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Biomedical subjects

I R Crocker

Publications and source records attributed to I R Crocker.

At least 19 recordsLinked to original sources
PubMed2001

High-dose external beam irradiation inhibits neointima formation in stented pig coronary arteries.

PURPOSE: To evaluate high-dose external beam irradiation (EBRT) in a pig coronary stent preparation because low and intermediate-dose EBRT failed to show inhibition of neointima formation in stented animal models. METHODS AND MATERIALS: Thirty-five stents were implanted in the coronary arteries of 17 pigs. Seven pigs were exposed to a single dose of 21 Gy EBRT immediately after stenting. Ten stented, nonirradiated pigs served as controls. After 4 weeks, the study arteries and myocardium were examined by light and scanning electron microscopy. RESULTS: Compared with controls, 21 Gy EBRT resulted in a larger lumen area (7.57 +/- 1.67 mm2 vs. 4.00 +/- 1.63 mm2, p <0.001), a smaller neointima area (0.47 +/- 0.43 mm2 vs. 3.36 +/- 2.26 mm2, p <0.001) and a smaller maximal intimal thickness (0.16 +/- 0.09 mm vs. 0.68 +/- 0.31 mm, p <0.001). Unresorbed intramural hemorrhages and adherent mural thrombi were present in the irradiated vessels, which also showed incomplete re-endothelialization. The irradiated hearts demonstrated diffuse interstitial and perivascular inflammation and fibrosis. CONCLUSIONS: EBRT at 21 Gy to the entire heart significantly inhibited neointima formation in stented pig coronary arteries but also resulted in incomplete re-endothelialization, myocardial inflammation, and fibrosis. Improvements in localization and delivery techniques are required to allow clinical implementation of this technique.

Animals↗
PubMed2001

Inhibition of vascular cell growth by X-ray irradiation: comparison with gamma radiation and mechanism of action.

PURPOSE: Catheter-based delivery of gamma and beta radiation effectively inhibits restenosis. Major disadvantages of these radioisotopes include continuous emission; excessive depth of penetration, creating safety hazards (gamma); and inadequate penetration, limiting effectiveness (beta). Low-voltage X-rays have a distinct potential advantage, because the source is active only when current is applied, and depth of penetration is voltage dependent. This study was performed to determine if low-voltage X-rays inhibit smooth muscle and adventitial cell growth in vitro and to determine the molecular mechanisms involved in this cellular response. METHODS AND RESULTS: Vascular cells in culture were exposed to low-voltage X-ray radiation and analyzed for their subsequent ability to proliferate. X-ray irradiation caused a dose-dependent inhibition in proliferation, similar to the effect seen with equivalent doses of gamma radiation. The radiation-induced inhibition of proliferation did not appear to be related to apoptosis, but rather to delayed progression through the cell cycle, because a 65% increase in the proportion of cells in S phase was seen 24-96 h after X-ray exposure compared to control. Expression of p53, a cell cycle transcriptional activator, and p21, a cell cycle inhibitor, were significantly elevated after exposure to low-voltage X-rays, providing a potential mechanism for this delay. CONCLUSIONS: Low-voltage X-rays can effectively inhibit proliferation of vascular smooth muscle and adventitial cells. This inhibition is apparently due to a delay in progression through the cell cycle, which is mediated by increases in the levels of cell cycle inhibitors.

Animals↗
PubMed2000

Extraneural metastatic glioblastoma after interstitial brachytherapy.

