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1.
Phys Med Biol ; 66(11)2021 06 04.
Article in English | MEDLINE | ID: mdl-33794510

ABSTRACT

Inorganic scintillators are widely used for fast timing applications in high-energy physics (HEP) experiments, time-of-flight positron emission tomography and time tagging of soft and hard x-ray photons at advanced light sources. As the best coincidence time resolution (CTR) achievable is proportional to the square root of the scintillation decay time it is worth studying fast cross-luminescence, for example in BaF2which has an intrinsic yield of about 1400 photons/MeV. However, emission bands in BaF2are located in the deep-UV at 195 nm and 220 nm, which sets severe constraints on photodetector selection. Recent developments in dark matter and neutrinoless double beta decay searches have led to silicon photomultipliers (SiPMs) with photon detection efficiencies of 20%-25% at wavelengths of 200 nm. We tested state-of-the-art devices from Fondazione Bruno Kessler and measured a best CTR of 51 ± 5 ps full width at half maximum when coupling 2 mm × 2 mm × 3 mm BaF2crystals excited by 511 keV electron-positron annihilation gammas. Using these vacuum ultraviolet SiPMs we recorded the scintillation kinetics of samples from Epic Crystal under 511 keV excitation, confirming a fast decay time of 855 ps with 12.2% relative light yield and 805 ns with 84.0% abundance, together with a smaller rise time of 4 ps beyond the resolution of our setup. The total intrinsic light yield was determined to be 8500 photons/MeV. We also revealed a faster component with 136 ps decay time and 3.7% light yield contribution, which is extremely interesting for the fastest timing applications. Timing characteristics and CTR results on BaF2samples from different producers and with different dopants (yttrium, cadmium and lanthanum) are given, and clearly show that the the slow 800 ns emission can be effectively suppressed. Such results ultimately pave the way for high-rate ultrafast timing applications in medical diagnosis, range monitoring in proton or heavy ion therapy and HEP.


Subject(s)
Luminescence , Scintillation Counting , Photons , Positron-Emission Tomography , Vacuum
2.
Int Psychogeriatr ; 32(3): 359-370, 2020 03.
Article in English | MEDLINE | ID: mdl-31948510

ABSTRACT

OBJECTIVE: Nearly half of care home residents with advanced dementia have clinically significant agitation. Little is known about costs associated with these symptoms toward the end of life. We calculated monetary costs associated with agitation from UK National Health Service, personal social services, and societal perspectives. DESIGN: Prospective cohort study. SETTING: Thirteen nursing homes in London and the southeast of England. PARTICIPANTS: Seventy-nine people with advanced dementia (Functional Assessment Staging Tool grade 6e and above) residing in nursing homes, and thirty-five of their informal carers. MEASUREMENTS: Data collected at study entry and monthly for up to 9 months, extrapolated for expression per annum. Agitation was assessed using the Cohen-Mansfield Agitation Inventory (CMAI). Health and social care costs of residing in care homes, and costs of contacts with health and social care services were calculated from national unit costs; for a societal perspective, costs of providing informal care were estimated using the resource utilization in dementia (RUD)-Lite scale. RESULTS: After adjustment, health and social care costs, and costs of providing informal care varied significantly by level of agitation as death approached, from £23,000 over a 1-year period with no agitation symptoms (CMAI agitation score 0-10) to £45,000 at the most severe level (CMAI agitation score >100). On average, agitation accounted for 30% of health and social care costs. Informal care costs were substantial, constituting 29% of total costs. CONCLUSIONS: With the increasing prevalence of dementia, costs of care will impact on healthcare and social services systems, as well as informal carers. Agitation is a key driver of these costs in people with advanced dementia presenting complex challenges for symptom management, service planners, and providers.


