A quantitative evaluation of aerosol generation during cardiopulmonary resuscitation.

It is unclear if cardiopulmonary resuscitation is an aerosol-generating procedure and whether this poses a risk of airborne disease transmission to healthcare workers and bystanders. Use of airborne transmission precautions during cardiopulmonary resuscitation may confer rescuer protection but risks patient harm due to delays in commencing treatment. To quantify the risk of respiratory aerosol generation during cardiopulmonary resuscitation in humans, we conducted an aerosol monitoring study during out-of-hospital cardiac arrests. Exhaled aerosol was recorded using an optical particle sizer spectrometer connected to the breathing system. Aerosol produced during resuscitation was compared with that produced by control participants under general anaesthesia ventilated with an equivalent respiratory pattern to cardiopulmonary resuscitation. A porcine cardiac arrest model was used to determine the independent contributions of ventilatory breaths, chest compressions and external cardiac defibrillation to aerosol generation. Time-series analysis of participants with cardiac arrest (n = 18) demonstrated a repeating waveform of respiratory aerosol that mapped to specific components of resuscitation. Very high peak aerosol concentrations were generated during ventilation of participants with cardiac arrest with median (IQR [range]) 17,926 (5546-59,209 [1523-242,648]) particles.l-1 , which were 24-fold greater than in control participants under general anaesthesia (744 (309-2106 [23-9099]) particles.l-1 , p < 0.001, n = 16). A substantial rise in aerosol also occurred with cardiac defibrillation and chest compressions. In a complimentary porcine model of cardiac arrest, aerosol recordings showed a strikingly similar profile to the human data. Time-averaged aerosol concentrations during ventilation were approximately 270-fold higher than before cardiac arrest (19,410 (2307-41,017 [104-136,025]) vs. 72 (41-136 [23-268]) particles.l-1 , p = 0.008). The porcine model also confirmed that both defibrillation and chest compressions generate high concentrations of aerosol independent of, but synergistic with, ventilation. In conclusion, multiple components of cardiopulmonary resuscitation generate high concentrations of respiratory aerosol. We recommend that airborne transmission precautions are warranted in the setting of high-risk pathogens, until the airway is secured with an airway device and breathing system with a filter.

A quantitative evaluation of aerosol generation during awake tracheal intubation.

Aerosol-generating procedures are medical interventions considered high risk for transmission of airborne pathogens. Tracheal intubation of anaesthetised patients is not high risk for aerosol generation; however, patients often perform respiratory manoeuvres during awake tracheal intubation which may generate aerosol. To assess the risk, we undertook aerosol monitoring during a series of awake tracheal intubations and nasendoscopies in healthy participants. Sampling was undertaken within an ultraclean operating theatre. Procedures were performed and received by 12 anaesthetic trainees. The upper airway was topically anaesthetised with lidocaine and participants were not sedated. An optical particle sizer continuously sampled aerosol. Passage of the bronchoscope through the vocal cords generated similar peak median (IQR [range]) aerosol concentrations to coughing, 1020 (645-1245 [120-48,948]) vs. 1460 (390-2506 [40-12,280]) particles.l-1 respectively, p = 0.266. Coughs evoked when lidocaine was sprayed on the vocal cords generated 91,700 (41,907-166,774 [390-557,817]) particles.l-1 which was significantly greater than volitional coughs (p < 0.001). For 38 nasendoscopies in 12 participants, the aerosol concentrations were relatively low, 180 (120-525 [0-9552]) particles.l-1 , however, five nasendoscopies generated peak aerosol concentrations greater than a volitional cough. Awake tracheal intubation and nasendoscopy can generate high concentrations of respiratory aerosol. Specific risks are associated with lidocaine spray of the larynx, instrumentation of the vocal cords, procedural coughing and deep breaths. Given the proximity of practitioners to patient-generated aerosol, airborne infection control precautions are appropriate when undertaking awake upper airway endoscopy (including awake tracheal intubation, nasendoscopy and bronchoscopy) if respirable pathogens cannot be confidently excluded.

Anaesthetists' current practice and perceptions of aerosol-generating procedures: a mixed-methods study.

