Abstract: There are no data regarding changes in plasma brain natriuretic peptide (BNP) levels in patients with Fabry's diseases during enzyme replacement therapy (ERT). We describe a patient with Fabry's disease who demonstrated the improvement in plasma brain BNP levels in response to ERT. Fabry's disease is an X-linked lysosomal storage disorder caused by a deficiency of the enzyme alpha-galactosidase A, which results in progressive intracellular accumulation of globotriaosylceramide (Gb3) in various organs including the heart. Cardiac involvement is frequent in Fabry's disease, resulting in cardiac dysfunction due to hypertrophic changes of the myocardium and thickening of the valves. Although ERT has been reported to improve cardiac function, no consensus has been reached regarding the effectiveness of ERT in female patients with heterozygous Fabry's disease. We report a 44-year-old woman having heterozygous Fabry's disease, who showed mitral valve thickening and regurgitation on echocardiogram. ERT was performed by intravenous infusion of recombinant alpha-galactosidase A every 2 weeks. We assessed the influences of ERT on cardiac function by measuring echocardiograhic parameters and monitoring BNP levels, which show treatment-induced drop in patients with heart failure. Although her cardiac function and mitral regurgitation assessed by echocardiography had not improved 18 months after the beginning of ERT, the plasma BNP level, which was 91.5 pg/ml before ERT, fell to 18.9 pg/ml. In conclusion, plasma BNP levels may be useful for evaluating the effectiveness of ERT for heterozygous Fabry's disease, even in patients who demonstrate no improvement in echocardiographic parameters of cardiac structure and function.
Abstract: Recent automated applanation tonometry can measure radial pulse wave-derived central blood pressure (CBP), which has shown a prognostic value independently of peripheral blood pressure. However, CBP's clinical significance has not been fully established. We examined the associations between CBP and cardiac structure and function by comparing them with those of arterial stiffness assessed by cardio-ankle vascular index (CAVI) in treated hypertensive patients. Enrolled in the study were 102 patients (71+/-7 years) with treated hypertension. The transmitral early-to-atrial velocity ratio (E/A), peak systolic (S'), early diastolic (E') mitral annular velocities and the Tei index were measured as indexes of cardiac function derived from conventional and tissue Doppler echocardiography. Left ventricular mass index (LVMI) was measured as an index of LV hypertrophy. CBP and CAVI were measured just after echocardiographic examination. CBP, but not CAVI, correlated with LVMI (r=0.306, P<0.01). Although CBP correlated only with the Tei index (r=0.201, P<0.05), CAVI correlated with E/A (r=-0.387, P<0.001), S' (r=-0.270, P<0.01), E' (r=-0.362, P<0.01) and the Tei index (r=0.339, P<0.01). Stepwise regression analysis revealed that neither CBP nor CAVI was independently associated with E/A, S' or E'. However, CAVI, but not CBP, was independently associated with the Tei index (beta coefficient=0.311, P<0.001), reflecting both LV systolic and diastolic function. In conclusion, CBP may be suitable for detecting LV hypertrophy. In contrast, CAVI may be suitable for detecting LV dysfunction. This difference, suggesting the clinical value of each parameter, should be kept in mind when we use CBP and CAVI for assessing arteriosclerosis in treated hypertension.Hypertension Research advance online publication, 25 September 2009; doi:10.1038/hr.2009.157.
Abstract: Cardio-ankle vascular index (CAVI) has been established as a marker of arterial stiffness, which is increased in hypertensive patients. CAVI reflects the stiffness of the aorta, femoral artery, and tibial artery. Sunitinib, multi-targeted tyrosine kinase inhibitor with both anti-angiogenic and anti-tumor activities, has been proved effective in patients with gastrointestinal stromal tumors. However, the treatment with sunitinib is often complicated by side effects such as hypertension. We describe an 84-year-old woman with gastrointestinal stromal tumor, who showed changes in arterial stiffness preceding the appearance of hypertension in the early phase after sunitinib initiation. The patient received sunitinib (50 mg given daily) for gastrointestinal stromal tumor. We assessed the influence of sunitinib on arterial stiffness every 7 days by measuring CAVI. The CAVI, which reflects arterial stiffness, was increased from 9.95 at baseline to 11.65 at 7 days after the initiation of sunitinib, whereas the blood pressure remained unchanged (117/72 and 119/76 mmHg). At 14 days after sunitinib initiation, the blood pressure was increased to 159/89 mmHg, indicating the occurrence of hypertension, while the CAVI was 11.90, the similar level detected at 7 days. Subsequently, sunitinib treatment was discontinued, because of the marked decrease in blood platelets. Both blood pressure and CAVI, together with blood platelets, were restored to the baseline values at 12 days after cessation of sunitinib. In conclusion, the increase in the CAVI preceded the appearance of sunitinib-induced hypertension. Arterial stiffness assessed by CAVI may be useful for early detection of sunitinib-induced hypertension.
