Effects of single-dose protons or oxygen ions on function and structure of the cardiovascular system in male Long Evans rats.

PURPOSE: Studies are required to determine whether exposures to radiation encountered during manned missions in deep space may have adverse effects on the cardiovascular system. Most of the prior studies on effects of simulated space radiation on the heart and vasculature have been performed in mouse models. To provide data from a second animal species, two studies were performed to assess effects of high-energy charged particle radiation on the heart and abdominal aorta in a rat model. MATERIALS AND METHODS: In study A, male Long Evans rats were exposed to whole-body protons (250 MeV, 0.5 Gy) or oxygen ions (16O, 600 MeV/n, 0.5 Gy), and ultrasonography was used to measure in vivo cardiac function and blood flow parameters at 3, 5, 9 and 12 months after radiation, followed by tissue collection at 12 months. In study B, male Long Evans rats were exposed to 16O (1 GeV/n, 0.01-0.25 Gy), and hearts collected at 6 to 7 and 12 months for histology and western-blots. RESULTS: Both protons (250 MeV) and 16O (600 MeV/n) caused a decrease in left ventricular posterior wall thickness at 3-5 months, but did not change echocardiographic measures of cardiac function. In Pulsed-wave Doppler assessment of the abdominal aorta, an increase was seen in mean velocity, peak velocity, and velocity time integral at 12 months after 16O (600 MeV/n), suggesting a change in vascular function. There were no significant changes in histopathology or histological quantification of total collagens in heart or aorta. On the other hand, an increase was seen in a 75 kDa peptide of collagen type III in the left ventricle of rats exposed to protons (250 MeV) and 16O (600 MeV/n and 1 GeV/n), suggesting that radiation caused remodeling of existing collagens in the heart. 16O (600 MeV/n and 1 GeV/n) caused increases in left ventricular protein levels of immune cell markers CD2, CD4, CD8, and CD68. CONCLUSION: A single low dose of whole body protons or 16O in male Long Evans rats did not change cardiac function or induce gross pathological changes in the heart or aorta, but induced mild changes in vascular function and remodeling of existing collagens in the heart. Altogether, studies in prior mouse models and the current work in rats indicate minor changes in cardiac function and structure after a low dose of single-ion radiation.

Failure patterns after curative resection for intrahepatic cholangiocarcinoma: possible implications for postoperative radiotherapy.

BACKGROUND: To explore the patterns of failures and areas at highest risk of recurrence for postoperative intrahepatic cholangiocarcinoma (IHCC), with the aim to guide IHCC adjuvant radiotherapy. METHODS: Patients with IHCC who had undergone radical surgery at our institution from July 2010 to August 2017 were retrospectively analyzed. The survival and prognostic factors were analyzed by univariate and multivariate analysis. All sites of recurrence were found out and classified as the surgical margin, regional lymph nodes, liver remnant and distant metastasis. According to the recurring area at highest risk, the target volume of adjuvant radiotherapy was proposed. RESULTS: The median follow-up time was 23.5 months (2-85 months). The median recurrence free survival (RFS) and overall survival (OS) were 12.1 months and 24.8 months, respectively. Seventy-three (73/127, 57.5%) IHCC patients developed tumor recurrence. Initial recurrences occurred in the potential postoperative radiotherapy (PORT) volume, remnant liver and distant sits were 46 (46/73, 63.0%), 36 (36/73, 49.3%) and 22 (22/73, 30.1%) cases, respectively. Of the 46 patients whose initial recurrence inside the potential PORT volume, 29 (29/73, 39.7%) developed recurrence only inside the potential PORT volume, including 13 tumor bed recurrences, 7 lymph node metastases, and 9 with both tumor bed recurrences and lymph node metastases. The most common lymph node metastases sites were nodes around the abdominal aorta, followed by lymph nodes along the celiac artery, the common hepatic artery, and in the hepatoduodenal ligament. CONCLUSIONS: High proportion of the recurrences occurred only inside the potential PORT volume, implying adjuvant radiotherapy might improve the local-regional control. Surgical margins and lymph node stations No.16a2, 9, 8, 12, 13, and 14 are suggested to be included in the radiation volume.

