DNA damage and repair in peripheral blood mononuclear cells after internal ex vivo irradiation of patient blood with 131I.

AIM: The aim of this study was to provide a systematic approach to characterize DNA damage induction and repair in isolated peripheral blood mononuclear cells (PBMCs) after internal ex vivo irradiation with [131I]NaI. In this approach, we tried to mimic ex vivo the irradiation of patient blood in the first hours after radioiodine therapy. MATERIAL AND METHODS: Blood of 33 patients of two centres was collected immediately before radioiodine therapy of differentiated thyroid cancer (DTC) and split into two samples. One sample served as non-irradiated control. The second sample was exposed to ionizing radiation by adding 1 ml of [131I]NaI solution to 7 ml of blood, followed by incubation at 37 °C for 1 h. PBMCs of both samples were isolated, split in three parts each and (i) fixed in 70% ethanol and stored at - 20 °C directly (0 h) after irradiation, (ii) after 4 h and (iii) 24 h after irradiation and culture in RPMI medium. After immunofluorescence staining microscopically visible co-localizing γ-H2AX + 53BP1 foci were scored in 100 cells per sample as biomarkers for radiation-induced double-strand breaks (DSBs). RESULTS: Thirty-two of 33 blood samples could be analysed. The mean absorbed dose to the blood in all irradiated samples was 50.1 ± 2.3 mGy. For all time points (0 h, 4 h, 24 h), the average number of γ-H2AX + 53BP1 foci per cell was significantly different when compared to baseline and the other time points. The average number of radiation-induced foci (RIF) per cell after irradiation was 0.72 ± 0.16 at t = 0 h, 0.26 ± 0.09 at t = 4 h and 0.04 ± 0.09 at t = 24 h. A monoexponential fit of the mean values of the three time points provided a decay rate of 0.25 ± 0.05 h-1, which is in good agreement with data obtained from external irradiation with γ- or X-rays. CONCLUSION: This study provides novel data about the ex vivo DSB repair in internally irradiated PBMCs of patients before radionuclide therapy. Our findings show, in a large patient sample, that efficient repair occurs after internal irradiation with 50 mGy absorbed dose, and that the induction and repair rate after 131I exposure is comparable to that of external irradiation with γ- or X-rays.

α-Particle-induced DNA damage tracks in peripheral blood mononuclear cells of [223Ra]RaCl2-treated prostate cancer patients.

PURPOSE: One therapy option for prostate cancer patients with bone metastases is the use of [223Ra]RaCl2. The α-emitter 223Ra creates DNA damage tracks along α-particle trajectories (α-tracks) in exposed cells that can be revealed by immunofluorescent staining of γ-H2AX+53BP1 DNA double-strand break markers. We investigated the time- and absorbed dose-dependency of the number of α-tracks in peripheral blood mononuclear cells (PBMCs) of patients undergoing their first therapy with [223Ra]RaCl2. METHODS: Multiple blood samples from nine prostate cancer patients were collected before and after administration of [223Ra]RaCl2, up to 4 weeks after treatment. γ-H2AX- and 53BP1-positive α-tracks were microscopically quantified in isolated and immuno-stained PBMCs. RESULTS: The absorbed doses to the blood were less than 6 mGy up to 4 h after administration and maximally 16 mGy in total. Up to 4 h after administration, the α-track frequency was significantly increased relative to baseline and correlated with the absorbed dose to the blood in the dose range < 3 mGy. In most of the late samples (24 h - 4 weeks after administration), the α-track frequency remained elevated. CONCLUSION: The γ-H2AX+53BP1 assay is a potent method for detection of α-particle-induced DNA damages during treatment with or after accidental incorporation of radionuclides even at low absorbed doses. It may serve as a biomarker discriminating α- from ß-emitters based on damage geometry.

Multicentre Trials on Standardised Quantitative Imaging and Dosimetry for Radionuclide Therapies.