Abstract: It has been reported that left ventricular (LV) diastolic functional parameters assessed by conventional Doppler echocardiography, which measures blood flow velocities in cardiac cavity, correlate with arterial stiffness assessed by the cardio-ankle vascular index (CAVI) and are markers for increased risk of cardiovascular events. Recently, tissue Doppler echocardiography, which measures velocities of regional cardiac wall, has been widely used for assessment of LV diastolic function because of more accuracy than conventional Doppler echocardiography. However, there are no data regarding the ability of tissue Doppler echocardiography for predicting increased arterial stiffness. We investigated the correlation of LV diastolic functional parameters from tissue Doppler echocardiography to CAVI in order to clarify the ability of tissue Doppler echocardiography for predicting increased arterial stiffness in patients with cardiovascular risk factors. Enrolled in the study were 70 patients (69 +/- 8 years) who had no overt heart disease, but had at least one of hypertension, diabetes, and dyslipidemia. The peak early diastolic mitral annular velocity (E') was measured as an index of LV diastolic function using tissue Doppler echocardiography. The E' was correlated with CAVI (r = -0.518, p < 0.001). The optimal cut-off point for the detection of abnormal CAVI (> or = 8.81) was 5.6 cm/s for E' (sensitivity 71%, specificity 71%). The decrease in E' correlated with both LV diastolic dysfunction and increased arterial stiffness. Therefore, the LV diastolic dysfunction assessed by tissue Doppler echocardiography may be useful for predicting increased arterial stiffness and cardiovascular events in the patients with risk factors.
Abstract: The clinical usefulness of the Tei index, which reflects left ventricular (LV) systolic and diastolic function, is known to have prognostic value in patients with overt heart disease such as ischemic heart disease or congestive heart failure. Additionally, LV diastolic functional parameters such as the transmitral E/A (early to atrial velocity) ratio have been shown to have prognostic value in hypertensive patients. However, the clinical usefulness of the Tei index for hypertensive patients without overt heart disease has not yet been fully studied. We compared the Tei index between hypertensive and normotensive patients and examined independent determinants of the Tei index in hypertensive patients with preserved LV systolic function. Our subjects were 319 patients with cardiovascular risk factors including hypertension and diabetes, all of whom had preserved LV systolic function (LV ejection fraction > or = 55%). They were divided into two groups: 100 normotensives (67 +/- 11 years) and 219 hypertensives (69 +/- 13 years). LV structural and functional parameters including transmitral E/A ratio and the Tei index were measured with Doppler echocardiography. The correlations of the transmitral E velocity to the Tei index (r = -0.311, P < 0.001) were the closest in all echocardiographic parameters in hypertensives. Stepwise regression analysis showed that E velocity (beta coefficient = -0.315, P < 0.001) and relative wall thickness (beta coefficient = 0.262, P < 0.001) were independently associated with the Tei index. The Tei index in hypertensives with preserved LV systolic function may be determined primarily by LV diastolic dysfunction during early diastole with LV concentric remodeling and may, together with the E/A ratio, have prognostic value in hypertensive patients.
Abstract: Involvement of the gastrointestinal tract in cytomegalovirus (CMV) infection is commonly observed in immunocompromised hosts. We encountered an immunocompetent patient with CMV associated-acute gastric mucosal lesion (AGML). The emergence of inclusion bodies characteristic of CMV infection in the specimens obtained from the patient's gastric ulcers was helpful in identifying the cause of AGML. The patient recovered without the administration of antiviral drugs. This case illustrates that CMV infection can be one of the causative agents that trigger AGML even in immunocompetent hosts, and that gastric biopsies are extremely useful for ascertaining the etiology of AGML.
Abstract: Large vessel vasculitis leads to arterial wall thickening and stiffening because of chronic inflammatory changes. The cardio-ankle vascular index (CAVI) is recently utilized for assessing arterial stiffening caused by atherosclerosis-related diseases, including hypertension and diabetes, as well as aging. CAVI is mathematically calculated from stiffness index beta, which is established as a parameter of arterial stiffness independent of blood pressure. However, there are no data regarding arterial stiffness assessed by CAVI for large vessel vasculitis. We describe a patient with large vessel vasculitis who showed aortic wall thickening and increased CAVI without hypertension. A 68-year-old woman presented at our hospital with recurrent fever of 2-month duration, fatigue, neck pain, and weight loss. The images of 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET) demonstrated significant 18FDG uptake (indicating increased metabolic activity and presence of inflammation) in the aorta and its major branches, including the carotid and subclavian arteries. Contrast-enhanced magnetic resonance imaging demonstrated wall thickening of the thoracic aorta. These imaging findings resulted in the diagnosis of large vessel vasculitis. The patient showed normal brachial blood pressure (right, 122/72 and left, 121/66 mmHg). However, CAVIs on both sides (right, 10.3 and left, 10.4) were elevated (normal value for her age, 9.1 +/- 0.8). In conclusion, arterial stiffness in patients with large vessel vasculitis may be increased because of the arterial wall thickening and inflammatory changes. Thus, CAVI may be promising for detection of increased arterial stiffness in patients with large vessel vasculitis in the early stage, in which blood pressure is normal.