Subject(s)
Dementia/economics , Health Care Costs/statistics & numerical data , Patient Acceptance of Health Care/statistics & numerical data , Patient Care/economics , Psychomotor Agitation/economics , Aged , Aged, 80 and over , Cohort Studies , Cost-Benefit Analysis , Costs and Cost Analysis , Dementia/therapy , Female , Humans , Male , Nursing Homes , Prospective Studies , Psychomotor Agitation/therapy , Social Work/economics , State Medicine , United Kingdom
3.
Radiat Res ; 175(5): 665-76, 2011 May.
Article in English | MEDLINE | ID: mdl-21375359

ABSTRACT

The hypothesis that single low-dose exposures (0.025-0.5 Gy) to low-LET radiation given at either high (about 150 mGy/min) or low (1 mGy/min) dose rate would promote aortic atherosclerosis was tested in female C57BL/6J mice genetically predisposed to this disease (ApoE⁻/⁻). Mice were exposed either at an early stage of disease (2 months of age) and examined 3 or 6 months later or at a late stage of disease (8 months of age) and examined 2 or 4 months later. Changes in aortic lesion frequency, size and severity as well as total serum cholesterol levels and the uptake of lesion lipids by lesion-associated macrophages were assessed. Statistically significant changes in each of these measures were observed, depending on dose, dose rate and disease stage. In all cases, the results were distinctly non-linear with dose, with maximum effects tending to occur at 25 or 50 mGy. In general, low doses given at low dose rate during either early- or late-stage disease were protective, slowing the progression of the disease by one or more of these measures. Most effects appeared and persisted for months after the single exposures, but some were ultimately transitory. In contrast to exposure at low dose rate, high-dose-rate exposure during early-stage disease produced both protective and detrimental effects, suggesting that low doses may influence this disease by more than one mechanism and that dose rate is an important parameter. These results contrast with the known, generally detrimental effects of high doses on the progression of this disease in the same mice and in humans, suggesting that a linear extrapolation of the known increased risk from high doses to low doses is not appropriate.


Subject(s)
Apolipoproteins E/deficiency , Atherosclerosis/etiology , Atherosclerosis/metabolism , Animals , Atherosclerosis/blood , Atherosclerosis/pathology , Cholesterol/blood , Dose-Response Relationship, Radiation , Female , Lipid Metabolism/radiation effects , Macrophages/metabolism , Macrophages/radiation effects , Mice , Time Factors
4.
Int J Cardiol ; 146(2): 181-5, 2011 Jan 21.
Article in English | MEDLINE | ID: mdl-19632731

ABSTRACT

UNLABELLED: A possible role of anomalies in number and insertion of pulmonary veins (PV) in initiating atrial fibrillation (AF) has been suggested. It has been shown as well that changes in anatomy of PVs such as enlargement may have an effect on arrhythmogenesis. The aim of the study was to compare anatomy of the left atrium (LA) and PVs in patients with AF and control subjects. METHODS: Eighty two patients were evaluated with 64-slice computed tomography (MSCT). Fifty one of them were referred to catheter ablation with history of highly symptomatic AF--AF(+) group. Thirty one control subjects had no history of AF and were referred to MSCT for noninvasive evaluation of different pathologies which finally were excluded--AF(-) group. Study groups did not differ in regard to age, sex, presence of hypertension and left ventricular systolic function. Diameters of PV ostia were measured in anterior-posterior (AP) and superior-inferior (SI) directions. Venous ostium index was calculated as a ratio between these measurements. RESULTS: The diameter of LA was higher in AF(+) patients than in the AF(-) patients (39±6 mm vs. 35±4 mm, p<0.005). In 68.6% of AF(+) patients and in 83.9% of AF(-) patients the anatomical pattern was typical with two right and two left PVs. Additional PVs were detected in 6 patients, only in AF(+) group (p<0.05). Common ostia were more frequently found in AF(+) subjects (37.2% vs. 19.3, p=0,08), mainly left-sided. In AF(+) group mean SI diameters of both-sided superior PVs and left inferior veins were larger. All AP diameters except for right inferior PVs were also larger in AF(+) group than in control cases. CONCLUSIONS: Variations in the PVs anatomy are more common and diameters of ostial portions of the veins are larger in AF patients than in control subjects. These findings suggest that further studies on the role of structural abnormalities of PVs in arrhythmogenesis are needed.