The aim of this review is to summarise the efforts undertaken so far to compare or standardise quantitative imaging with gamma cameras across centres for multicentre trials in radionuclide therapies. Overall, 10 studies were identified, five of which were set up as a multicentre effort for standardising and comparing methods for quantitative imaging. One study used positron emission tomography imaging with 124I. In the remaining studies, measurements were carried out with planar imaging, single photon emission computed tomography/computed tomography (SPECT/CT) or a combination of both. Three studies used radioactive calibration sources that were traceable to national standards. Most of the studies were set up in the framework of multicentre clinical trials in an effort to obtain comparable quantification across sites. The use of state-of-the-art SPECT/CT systems and reconstructions has emerged as the method of choice for dosimetry in clinical trials for radionuclide therapies.

Targeted alpha-particle therapy: imaging, dosimetry, and radiation protection.

Systemic or locoregionally administered alpha-particle emitters are highly potent therapeutic agents used in oncology that are fundamentally novel in their mechanism and, most likely, overcome radiation resistance as the alpha particles emitted have a short range and a high linear energy transfer. The use of alpha emitters in a clinic environment requires extra measures with respect to imaging, dosimetry, and radiation protection. This is shown for the example of 223Ra dichloride therapy. After intravenous injection, 223Ra leaves the blood and is taken up rapidly in bone and bone metastases; it is mainly excreted via the intestinal tract. 223Ra can be imaged in patients with a gamma camera. Dosimetry shows that, after a series of six treatments for a 70-kg person with an overall administered activity of 23 MBq, 223Ra results in an absorbed alpha dose of approximately 17 Gy to the bone endosteum and approximately 1.7 Gy to the red bone marrow. During administration, special care must be taken to ensure that no spill is present on the skin of either the patient or staff. Due to the low dose rate, the treatment is normally performed on an outpatient basis; the patient and carers should receive written instructions about the therapy and radiation protection.

Self-irradiation of the blood from selected nuclides in nuclear medicine.

Nuclear medicine dosimetry and research in biodosimetry often require the knowledge of the absorbed dose to the blood. This study provides coefficients for the absorbed dose rates to the blood related to the activity concentration in the blood as a function of the vessel radius for radionuclides commonly used in targeted radiotherapy and in PET-diagnostics: C-11, F-18, Ga-68, Y-90, Tc-99 m, I-124, I-131, and Lu-177. The energy deposition patterns after nuclear disintegrations in blood vessel lumina (cylinders homogeneously filled with blood) with radii from 0.01 to 25.0 mm were simulated with the Monte-Carlo radiation transport code MCNPX. An additional contribution from photon radiation from activity in blood in the remainder of the body was taken into account based on a reasonable blood distribution model. The fraction of energy absorbed from non-penetrating radiation in the blood is low in thin blood vessels but approaches the total energy emitted by particles with increasing lumen radius. For photon radiation, irradiation to blood in small vessels is almost completely due to radioactive decays in distant blood distributed throughout the body, whereas the contribution from activity in the vessel becomes dominant for lumen radii exceeding 13 mm. The dependences of the absorbed dose rates on the lumen radius can be described with good accuracy by empirical functions which can be used to determine the absorbed doses to the blood and to the surrounding tissue.

Dosimetry of [68Ga]-labeled compounds.

This review compiles and analyzes the available dosimetry data of [(68)Ga] labeled compounds. Dosimetry data are given for [(68)Ga]DOTA-NOC, TOC, TATE, and NODAGA-RGDyK. The number of PET-scans with [(68)Ga]DOTA-compounds for imaging neuroendocrine tumors is increasing because [(68)Ga] has a higher affinity to somatostatin receptors (SSTR) in comparison to comparable [(111)In]-compounds. In addition, the better image resolution of the PET images provides improved diagnostics. Despite its widespread use literature on dosimetry of [(68)Ga]-labeled radiopharmaceuticals is sparse. In some cases the description of the underlying methodology is missing or human data are gained from the extrapolation of animal experiments. More and better documented dosimetry data will further promote the use of these promising new agents.