Abstract: Although patients with type 2 diabetes demonstrate cardiac diastolic dysfunction, it is well known that cardiac diastolic dysfunction is produced by hypertension and aging. The purpose of the present study was to elucidate the cardiac structure and function in normotensive patients with type 2 diabetes in various age strata in order to assess the effect of diabetes mellitus itself on cardiac function. Echocardiographic examination was performed in 77 normotensive patients with type 2 diabetes (age: 63+/-11 years) and 76 healthy control subjects (age: 60+/-11 years) who were in their forties, fifties, sixties, and seventies. The left ventricular (LV) wall thickness and dimension were measured by M-mode echocardiography. The relative wall thickness, LV mass index, and LV ejection fraction (LVEF) were calculated. LV diastolic function was assessed by the peak velocity of early rapid filling (E velocity) and the peak velocity of atrial filling (A velocity), and the ratio of E to A (E/A) using the transmitral flow velocity, which were obtained by Doppler echocardiography. No difference was observed in the relative wall thickness, LV mass index, or LVEF between the diabetic patients and control subjects in any of the age strata. The E/A ratio in the patients with type 2 diabetes was not different from that in the control subjects in their 40s (1.17+/-0.35 versus 1.20+/-0.36). However, E/A was significantly lower in the diabetic patients than in the control subjects in their 50s (0.87+/-0.28 versus 1.14+/-0.24), 60s (0.78+/-0.22 versus 0.97+/-0.27), and 70s (0.66+/-0.19 versus 0.84+/-0.21) (p<0.05). The duration of type 2 diabetes was significantly longer in patients in their 50s (7.0+/-2.5 years), 60s (8.0+/-3.2 years), and 70s (10.4+/-3.2 years) than in patients in their 40s (3.3+/-1.9 years) (p<0.001). The value of E/A in the diabetic patients correlated with the duration of type 2 diabetes (r=-0.62, p<0.001). These results indicate that cardiac diastolic dysfunction without LV systolic dysfunction in patients with well-controlled type 2 diabetes is related neither to hypertension nor LV hypertrophy, but rather to aging and the duration of type 2 diabetes.
Abstract: Left ventricular (LV) hypertrophy and dysfunction due to hypertension have been established as risk markers for stroke in hypertensive patients. The purpose of this study was to examine the differences in LV hypertrophy and dysfunction between patients with cerebral hemorrhage and those with cerebral infarction. The study enrolled 23 hypertensive patients with cerebral infarction, 25 hypertensive patients with cerebral hemorrhage, and 24 normotensive controls (controls). Standard echocardiography was performed; LV mass index was measured to evaluate LV hypertrophy, and conventional diastolic transmitral flow velocities were measured to assess LV diastolic function, which was also evaluated by measuring mitral annular velocities using tissue Doppler echocardiography. The Tei index, which reflects both the diastolic and systolic function of LV, was also calculated. The LV mass index and Tei index were significantly higher in cerebral hemorrhage (116 +/- 38 g/m(2) and 0.57 +/- 0.13) than those in controls (92 +/- 20 g/m(2) and 0.46 +/- 0.10) (p < 0.05). In contrast, the LV mass index and Tei index in cerebral infarction (100 +/- 27 g/m(2) and 0.46 +/- 0.12) were not different from those in controls. Thus, the Tei index was significantly worse in the patients with cerebral hemorrhage than in those with cerebral infarction (p < 0.05). On the other hand, the parameters, which reflect diastolic function, showed no significant differences between cerebral hemorrhage and cerebral infarction. These results indicate that LV hypertrophy and dysfunction due to hypertension are more apparent in patients with cerebral hemorrhage than in those with cerebral infarction.