Irradiation abolishes smooth muscle investment into vascular lesions in specific vascular beds.

The long-term adverse effects of radiotherapy on cardiovascular disease are well documented. However, the underlying mechanisms responsible for this increased risk are poorly understood. Previous studies using rigorous smooth muscle cell (SMC) lineage tracing have shown abundant SMC investment into atherosclerotic lesions, where SMCs contribute to the formation of a protective fibrous cap. Studies herein tested whether radiation impairs protective adaptive SMC responses during vascular disease. To do this, we exposed SMC lineage tracing (Myh11-ERT2Cre YFP+) mice to lethal radiation (1,200 cGy) followed by bone marrow transplantation prior to atherosclerosis development or vessel injury. Surprisingly, following irradiation, we observed a complete loss of SMC investment in 100% of brachiocephalic artery (BCA), carotid artery, and aortic arch lesions. Importantly, this was associated with a decrease in multiple indices of atherosclerotic lesion stability within the BCA. Interestingly, we observed anatomic heterogeneity, as SMCs accumulated normally into lesions of the aortic root and abdominal aorta, suggesting that SMC sensitivity to lethal irradiation occurs in blood vessels of neural crest origin. Taken together, these results reveal an undefined and unintended variable in previous studies using lethal irradiation and may help explain why patients exposed to radiation have increased risk for cardiovascular disease.

Radiation suppresses neointimal hyperplasia through affecting proliferation and apoptosis of vascular smooth muscle cells.

PURPOSE: To study the effect of x-ray radiotherapy on vascular smooth muscle cells (VSMCs) and elucidate the mechanisms in preventing neointimal hyperplasia of prosthetic vascular grafts. MATERIALS AND METHODS: In model I, twelve mongrel dogs underwent revascularization with prosthetic grafts and half the dogs underwent irradiation of the grafts at 28 Gy. In model II, human VSMCs (hVSMCs) were maintained and divided into six groups to which external radiation was applied at six different doses: 0 Gy, 2 Gy, 8 Gy, 16 Gy, 24 Gy and 30 Gy. In both models, specimens were harvested and examined by using morphological, immunological, cellular and molecular methods. RESULTS: After irradiation, the neointima thickness was significantly lower in irradiated groups (p≤0.01). The radiotherapy could up-regulate p27kip1, and down-regulate proliferating cell nuclear antigen (PCNA) and S phase kinase associated protein 2 (Skp2). X-ray irradiation inhibits the proliferation of hVSMCs via acting on G1/S phase of cell cycle. The apoptosis of hVSMCs increased significantly with dose and time. The expression of PCNA and Skp2 were decreased after a first increasing trend with dose, but had a significant negative correlation with time. The expression of p27kip1 had a significant positive correlation with dose and time. CONCLUSIONS: Postoperative external fractionated irradiation after prosthetic vessel replacement of the abdominal aorta suppressed the development of hyperplasia in the graft neointima in the short term. There was a prominent time- and dose-dependent inhibition of VSMC proliferation by radiation when it was administered.

Ultraviolet B Exposure Inhibits Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Mice by Expanding CD4+Foxp3+ Regulatory T Cells.

BACKGROUND: Pathogenic immune responses are known to play an important role in abdominal aortic aneurysm (AAA) development. Ultraviolet B (UVB) irradiation has been demonstrated to have therapeutic potential not only for cutaneous diseases but also for systemic inflammatory diseases in mice by suppressing immunoinflammatory responses. We investigated the effect of UVB irradiation on experimental AAA. METHODS AND RESULTS: We used an angiotensin II-induced AAA model in apolipoprotein E-deficient mice fed a high-cholesterol diet. Mice aged 10 weeks were irradiated with 5 kJ/m2 UVB once weekly for 6 weeks (UVB-irradiated, n=38; nonirradiated, n=42) and were euthanized for evaluation of AAA formation at 16 weeks. Overall, 93% of angiotensin II-infused mice developed AAA, with 60% mortality possibly because of aneurysm rupture. UVB irradiation significantly decreased the incidence (66%) and mortality (29%) of AAA (P=0.004 and P=0.006, respectively). UVB-irradiated mice had significantly smaller diameter AAA (P=0.008) and fewer inflammatory cells in the aortic aneurysm tissue than nonirradiated mice, along with systemic expansion of CD4+Foxp3+ regulatory T cells and decreased effector CD4+CD44highCD62Llow T cells in para-aortic lymph nodes. Genetic depletion of regulatory T cells abrogated these beneficial effects of UVB treatment, demonstrating a critical role of regulatory T cells. CONCLUSIONS: Our data suggest that UVB-dependent expansion of regulatory T cells has beneficial effects on experimental AAA and may provide a novel strategy for the treatment of AAA.