Lithium as an adjunct to radioiodine therapy in Graves' disease for prolonging the intrathyroidal effective half-life of radioiodine. Useful or not?

AIM: Evaluation of intrathyroidal kinetics of radioiodine with and without lithium as adjunct with respect to the increase in radiation dose delivered to the thyroid. PATIENTS, METHODS: 267 patients in three groups were included in the study. Group I with 227 patients served as control group, Group II with 21 patients and Group III with 19 patients were distinguished by an intrathyroidal half-life of radioiodine below 3.5 days in the diagnostic test. Patients in Group III received 885 mg lithium carbonate a day for 2 weeks as adjunct to radioiodine therapy. Both diagnostic and therapeutic radioiodine kinetics were followed up by at least 10 uptake measurements within a minimum of 48 h. Kinetics of radioiodine were defined mathematically as balance of the thyroidal iodine intake and excretion by a two-compartment model. RESULTS: Under therapy the maximum uptake of radioiodine was reduced by nearly 10% in all groups, in Group I, the effective half-life as well as the product of maximum uptake x effective half-life as an equivalent of radiation dose independent of thyroid volume was lowered in the same magnitude. In Group II, the energy-dose equivalent remained constant under therapy. With adjunct lithium in Group III, the effective half-life was prolonged significantly by factor 1.61 +/- 0.49 and the volume-independent energy-dose equivalent by factor 1.39 +/- 0.37. No severe side effects of lithium were observed. CONCLUSION: Using lithium as adjunct to radioiodine therapy increases the radiation dose delivered to the thyroid by 39% on average and nearly 30% of radioiodine activity can be saved in these patients. Lithium is recommended in patients with very short effective half-life in the diagnostic test in order to reduce the activity required and whole-body radiation dose.

The influence of age and other risk factors on the results of coronary reoperation.

In a retrospective analysis of 115 patients who underwent a coronary reoperation between 1984 and 1989, we studied the influence of age and other risk factors on the perioperative morbidity and mortality and on the long-term results. The mean age of the population was 59.4 years, 55 patients were below 60, 52 between 60 and 70 and 8 patients over 70 years, respectively. The distribution of risk factors was similar to other populations suffering from coronary heart disease. The mean time between first and second coronary operation was 7.1 years. Complete revascularisation at the reoperation could be achieved in only 20.9% (n = 24) of the patients. A mean of 1.9 vein grafts were implanted. The perioperative mortality (within 30 days) was 5.2% (n = 6) for the whole group, whereas the highest mortality rate could be observed in the patients aged over 70 with 25% (n = 2). The incidence of perioperative complications was also higher in the elderly patients, comparing them to the whole group. Mean follow-up time was 39 months. During follow up 14 patients (12.4%) died, most of the deaths were cardiac related. The cumulative survival rate was 91% after one, 90% after three, and 88% after five years. We found no statistically significant differences in the survival rates and the myocardial infarction rates regarding the different age groups. The exercise capacity and functional status at the time of follow up were quite acceptable.(ABSTRACT TRUNCATED AT 250 WORDS)

[Cardiac surgery interventions in patients over 70 years of age]. / Kardiochirurgische Eingriffe bei über Siebzigjährigen.

In consequence of a longer life expectancy and improved surgical results, patients aged over 70 years now account for 10 to 15% of patients undergoing surgery on the heart. Such patients do, however, make greater demands on peri-operative management; the adaptability of the cardiopulmonary and renal functions to stress is reduced, homeostasis is fragile, and the diseases that commonly accompany old age represent an additional risk. Furthermore, greater demands are also made on the operating skills of the surgeon. Nevertheless, no patient should be considered inoperable merely on account of advanced age. However, the indications for surgery must always be established on an individual basis, and against the background of the expected risk/benefit ratio. The biological rather than the chronological age is always decisive. The main aim of surgical treatment is to achieve an improvement in the patient's quality of life.