The evidence base surrounding the transmission risk of 'aerosol-generating procedures' has evolved primarily through quantification of aerosol concentrations during clinical practice. Consequently, infection prevention and control guidelines are undergoing continual reassessment. This mixed-methods study aimed to explore the perceptions of practicing anaesthetists regarding aerosol-generating procedures. An online survey was distributed to the Membership Engagement Group of the Royal College of Anaesthetists during November 2021. The survey included five clinical scenarios to identify the personal approach of respondents to precautions, their hospital's policies and the associated impact on healthcare provision. A purposive sample was selected for interviews to explore the reasoning behind their perceptions and behaviours in greater depth. A total of 333 survey responses were analysed quantitatively. Transcripts from 18 interviews were coded and analysed thematically. The sample was broadly representative of the UK anaesthetic workforce. Most respondents and their hospitals were aware of, supported and adhered to UK guidance. However, there were examples of substantial divergence from these guidelines at both individual and hospital level. For example, 40 (12%) requested respiratory protective equipment and 63 (20%) worked in hospitals that required it to be worn whilst performing tracheal intubation in SARS-CoV-2 negative patients. Additionally, 173 (52%) wore respiratory protective equipment whilst inserting supraglottic airway devices. Regarding the use of respiratory protective equipment and fallow times in the operating theatre: 305 (92%) perceived reduced efficiency; 376 (83%) perceived a negative impact on teamworking; 201 (64%) were worried about environmental impact; and 255 (77%) reported significant problems with communication. However, 269 (63%) felt the negative impacts of respiratory protection equipment were appropriately balanced against the risks of SARS-CoV-2 transmission. Attitudes were polarised about the prospect of moving away from using respiratory protective equipment. Participants' perceived risk from COVID-19 correlated with concern regarding stepdown (Spearman's test, R = 0.36, p < 0.001). Attitudes towards aerosol-generating procedures and the need for respiratory protective equipment are evolving and this information can be used to inform strategies to facilitate successful adoption of revised guidelines.

Quantitative evaluation of aerosol generation during manual facemask ventilation.

Manual facemask ventilation, a core component of elective and emergency airway management, is classified as an aerosol-generating procedure. This designation is based on one epidemiological study suggesting an association between facemask ventilation and transmission during the SARS-CoV-1 outbreak in 2003. There is no direct evidence to indicate whether facemask ventilation is a high-risk procedure for aerosol generation. We conducted aerosol monitoring during routine facemask ventilation and facemask ventilation with an intentionally generated leak in anaesthetised patients. Recordings were made in ultraclean operating theatres and compared against the aerosol generated by tidal breathing and cough manoeuvres. Respiratory aerosol from tidal breathing in 11 patients was reliably detected above the very low background particle concentrations with median [IQR (range)] particle counts of 191 (77-486 [4-1313]) and 2 (1-5 [0-13]) particles.l-1 , respectively, p = 0.002. The median (IQR [range]) aerosol concentration detected during facemask ventilation without a leak (3 (0-9 [0-43]) particles.l-1 ) and with an intentional leak (11 (7-26 [1-62]) particles.l-1 ) was 64-fold (p = 0.001) and 17-fold (p = 0.002) lower than that of tidal breathing, respectively. Median (IQR [range]) peak particle concentration during facemask ventilation both without a leak (60 (0-60 [0-120]) particles.l-1 ) and with a leak (120 (60-180 [60-480]) particles.l-1 ) were 20-fold (p = 0.002) and 10-fold (0.001) lower than a cough (1260 (800-3242 [100-3682]) particles.l-1 ), respectively. This study demonstrates that facemask ventilation, even when performed with an intentional leak, does not generate high levels of bioaerosol. On the basis of this evidence, we argue facemask ventilation should not be considered an aerosol-generating procedure.

A quantitative evaluation of aerosol generation during supraglottic airway insertion and removal.

Many guidelines consider supraglottic airway use to be an aerosol-generating procedure. This status requires increased levels of personal protective equipment, fallow time between cases and results in reduced operating theatre efficiency. Aerosol generation has never been quantitated during supraglottic airway use. To address this evidence gap, we conducted real-time aerosol monitoring (0.3-10-µm diameter) in ultraclean operating theatres during supraglottic airway insertion and removal. This showed very low background particle concentrations (median (IQR [range]) 1.6 (0-3.1 [0-4.0]) particles.l-1 ) against which the patient's tidal breathing produced a higher concentration of aerosol (4.0 (1.3-11.0 [0-44]) particles.l-1 , p = 0.048). The average aerosol concentration detected during supraglottic airway insertion (1.3 (1.0-4.2 [0-6.2]) particles.l-1 , n = 11), and removal (2.1 (0-17.5 [0-26.2]) particles.l-1 , n = 12) was no different to tidal breathing (p = 0.31 and p = 0.84, respectively). Comparison of supraglottic airway insertion and removal with a volitional cough (104 (66-169 [33-326]), n = 27), demonstrated that supraglottic airway insertion/removal sequences produced <4% of the aerosol compared with a single cough (p < 0.001). A transient aerosol increase was recorded during one complicated supraglottic airway insertion (which initially failed to provide a patent airway). Detailed analysis of this event showed an atypical particle size distribution and we subsequently identified multiple sources of non-respiratory aerosols that may be produced during airway management and can be considered as artefacts. These findings demonstrate supraglottic airway insertion/removal generates no more bio-aerosol than breathing and far less than a cough. This should inform the design of infection prevention strategies for anaesthetists and operating theatre staff caring for patients managed with supraglottic airways.