Focal induction of ROS-release to trigger local vascular degeneration.

Reactive oxygen species (ROS) play an important role in the process of cardiovascular degeneration. We evaluated the potential of a controlled, local induction of ROS-release by application of rose bengal (RB) and photo energy to induce atherosclerosis-like focal vascular degeneration in vivo. After injection of RB, rats fed with a pro-degenerative diet underwent focal irradiation of the abdominal aorta by a green laser (ROS group), while the controls received irradiation without RB. Aortic tissue was analyzed by histology and immunohistochemistry at 0, 2, 4, 8, 28 and 56 days (n = 5). The intimal surface topography was analyzed by scanning electron microscopy. In the ROS group, an initial thrombus formation had disappeared by day 8. Similarly, ROS-derived products displayed the highest concentrations at day 0. Relative matrix metalloproteinase (MMP) activity achieved a maximum after 8 days (ROS group vs. CONTROL GROUP: 1.60 ± 0.11 vs. 0.98 ± 0.01; p < 0.001). After 28 days, no significant differences in any aspect were found between the ROS group and the controls. However, after 56 days, the aortic tissue of ROS animals exhibited relative media-pronounced thickening (ROS vs. CONTROL: 2.15 ± 0.19 vs. 0.87 ± 0.10; p < 0.001) with focal calcification and reduced expression of alpha smooth muscle actin (aSMA). The ROS-releasing application of RB and photo energy allowed for the induction of vascular degeneration in a rodent model. This protocol may be used for the focal induction of vascular disease without systemic side effects and can thereby elucidate the role of ROS in the multifactorial processes of vessel degeneration and atherogenesis.

Hemodynamics changes with acute carotid baroreceptor field stimulation are age-dependent in normotensive rats.

Carotid baroreceptor stimulation can treat resistant hypertension with possible effects on the vasculature beyond the decrease in arterial pressure. This study aims to characterize age-dependency of vascular hemodynamics changes with unilateral field stimulation of carotid baroreceptors in normotensive rats to infer underlying hemodynamic mechanisms. Anesthetized Wistar-Kyoto rats divided into two groups (young: n=10, 13-33 weeks; old: n=6, 52-58 weeks) were instrumented to measure heart rate (HR) and mean arterial pressure (MAP), and flow in the abdominal aorta and renal artery. Measures of aortic and renal artery stiffness and resistance were calculated. Baroreceptor stimulation caused a consistent reduction in MAP, HR, pulse pressure and aortic pulse wave velocity. In young rats reduced MAP (77 ± 10 to 64 ± 13 mmHg, p<;0.001) was concomitant with reduced mean aortic (40 ± 15 to 32 ± 11 ml/min, p<;0.05) and renal flow (3.0 ± 1.6 2.2 ± 1.1 ml/min, p<;0.001). However, in old rats reduced MAP (76 ± 14 to 64 ± 10 mmHg, p<;0.05) occurred with a reduced aortic resistance (1.8 ± 0.9 to 1.6 ± 0.9 mmHg.min/ml, p<;0.05), renal artery resistance (17.4 ± 2.4 to 16.5 ± 2.3 mmHg.min/ml, p<;0.05) and mean renal flow (4.5 ± 1.2 to 4.0 ± 1.1 ml/min, p<;0.05). This was consistent with reduced characteristic impedance in older rats in both the aorta (0.17 ± 0.08 to 0.13 ± 0.08 mmHg.min/ml, p<;0.05) and renal artery (4.97 ± 1.16 to 3.97 ± 1.08 mmHg.min/ml, p<;0.05). Stimulation caused a leftward shift in renal impedance phase frequency spectrum in both age groups indicating changes in wave reflection from the renal bed. Findings show that the reduction in MAP due to carotid barostimulation is associated with different hemodynamic mechanisms that depend on age.