Asymptomatic strut fracture in DeBakey-Surgitool aortic valves: incidence, management, and metallurgic aspects.

From August 1971 through November 1972, we implanted 62 Model 2 DeBakey-Surgitool aortic valve prostheses in 62 patients, 4 of whom later had clinically asymptomatic strut fractures. In 1 case, the patient died suddenly, and autopsy revealed detachment of the ball-cage; in each of the other 3 cases, fractures of 2 struts close to the base of the prosthesis were diagnosed fluoroscopically, and the patients underwent successful reoperation. The interval between implantation and reoperation ranged from 11 months to 16 years, 9 months. In 1 patient, retrospective study of chest radiographs revealed that the fracture had been present for 2(1/2) years. Larger valves (>/= A6) were affected significantly more often than smaller ones. We performed metallurgic analysis of 1 prosthesis: results revealed strut wear from fatigue cracking and secondary abrasion. Strut fracture was also promoted by suspension of the cage at right angles to the prosthetic ring and by use of a pyrolytic carbon ball in a titanium cage (i.e., an occluder harder than its holder). Patients with DeBakey-Surgitool aortic valve prostheses should undergo annual radiologic examinations to enable early detection of strut fractures. Prophylactic valve replacement is not indicated.

Thromboembolic and bleeding complications after mitral valve replacement.

One thousand six hundred and sixty-eight consecutive patients who underwent isolated mitral valve replacement (MVR) from 1963 to 1984 were evaluated retrospectively. Thromboembolism occurred with a linearised rate of 2.5% +/- 0.2%/patient-year (PY) for Starr-Edwards disc prosthesis Model 6520, 2.4% +/- 0.3%/PY for Bjørk-Shiley plane prosthesis, 3.0% +/- 0.8%/PY for Bjørk-Shiley convexo-concave 60 degrees prosthesis, 3.0% +/- 0.8%/PY for St. Jude Medical prosthesis and 3.4% +/- 0.5%/PY for Carpentier-Edwards tissue valve without the differences reaching significance. In the SJM group, the incidence of thromboembolism was significantly higher (P less than 0.025) in smaller sizes (less than M29) probably due to a more turbulent flow. The linearised rate for major haemorrhage was 1.6% +/- 0.1%/PY. Twenty-three percent of the thromboembolic and 18% of the bleeding events were fatal. Sixty-eight percent of the emboli involved the central nervous system and bleeding apart from fatalities was predominantly non-cerebral (81%). Whereas thromboembolism was a time-related event with more than twice as high a risk in the first postoperative year (4.2% +/- 0.5% vs. 1.7% +/- 0.8%, P less than 0.01), bleeding occurred with a constant rate over time (0.9% +/- 0.4%). Adequacy of anticoagulation was an important risk factor for postoperative embolism with the prothrombin time (PT) exceeding the therapeutic range in 65% of all events. A preoperative history of embolism was the only additional patient-related risk factor for postoperative embolism (18.3% vs. 9.6%, P less than 0.001). In 30% of all haemorrhage, the PT was below 15%.(ABSTRACT TRUNCATED AT 250 WORDS)

R peak delay in V6. Diagnostic implications in coronary heart disease.