PURPOSE: This is a report of 3 cases of extraneural metastasis of glioblastoma after interstitial radiation and assessment of pertinent literature addressing concern over an increased risk of these events with this therapy. METHODS AND MATERIALS: In a series of 82 patients treated with (125)I brachytherapy for primary malignant brain tumors over a 7-year interval, 3 cases of extraneural glioblastoma were identified. The multicatheter technique for delivery of (125)I sources was utilized in all. Extraneural metastases were documented by imaging studies or biopsy. Over the same period, 310 patients with primary malignant brain tumors were treated without brachytherapy. RESULTS: Biopsy-proven scalp and skull metastases occurred in 2 patients, at 3 and 8 months following brachytherapy. Each developed radiographic evidence of systemic metastases at 7 and 14 months postbrachytherapy, respectively. The third patient developed biopsy-proven cervical node involvement 4 months after brachytherapy. No patients with malignant gliomas undergoing craniotomy or stereotactic biopsy, but not brachytherapy, during the same time period developed extraneural metastases. Incidence in previously reported series commenting on this otherwise rare process range from 0% to 4.3%. The incidence of extraneural metastases in this series is 3.7% (3/82) and is comparable to those reports. CONCLUSIONS: Percutaneous catheter-delivered brachytherapy may be associated with an increased incidence of extraneural metastatic glioma.

Adult↗
PubMed2000

The effect of endovascular irradiation on platelet recruitment at sites of balloon angioplasty in pig coronary arteries.

BACKGROUND: Endovascular irradiation (EI) inhibits balloon-induced neointima formation in animals and is now in clinical trials for restenosis prevention. However, little is known of the effect of EI on vessel thrombogenicity due to delayed arterial healing. We investigated EI effects on platelet recruitment in pig coronary arteries. METHODS AND RESULTS: EI was performed using (90)Sr/Y at 0 Gray (Gy), 15Gy, or 30Gy at 2 mm after balloon overstretch injury. At 1 day, 1 week, and 1 month, platelet recruitment and thrombus formation were assessed using autologous (111)In-oxine-platelet labeling and light and scanning electron microscopy. In balloon-injured nonirradiated vessels, there was complete reendothelialization at 1 month, and platelet recruitment was similar to normal uninjured arteries. In irradiated vessels, scanning electron microscopy showed incomplete reendothelialization at 1 month, and these areas demonstrated attachment of activated platelets. Light microscopy of irradiated coronaries showed adherent partially organized thrombi and incomplete resolution of intramural hemorrhages. There was a significant increase in platelet recruitment at 1 month in arteries receiving EI at 15Gy (5.1+/-2. 8x10(6), P=0.02) or 30Gy (12.5+/-9.9x10(6), P=0.005) compared with nonirradiated controls (2.7+/-1.5x10(6)); 30Gy was also higher than 15Gy (P=0.05). Platelet recruitment was also increased for 30Gy compared with control at 1 day. CONCLUSIONS: Endovascular irradiation at 15Gy or 30Gy after balloon angioplasty results in incomplete endothelial recovery, impaired resolution of intramural hemorrhage, and a dose-dependent increase in platelet recruitment at 1 month.

Angioplasty, Balloon, Coronary↗
PubMed2000

Irradiation and postangioplasty restenosis: a recent overview.

One of the most intriguing developments in recent years towards prevention of restenosis after angioplasty is the use of ionizing radiation. The background for the use of radiation treatment for this application is sound, since radiation is used not only to treat malignant cancerous growths but also is used for treatment of benign hyperplastic disorders such as post-surgical keloid formation and recurrence of pterygium after surgical removal. Restenosis can be considered a form of overexuberant wound healing triggered by angioplasty. Ionizing radiation inhibits serum-stimulated proliferation of many cell types including fibroblasts and smooth muscle cells in vitro and also suppresses the synthesis of collagen by cultured fibroblasts. Liermann who showed inhibition of post-stent restenosis first used ionizing radiation for restenosis prevention clinically in iliac and iliofemoral arteries. Subsequently, extensive animal studies in various restenosis models have shown a profound inhibitory effect of catheter-based radiation (endovascular brachytherapy) on neointima formation and overall vessel shrinkage (negative remodeling). Based on these results clinical trials have been initiated with several types of devices and isotopes. Among these are 192Ir, 32P, 90Y, 90Sr/Y and 188Re. Additionally, radioactive stents have been developed; devices for clinical use are made radioactive at the microCi level by surface implantation of 32P ions. Results from early clinical trials are encouraging and brachytherapy appears safe for clinical use and at an appropriate dose, may be highly effective for restenosis prevention.