Disseminating technology in global surgery.

BACKGROUND: Effective dissemination of technology in global surgery is vital to realize universal health coverage by 2030. Challenges include a lack of human resource, infrastructure and finance. Understanding these challenges, and exploring opportunities and solutions to overcome them, are essential to improve global surgical care. METHODS: This review focuses on technologies and medical devices aimed at improving surgical care and training in low- and middle-income countries. The key considerations in the development of new technologies are described, along with strategies for evaluation and wider dissemination. Notable examples of where the dissemination of a new surgical technology has achieved impact are included. RESULTS: Employing the principles of frugal and responsible innovation, and aligning evaluation and development to high scientific standards help overcome some of the challenges in disseminating technology in global surgery. Exemplars of effective dissemination include low-cost laparoscopes, gasless laparoscopic techniques and innovative training programmes for laparoscopic surgery; low-cost and versatile external fixation devices for fractures; the LifeBox pulse oximeter project; and the use of immersive technologies in simulation, training and surgical care delivery. CONCLUSION: Core strategies to facilitate technology dissemination in global surgery include leveraging international funding, interdisciplinary collaboration involving all key stakeholders, and frugal scientific design, development and evaluation.

Susceptibility of Pacific white snook Centropomus viridis to Vibrio species.

To examine the pathogenicity of Vibrio strains, several doses of Vibrio harveyi (CAIM 1622 and CAIM 1508), Vibrio ponticus (CAIM 1751) and Vibrio anguillarum (CAIM 8) were used to challenge Pacific white snook Centropomus viridis Lockington, 1877 juveniles, and survival, gross signs and histological lesions were observed. Susceptibility of pathogenic vibrios CAIM 1508 and CAIM 1751 to antibiotics used in aquaculture was also evaluated. The growth ability of the tested strains was not related to their pathogenicity. One of the V. harveyi strains (CAIM 1508) was the most virulent, causing per-acute septicaemia in C. viridis even at a low dose (1.4 × 104 CFU g-1). Although the V. ponticus strain (CAIM 1751) was less virulent, this is the first report of it as a pathogen of white snook. Fish challenged with V. ponticus displayed external, generalized haemorrhaging. Necrosis of the digestive tract and intravascular haemosiderosis were the most remarkable histological lesions in fish challenged with both strains. Multifocal necrosis of the internal organs and bacterial masses was also observed. The lowest minimum inhibitory concentration of the pathogenic strains (CAIM 1508 and CAIM 1751) was calculated for enrofloxacin (20 and 10 µg ml-1, respectively), and both bacteria were resistant to amoxicillin, ampicillin and trimethoprim-sulfamethoxazole.

Correction to: Solochrome cyanine: A histological stain for cobalt-chromium wear particles in metal-on-metal periprosthetic tissues.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Solochrome cyanine: A histological stain for cobalt-chromium wear particles in metal-on-metal periprosthetic tissues.

Metal-on-metal (MoM) hip arthroplasties produce abundant implant-derived wear debris composed mainly of cobalt (Co) and chromium (Cr). Cobalt-chromium (Co-Cr) wear particles are difficult to identify histologically and need to be distinguished from other wear particle types and endogenous components (e.g., haemosiderin, fibrin) which may be present in MoM periprosthetic tissues. In this study we sought to determine whether histological stains that have an affinity for metals are useful in identifying Co-Cr wear debris in MoM periprosthetic tissues. Histological sections of periprosthetic tissue from 30 failed MoM hip arthroplasties were stained with haematoxylin-eosin (HE), Solochrome Cyanine (SC), Solochrome Azurine (SA) and Perls' Prussian Blue (PB). Sections of periprosthetic tissue from 10 cases of non-MoM arthroplasties using other implant biomaterials, including titanium, ceramic, polymethylmethacrylate (PMMA) and ultra-high molecular weight polyethylene (UHMWP) were similarly analysed. Sections of 10 cases of haemosiderin-containing knee tenosynovial giant cell tumour (TSGCT) were also stained with HE, SC, SA and PB. In MoM periprosthetic tissues, SC stained metal debris in phagocytic macrophages and in the superficial necrotic zone which exhibited little or no trichrome staining for fibrin. In non-MoM periprosthetic tissues, UHMWP, PMMA, ceramic and titanium particles were not stained by SC. Prussian Blue, but not SC or SA, stained haemosiderin deposits in MoM periprosthetic tissues and TSGT. Our findings show that SC staining (most likely Cr-associated) is useful in distinguishing Co-Cr wear particles from other metal/non-metal wear particles types in histological preparations of periprosthetic tissue and that SC reliably distinguishes haemosiderin from Co-Cr wear debris.