Abstract: Although left ventricular (LV) hypertrophy and diastolic dysfunction assessed by echocardiography are established risk markers of cardiovascular events in hypertensive patients, relationships between these echocardiographic findings and atherosclerosis have not been fully elucidated. The purpose of this study was to examine the relationships between atherosclerosis of the retinal arteries and echocardiographic findings in hypertensive patients. Forty hypertensive patients were divided into two groups according to Scheie's classification by ophthalmologists: 20 patients with stage 1 changes (visible broadening of the light reflex from the artery with minimal arteriovenous compression) and 20 patients with stage 2 changes (more prominent than those in stage 1). Standard echocardiography was performed to measure LV mass index for evaluating LV hypertrophy and conventional diastolic transmitral flow velocities for assessing LV diastolic function. Mitral annular velocities were also measured for evaluating LV diastolic function using tissue Doppler echocardiography. The LV mass index was larger in stage 2 (130 +/- 39 g/m(2)) than stage 1 (96 +/- 16 g/m(2)) patients (p = 0.001). Peak early diastolic mitral annular velocity (E') was lower in stage 2 (5.9 +/- 0.9 cm/s) than stage 1 (7.9 +/- 1.7 cm/s) patients (p = 0.001). The optimal cutoff points for the diagnosis of Scheie stage 2 were 6.6 cm/sec for E' (sensitivity 75%, specificity 85%) and 111 g/m(2) for LV mass index (sensitivity 70%, specificity 90%). In conclusion, in hypertensive patients, the extent of atherosclerosis in the retinal arteries can be estimated by LV hypertrophy and diastolic dysfunction assessed by echocardiography.
Abstract: Cerebral white matter lesions on magnetic resonance imaging (MRI) are considered to be the result of brain ischemic injury and a risk factor for clinical stroke. The purpose of this study was to elucidate the relationship between the cardiac diastolic function and cerebral white matter lesions in elderly patients with risk factors for atherosclerosis. The study subjects were 55 patients (75 +/- 7 years) with risk factors for atherosclerosis including hypertension, diabetes mellitus, and dyslipidemia. Patients with symptomatic cerebrovascular events were excluded from the study. Cerebral white matter lesions, which were defined as exhibiting high intensity regions on brain MRI, were evaluated with the degrees of periventricular hyperintensity (PVH) according to the Japanese Brain Dock Guidelines of 2003. Peak early diastolic mitral annular velocity (E' velocity) was measured by tissue Doppler echocardiography, and was used as a parameter of cardiac diastolic function. The mean value of E' velocity was decreased due to the cardiac diastolic dysfunction (5.2 +/- 1.4 cm/s). In addition, the E' velocity was inversely correlated with the degree of PVH (rho = -0.701, p < 0.001). Stepwise regression analysis showed that the decrease in the E' velocity (beta coefficient = -0.42, p < 0.001) and the presence of hypertension (beta coefficient = 0.31, p = 0.001) were independent determinants of the degree of PVH. Thus, cardiac diastolic dysfunction is correlated to the severity of cerebral white matter lesions, suggesting the cardio-cerebral connection in elderly patients with risk factors for atherosclerosis.
Abstract: Although pulse wave velocity is the primary indicator of arteriosclerosis and is widely used as an index of vascular age in anti-aging medicine, no index is available to quantify cardiac age. We proposed a "cardiac age" index and sought to clarify its clinical significance. The study subjects were 234 patients with atherosclerosis-related diseases. These patients were divided into 127 normotensive (mean age: 64+/-12 years) and 107 hypertensive (mean age: 65+/-11 years) patients. Echocardiography was performed, and brachial-ankle pulse wave velocity (baPWV) was measured using an automatic waveform analyzer. The index of cardiac age was determined as 1,000xVS(ot)/BSA/(VS-AO), where VSot (mm) was the ventricular septal thickness at the left ventricular outflow tract, BSA (m2) was the body surface area, and VS-AO (degree) was the angle between the basal ventricular septum and the ascending aorta. The index of cardiac aging correlated significantly with age in both the normotensive (r=0.63, p<0.001) and hypertensive (r=0.58, p<0.001) patients, and these correlations were closer than those between transmitral E/A (early to atrial velocity) ratio and age in normotensive (r=0.54, p<0.001) and hypertensive (r=0.44, p<0.001) patients. The slope between age (x-axis) and the index of cardiac age (y-axis) was greater in hypertensive (1.50) than normotensive (1.32) patients. Stepwise regression analysis showed that age (beta coefficient=0.35, p<0.001), the presence of hypertension (beta coefficient=0.26, p<0.001), the left ventricular mass index (beta coefficient=0.34, p<0.001), the left ventricular end-diastolic dimension (beta coefficient=-0.35, p<0.001), the dimension of the left atrium (beta coefficient=0.14, p=0.014), and the ratio of E to A (E/A) (beta coefficient=-0.12, p=0.046) were independently associated with the index of cardiac age. The index was also significantly correlated with baPWV (r=0.53, p<0.001). The proposed index of cardiac age can quantitatively assess cardiac morphological changes due to aging and/or hypertension and may be a useful marker of peripheral arterial stiffening.