Angioplasty, Balloon↗
PubMed1999

Fibrocellular tissue responses to endovascular and external beam irradiation in the porcine model of restenosis.

PURPOSE: Endovascular radiation has reduced postangioplasty restenosis in preclinical and early clinical studies. External radiation treatment may have advantages over endovascular therapy. We examined vascular and perivascular tissue responses to endovascular and external irradiation in pig coronary arteries. METHODS AND MATERIALS: Ninety-one animals received endovascular or external radiation following balloon injury and were sacrificed at 14, 30, or 180 days. Injured segments of coronary vessels including perivascular and myocardial tissues were evaluated with histochemistry. RESULTS: Endovascular radiation was associated with delayed arterial wound healing as late as 6 months, evidenced by paucity of smooth muscle alpha-actin in neointimal cells compared to control. External treatment was associated with increased collagen in neointima and adventitia, and focal interstitial necrosis in adjacent myocardium. CONCLUSIONS: These investigations showed whole-heart 14 Gy external radiation treatment following coronary injury exacerbated certain aspects of arterial healing. In addition focal myocardial necrosis and fibrosis was observed following external but not endovascular irradiation. Endovascular radiation has some advantages over external irradiation; however the persistence of a synthetic smooth muscle cell phenotype in the neointima at 6 months suggests ionizing radiation in general may have profound effects on vessel architecture over the long term.

Actins↗
PubMed1999

Effects of intracoronary beta-radiation therapy after coronary angioplasty: an intravascular ultrasound study.

BACKGROUND: Endovascular radiation is emerging as a potential solution for the prevention and treatment of restenosis. Its effects on the morphology of unstented vessels cannot be determined by angiography and therefore require the use of intravascular ultrasound. METHODS AND RESULTS: Through a 5F noncentered catheter for delivery of a 90Sr/Y source train, 12, 14, or 16 Gy at 2 mm was delivered to native coronary arteries after successful balloon angioplasty in 30 patients. Four patients required stent deployment in the first week. Quantitative coronary angiography and IVUS were performed during the initial procedure and at 6-month follow-up. Binary angiographic restenosis was present in 3 of 30 patients, with target lesion and vessel revascularization performed in 3 and 5 patients, respectively. Angiographic late loss was -0.02+/-0.60 mm, with a -0.09+/-0.46 loss index. IVUS demonstrated no significant reduction in lumen area (from 5.69+/-1.72 mm2 after treatment to 6. 04+/-2.63 mm2 at follow-up), with no significant change in external elastic membrane area (13.71+/-4.54 to 14.22+/-4.71 mm2) over the 6-month follow-up. Wall area was 8.01+/-3.85 mm2 after radiation therapy and 8.19+/-3.44 mm2 at follow-up (P=NS). No significant differences were noted between the different dose groups. CONCLUSIONS: beta-Radiation therapy resulted in a low restenosis rate with negligible late loss by angiography. By IVUS, beta-radiation was shown to inhibit neointima formation, with no reduction of total vessel area at 6-month follow-up.

Adult↗
PubMed1998

Endovascular beta-radiation to reduce restenosis after coronary balloon angioplasty: results of the beta energy restenosis trial (BERT).

BACKGROUND: In the porcine overstretch injury model of restenosis, endovascular beta-radiation reduces neointima formation. To determine whether this therapy could be applied to patients with coronary artery disease, a special device was developed to allow delivery of 12 encapsulated 90Sr/Y sources, measuring a total of 30 mm, to various sites within the coronary arterial tree. This study was designed to evaluate the feasibility of the delivery of 12, 14, or 16 Gy at 2 mm after balloon angioplasty of stenoses of native coronary vessels. METHODS AND RESULTS: Delivery of beta-radiation was attempted in 23 patients after successful balloon angioplasty. Source delivery was successful in 21 of the 23 patients (91%). There was no in-hospital or 30-day morbidity or mortality. Follow-up quantitative coronary arteriography in 20 patients demonstrated a late loss of 0.05 mm, a late loss index of 4%, and a restenosis rate of 15%. The use of the beta-emitter 90Sr/Y significantly reduced treatment time and operator exposure compared with previous trials with the gamma-emitter 192Ir. CONCLUSIONS: In this study, the administration of endovascular beta-radiation after angioplasty was safe and feasible and substantially altered the postangioplasty late lumen loss, resulting in a lower-than-expected rate of restenosis. On the basis of these encouraging results, a multicenter, randomized trial with operators and patients blinded to treatment assignment is planned.