IntAct: intra-operative fluorescence angiography to prevent anastomotic leak in rectal cancer surgery: a randomized controlled trial.

AIM: Anastomotic leak (AL) is a major complication of rectal cancer surgery. Despite advances in surgical practice, the rates of AL have remained static, at around 10-15%. The aetiology of AL is multifactorial, but one of the most crucial risk factors, which is mostly under the control of the surgeon, is blood supply to the anastomosis. The MRC/NIHR IntAct study will determine whether assessment of anastomotic perfusion using a fluorescent dye (indocyanine green) and near-infrared laparoscopy can minimize the rate of AL leak compared with conventional white-light laparoscopy. Two mechanistic sub-studies will explore the role of the rectal microbiome in AL and the predictive value of CT angiography/perfusion studies. METHOD: IntAct is a prospective, unblinded, parallel-group, multicentre, European, randomized controlled trial comparing surgery with intra-operative fluorescence angiography (IFA) against standard care (surgery with no IFA). The primary end-point is rate of clinical AL at 90 days following surgery. Secondary end-points include all AL (clinical and radiological), change in planned anastomosis, complications and re-interventions, use of stoma, cost-effectiveness of the intervention and quality of life. Patients should have a diagnosis of adenocarcinoma of the rectum suitable for potentially curative surgery by anterior resection. Over 3 years, 880 patients from 25 European centres will be recruited and followed up for 90 days. DISCUSSION: IntAct will rigorously evaluate the use of IFA in rectal cancer surgery and explore the role of the microbiome in AL and the predictive value of preoperative CT angiography/perfusion scanning.

Carrier-wave shape effects in optical filamentation.

Strong-field ionization in optical filaments created by ultrashort pulses with sub-cycle engineered waveforms is studied theoretically. To elucidate the physics of the recently demonstrated enhanced ionization yield and spatial control of the optical filament core in two color pulses, we employ two types of quantum models integrated into spatially resolved pulse-propagation simulations. We show that the dependence of the ionization on the shape of the excitation carrier is adiabatic in nature, and is driven by local temporal peaks of the electric field. Implications for the modeling of light-matter interactions in multicolor optical fields are also discussed.

A role for ecology in the evolution of colour variation and sexual dimorphism in Hawaiian damselflies.

Variation in traits that are sexually dimorphic is usually attributed to sexual selection, in part because the influence of ecological differences between sexes can be difficult to identify. Sex-limited dimorphisms, however, provide an opportunity to test ecological selection disentangled from reproductive differences between the sexes. Here, we test the hypothesis that ecological differences play a role in the evolution of body colour variation within and between sexes in a radiation of endemic Hawaiian damselflies. We analysed 17 Megalagrion damselflies species in a phylogenetic linear regression, including three newly discovered cases of species with female-limited dimorphism. We find that rapid colour evolution during the radiation has resulted in no phylogenetic signal for most colour and habitat traits. However, a single ecological variable, exposure to solar radiation (as measured by canopy cover) significantly predicts body colour variation within sexes (female-limited dimorphism), between sexes (sexual dimorphism), and among populations and species. Surprisingly, the degree of sexual dimorphism in body colour is also positively correlated with the degree of habitat differences between sexes. Specifically, redder colouration is associated with more exposure to solar radiation, both within and between species. We discuss potential functions of the pigmentation, including antioxidant properties that would explain the association with light (specifically UV) exposure, and consider alternative mechanisms that may drive these patterns of sexual dimorphism and colour variation.

The effects of accumulated muscle fatigue on the mechanomyographic waveform: implications for injury prediction.