Abstract: Henoch-Schönlein purpura (HSP) is often seen in childhood and is a self-limiting illness, and complication with intussusception is rare in adults. The case is reported of a 74-year-old man who was diagnosed with intussusception with HSP by ultrasonography on day of admission. Conservative therapy was started. However, his abdominal symptoms worsened, so he underwent laparotomy 3 days after admission. Histological study of the resected specimens demonstrated necrosis in the intussuscepted colon induced by HSP vasculitis. Bowel necrosis with intussusception in adult HSP is rare and might easily be overlooked. Thus special attention should be paid to gastrointestinal manifestations and, in an abdominal emergency, timely surgical intervention is life-saving.
Abstract: Although several studies have demonstrated that cardiac diastolic function is impaired but cardiac systolic function is preserved with aging, no large-scale analysis of cardiac function by echocardiography in subjects aged > or = 90 years exists. The purpose of the present study was to elucidate the cardiac structure and function in the oldest old in order to assess the effect of aging on cardiac function. Echocardiographic examination was performed in 1793 subjects who were in their fifties, sixties, seventies, eighties, and nineties. Left ventricular (LV) wall thickness and dimension were measured by M-mode echocardiography. LV ejection fraction (LVEF) was calculated and used as the parameter representing LV systolic function. LV diastolic function was assessed using the peak velocity of early rapid filling (E velocity) and the peak velocity of atrial contraction (A velocity), and the ratio of E to A (E/A) by the transmitral flow. The Tei index, which reflects both LV diastolic and systolic function, was also calculated. The E/A decreased progressively with aging, and demonstrated the closest correlation with age among all the indexes of cardiac function (r = -0.44, P < 0.001). In contrast, LVEF and the Tei index demonstrated a very weak correlation with age (r = -0.13, P < 0.001 and r = 0.16, P < 0.001, respectively). The mean value for LVEF remained normal with aging in all age strata (50s: 71 +/- 8%, 60s: 71 +/- 8%, 70s: 70 +/- 9%, and 80s: 71 +/- 10%), but decreased significantly in subjects in their 90s (66 +/- 10%, P < 0.001). In addition, the mean value for the Tei index also remained normal with aging in subjects in their 50s (0.35 +/- 0.10), 60s (0.38 +/- 0.14), 70s (0.38 +/- 0.12), and 80s (0.39 +/- 0.15), but showed an abnormal value in subjects in their 90s (0.45 +/- 0.12, P < 0.001). In conclusion, both diastolic dysfunction and systolic dysfunction with advancing age were observed in the oldest old aged > or = 90 years. The age-related impairment of systolic function as well as diastolic function should be considered when echocardiography is used to evaluate the causes of heart failure in the oldest old.
Abstract: To determine the safety profile and activity of IP docetaxel combined with S-1 for patients with peritoneal dissemination of gastric cancer, a multi-centric phase I/II study has started. Patients with histologically confirmed peritoneal dissemination by laparoscopy or laparotomy were eligible to participate in this study, but the patients with a large amount of malignant ascites were excluded. In phase I part, the patients received variable doses of intraperitoneal docetaxel on day 1 and day 15 and 80 mg/m2 of daily oral S-1 on days 1-14 every 4 weeks. Phase I part determines the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD) and recommended dose (RD), and phase II part evaluates a safe successful execution. The response rate of peritoneal dissemination was explored as the secondary endpoint. After 2 cycles, peritoneal tumor response was assessed according to the new criteria of Society for the Study of Peritoneal Dissemination in Gastric Cancer. The response criteria included the following: a decrease in ascites and change in cytology negative; at least a 50% decrease in the sum of the longest diameter of peritoneal tumor using photographs of peritoneal lesions taken to confirm an objective response before and after the treatment.
Abstract: The aim of this study was to elucidate the cardiac function in bed-bound patients following cerebrovascular accidents. In accord with the criteria for activities of daily living (ADL) of the Japanese Ministry of Health, Labour and Welfare, 51 age-matched poststroke patients without heart disease were classified into 3 groups: rank A (house-bound) (n = 16, age, 85 +/- 6 years), rank B (chair-bound) (n = 16, age, 84 +/- 8 years), and rank C (bed-bound) (n = 19, age, 85 +/- 9 years). Using echocardiography, the left ventricular (LV) diastolic function was assessed by the ratio of early filling (E) and atrial contraction (A) transmitral flow velocities (E/A) of LV inflow. LV systolic function was assessed by LV ejection fraction (LVEF), and the Tei index was also measured to assess both LV systolic and diastolic function. No difference was observed in the E/A and LVEF among the 3 groups. The Tei index was higher in rank C (0.56 +/- 0.17) than in rank A (0.39 +/- 0.06) and rank B (0.48 +/- 0.17), and a statistically significant difference was observed between rank A and rank C (P < 0.05). Serum albumin and blood hemoglobin were significantly lower in rank C (3.1 +/- 0.4 and 10.6 +/- 1.8 g/dL) than in rank A (4.1 +/- 0.3 and 12.4 +/- 1.2 g/dL) (P < 0.001 and P < 0.05, respectively). These results indicate that latent cardiac dysfunction and poor nutritional status may exist in bed-bound patients (rank C) following cerebrovascular accidents. The Tei index may be a useful index of cardiac dysfunction in bed-bound patients because it is independent of the cardiac loading condition.