Concomitant aortic leiomyosarcoma and takayasu arteritis in a 55-year-old male patient.

Takayasu arteritis is a form of large vessel granulomatous vasculitis affecting often young or middle-aged women, especially of Asian descent. It mainly affects the aorta and its branches. Primary malignancies, such as leiomyosarcoma of the aorta are extremely rare. This report discusses the exceptional and concomitant association of Takayasu arteritis and aortic leiomyosarcoma in a 55-year-old male. The patient suffered from systemic signs and symptoms related to arteritis together with claudication of left upper limb due to left artery subclavian stenosis. After instrumental evaluation, an infiltrating neoplasm at the level of abdominal aortic wall was detected and the patient underwent en bloc excision of the mass together with abdominal aorta and subsequent aortoaortic by pass reconstruction. Histologic findings showed an arterial leiomyosarcoma combined with elements of arterial inflammation. Patients completed therapeutic scheme with chemotherapy (doxorubicin and isosfamide) and radiotherapy for the cancer condition, as well as medical treatment (prednisone and adalimumab) for Takayasu arteritis. After 12 months, the patient showed no cancer recurrence and complete normalization of inflammatory indexes and symptoms of Takayasu arteritis.

Radiation-induced aortic occlusion.

Arterial occlusion is a late complication of radiotherapy usually seen in extracranial vessels following treatment for head and neck malignancy. Determining the etiology behind vessel occlusion can be difficult and involves consideration of several factors. We present a case of radiotherapy induced aortic occlusion and discuss the relevant clinical and imaging factors that allow the diagnosis to be made.

Effect of postoperative fractionated radiotherapy on canine ePTFE graft neointima and anastomotic stoma healing: a preliminary experimental study.

OBJECTIVE: The present study aimed to determine whether postoperative fractionated radiotherapy, at a total dose of 35 Gy, affected expanded polytetrafluoroethylene (ePTFE) graft anastomotic stoma healing and neointima formation. METHODS: The subrenal abdominal aortas of 20 mongrel dogs were replaced with an ePTFE graft. The dogs were randomly divided into either a radiotherapy or nonradiotherapy control group. Grafts were harvested at 4 or 8 weeks after surgery. Hematoxylin-eosin staining, and immunohistochemistry tests for proliferating cell nuclear antigen (PCNA) and CD34 were undertaken to analyze the anastomotic healing and neointima formation. RESULTS: The patency rate of grafts was 100% in each group. No disunion, rupture, or aneurysm was observed in the anastomotic stoma. Eight weeks after surgery, the graft neointima and anastomotic vessel wall of the radiotherapy group were significantly thinner than those of the control group (p < 0.05). Immunohistochemical examination was carried out in accordance with histomorphology. CONCLUSION: Postoperative fractionated radiotherapy after an ePTFE graft replacement of the abdominal aorta did not affect the healing of the anastomotic stoma. However, it suppressed the development of hyperplasia in the anastomotic stoma neointima and graft neointima formation in the short term.

Hemodynamic changes induced by preventive exposure to terahertz radiation at a frequency range corresponding to molecular emission and absorption spectrum of nitric oxide in animals under conditions of acute stress.

We studied the influence of preventive irradiation with terahertz electromagnetic waves at frequencies corresponding to nitric oxide emission and absorption molecular spectrum (150,176-150,664 GHz) on hemodynamic parameters in arteries of albino rats upon acute immobilization stress. We showed that exposure to the specified frequencies can produce adaptogenic effect manifesting in the absence of post-stress changes in the linear, systolic, and diastolic blood flow velocities and pressure gradient in various blood vessels of experimental animals.

Vascular radiolesion as a deleterious effect of high-dose-rate intraarterial brachytherapy with samarium-153 in hypercholesterolemic rabbits.

