Measurements of Cherenkov emission in tissue during radiation therapy are shown to enable estimation of hemoglobin oxygen saturation non-invasively, through spectral fitting of the spontaneous emissions from the treated tissue. Tissue oxygenation plays a critical role in the efficacy of radiation therapy to kill tumor tissue. Yet in-vivo measurement of this has remained elusive in routine use because of the complexity of oxygen measurement techniques. There is a spectrally broad emission of Cherenkov light that is induced during the time of irradiation, and as this travels through tissue from the point of the radiation deposition, the tissue absorption and scatter impart spectral changes. These changes can be quantified by diffuse spectral fitting of the signal. Thus Cherenkov emission spectroscopy is demonstrated for the first time quantitatively in vitro and qualitatively in vivo, and has potential for real-time online tracking of tissue oxygen during radiation therapy when fully characterized and developed.

Purpose

Lack of methods for repeated assessment of tumor pO2 limits the ability to test and optimize hypoxia modifying procedures being developed for clinical applications. We report the repeated measurements of orthotopic F98 tumor pO2, and relate this to the effect of carbogen inhalation on tumor growth when combined with hypofractionated radiotherapy.

Methods and Materials

Electron Paramagnetic Resonance (EPR) oximetry was used for repeated measurements of tumor and contralateral brain pO2 in rats during 30% O2 and carbogen inhalation for 5 consecutive days. The T1 enhanced volumes and diffusion coefficients of the tumors were assessed by MRI. The tumors were irradiated with 9.3 Gy × 4 in rats breathing 30% O2 or carbogen to determine the effect on tumor growth.

Results

The pre-treatment F98 tumor pO2 varied between 8 – 16 mmHg, while the contralateral brain had 41 – 45 mmHg pO2 during repeated measurements. Carbogen breathing led to a significant increase in tumor and contralateral brain pO2; however this effect declined over days. Irradiation of the tumors in rats breathing carbogen resulted in a significant decrease in tumor growth and an increase in the diffusion coefficient measured by MRI.

Conclusions

The results provide quantitative measurements of the effect of carbogen inhalation on intracerebral tumor pO2 and its consequence on therapeutic outcome. Such direct repeated pO2 measurements by EPR oximetry can provide temporal information that could be used to improve therapeutic outcome by scheduling doses at times of improved tumor oxygenation. EPR oximetry is currently being tested for clinical applications.

Background

Survivors of anterior MI are at increased risk for stroke with predilection to form ventricular thrombus. Commonly patients are discharged on dual antiplatelet therapy. Given the frequency of early coronary reperfusion and risk of bleeding, it remains uncertain whether anticoagulation offers additional utility. We examined the effectiveness of anticoagulation therapy for the prevention of stroke after anterior MI.

Methods and Findings

We performed a population-based cohort analysis of 10,383 patients who survived hospitalization for an acute MI in Ontario, Canada from April 1, 1999 to March 31, 2001. The primary outcome was four-year ischemic stroke rates compared between anterior and non-anterior MI patients. Risk factors for stroke were assessed by multivariate Cox proportional-hazards analysis. Warfarin use was determined at discharge and followed for 90 days among a subset of patients aged 66 and older (n = 1483). Among the 10,383 patients studied, 2,942 patients survived hospitalization for an anterior MI and 20% were discharged on anticoagulation therapy. Within 4 years, 169 patients (5.7%) were admitted with an ischemic stroke, half of which occurred within 1-year post-MI. There was no significant difference in stroke rate between anterior and non-anterior MI patients. The use of warfarin up to 90 days was not associated with stroke protection after anterior MI (hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.37–1.26). The use of angiotensin-converting-enzyme inhibitors (HR, 0.65; 95% CI, 0.44–0.95) and beta-blockers (HR, 0.60; 95% CI, 0.41–0.87) were associated with a significant decrease in stroke risk. There was no significant difference in bleeding-related hospitalizations in patients who used warfarin for up to 90 days post-MI.

Conclusion

Many practitioners still consider a large anterior-wall MI as high risk for potential LV thrombus formation and stroke. Among a cohort of elderly patients who survived an anterior MI there was no benefit from the use of warfarin up to 90 days post-MI to prevent ischemic stroke. Our data suggests that routine anticoagulation of patients with anterior-wall MI may not be indicated. Prospective randomized trials are needed to determine the optimal antithrombin strategy for preventing this common and serious adverse outcome.

Purpose

The Dunning R3327-MLL is a well established transplanted tumor line, and as such it makes a desirable model for evaluative studies of therapy. In the current study, the interstitial growth characteristics as well as the response of this tumor to a single fraction of high dose rate radiation is investigated.