Abstract: The purpose of the present study was to elucidate the cardiac structure and function in patients who have metabolic syndrome but no history of cardiovascular disease by analyzing echocardiographic findings. Echocardiographic examination was performed to screen for cardiovascular disease in 135 patients who were in their sixties. Patients were divided into metabolic syndrome (n=65, age: 65+/-2.7 years) and non-metabolic syndrome (n=70, age: 66+/-2.5 years) groups based on the criteria for metabolic syndrome proposed by the Japanese Society of Hypertension and seven other societies in 2005. The left ventricular (LV) wall thickness and dimension were measured by M-mode echocardiography. The relative wall thickness, LV mass index, and LV ejection fraction (LVEF) were calculated. LV diastolic function was assessed by the peak velocity of early rapid filling (E velocity) and the peak velocity of atrial filling (A velocity), and the ratio of E to A (E/A) was assessed by the transmitral flow. The Tei index, which reflects both LV diastolic and systolic function, was also calculated. There were no differences in relative wall thickness, LV mass index, or LVEF between the two groups. However, both the EIA and Tei index were significantly different between the metabolic syndrome (0.66+/-0.14 and 0.36+/-0.07, respectively) and non-metabolic syndrome (0.88+/-0.25 and 0.29+/-0.09) groups (p<0.001). These results indicate that patients with metabolic syndrome can have cardiac diastolic dysfunction even if they have neither LV hypertrophy nor systolic dysfunction.
Abstract: BACKGROUND: This study aimed to determine the frequency of anatomic variations of bile ducts (aberrant bile ducts) using multislice helical computed tomography (MCT) cholangiography. METHODS: MCT scanning was performed after slow infusion of 100 mL meglumine iotroxate. Overlapping axial images, taken at 0.5-mm intervals, were reconstructed to create a multiplanar reconstruction with volume rendering. We analyzed anatomical variations of the biliary tree by MCT cholangiography. RESULTS: In a total of 113 patients, MCT cholangiography provided clear images of aberrant bile ducts in 18 patients. Major type (draining a particular segment of the liver) was found in 9 cases (8%) and minor type (draining a particular subsegment of the liver) in 9 cases (8%). CONCLUSIONS: Preoperative MCT cholangiography provides important information about the precise biliary anatomy and can reveal unexpected aberrant bile ducts prior to biliary surgery, especially laparoscopic cholecystectomy.
Abstract: The patient was a 76-year-old man having gastric cancer with peritoneal dissemination. He underwent total gastrectomy for resection of the primary tumor and improvement of the oral intake. He developed ileus and peritonitis after the surgery, which necessitated two additional operations. An intestinal stoma was thus therefore created using a catheter for tube feeding, and tube feeding was initiated after the surgery. Nutrients, as well as TS-1 (taken out of the capsule; 80 mg/day) were administered via the catheter for tube feeding. This therapy was followed by a reduction in tumor marker levels and improvement of the patient's performance status (PS), after which the patient could be discharged. He stayed at home for about 8 months, with a much-improved quality of life during this period. We concluded that the TS-1 therapy via the catheter used for alimentation was effective for the treatment of cancer in this patient. We report our experience with this case, in which tube feeding became necessary after total gastrectomy, but administration of TS-1 via the same catheter used for alimentation improved the patient's PS and made it possible for him to receive chemotherapy at home.
Abstract: BACKGROUND AND OBJECTIVES: Tumor infiltrating lymphocytes (TILs) have been recognized as a tumor-host reaction in various primary neoplasms. Although several studies reported TILs surrounding metastatic liver tumors, to the authors' knowledge few evaluations of the clinical significance of such features in patients with colorectal liver metastases have been carried out. METHODS: Forty-one patients who underwent initial hepatic resection for liver metastases from colorectal cancer were studied. Lymphocytic infiltration surrounding metastatic liver tumor was graded as weak or dense according to the mean number of TILs from 10 high-power microscopic fields (< or =50 or >50/HPF). RESULTS: Dense lymphocytic infiltration between the metastatic tumor and hepatic parenchyma was seen in 18 of 41 patients (44%). Histologically, tumor invasion of the portal vein was rare in patients with dense TILs (12%) compared with patients with weak TILs (36%). Patients with dense TILs survived longer than patients with weak TILs after hepatic resection (P = 0.013). Multivariate analysis using the Cox proportional hazard model identified this pathological variable as a significant independent prognostic factor after hepatic resection. CONCLUSIONS: The extent of lymphocytic infiltration between the metastatic nodule and hepatic parenchyma may reflect host defensive activity in the liver and is closely related to prognosis in patients who underwent hepatic resection for liver metastases from colorectal cancer.
