively large amounts of normal tissues receiving high doses, the goal was to maximize tumor response for an acceptable level of normal tissue injury. The development of SRS and SBRT have come about because of technologic advances in image guidance and treatment delivery techniques that enable the delivery of large doses to tumors with reduced margins and high gradients outside the target, thereby minimizing doses to surrounding normal tissues. Because the results obtained with SRS and SBRT have been impressive, they have raised the question whether classic radiobiological modeling, and the linear-quadratic (LQ) model, are appropriate for large doses per fraction. In addition to objections to the LQ model, the possibility of additional biological effects resulting from endothelial cell damage, enhanced tumor immunity, or both have been raised to account for the success of SRS and SBRT. In this review, we conclude that the available preclinical and clinical data do not support a need to change the LQ model or to invoke phenomena over and above the classic 5 Rs of radiobiology and radiation therapy, with the likely exception that for some tumors high doses of irradiation may produce enhanced antitumor immunity. Thus, we suggest that for most tumors, the standard radiobiology concepts of the 5 Rs are sufficient to explain the clinical data, and the excellent results obtained from clinical studies are the result of the much larger biologically effective doses that are delivered with SRS and SBRT.
The inactivation of programmed cell death, or apoptosis, is central to the development of cancer. This disabling of apoptotic responses might be a major contributor both to treatment resistance and ...to the observation that, in many tumours, apoptosis is not the main mechanism for the death of cancer cells in response to common treatment regimens. Importantly, this suggests that other modes of cell death are involved in the response to therapy.
Rising prevalence of obesity is a worldwide health concern because excess weight gain within populations forecasts an increased burden from several diseases, most notably cardiovascular diseases, ...diabetes, and cancers. In this report, we used a simulation model to project the probable health and economic consequences in the next two decades from a continued rise in obesity in two ageing populations—the USA and the UK. These trends project 65 million more obese adults in the USA and 11 million more obese adults in the UK by 2030, consequently accruing an additional 6–8·5 million cases of diabetes, 5·7–7·3 million cases of heart disease and stroke, 492 000–669 000 additional cases of cancer, and 26–55 million quality-adjusted life years forgone for USA and UK combined. The combined medical costs associated with treatment of these preventable diseases are estimated to increase by $48–66 billion/year in the USA and by £1·9–2 billion/year in the UK by 2030. Hence, effective policies to promote healthier weight also have economic benefits.
Solid tumours contain regions at very low oxygen concentrations (hypoxia), often surrounding areas of necrosis. The cells in these hypoxic regions are resistant to both radiotherapy and chemotherapy. ...However, the existence of hypoxia and necrosis also provides an opportunity for tumour-selective therapy, including prodrugs activated by hypoxia, hypoxia-specific gene therapy, targeting the hypoxia-inducible factor 1 transcription factor, and recombinant anaerobic bacteria. These strategies could turn what is now an impediment into a significant advantage for cancer therapy.
Abstract Despite the approval of antiangiogenic therapy for glioblastoma multiforme (GBM) patients, survival benefits are still limited. One of the resistance mechanisms for antiangiogenic therapy is ...the induction of hypoxia and subsequent recruitment of macrophages by stromal-derived factor (SDF)-1α (CXCL-12). In this study, we tested whether olaptesed pegol (OLA-PEG, NOX-A12), a novel SDF-1α inhibitor, could reverse the recruitment of macrophages and potentiate the antitumor effect of anti–vascular endothelial growth factor (VEGF) therapy. We also tested whether magnetic resonance imaging (MRI) with ferumoxytol as a contrast agent could provide early information on macrophage blockade. Orthotopic human G12 glioblastomas in nude mice and rat C6 glioblastomas were employed as the animal models. These were treated with bevacizumab or B-20, both anti-VEGF antibodies. Rats were MR imaged with ferumoxytol for macrophage detection. Tumor hypoxia and SDF-1α expression were elevated by VEGF blockade. Adding OLA-PEG to bevacizumab or B-20 significantly prolonged the survival of rodents bearing intracranial GBM compared with anti-VEGF therapy alone. Intratumoral CD68+ tumor associated macrophages (TAMs) were increased by VEGF blockade, but the combination of OLA-PEG + VEGF blockade markedly lowered TAM levels compared with VEGF blockade alone. MRI with ferumoxytol as a contrast agent noninvasively demonstrated macrophage reduction in OLA-PEG + anti-VEGF–treated rats compared with VEGF blockade alone. In conclusion, inhibition of SDF-1 with OLA-PEG inhibited the recruitment of TAMs by VEGF blockage and potentiated its antitumor efficacy in GBM. Noninvasive MRI with ferumoxytol as a contrast agent provides early information on the effect of OLA-PEG in reducing TAMs.
Summary Background Stenting is an alternative to endarterectomy for treatment of carotid artery stenosis, but long-term efficacy is uncertain. We report long-term data from the randomised ...International Carotid Stenting Study comparison of these treatments. Methods Patients with symptomatic carotid stenosis were randomly assigned 1:1 to open treatment with stenting or endarterectomy at 50 centres worldwide. Randomisation was computer generated centrally and allocated by telephone call or fax. Major outcomes were assessed by an independent endpoint committee unaware of treatment assignment. The primary endpoint was fatal or disabling stroke in any territory after randomisation to the end of follow-up. Analysis was by intention to treat (ITT all patients) and per protocol from 31 days after treatment (all patients in whom assigned treatment was completed). Functional ability was rated with the modified Rankin scale. This study is registered, number ISRCTN25337470. Findings 1713 patients were assigned to stenting (n=855) or endarterectomy (n=858) and followed up for a median of 4·2 years (IQR 3·0–5·2, maximum 10·0). Three patients withdrew immediately and, therefore, the ITT population comprised 1710 patients. The number of fatal or disabling strokes (52 vs 49) and cumulative 5-year risk did not differ significantly between the stenting and endarterectomy groups (6·4% vs 6·5%; hazard ratio HR 1·06, 95% CI 0·72–1·57, p=0·77). Any stroke was more frequent in the stenting group than in the endarterectomy group (119 vs 72 events; ITT population, 5-year cumulative risk 15·2% vs 9·4%, HR 1·71, 95% CI 1·28–2·30, p<0·001; per-protocol population, 5-year cumulative risk 8·9% vs 5·8%, 1·53, 1·02–2·31, p=0·04), but were mainly non-disabling strokes. The distribution of modified Rankin scale scores at 1 year, 5 years, or final follow-up did not differ significantly between treatment groups. Interpretation Long-term functional outcome and risk of fatal or disabling stroke are similar for stenting and endarterectomy for symptomatic carotid stenosis. Funding Medical Research Council, Stroke Association, Sanofi-Synthélabo, European Union.
When a sessile droplet of a complex mixture evaporates, its nonvolatile components may deposit into various patterns. One such phenomena, the coffee ring effect, has been a topic of interest for ...several decades. Here, we identify what we believe to be a fascinating phenomenon of droplet pattern deposition for another well-known beveragewhat we have termed a “whiskey web”. Nanoscale agglomerates were generated in diluted American whiskeys (20–25% alcohol by volume), which later stratified as microwebs on the liquid–air interface during evaporation. The web’s strandlike features result from monolayer collapse, and the resulting pattern is a function of the intrinsic molecular constituents of the whiskey. Data suggest that, for our conditions (diluted 1.0 μL drops evaporated on cleaned glass substrates), whiskey webs were unique to diluted American whiskey; however, similar structures were generated with other whiskeys under different conditions. Further, each product forms their own distinct pattern, demonstrating that this phenomenon could be used for sample analysis and counterfeit identification.
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