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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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.
This review, mostly of preclinical data, summarizes the evidence that radiation at doses relevant to radiation therapy initiates a pathway that promotes the reconstitution of the tumor vasculature ...leading to tumor recurrence. The pathway is not specific to tumors; it promotes repair of damaged and ischemic normal tissues by attracting proangiogenic cells from the bone marrow. For irradiated tumors the pathway comprises: (1) loss of endothelial cells and reduced tumor blood perfusion leading to increased tumor hypoxia and increased levels of hypoxia inducible factor-1 (HIF-1). Alternatively, increased HIF-1 levels may arise by reactive oxygen species (ROS) production caused by tumor reoxygenation. (2) Increased HIF-1 levels lead to increased levels in the tumor of the chemokine stromal cell-derived factor-1 (SDF-1, CXCL12), which captures monocytes/macrophages expressing the CXCR4 receptor of CXCL12. (3) The increased levels of tumor-associated macrophages (TAMs) become highly proangiogenic (M2 polarized) and restore the tumor vasculature, thereby promoting tumor recurrence. The relevance of this pathway for radiation therapy is that it can be blocked in a number of different ways including by inhibitors of monocytes/macrophages, of HIF-1, of CXCL12, of CXCR4, and of CSF-1R, the latter of which is responsible for the M2 polarization of the TAMs. All of these inhibitors produce a robust enhancement of the radiation response of a wide variety of preclinical tumor models. Further, the same inhibitors actually provide protection against radiation damage of several normal tissues. Some of these pathway inhibitors are available clinically, and a first-in-human trial of the CXCR4 inhibitor, plerixafor, with radiation therapy of glioblastoma has yielded promising results, including an impressive increase in local tumor control. Further clinical trials are warranted.
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.
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.
Inflammation within atherosclerotic lesions contributes to plaque instability and vulnerability to rupture. We set out to evaluate the use of a macrophage labeling agent to identify carotid plaque ...inflammation by in vivo magnetic resonance imaging (MRI).
Thirty patients with symptomatic severe carotid stenosis scheduled for carotid endarterectomy underwent multi-sequence MRI of the carotid bifurcation before and after injection of ultrasmall superparamagnetic particles of iron oxide (USPIOs). USPIO particles accumulated in macrophages in 24 of 30 plaques (80%). Areas of signal intensity reduction, corresponding to USPIO/macrophage-positive histological sections, were visualized in 24 of 27 (89%) patients, with an average reduction in signal intensity induced by the USPIO particles of 24% (range, 3.1% to 60.8%).
USPIO-enhanced MRI can identify plaque inflammation in vivo by accumulation of USPIO within macrophages in carotid plaques.
Summary CNS metastases are the most common cause of malignant brain tumours in adults. Historically, patients with brain metastases have been excluded from most clinical trials, but their inclusion ...is now becoming more common. The medical literature is difficult to interpret because of substantial variation in the response and progression criteria used across clinical trials. The Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) working group is an international, multidisciplinary effort to develop standard response and progression criteria for use in clinical trials of treatment for brain metastases. Previous efforts have focused on aspects of trial design, such as patient population, variations in existing response and progression criteria, and challenges when incorporating neurological, neuro-cognitive, and quality-of-life endpoints into trials of patients with brain metastases. Here, we present our recommendations for standard response and progression criteria for the assessment of brain metastases in clinical trials. The proposed criteria will hopefully facilitate the development of novel approaches to this difficult problem by providing more uniformity in the assessment of CNS metastases across trials.
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.
Abstract Background and purpose Two aspects of stereotactic radiotherapy (SRT) require clarification: First, are tumoricidal mechanisms at high-doses/fraction the same as at lower doses? Second, is ...single high-dose SRT treatment advantageous for tumor control (TCP) vs. multi-fraction SRT? Material and methods We analyzed published TCP data for lung tumors or brain metastases from 2965 SRT patients, covering a wide range of doses and fraction numbers. We used: (a) a linear-quadratic model (including heterogeneity), which assumes the same mechanisms at all doses, and (b) alternative models with terms describing distinct tumoricidal mechanisms at high doses. Results Both for lung and brain data, the LQ model provided a significantly better fit over the entire range of treatment doses than did any of the models requiring extra terms at high doses. Analyzing the data as a function of fractionation (1 fraction vs . >1 fraction), there was no significant effect on TCP in the lung data, whereas for brain data multi-fraction SRT was associated with higher TCP than single-fraction treatment. Conclusion Our analysis suggests that distinct tumoricidal mechanisms do not determine tumor control at high doses/fraction. In addition, there is evidence suggesting that multi-fraction SRT is superior to single-dose SRT.
The quality of the retrieved temperature-versus-pressure (or T(p)) profiles is described for the middle atmosphere for the publicly available Sounding of the Atmosphere using Broadband Emission ...Radiometry (SABER) Version 1.07 (V1.07) data set. The primary sources of systematic error for the SABER results below about 70 km are (1) errors in the measured radiances, (2) biases in the forward model, and (3) uncertainties in the corrections for ozone and in the determination of the reference pressure for the retrieved profiles. Comparisons with other correlative data sets indicate that SABER T(p) is too high by 1-3 K in the lower stratosphere but then too low by 1 K near the stratopause and by 2 K in the middle mesosphere. There is little difference between the local thermodynamic equilibrium (LTE) algorithm results below about 70 km from V1.07 and V1.06, but there are substantial improvements/differences for the non-LTE results of V1.07 for the upper mesosphere and lower thermosphere (UMLT) region. In particular, the V1.07 algorithm uses monthly, diurnally averaged CO2 profiles versus latitude from the Whole Atmosphere Community Climate Model. This change has improved the consistency of the character of the tides in its kinetic temperature (T(sub k)). The T(sub k) profiles agree with UMLT values obtained from ground-based measurements of column-averaged OH and O2 emissions and of the Na lidar returns, at least within their mutual uncertainties. SABER T(sub k) values obtained near the mesopause with its daytime algorithm also agree well with the falling sphere climatology at high northern latitudes in summer. It is concluded that the SABER data set can be the basis for improved, diurnal-to-interannual-scale temperatures for the middle atmosphere and especially for its UMLT region.
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