Abstract: The prognosis and QOL of unresectable pancreatic cancer are very poor. A symptomless 60-year-old male was admitted for examination of a high serum CA19-9 level. Following ultrasound and abdominal CT, we diagnosed unresectable advanced pancreatic cancer with multiple liver metastasis. After we obtained his informed consent, we administered continuous infusion of 5-FU and low-dose cisplatin (CDDP) infusion (low-dose FP therapy) for 3 weeks. He then underwent combination chemotherapy with low-dose CDDP and TS-1 on an outpatient basis. During the chemotherapy, he did not experience any major adverse event and his QOL was relatively good. On follow-up CT 3 months later, the primary tumor in the pancreas was found to be stable. However, the size and number of liver tumors were remarkably reduced. The serum CA19-9 level had also remarkably decreased from 48,300 U/ml to 1,480 U/ml. In conclusion, the combination chemotherapy using low-dose CDDP and TS-1 can be effective in cases of unresectable pancreatic cancer with multiple liver metastasis.
Abstract: BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) is an enzyme that catabolizes 5-fluorouracil (5-FU). The effect of DPD inhibitory fluoropyrimidines (DIF) is presumably related to DPD activity. We studied the efficacy of DIF (tegafur + uracil UFT], tegafur + gimeracil + osteracil [S-1 (TS-1)]) relative to DPD activity, with other fluoropyrimidines as controls. METHODS: The efficacy of DIF relative to DPD activity was evaluated in 58 gastric cancer patients who received postoperative administration of fluoropyrimidines, consisting of DIF in 42 patients (UFT in 23; S-1 in 19) and non-DIF in 16 patients. RESULTS: In patients with low DPD activity (under 40 U/mg protein), curative potential tended to be lower for DIF than for non-DIF, but the survival rate was the same for both. In patients with high DPD activity (40 U/mg protein or more), such a tendency was not detected. In a comparison between those treated with UFT and those treated with S-1, prognosis was better in the latter group, in spite of their predominance of lower curative potentials of B or C. In 27 patients with measurable lesions, a partial response (PR) or higher response occurred in 33% (5/15) of those with low DPD activity, and in 17% (2/12) of those with high DPD activity. In the patients with low DPD activity, non-DIF induced no change (NC) in 17% (16), and progressive disease (PD) in the rest. UFF induced PD in all 5 patients, while S-1 induced a response rate of 44% (7/16), with NC in 25% (4/16). In the patients with high DPD activity, on the other hand, non-DIF (n = 3) and UFT (n = 3) induced PD in all the patients, while S-1 induced PR in 33% (2/6) and NC or a higher response in 67% (4/6). CONCLUSION: It is recommended to use S-1 rather than UFF in patients with high DPD activity. Measurement of DPD was useful in drug selection.
Abstract: A recent advance in computed tomography (CT) technology, multislice helical CT, has enabled production of clearer three-dimensional (3D) images and has drawn interest. We report the usefulness of CT cholangiography using a multislice helical CT scanner for the diagnosis and preoperative imaging of the biliary duct in a case of peculiarly shaped gallbladder with cholecystitis. A 34-year-old woman admitted to our hospital presented with chronic hypochondralgia. A CT scan showed that the gallbladder was normal without wall thickening or stones. However, there appeared to be a tumor, containing a stone approximately 1 cm in diameter, attached under the gallbladder in front of the right kidney and extending up to its lower level. Magnetic resonance cholangiography also depicted a normal gallbladder without wall thickening or stones. Hence, gallbladder stones were not diagnosed by previously the mentioned investigations. In contrast, a 3D image produced by multislice helical CT cholangiography was very clear. From the bottom of the gallbladder, a narrow canal continued to a stone. We diagnosed that the wall of the lower part of the long gallbladder had become thick and elongated because of chronic cholecystitis caused by a gallbladder stone, and laparoscopic cholecystectomy was performed. Macroscopically, the resected gallbladder showed an extremely thickened wall from the lower body to the fundus, in which a stone was located in the center. Multislice helical CT cholangiography has the potential to become one of the most significant examinations for diagnosis and anatomical analysis of biliary disease prior to laparoscopic cholecystectomy.