OBJECTIVE: This study was designed to evaluate vascular morphological and morphometric changes induced by brachytherapy with samarium-153 (Sm-153) at high doses in hypercholesterolemic rabbits. METHODS: Forty-three New Zealand White hypercholesterolemic rabbits were analyzed, and the total of 86 iliac arteries underwent balloon angioplasty injury. The rabbits were divided into three different groups: two irradiation groups (IG) assigned to 15 Gy (n=14) and 60 Gy (n=36) irradiation doses, respectively, and a control group (n = 36). Histomorphometric and qualitative histological analyses were performed for tissue evaluation. RESULTS: Significant reductions were found in neointimal proliferation (NIP) (p< 0.0001), media area (MA) (p<0.0001) and percent stenosis (p<0.0001) in the 15-Gy IG, compared to the other groups. The 60-Gy IG had the higher rate of NIP, increase in media and vessel areas (VA) and percent stenosis. The 60-Gy IG also showed the greatest number of xanthomatous cells (60-Gy IG: 86.11% and 15-Gy IG: 14.29%, p<0.0001) and the highest amount of hyaline amorphous tissue (60-Gy IG:58.33% and 15-Gy IG:0%, p=0.0001) and vascular proliferation (60-Gy IG:30.56% and 15-Gy IG:0%, p=0.0221). No statistically significant differences were found among groups concerning other tissue analyses. CONCLUSION: The high-dose irradiation of 60 Gy resulted in intense cell proliferation considered vascular radiolesion, unlike the 15-Gy dose, which was associated with an excellent inhibition of neointimal proliferation.

Is radiation a risk factor for atherosclerosis? An echo-color Doppler study on Hodgkin and non-Hodgkin patients.

AIMS AND BACKGROUND: The aim of the present paper was to study the role of irradiation in the atherosclerotic process in patients affected by Hodgkin and non-Hodgkin lymphoma. METHODS: We studied 84 subjects, 42 with Hodgkin or non-Hodgkin disease and 42 controls. All 42 cases had been irradiated and were comparable in terms of risk factors for atherosclerosis. All 84 subjects underwent echo-color Doppler of the arterial axis (carotids, abdominal aorta, and femoral arteries), and the intima-media thickness was measured. RESULTS: The irradiated cases had a greater intima-media thickness in the carotid district, even after dividing them according to age and sex; males were affected more than females. The irradiated patients were at greater risk of developing cardiovascular events than the controls. CONCLUSIONS: An echo-color Doppler of the carotid district is advisable in all patients who have been submitted to radiotherapy, and the patients with a significantly greater than normal intima-media thickness need a strict follow-up, and antioxidant or antiaggregant therapy should be considered.

Radiolesão vascular como efeito deletério da braquiterapia intra-arterial com dose elevada de Samário-153 em coelhos hipercolesterolêmicos / Vascular radiolesion as a deleterious effect of high-dose-rate intraarterial brachytherapy with Samarium-153 in hypercholesterolemic rabbits / Vascular radiolesion as a deleterious effect of high-dose-rate intraarterial brachytherapy with Samarium-153 in hypercholesterolemic rabbits

OBJETIVO: Este estudo tem por objetivo avaliar as alterações vasculares morfológicas e morfométricas induzidas pela braquiterapia com Samário-153 (153 Sm) em coelhos hipercolesterolêmicos, com doses elevadas. MÉTODOS: Foram analisados 43 coelhos hipercolesterolêmicos, brancos, da raça New Zealand, e o total de 86 artérias ilíacas submetidas a lesão por balão de angioplastia. Divididos em três grupos: dois (GI) irradiados com as doses de 15Gy (n=14) e 60Gy (n=36) e um grupo controle (n=36). Foram realizadas avaliação histológica morfométrica e análise histológica qualitativa para análise tecidual. RESULTADOS: Foram observadas uma redução significativa da neoproliferação intimal (NPI) no GI 15 Gy (p<0,0001), uma redução da área de camada média (ACM) (p<0,0001) e por cento estenose (p<0,0001) comparada com os demais grupos. O GI 60 Gy teve o maior índice de PNI, aumento da ACM, AV e porcentagem de estenose. No GI 60 Gy, observou-se maior número de células xantomatosas (GI 60Gy:86,11 por cento e GI 15Gy:14,29 por cento, p<0,0001), tecido amorfo hialino (GI 60Gy:58,33 por cento e GI 15 Gy:0 por cento, p=0,0001) e proliferação vascular (GI60 Gy:30,56 por cento e GI15 Gy:0 por cento, p=0,0221). Outras análises teciduais não apresentaram diferença estatística entre os grupos. CONCLUSÃO: A dose elevada de 60Gy ocasionou intensa proliferação celular considerada radiolesão vascular, ao contrário da dose de 15Gy que apresentou excelente inibição da neo-proliferação intimal.