Subject(s)
Atrial Fibrillation/diagnostic imaging , Atrial Fibrillation/pathology , Pulmonary Veins/abnormalities , Pulmonary Veins/diagnostic imaging , Tomography, X-Ray Computed/methods , Adult , Female , Heart/anatomy & histology , Heart/diagnostic imaging , Heart Atria/anatomy & histology , Heart Atria/diagnostic imaging , Humans , Imaging, Three-Dimensional , Male , Middle Aged , Pulmonary Veins/anatomy & histology
5.
Int J Cardiol ; 148(1): e16-8, 2011 Apr 01.
Article in English | MEDLINE | ID: mdl-19324431

ABSTRACT

We intended to estimate how the zero coronary artery calcium (CAC) score in symptomatic patients with intermediate probability of coronary artery disease predicts the absence of obstructive non-calcified coronary plaques (NCAPs). CAC scoring and coronary arteries were evaluated by means of 64-multislice CT coronary angiography (CCTA). In 166 subject with CAC=0, Non-obstructive NCAPs (less than 50%) were found in 17 patients (10.2%), while significant stenosis were diagnosed in 3 (2%). In the female insignificant stenoses were more frequent (12%) than in men (6%), however, all 3 cases with significant stenosis were male. In our study, where CCTA has been used as diagnostic method for CAD diagnosing, the prevalence of non-calcified plaques in CAC=0 subjects is relatively high. Our study confirms a relatively low incidence of significant coronary stenosis in this subset of CAD-suspected subjects.


Subject(s)
Calcium/analysis , Coronary Artery Disease/diagnostic imaging , Arterial Occlusive Diseases/diagnostic imaging , Arterial Occlusive Diseases/epidemiology , Coronary Angiography/methods , Coronary Artery Disease/epidemiology , Coronary Stenosis/diagnostic imaging , Coronary Stenosis/epidemiology , Female , Humans , Male , Middle Aged
6.
Rev Sci Instrum ; 81(4): 044301, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20441357

ABSTRACT

In this work, we present the results of the experimental characterization of the DRAGO (DRift detector Array-based Gamma camera for Oncology), a detection system developed for high-spatial resolution gamma-ray imaging. This camera is based on a monolithic array of 77 silicon drift detectors (SDDs), with a total active area of 6.7 cm(2), coupled to a single 5-mm-thick CsI(Tl) scintillator crystal. The use of an array of SDDs provides a high quantum efficiency for the detection of the scintillation light together with a very low electronics noise. A very compact detection module based on the use of integrated readout circuits was developed. The performances achieved in gamma-ray imaging using this camera are reported here. When imaging a 0.2 mm collimated (57)Co source (122 keV) over different points of the active area, a spatial resolution ranging from 0.25 to 0.5 mm was measured. The depth-of-interaction capability of the detector, thanks to the use of a Maximum Likelihood reconstruction algorithm, was also investigated by imaging a collimated beam tilted to an angle of 45 degrees with respect to the scintillator surface. Finally, the imager was characterized with in vivo measurements on mice, in a real preclinical environment.


Subject(s)
Gamma Cameras , Algorithms , Animals , Bone and Bones/diagnostic imaging , Equipment Design , Forelimb/diagnostic imaging , Image Processing, Computer-Assisted/methods , Likelihood Functions , Lung/diagnostic imaging , Medical Oncology/instrumentation , Mice , Radionuclide Imaging/instrumentation , Radionuclide Imaging/methods
7.
J Phys Chem A ; 109(32): 7166-71, 2005 Aug 18.
Article in English | MEDLINE | ID: mdl-16834080

ABSTRACT

The complex index of refraction of liquid HNO3/H2O and H2SO4/HNO3/H2O has been obtained at different temperatures and acid concentrations. FT-IR specular reflectance spectra were obtained for 30, 54, and 64 wt % aqueous HNO3 and for four different H2SO4/HNO3/H2O mixtures in the temperature region from 293 to 183 K. The complex index of refraction was obtained from the reflectance spectra with the Kramers-Kronig transformation. The optical constants of the binary and ternary mixtures vary with the acid concentration and the temperature. The results demonstrate that vibrational bands originating from the sulfate species are more sensitive to changes in temperature than the bands originating from vibrations in the nitrate species; only minor changes in the nitrate vibrational bands are observed as the temperature decreases below 248 K.