Adolescent↗
PubMed1998

Efficacy of beta radiation in prevention of post-angioplasty restenosis. An interim report from the beta energy restenosis trial.

UNLABELLED: Restenosis remains a major limitation of coronary angioplasty in spite of major advances in techniques and technology. Recent studies have demonstrated that ionizing radiation may limit the degree of this problem. Gamma radiation has been shown to be effective in reducing in stent restenosis in humans, and beta radiation following encouraging results in animals has been shown to be feasible in humans. The objective of this study was to assess the feasibility of a 5 F non-centered catheter to deliver beta radiation emitting seeds to the lesion site post angioplasty and its effect on restenosis. Following successful angioplasty, patients were randomized to treatment with 12, 14 or 16 Gy at the angioplasty site. This was delivered with a 5 F non-centered catheter. Twelve beta radiation emitting seeds (90Sr/Y) were delivered to an area 3 cm in length to cover the angioplasty site. Angiographic follow-up was performed at 6 months. Baseline and follow-up angiograms were performed by blinded investigators at a core laboratory. This interim report comprises the first 35 patients to complete 6-month angiographic follow-up. There were no major radiation incidents. Four patients had evidence of angiographic restenosis. The MLD (mm) and percent stenosis were 0.77 +/- 0.27/72.5 +/- 8.6 pre angioplasty, 2.08 +/- 0.4/25.7 +/- 9.8 post angioplasty and radiation and 2.05 +/- 0.59/25.7 +/- 19.8 at follow-up respectively. CONCLUSION: Beta radiation can be feasibly and safely delivered post coronary angioplasty with a very encouraging reduction of restenosis.

Adult↗
PubMed1998

Single-field total lymphoid irradiation in the treatment of refractory rejection after heart transplantation.

Nine heart transplant recipients were treated with single-field total lymphoid irradiation (TLI) for early (<1 year) or late (>1 year) rejection that was refractory to multiple regimens of immunosuppressive therapy. For patients with early rejection (n = 6), the rejection frequency (rejections/patient/month) decreased from pre-TLI of 1.63 to post-TLI of .02 (p < .001), and for patients with late rejection (n = 3), the rejection frequency decreased from pre-TLI of .23 to post-TLI of .05 (p < .02). The reduced rejection frequencies have been maintained for a mean follow-up of 28.6 (8 to 78) months, and adverse events during or late after TLI were uncommon. Single-field TLI is a safe and effective technique in the management of refractory rejection early or late after heart transplantation.

Adolescent↗
PubMed1997

Effect of intravascular irradiation on cell proliferation, apoptosis, and vascular remodeling after balloon overstretch injury of porcine coronary arteries.

BACKGROUND: Ionizing radiation has been shown to reduce vascular lesion formation after balloon overstretch injury of pig coronary arteries. The present series of experiments examines the mechanism by which this occurs. METHODS AND RESULTS: Balloon injury was performed on porcine coronary arteries, followed immediately by ionizing radiation using either a source train of 90Sr/Y or 192Ir seeds designed to deliver 14 or 28 Gy at a depth of 2 mm from the source. The animals were killed 3, 7, or 14 days after injury. Bromodeoxyuridine was administered 24 hours before euthanasia to label proliferating cells. Cell proliferation was significantly reduced on day 3 in the adventitia and media of the irradiated vessels compared with controls. Two weeks after injury, there were fewer alpha-actin-positive myofibroblasts in the adventitia of the irradiated vessels than in nonirradiated controls, and morphometric analysis indicated that the vessel perimeter of the irradiated vessels was significantly larger than in controls. Together, these results suggest a positive effect of intravascular irradiation on vascular remodeling. Apoptosis was estimated by terminal transferase dUTP-biotin nick-end labeling (TUNEL) 3 and 7 days after injury. TUNEL-labeled cells were found primarily in the adventitia at the medial tear, but no differences were detected between irradiated and control vessels. CONCLUSIONS: These studies suggest that intracoronary radiation primarily inhibits the first wave of cell proliferation in the vessel wall and demonstrates a favorable effect on late remodeling by preventing adventitial fibrosis at the injury site.