PURPOSE: Muscle fatigue has been identified as a risk factor for spontaneous muscle injuries in sport. However, few studies have investigated the accumulated effects of muscle fatigue on human muscle contractile properties. This study aimed to determine whether repeated bouts of exercise inducing acute fatigue leads to longer-term fatigue-related changes in muscle contractile properties. METHODS: Maximum voluntary contraction (MVC), electromyographic (EMG) and mechanomyographic (MMG) measures were recorded in the biceps brachii of 11 participants for 13 days, before and after a maximally fatiguing exercise protocol. The exercise protocol involved participants repetitively lifting a weight (concentric contractions only) equal to 40 % MVC, until failure. RESULTS: A significant (p < 0.05) acute pre- to post-exercise decline of biceps brachii MVC and median power frequency (MPF) was observed each day, whilst no difference existed between pre-exercise MVC or MPF values on subsequent days (days 2-13). However, decreases in number of lift repetitions and in pre-exercise MMG values of muscle belly displacement, contraction velocity and half-relaxation velocity were observed through to day 13. CONCLUSIONS: Whilst MVC and MPF measures resolved by the following day's test session, MMG measures indicated an ongoing decrement in muscle performance through days 2-13 consistent with the decline in lift repetitions observed. These results suggest that MMG may be more sensitive in detecting accumulated muscle fatigue than the 'gold standard' measures of MVC/MPF. Considering that muscle fatigue leads to injury, the on-going monitoring of MMG derived contractile properties of muscles in athletes may aid in the prediction of fatigued-induced muscle injury.

Anatomy of the long head of biceps femoris: An ultrasound study.

Hamstring strains, particularly involving the long head of biceps femoris (BFlh) at the proximal musculotendinous junction (MTJ), are commonly experienced by athletes. With the use of diagnostic ultrasound increasing, an in-depth knowledge of normal ultrasonographic anatomy is fundamental to better understanding hamstring strain. The aim of this study was to describe the architecture of BFlh, using ultrasonography, in young men and cadaver specimens. BFlh morphology was examined in 19 healthy male participants (mean age 21.6 years) using ultrasound. Muscle, tendon and MTJ lengths were recorded and architectural parameters assessed at four standardised points along the muscle. Measurement accuracy was validated by ultrasound and dissection of BFlh in six male cadaver lower limbs (mean age 76 years). Intra-rater reliability of architectural parameters was examined for repeat scans, image analysis and dissection measurements. Distally the BFlh muscle had significantly (P < 0.05) shorter fascicles and larger pennation angles than proximal sites. Agreement between ultrasound and dissection (cadaver study) was excellent for all architectural parameters, except pennation angle (PA), and MTJ length. All other measures demonstrated good-excellent repeatability. BFlh is not uniform in architecture when imaged using ultrasound. It is likely that its distal-most segment is better suited for force production in comparison to the more proximal segments, which show excursive potential, traits which possibly contribute to the high rate of injury at the proximal MTJ. The data presented in this study provide specific knowledge of the normal ultrasonographic anatomy of BFlh, which should be of assistance in analysing BFlh injury via imaging. Clin. Anat. 29:738-745, 2016. © 2016 Wiley Periodicals, Inc.

Pattern of association between endemic Hawaiian fruit flies (Diptera, Tephritidae) and their symbiotic bacteria: Evidence of cospeciation events and proposal of "Candidatus Stammerula trupaneae".

Several insect lineages have evolved mutualistic association with symbiotic bacteria. This is the case of some species of mealybugs, whiteflies, weevils, tsetse flies, cockroaches, termites, carpenter ants, aphids and fruit flies. Some species of Tephritinae, the most specialized subfamily of fruit flies (Diptera: Tephritidae), harbour co-evolved vertically transmitted, bacterial symbionts in their midgut, known as "Candidatus Stammerula spp.". The 25 described endemic species of Hawaiian tephritids, plus at least three undescribed species, are taxonomically distributed among three genera: the cosmopolitan genus Trupanea (21 described spp.), the endemic genus Phaeogramma (2 spp.) and the Nearctic genus Neotephritis (2 spp.). We examined the presence of symbiotic bacteria in the endemic tephritids of the Hawaiian Islands, which represent a spectacular example of adaptive radiation, and tested the concordant evolution between host and symbiont phylogenies. We detected through PCR assays the presence of specific symbiotic bacteria, designated as "Candidatus Stammerula trupaneae", from 35 individuals of 15 species. The phylogeny of the insect host was reconstructed based on two regions of the mitochondrial DNA (16S rDNA and COI-tRNALeu-COII), while the bacterial 16S rRNA was used for the symbiont analysis. Host and symbiont phylogenies were then compared and evaluated for patterns of cophylogeny and strict cospeciation. Topological congruence between Hawaiian Tephritinae and their symbiotic bacteria phylogenies suggests a limited, but significant degree of host-symbiont cospeciation. We also explored the character reconstruction of three host traits, as island location, host lineage, and host tissue attacked, based on the symbiont phylogenies under the hypothesis of cospeciation.