8.
Oncol Rep ; 7(4): 887-90, 2000.
Article in English | MEDLINE | ID: mdl-10854564

ABSTRACT

Cardiotoxicity has been reported with increasing frequency after 5-FU administration. Since 5-FU-based regimens are increasingly used as adjuvant treatment for resected colon cancer patients, this carries a potential increased risk of cardiotoxicity. In the present study, we evaluated if fluoro-folate chemotherapy has any effect on left ventricular (LV) diastolic function in resected colon cancer. Twenty-five resected colon cancer patients receiving adjuvant fluoro-folate chemotherapy, were prospectively studied. Both digitized M-mode and Doppler echocardiography were performed, in order to investigate different aspects of LV diastolic function. None of the studied parameters was influenced by chemotherapy administration. Indeed, values recorded at the end of the 6-month treatment and 6 months later were not statistically different from baseline values. This study suggests that the use of fluoro-folate chemotherapy in otherwise normal subjects carries a very low risk of severe cardiotoxicity.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colonic Neoplasms/drug therapy , Colonic Neoplasms/physiopathology , Echocardiography/drug effects , Fluorouracil/therapeutic use , Ventricular Function, Left , Aged , Chemotherapy, Adjuvant , Cohort Studies , Diastole/drug effects , Female , Follow-Up Studies , Humans , Male , Middle Aged , Systole/drug effects , Ventricular Function, Left/drug effects
10.
G Ital Cardiol ; 26(10): 1123-37, 1996 Oct.
Article in Italian | MEDLINE | ID: mdl-9005158

ABSTRACT

BACKGROUND: In many cardiac conditions, Doppler of transmitral flow has been showed to be related to left ventricular filling pressure, but several factors may limit its practical value in estimating pulmonary wedge pressure in patients with chronic heart failure. Pulmonary venous velocities directly depend on the oscillations of left atrial pressure. Recent studies suggest that transthoracic Doppler of pulmonary venous flow provides a more accurate estimation of pulmonary wedge pressure. However the relative values of transmitral and pulmonary venous flow for assessing pulmonary wedge pressure in patients with chronic heart failure have not been fully classified until now. Accordingly, we performed this study to assess the feasibility of transthoracic Doppler of pulmonary venous flow in patients with chronic heart failure and to evaluate whether it provides additional information regarding pulmonary wedge pressure when compared with Doppler indices of transmitral flow. METHODS: Simultaneous Doppler echocardiographic examinations and right heart catheterizations were performed prospectively in 300 consecutive patients with chronic heart failure due to dilated cardiomyopathy. The correlations of mitral and pulmonary venous flow velocity variables, left atrial volumes, mitral regurgitation jet area and left ventricular ejection fraction with pulmonary artery wedge pressure were evaluated. RESULTS: A complete recording of transthoracic pulmonary venous flow including all components was obtained in 66% of patients, while only systolic and diastolic forward flow were recorded in 88% of patients. Several indices, derived from pulmonary venous flow, were correlated with pulmonary wedge pressure; the strongest correlation was between systolic fraction of peak velocities and pulmonary wedge pressure (r = -0.76). This value was similar to that obtained between deceleration rate (r = 0.78) and deceleration time (r = -0.67) of transmitral flow and pulmonary wedge pressure. A systolic fraction > 40% showed a greater positive predictive value than restrictive pattern of transmitral flow for identifying patients with pulmonary wedge pressure > 18 mmHg (95% vs 86% p < 0.05). This accuracy is confirmed also in patients who had a single peak of transmitral flow. CONCLUSIONS: Doppler of pulmonary venous flow can be performed in a high percentage of patients with chronic heart failure due to dilated cardiomyopathy. The indices derived from transthoracic pulmonary venous flow are strongly correlated with pulmonary wedge pressure and improve the noninvasive identification of patients with high pulmonary wedge pressure, even when transmitral flow pattern is difficult to be interpreted.