Materials and Methods

The in-vitro response to radiation of the Dunning R3327-MLL was studied via a colony forming assay using a Cs-137 irradiator. In-vitro radiosensitivity was determined on tumors implanted intramuscularly in the left gastrocnemius muscle of the rat and irradiated using an Ir-192 afterloader.

Results

The results demonstrate a faster growth rate when compared to the reported subcutaneous growth rates. The Dunning R3327-MLL’s radiosensitivity is comparable to that of late response tissues. The dose required to achieve a specific radiobiological response (the α:β ratio) of the in-vitro cell line is 2.4 Gy, whereas the ratio for the intramuscularly growing tumor was 0.99 Gy.

Conclusions

These findings signify the intramuscularly implanted Dunning R3327-MLL tumor model as a desirable model for the study of single fraction high dose rate radiation treatments.

Purpose

Tumor hypoxia is a well-known therapeutic problem; however, a lack of methods for repeated measurements of glioma partial pressure of oxygen (pO2) limits the ability to optimize the therapeutic approaches. We report the effects of 9.3 Gy of radiation and carbogen inhalation on orthotopic 9L and C6 gliomas and on the contralateral brain pO2 in rats using a new and potentially widely useful method, multisite in vivo electron paramagnetic resonance oximetry.

Methods and Materials

Intracerebral 9L and C6 tumors were established in the left hemisphere of syngeneic rats, and electron paramagnetic resonance oximetry was successfully used for repeated tissue pO2 measurements after 9.3 Gy of radiation and during carbogen breathing for 5 consecutive days.

Results

Intracerebral 9L gliomas had a pO2 of 30–32 mm Hg and C6 gliomas were relatively hypoxic, with a pO2 of 12–14 mm Hg (p < 0.05). The tissue pO2 of the contralateral brain was 40–45 mm Hg in rats with either 9L or C6 gliomas. Irradiation resulted in a significant increase in pO2 of the 9L gliomas only. A significant increase in the pO2 of the 9L and C6 gliomas was observed in rats breathing carbogen, but this effect decreased during 5 days of repeated experiments in the 9L gliomas.

Conclusion

These results highlight the tumor-specific effect of radiation (9.3.Gy) on tissue pO2 and the different responses to carbogen inhalation. The ability of electron paramagnetic resonance oximetry to provide direct repeated measurements of tissue pO2 could have a vital role in understanding the dynamics of hypoxia during therapy that could then be optimized by scheduling doses at times of improved tumor oxygenation.

Background

Canadian data on the characteristics, management and outcomes of patients with transient ischemic attack (TIA) are lacking. We studied prospectively a cohort of consecutive patients presenting with TIA to the emergency department of 4 regional stroke centres in Ontario.

Methods

Using data from the Ontario Stroke Registry linked with provincial administrative databases, we determined the short-term outcomes after TIA and assessed patient management in the emergency department and within 30 days after the index TIA. We compared the TIA patients with a cohort of patients who had ischemic stroke.

Results

Three-quarters of the TIA patients were discharged from the emergency department. After discharge, the 30-day stroke risk was 5% (13/265) overall and 8% (13/167) among those with a first-ever TIA; the 30-day risk of stroke or death was 9% (11/127) among the TIA patients with a speech deficit and 12% (9/76) among those with a motor deficit. Half of the cases of stroke occurred within the first 2 days after the TIA. Diagnostic investigations were underused in hospital and on an outpatient basis within 30 days after the index TIA, the rates being as follows: CT scanning, 58% (211/364); carotid Doppler ultrasonography, 44% (162/364); echocardiography, 19% (70/364); cerebral angiography, 5% (19/364); and MRI, 3% (11/364). Antithrombotic therapy was not prescribed for more than one-third of the patients at discharge. Carotid endarterectomy was performed in 2% within 90 days.

Interpretation

Patients in whom TIA is diagnosed in the emergency department have high immediate and short-term risks of stroke. However, their condition is underinvestigated and undertreated compared with stroke: many do not receive the minimum recommended diagnostic tests within 30 days. We need greater efforts to improve the timely delivery of care for TIA patients, along with investigation of treatments administered early after TIA to prevent stroke.

TISSUE PLASMINOGEN ACTIVATOR (TPA) INJECTED INTRAVENOUSLY within 3 hours of symptom onset has emerged as a treatment option for acute ischemic stroke. Although controversial and not universally accepted, its use in carefully selected patients is supported by evidence from randomized controlled trials and by mounting community experience. In this paper we review the literature published in the past 5 years regarding the safety, clinical trial efficacy and real-world effectiveness of intravenous tPA for stroke. First we review data from the phase III clinical trials on which approval for tPA is based. Then we summarize a growing literature of postmarketing phase IV studies and discuss the limitations and challenges that lie ahead. Our aim is to provide clinicians with an overview of this evolving therapy.