Actins↗
PubMed1997

Intracoronary radiation decreases the second phase of intimal hyperplasia in a repeat balloon angioplasty model of restenosis.

PURPOSE: Repeat balloon angioplasty is likely to induce intimal proliferation, which is associated with a higher restenosis rate. This study examined the effect of intracoronary ionizing radiation on restenotic lesions using repeat balloon injury in a normolipemic swine. METHODS AND MATERIALS: Eight domestic normolipemic pigs underwent overstretch balloon angioplasty with a 3.5 mm balloon in the LAD and LCX, followed by repeat balloon injury at the same sites 4 weeks after the initial injury. At that time a high activity 192Iridium source was introduced immediately after the angioplasty by random assignment to deliver 14 Gy at 2 mm in eight of the injured coronary arteries (LAD and LCX). One month later the animals were killed and the coronary arteries pressure perfusion fixed. Serial sections were stained with H&E and VVG, then evaluated by histopathologic and morphometric techniques. Maximal intimal thickness (MIT), intimal area (IA), and intimal area corrected for the extent of injury (IA/FL) were measured in the irradiated and control arteries and were compared to control arteries with single injuries from previous studies. RESULTS: Repeat balloon injury induced significant additional medial damage, which was associated with marked intimal hyperplasia in a concentric pattern. Intracoronary irradiation significantly decreased the total of neointima area formation (IA 93 + 0.35 mm2 compared to control 1.38 + 0.33 mm2 p < 0.01) and the MIT was also significantly reduced in the irradiated vessels (0.57 + 0.18 mm vs. 0.71 + 0.08 mm, p = 0.05). CONCLUSIONS: Intracoronary irradiation immediately after the second balloon dilatation inhibits the intimal hyperplasia due to that injury. However, there was no effect on the existing neointima from the initial injury.

Angioplasty, Balloon↗
PubMed1997

Long-term angiographic and clinical outcome after percutaneous transluminal coronary angioplasty and intracoronary radiation therapy in humans.

BACKGROUND: Ionizing radiation has been shown to reduce neointimal formation after balloon angioplasty in experimental models of restenosis. This study was designed to evaluate the feasibility, safety, and effectiveness of intracoronary radiation therapy (ICRT) after percutaneous transluminal coronary angioplasty (PTCA) for preventing restenosis in human coronary arteries. METHODS AND RESULTS: Twenty-one patients (22 arteries) with unstable angina underwent standard balloon angioplasty. ICRT was performed with the use of an 192Ir source wire that was hand delivered to the angioplasty site. Angiographic follow-up was performed at 24 hours, between 30 and 60 days, and at 6 months. Angioplasty was successful in 19 of 22 lesions, and insertion of the radioactive source wire was successful at all treated sites. Angiographic study at 24 hours demonstrated early late loss of the luminal diameter from 1.92+/-0.55 to 1.40+/-0.27 mm. Between 30 and 60 days, repeat angiography demonstrated total occlusion in 2 arteries, a new pseudoaneurysm in 1 artery, and significant dilatation at the treatment site in 2 additional vessels. At > or = 6 months' follow-up, all remaining arteries (n=20) maintained patent, with a mean lumen diameter of 1.65+/-0.8 mm. The calculated late lumen loss was 0.27+/-0.56 mm, and the late loss index was 0.19. Clinical events at 1 year included myocardial infarction in 1 patient, repeat angioplasty to the treated site in 3 patients, and persistent angina in 7 patients. CONCLUSIONS: These preliminary results demonstrate that ICRT after coronary intervention is feasible and is associated with an acceptable degree of complications and lower rates of angiographic restenosis indexes.