Subject(s)
Echocardiography, Doppler , Heart Failure/physiopathology , Hemodynamics , Mitral Valve/physiopathology , Pulmonary Circulation , Aged , Blood Flow Velocity , Cardiomyopathy, Dilated/complications , Chronic Disease , Confounding Factors, Epidemiologic , Feasibility Studies , Female , Heart Failure/diagnostic imaging , Heart Failure/etiology , Humans , Male , Middle Aged , Mitral Valve/diagnostic imaging , Prospective Studies , Pulmonary Wedge Pressure , Stroke Volume
11.
Am J Cardiol ; 78(6): 708-12, 1996 Sep 15.
Article in English | MEDLINE | ID: mdl-8831417

ABSTRACT

Noninvasive cardiac output estimation by Doppler echocardiography was compared with thermodilution and Fick oxygen methods in 73 patients with advanced chronic congestive heart failure due to dilated cardiomyopathy. In these patients, Doppler echocardiographic measurements showed a closer agreement with Fick measurements than that of thermodilution.


Subject(s)
Cardiac Output , Echocardiography, Doppler , Heart Failure/diagnosis , Heart Failure/physiopathology , Thermodilution , Female , Heart Failure/diagnostic imaging , Hemodynamics , Humans , Male , Middle Aged
12.
Pol Tyg Lek ; 51(19-22): 289-90, 1996 May.
Article in Polish | MEDLINE | ID: mdl-9289713

ABSTRACT

Among 200 patients treated for chronic granulocytic leukaemia (CGL) 6 (3%) cases have been selected in whom a second synchronic or metachronic neoplasma coexisted. In one patient CGL was the first neoplasma and skin basalioma the second in line. In the remaining fife; Thyroid adenocarcinoma, adeno-carcinoma of the bowl (bis), epithelial carcinoma of the penis, epithelial carcinoma of the pulmonary, were followed respectively CGL as secondary tumor in same patient.


Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Neoplasms, Second Primary/diagnosis , Adenocarcinoma/diagnosis , Aged , Humans , Intestinal Neoplasms/diagnosis , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy , Lung Neoplasms/diagnosis , Male , Middle Aged , Skin Neoplasms/diagnosis , Thyroid Neoplasms/diagnosis
14.
Acta Haematol Pol ; 25(2 Suppl 1): 136-41, 1994.
Article in Polish | MEDLINE | ID: mdl-7520658

ABSTRACT

Interferon combined with cytostatics yielded in multiple myeloma more objective reactions than conventional chemotherapy. Survival time elongation was achieved solely by maintaining myeloma remissions with long term interferon administration. In non-Hodgkin's lymphoma combinations of cytostatics with interferon were more effective than conventional chemo-and radiotherapy only when used in low grade lymphomas of the nodular type. Evidence for longer survival of these patients still waits for presentation.


Subject(s)
Interferons/therapeutic use , Lymphoma, Non-Hodgkin/therapy , Multiple Myeloma/therapy , Humans , Multiple Myeloma/mortality , Survival Rate
15.
Pol Arch Med Wewn ; 90(2): 134-41, 1993 Aug.
Article in Polish | MEDLINE | ID: mdl-8247946

ABSTRACT

In 19 patients with recently diagnosed multiple myeloma 3-week cycles of vincristine, BCNU, melphalan, cyclophosphamide and prednisone alternating with interferon were administered over 6-12 months. Results were compared with a control group of 33 myeloma patients treated exclusively with VBMCP cytostatics. In interferon treated patients objective response was more frequent (76%) and median survival time longer (above 35 months).


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Interferon-alpha/therapeutic use , Multiple Myeloma/therapy , Adult , Aged , Carmustine/administration & dosage , Cyclophosphamide/administration & dosage , Female , Humans , Interferon alpha-2 , Male , Melphalan/administration & dosage , Middle Aged , Multiple Myeloma/mortality , Prednisone/administration & dosage , Recombinant Proteins , Survival Rate , Vincristine/administration & dosage
16.
Am J Hypertens ; 6(8): 708-12, 1993 Aug.
Article in English | MEDLINE | ID: mdl-8217034