OBJECTIVE: This study was designed to evaluate vascular morphological and morphometric changes induced by brachytherapy with samarium-153 (Sm-153) at high doses in hypercholesterolemic rabbits. METHODS: Forty-three New Zealand White hypercholesterolemic rabbits were analyzed, and the total of 86 iliac arteries underwent balloon angioplasty injury. The rabbits were divided into three different groups: two irradiation groups (IG) assigned to 15 Gy (n=14) and 60 Gy (n=36) irradiation doses, respectively, and a control group (n = 36). Histomorphometric and qualitative histological analyses were performed for tissue evaluation. RESULTS: Significant reductions were found in neointimal proliferation (NIP) (p< 0.0001), media area (MA) (p<0.0001) and percent stenosis (p<0.0001) in the 15-Gy IG, compared to the other groups. The 60-Gy IG had the higher rate of NIP, increase in media and vessel areas (VA) and percent stenosis. The 60-Gy IG also showed the greatest number of xanthomatous cells (60-Gy IG: 86.11 percent and 15-Gy IG: 14.29 percent, p<0.0001) and the highest amount of hyaline amorphous tissue (60-Gy IG:58.33 percent and 15-Gy IG:0 percent, p=0.0001) and vascular proliferation (60-Gy IG:30.56 percent and 15-Gy IG:0 percent, p=0.0221). No statistically significant differences were found among groups concerning other tissue analyses. CONCLUSION: The high-dose irradiation of 60 Gy resulted in intense cell proliferation considered vascular radiolesion, unlike the 15-Gy dose, which was associated with an excellent inhibition of neointimal proliferation.

Low-level laser irradiation modulates matrix metalloproteinase activity and gene expression in porcine aortic smooth muscle cells.

BACKGROUND AND OBJECTIVES: The vascular extracellular matrix is maintained by a dynamic balance between matrix synthesis and degradation. This equilibrium is disrupted in arterial pathologies such as abdominal aortic aneurysm. Low-level laser irradiation (LLLI) promotes wound healing. However, its effect on smooth muscle cells (SMCs), a central player in these responses, has not been established. The current study was designed to determine the effects of LLLI on arterial SMC proliferation, inflammatory markers, and matrix proteins. STUDY DESIGN/MATERIALS AND METHODS: Porcine primary aortic SMCs were irradiated with a 780 nm laser diode (1 and 2 J/cm(2)). Trypan blue exclusion assay, immunofluorescent staining for collagen I and III, Sircol assay, gelatin zymography, and RT-PCR were used to monitor proliferation; collagen trihelix formation; collagen synthesis; matrix metalloproteinase-2 (MMP-2) activity, and gene expression of MMP-1, MMP-2, tissue inhibitor of MMP-1 (TIMP-1), TIMP-2, and IL-1-beta, respectively. RESULTS: LLLI-increased SMC proliferation by 16 and 22% (1 and 2 J/cm(2), respectively) compared to non-irradiated cells (P<0.01 and P<0.0005). Immediately after LLLI, trihelices of collagen I and III appeared as perinuclear fluorescent rings. Collagen synthesis was increased twofold (2 days after LLLI: 14.3+/-3.5 microg, non-irradiated control: 6.6+/-0.7 microg, and TGF-beta stimulated control: 7.1+/-1.2 microg, P<0.05), MMP-2 activity after LLLI was augmented (over non-irradiated control) by 66+/-18% (2 J/cm(2); P<0.05), and MMP-1 gene expression upregulated. However, TIMP-2 was upregulated, and MMP-2 gene expression downregulated. IL-1-beta gene expression was reduced. CONCLUSIONS: LLLI stimulates SMC proliferation, stimulates collagen synthesis, modulates the equilibrium between regulatory matrix remodeling enzymes, and inhibits pro-inflammatory IL-1-beta gene expression. These findings may be of therapeutic relevance for arterial diseases such as aneurysm where SMC depletion, weakened extracellular matrix, and an increase in pro-inflammatory markers are major pathologic components.