Assessment of the metastable electronic state approach as a microscopically self-consistent description for the nonlinear response of atoms.

This Letter presents the first quantitative assessment of the recently proposed metastable electronic state approach (MESA) for calculation of the nonlinear optical response of noble gas atoms. Based on the single active electron potentials for several atomic species, Stark resonant states are used to extract the nonlinear polarization and ionization rates free of any additional fitting parameters. It is shown that even the simplest version of the method provides a viable, first-principle-based, and self-consistent alternative to the standard model commonly used for simulations in the field of extreme nonlinear optics.

Mass-like peripheral zone enhancement on CT is predictive of higher-grade (Gleason 4 + 3 and higher) prostate cancer.

PURPOSE: To determine whether focal peripheral zone enhancement on routine venous-phase CT is predictive of higher-grade (Gleason 4 + 3 and higher) prostate cancer. MATERIALS AND METHODS: IRB approval was obtained and informed consent waived for this HIPAA-compliant retrospective study. Forty-three patients with higher-grade prostate cancer (≥Gleason 4 + 3) and 96 with histology-confirmed lower-grade (≤Gleason 3 + 4 [n = 47]) or absent (n = 49) prostate cancer imaged with venous-phase CT comprised the study population. CT images were reviewed by ten blinded radiologists (5 attendings, 5 residents) who scored peripheral zone enhancement on a scale of 1 (benign) to 5 (malignant). Mass-like peripheral zone enhancement was considered malignant. Likelihood ratios (LR) and specificities were calculated. Multivariate conditional logistic regression analyses were conducted. RESULTS: Scores of "5" were strongly predictive of higher-grade prostate cancer (pooled LR+ 9.6 [95% CI 5.8-15.8]) with rare false positives (pooled specificity: 0.98 [942/960, 95% CI 0.98-0.99]; all 10 readers had specificity ≥95%). Attending scores of "5" were more predictive than resident scores of "5" (LR+: 14.7 [95% CI 5.8-37.2] vs. 7.6 [95% CI 4.2-13.7]) with similar specificity (0.99 [475/480, 95% CI 0.98-1.00] vs. 0.97 [467/480, 95% CI 0.96-0.99]). Significant predictors of an assigned score of "5" included presence of a peripheral zone mass (p < 0.0001), larger size (p < 0.0001), and less reader experience (p = 0.0008). Significant predictors of higher-grade prostate cancer included presence of a peripheral zone mass (p = 0.0002) and larger size (p < 0.0001). CONCLUSION: Focal mass-like peripheral zone enhancement on routine venous-phase CT is specific and predictive of higher-grade (Gleason 4 + 3 and higher) prostate cancer.

Inhibition of CXCR7 extends survival following irradiation of brain tumours in mice and rats.

BACKGROUND: In experimental models of glioblastoma multiforme (GBM), irradiation (IR) induces local expression of the chemokine CXCL12/SDF-1, which promotes tumour recurrence. The role of CXCR7, the high-affinity receptor for CXCL12, in the tumour's response to IR has not been addressed. METHODS: We tested CXCR7 inhibitors for their effects on tumour growth and/or animal survival post IR in three rodent GBM models. We used immunohistochemistry to determine where CXCR7 protein is expressed in the tumours and in human GBM samples. We used neurosphere formation assays with human GBM xenografts to determine whether CXCR7 is required for cancer stem cell (CSC) activity in vitro. RESULTS: CXCR7 was detected on tumour cells and/or tumour-associated vasculature in the rodent models and in human GBM. In human GBM, CXCR7 expression increased with glioma grade and was spatially associated with CXCL12 and CXCL11/I-TAC. In the rodent GBM models, pharmacological inhibition of CXCR7 post IR caused tumour regression, blocked tumour recurrence, and/or substantially prolonged survival. CXCR7 expression levels on human GBM xenograft cells correlated with neurosphere-forming activity, and a CXCR7 inhibitor blocked sphere formation by sorted CSCs. CONCLUSIONS: These results indicate that CXCR7 inhibitors could block GBM tumour recurrence after IR, perhaps by interfering with CSCs.