Epimyocardial excitation is delayed in areas overlying infarcted myocardium. On the assumption that a delayed R peak in V6 could indicate anterior myocardial infarction (AMI) in the absence of diagnostic Q waves, the findings of angiocardiography (n = 148) and thallium scanning (n = 46) of 194 patients with suspected coronary heart disease (CHD) were compared with regard to two criteria: A (R peak in V6 precedes S peak in V2, or both peaks occur simultaneously, n = 158) and B (R peak in V6 is later than S peak in V2 [R peak delay in V6], n = 36). Of 92 patients with unconfirmed CHD, 4 fit criterion B, and 3 of these had hypertensive heart disease. In 102 patients with confirmed CHD, B was present in 15 of 79 evaluated with angiocardiography and in 17 of 23 patients who had nuclear scanning. Anterior akinesis or dyskinesis was more prevalent in group B (13 cases, 86%) than in group A (17 cases, 26.6%; p = 0.000), as were irreversible anterior thallium defects, with 16 cases in group B (94.1% and 3 cases in group A (50%) (p = 0.016). Two of the three false positives had anterior hypokinesis and one had hypertensive cardiovascular disease. B was less sensitive (59.2%) but demonstrated a specificity of 95.2% and a positive predictive value of 80.6% for the detection of AMI. If used in conjunction with C (poor or reverse R wave progression from V1 to V4, notching at the R upstroke or rsR' in V4, V5, or V6), sensitivity was decreased (38.6%) but false positives were eliminated (specificity and positive predictive value reached 100%). Thus, in the setting of CHD, B can be recommended as a marker of non-Q wave AMI, and its diagnostic reliability is maintained, even in systemic arterial hypertension, if C is taken into consideration.

Assessment of left ventricular function from the electrocardiogram in left bundle branch block.

The QRS duration, maximum right precordial S amplitude, sum of amplitudes of the maximum right precordial S and T wave and T wave polarity in lead I have been analyzed in order to identify electrocardiographic predictors of left ventricular end-diastolic volume index and ejection fraction in 165 patients with complete left bundle branch block and various forms of heart disease. Multivariate analysis selected the duration, maximal amplitude of the S wave and polarity of the T wave in decreasing order of discriminatory power, which correctly identify 76.6% of the patients with a normal end-diastolic volume index less than or equal to 90 ml/m2 and a normal ejection fraction greater than or equal to 60% (n = 64) and 73.3% of those with an end-diastolic volume index greater than 90 ml/m2 or an ejection fraction less than 60% (n = 101). The comparisons of the QRS duration with the end-diastolic volume index and the ejection fraction give the best single correlations: r = 0.57 and -0.63, respectively. Multiple correlations lead to no substantial improvement of the r values: 0.06 and -0.65, respectively. A QRS duration less than 140 msec is almost always predictive of the presence of a normal end-diastolic volume index and a normal ejection fraction (sensitivity 100%, specificity 91.9%, positive predictive value 73.3%). A QRS duration greater than 170 msec is most accurate in predicting depressed left ventricular ejection fraction less than 55% (sensitivity 36.5%, specificity 98%, positive predictive value 92%). Thus, only the QRS duration provides a useful reference and guide for the evaluation of left ventricular function in the presence of left bundle branch block.

Electrocardiographic markers of impaired left ventricular ejection performance in aortic stenosis.

To determine whether the ECG would be useful in the prediction of impaired left ventricular ejection performance in aortic valve stenosis, the authors evaluated 121 patients according to (1) the time relationship of the R peak in V6 to the S peak in V2; and (2) the negative P wave terminal force in V1 (Morris index, n = 109). Left ventricular ejection fraction (LVEF) was significantly depressed in patients with the R peak in V6 later than the S peak in V2 (R peak delay in V6, n = 24), compared with those with the R peak in V6 preceding the S peak in V2 or with both peaks occurring simultaneously (n = 97) (LVEF 40.8 +/- 11.8% vs 69.9 +/- 13.3%, p = .000). LVEF less than 55% was present in 87.5% of patients with the R peak delay in V6 and in only 23.7% of those without this finding. The Morris Index was significantly greater in patients with LVEF less than 55% (n = 39) than in those with LVEF greater than or equal to 55% (n = 70) (Morris Index 0.063 +/- 0.035 msec vs 0.030 +/- 0.025 msec, p = .000). The R peak delay in V6 is a highly specific (96.1%), but less sensitive (47.7%), indicator of depressed LVEF, its positive predictive value and predictive accuracy being 87.5% and 78.5%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)