The potential nephrotoxic effects of intensity modulated radiotherapy delivered to the para-aortic area of women with gynecologic malignancies: preliminary results.

OBJECTIVE: To assess kidney function via creatinine clearance before and after radiotherapy in gynecologic cancer patients treated to the para-aortic (PA) area via Intensity Modulated Radiotherapy (IMRT). METHODS: Twenty-three patients underwent IMRT to the para-aortic area, were followed for at least 5 months, and had the necessary laboratory data to calculate creatinine clearance. Various patient-related factors and radiotherapy-treatment related factors were analyzed to determine their association with changes in CrCl. RESULTS: Median follow-up was 10.9 months (range, 5-19 months). Median patient age was 51.7 years (range, 22-78). The average initial CrCl was noted to be 109.23 mL/min (range, 38.64-188.38) before radiotherapy and decreased to 90.00 mL/min (29.31-175.61) after radiotherapy (P = 0.004). Although 17 patients had a decrease in their CrCl, 6 were found to have a slight elevation. Five factors were associated with a decrement in CrCl greater than the average decrease (17.6%): presence of hydronephrosis, age <50, no history of cisplatin treatment, a BED to gross adenopathy exceeding mean BED, and salvage treatment of PA node recurrence. Subgroup analysis revealed that the only statistically significant change within the group of patient and/or treatment-related factors was between patients who were <50-year-old and patients who were > or =50 years of age (P = 0.03). No patient exhibited clinical signs of radiation-induced nephropathy. CONCLUSION: With a median follow-up of 10.9 months, the estimated CrCl decreased by 17.6% after IMRT to the para-aortic area +/- cisplatin chemotherapy. The greatest decrease in CrCl occurred in patients who had a history of hydronephrosis. Subgroup analysis revealed that the decline in CrCl was significantly greater for patients younger than 50 years of age. Interestingly, a greater decline in CrCl was noted for those patients who did not have a history of cisplatin treatment. Our preliminary results indicate that IMRT +/- cisplatin chemotherapy to the para-aortic area of women is safe and is not associated with any clinical sequelae of renal toxicity despite a small decrement in CrCl in most, but not all patients.

Hyperplasia suppression by Ho:YAG laser intravascular irradiation in rabbit.

The proliferation of smooth muscle cells (SMCs) was suppressed in denudated rabbit aorta by holmium-yttrium-aluminum-garnet (Ho:YAG) laser intravascular irradiation. This study was dedicated to determine the applicability of the Ho:YAG laser irradiation on chronic restenosis after balloon angioplasty. The proliferation of SMCs in denudated rabbit aortas was suppressed in vivo 6 weeks after the laser irradiation of 20 pulses with 60 mJ per pulse. To investigate the mechanisms of this in vivo effect, the death of SMCs by the Ho:YAG laser-induced bubble collapse pressure was studied in vitro. No significant cell death attributed to this pressure was found. We conclude that the suppression of the proliferation of SMCs in vivo might not be caused by a reduction in density of SMCs induced by the collapse in pressure. We submit that the suppression of SMC proliferation in vivo could be caused by the bubble expansion pressure and/or heat induced by the laser irradiation.

Pelvic irradiation with concurrent chemotherapy versus pelvic and para-aortic irradiation for high-risk cervical cancer: an update of radiation therapy oncology group trial (RTOG) 90-01.