ABSTRACT

Using digitized M-mode echocardiograms, we evaluated the determinants of left ventricular (LV) systolic and diastolic function in 30 hypertensives with LV hypertrophy (LV mass > 230 g and normal LV diastolic diameter), before (LV mass 319 +/- 26 g) and after normalization of LV mass (196 +/- 21 g) by antihypertensive treatment with angiotensin converting enzyme inhibitors. As a control group we selected 50 normal subjects. Using multiple regression analysis we studied the relative role of preload (LV end-diastolic diameter), afterload (end-systolic wall stress), inotropic state (systolic pressure/end-systolic LV diameter ratio), and LV mass on LV systolic (peak shortening rate of LV diameter) and diastolic function (peak lengthening rate of LV diameter). The major determinant of systolic function was the end-systolic stress in hypertensives before treatment and the systolic pressure/end-systolic LV diameter ratio in normals and in hypertensives after treatment. The major determinant of diastolic function was LV mass in hypertensives before treatment and end-systolic stress in normals and in hypertensives after normalization of LV mass by treatment. Preload seems not to influence LV function in normals and in hypertensives with normal LV diameter. The inotropic state is the major determinant of systolic function in normals and in hypertensives after treatment, whereas this role is played by afterload in hypertensives before treatment. The diastolic function is primarily influenced by after-load in normals and in hypertensives after regression of myocardial hypertrophy, whereas in hypertensives with myocardial hypertrophy LV mass is the major determinant of diastolic function.


Subject(s)
Hypertension/complications , Hypertrophy, Left Ventricular/physiopathology , Ventricular Function, Left/physiology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Echocardiography , Female , Hemodynamics/physiology , Humans , Hypertension/drug therapy , Hypertrophy, Left Ventricular/etiology , Male , Middle Aged , Regression Analysis
18.
Acta Haematol Pol ; 23(4): 229-35, 1992.
Article in Polish | MEDLINE | ID: mdl-1293903

ABSTRACT

Median survival time in multiple myeloma treated with melphalan and prednisone does not differ significantly from survivals yielded by combination of alkylating cytostatics. Intensive chemotherapy linked with marrow transplantation provides elongated complete remission more frequently in patients, who reached early remission by conventional means. Multidrug resistance of myeloma plasmocytes has been overcome by adding of verapamil to the VAD program. In recently diagnosed myelomas, it is more rational to assay the survival prognosis and access to intensive therapy.


Subject(s)
Multiple Myeloma/therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bone Marrow Transplantation , Combined Modality Therapy , Drug Resistance , Humans , Multiple Myeloma/mortality , Survival Rate
19.
Neoplasma ; 39(1): 35-8, 1992.
Article in English | MEDLINE | ID: mdl-1528303

ABSTRACT

Drug resistance of marrow plasma cells had been measured in vitro before chemotherapy was started. Resistance to melphalan was found in 20, to BCNU in 27 and to epirubicin in 38 out of 65 myelomas. Nineteen myelomas were resistant to a single cytostatic, 14 to two cytostatics and further 13 to all three. Patients with plasma cells resistant to melphalan in vitro failed to reduce 50% of monoclonal Ig plasma level after therapy along the VBMCP (M2) protocol, whereas sensitive myelomas responded to this program satisfactorily. Patients with cells resistant to two or three cytostatics, beside a bad therapeutic response, had also a shorter survival time. Results in vitro were in conformity with in vivo effects in 78%.


Subject(s)
Carmustine/pharmacology , Epirubicin/pharmacology , Melphalan/pharmacology , Multiple Myeloma/drug therapy , Thymidine/metabolism , Adult , Bone Marrow/drug effects , Bone Marrow/immunology , Bone Marrow/pathology , Drug Resistance , Humans , Immunoglobulins/analysis , Middle Aged , Multiple Myeloma/immunology , Multiple Myeloma/pathology , Tritium , Tumor Cells, Cultured/drug effects
20.
Pol Tyg Lek ; 46(37-39): 697-9, 1991.
Article in Polish | MEDLINE | ID: mdl-1669135

ABSTRACT

The possible interaction between hematopoietic neoplasms and ischemia of the lower limbs in patients with both pathologies was subjected to analysis. Anaemia, polycythemia, thrombocythemia, increased leucocytosis in the peripheral blood, and hyperuricemia exerted unfavourable effect on the blood flow through the arteries of the lower limbs. In some cases effective cytostatic treatment diminished the ischemia of the lower limbs. Interactions between various drugs used in the chronic treatment of both pathologies in the same patient was also examined.


Subject(s)
Histiocytic Disorders, Malignant/complications , Ischemia/etiology , Leg/blood supply , Leukemia/complications , Lymphoma/complications , Aged , Antineoplastic Agents/adverse effects , Humans , Male , Middle Aged
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