Adult↗
PubMed1997

Systematic approach for detection of endocrine disorders in children treated for brain tumors.

Endocrine dysfunction can be challenging to diagnose in children treated for brain tumors. Treatments are available for hormonal replacement and when necessary, hormonal suppression. Without these endocrine treatment regimens, life can be unnecessarily difficult or unpleasant. An endocrine survey can be used to screen at-risk neuro-oncology patients once or twice a year to facilitate the recognition of endocrine dysfunction. It is hoped that through the use of a routine screening program, physicians will be able to diagnose and begin treatment of endocrine problems in a time-efficient manner.

Brain Neoplasms↗
PubMed1997

Basic physics and biology of radiation therapy.

The therapeutic use of ionizing radiation followed shortly after the discovery of X-rays by Roentgen in 1895. The radiobiological principles that underlie the clinical use of ionizing radiation have been ablated slowly over the past century. Ionizing radiation, which is used therapeutically for benign and malignant conditions, is characterized by the localized release of large amounts of energy. These radiations may be electromagnetic (X- or gamma rays) or particulate (electrons, protons, alpha particles, neutrons, etc.). In this paper we will review some basic radiation physics and radiation biology principles which might be unfamiliar to the interventional cardiologist interested in this evolving application of radiation to prevent restenosis.

Cell Cycle↗
PubMed1995

Intracoronary low-dose beta-irradiation inhibits neointima formation after coronary artery balloon injury in the swine restenosis model.

BACKGROUND: Neointima formation contributing to recurrent stenosis remains a major limitation of percutaneous transluminal angioplasty. Endovascular low-dose gamma-irradiation has been shown to reduce intimal thickening (hyperplasia) after balloon overstretch injury in pig coronary arteries, a model of restenosis. The objective of this study was to determine whether the use of a beta-emitting radioisotope for this application would have similar effects and to examine the dose-response relations with this approach. METHODS AND RESULTS: Normal domestic pigs underwent balloon overstretch injury in the left anterior descending and left circumflex and coronary arteries. A flexible catheter was introduced by random assignment into one of these arteries and was afterloaded with a 2.5-cm ribbon of encapsulated 90Strontium/90Yttrium sources (90Sr/Y, a pure beta-emitter). It was left in place for a period of time sufficient to deliver one of four doses: 7, 14, 28, or 56 Gy, to a depth of 2 mm. Animals were killed 14 days after balloon injury, the coronary vasculature was pressure-perfusion fixed, and histomorphometric analysis of arterial cross sections was performed. All arteries treated with radiation demonstrated significantly decreased neointima formation compared with control arteries. The ratio of intimal area to medial fracture length was inversely correlated with increasing radiation dose: control (no radiation), 0.47; 7 Gy, 0.34; 14 Gy, 0.20; 28 Gy, 0.08; and 56 Gy, 0.02 (r = -.78, P < .000001). Scanning electron microscopy demonstrated a confluent layer of endothelium-like cells both in control and in 14 Gy-irradiated arteries. There was neither evidence of significant necrosis nor excess fibrosis in the media, adventitia, or perivascular space of the coronary arteries or adjacent myocardium in the irradiated groups. Furthermore, the exposure to the staff and the total body exposure to the pig with the beta source was a small fraction of the dose previously measured and calculated with 192Ir, a gamma-emitting radioisotope. CONCLUSIONS: Administration of endovascular beta-radiation to the site of coronary arterial overstretch balloon injury in pigs with 90Sr/Y is technically feasible and safe. Radiation doses between 7 and 56 Gy showed evidence of inhibition of neointima formation. A dose-response relation was demonstrated, but no further inhibitory effect was seen beyond 28 Gy. These data suggest that intracoronary beta-irradiation is practical and feasible and may aid in preventing clinical restenosis.

Angioplasty, Balloon, Coronary↗