PURPOSE: To report mature results of a randomized trial that compared extended-field radiotherapy (EFRT) versus pelvic radiotherapy with concomitant fluorouracil and cisplatin (CTRT) in women with locoregionally advanced carcinomas of the uterine cervix. PATIENTS AND METHODS: Four hundred three women with cervical cancer were randomly assigned to receive either EFRT or CTRT. Patients were eligible if they had stage IIB to IVA disease, stage IB to IIA disease with a tumor diameter > or = 5 cm, or positive pelvic lymph nodes. Patients were stratified by stage and by method of lymph node evaluation. RESULTS: The median follow-up time for 228 surviving patients was 6.6 years. The overall survival rate for patients treated with CTRT was significantly greater than that for patients treated with EFRT (67% v 41% at 8 years; P <.0001). There was an overall reduction in the risk of disease recurrence of 51% (95% CI, 36% to 66%) for patients who received CTRT. Patients with stage IB to IIB disease who received CTRT had better overall and disease-free survival than those treated with EFRT (P <.0001); 116 patients with stage III to IVA disease had better disease-free survival (P =.05) and a trend toward better overall survival (P =.07) if they were randomly assigned to CTRT. The rate of serious late complications of treatment was similar for the two treatment arms. CONCLUSION: Mature analysis confirms that the addition of fluorouracil and cisplatin to radiotherapy significantly improved the survival rate of women with locally advanced cervical cancer without increasing the rate of late treatment-related side effects.

Longer term assessment of photodynamic therapy for intimal hyperplasia: a pilot study.

PURPOSE: To determine the potential long term (three or six months) effectiveness of photodynamic therapy (PDT) in reducing intimal hyperplasia in swine. METHODS: Intimal hyperplasia in the abdominal aortae of swine was created by a combination of fat-supplemented diet and balloon catheter injury prior to PDT. Swine were randomly allocated into one of three groups which received either: (i) both drug and light (PDT), (ii) drug only, or (iii) light only. Twenty-four hours following administration of the photosensitizer PHOTOFRIN (porfimer sodium) at 2.5 mg/kg, two distinct 1 cm spots on the posterior wall of the abdominal aorta were illuminated by an argon pumped dye laser tuned to 630 nm for an energy fluence of 120 J/cm2. After three or six months, swine were sacrificed, perfusion fixed, and had their aortae removed for light and electron microscopy. RESULTS: Intimal hyperplasia reduction following PDT persisted for the three or six months follow up period. Experimental vessels receiving PDT showed a 26.0+/-4.5% ( n = 2, ie. four spots) and 30.8+/-5.4% ( n = 1, ie. two spots) smaller percent intimal area after three or six months of recovery, respectively. Control groups receiving either light or drug only showed less than a 6% difference in percent intimal area. Medial and adventitial layers were unaffected in all groups. Electron microscopy demonstrated that the endothelium or endothelial-like cells had regenerated in both the posterior and adjacent areas of the abdominal aortae with no clear difference between them. CONCLUSIONS: These findings suggest that PDT may be beneficial in reducing intimal hyperplasia for up to three or six months in swine.

Late neointimal tissue growth behind the stent after intravascular gamma-radiation.

PURPOSE: To determine the nature of the changes of the vascular wall after intravascular brachytherapy in stented arteries leading to incomplete stent apposition. METHODS AND MATERIALS: Stents were implanted in the infrarenal aortas of rabbits, and gamma-intravascular brachytherapy (18 Gy) or a sham radiation procedure was immediately implemented. The arteries were harvested at 6 months for histologic analyses. RESULTS: The external elastic lamina area, as well as the vascular wall area behind the stent, were significantly greater in irradiated vs. control arteries (8.94 +/- 0.68 mm2 vs. 6.87 +/- 0.40 mm2 [p <0.001] and 1.56 +/- 0.13 mm2 vs. 0.72 +/- 0.07 mm2 [p <0.001], respectively). The ratio of the intimal area behind the stent related to the total intimal area was greater in the irradiated segments (control vs. irradiated: 9.0% +/- 5.9% vs. 55.3% +/- 15.5%, p <0.05). Neointimal growth of the irradiated vessels outside the stent was characterized by marked fibrin depositions and an inflammatory response around the stent struts. CONCLUSION: Our study revealed the presence of a neointimal layer specifically located behind the stent, which represented the result of an unhealed fibrin-rich tissue growth process 6 months after intravascular brachytherapy.