Abstract: OBJECTIVE: To assess the surgical results and clinicopathologic features of hepatic metastases from gastric adenocarcinoma to identify patients with a better probability of survival. SUMMARY BACKGROUND DATA: Many studies have reported the benefit of hepatic resection for metastatic tumors from colorectal cancer. However, indications for a surgical approach for gastric adenocarcinoma involving the liver have not been clearly defined. METHODS: Ninety (11%) of 807 patients with primary gastric cancer were diagnosed with synchronous (n = 78) or metachronous (n = 12) hepatic metastases. Of these, 19 underwent 20 resections intended to cure the metastatic lesion in the liver. The clinicopathologic features of the hepatic metastases in, and the surgical results for, the 19 patients were analyzed. RESULTS: The actuarial 1-year, 3-year, and 5-year survival rates after hepatic resection were, respectively, 77%, 34%, and 34%, and three patients survived for more than 5 years after surgery. Solitary and metachronous metastases were significant determinants for a favorable prognosis after hepatic resection. Pathologically, a fibrous pseudocapsule between the tumor and surrounding hepatic parenchyma was found in 13 of the 19 patients (68%). The presence of a peritumoral fibrous pseudocapsule and a well-differentiated histologic type of metastatic nodule were significant prognostic factors. Factors associated with the primary lesion were not significant prognostic determinants in patients who underwent curative resection of the primary cancer. CONCLUSIONS: Solitary and metachronous metastases from gastric cancer should be treated by a surgical approach and confer a better prognosis. A new prognostic factor, the presence of a pseudocapsule, may be helpful in defining indications for postoperative adjuvant treatment.
Abstract: BACKGROUND: Clinical parameters influencing the effect of preoperative portal vein embolization (PVE) in hypertrophying the nonembolized lobe of patients with either normal or abnormal liver parenchyma and its effect upon portal pressure were examined to identify the patient population for whom this approach is most suited. METHODS: The study population included 43 patients undergoing major hepatectomy after PVE. Patients were divided into 2 groups according to their liver parenchyma: 17 patients with normal liver parenchyma (N group) and 26 patients with damaged liver parenchyma due to viral hepatitis (D group). We calculated the correlation between volumetric increases in the nonembolized (left) lobe after PVE (hypertrophic ratio = post-PVE left lobe volume/pre-PVE left lobe volume) using computed tomography volumetry before and 2 weeks after PVE. Clinical parameters also were examined to identify those parameters modifying the hypertrophic ratio in each group, and changes in portal pressure by PVE and the subsequent hepatectomy were recorded. Finally, by comparing patients with or without postoperative liver failure after hepatectomy, the influence of the hypertrophic ratio and portal pressure on the outcome of subsequent hepatectomy was examined. RESULTS: The hypertrophic ratio was 1.34 +/- 0.23 in the N group, and 1.25 +/- 0.21 in the D group. This difference was not significant. Multiple regression analysis revealed that the parenchymal volumetric rate of the right lobe (PVR) in the D group and both PVR and prothrombin time in the N group were independent parameters predicting the hypertrophic ratio. The portal pressure increased immediately after PVE and was similar in both groups to levels after hepatectomy. Six patients in the D group experienced postoperative liver dysfunction. In 5 of these 6 patients, the hypertrophic ratio was below 1.2, and the portal pressure was higher than that in patients without liver dysfunction. CONCLUSIONS: PVE induces hypertrophy of the nonembolized lobe of both abnormal and normal liver parenchyma, and the effect was predictable. Postoperative liver failure appeared to be more severe in patients having a lower hypertrophic ratio and higher portal pressure in abnormal liver parenchyma, however. PVE also may have diagnostic use in predicting portal pressure after hepatectomy, which may be associated with surgical outcome.
Abstract: Total hepatic vascular exclusion and venovenous bypass are frequently used surgical procedures when concomitant resection of the inferior vena cava is required during surgery of liver cancer involving the retrohepatic inferior vena cava close to the hepatic veins. However, the duration of total hepatic vascular exclusion is limited due to the risk of hepatic ischemia. Three patients presented with severely compressed inferior vena cava and/or hepatic veins due to liver cancer. The surgical procedure involved initial taping of the inferior vena cava just below the hepatic veins by extrahepatic division and taping of the hepatic veins. After taping the inferior vena cava, hepatectomy with caval resection was performed by simply clamping the retrohepatic inferior vena cava, without the need for total hepatic vascular exclusion or venovenous bypass. In all patients the retrohepatic inferior vena cava were safely replaced with a prosthetic graft under stable hemodynamics. Duration of the inferior vena cava clamping was 31, 66, 75 minutes, respectively. No graft-related complications occurred, but 2 of the 3 patients showed temporal renal dysfunction associated with renal congestion postoperatively. The surgical procedure described herein is effective for the treatment of retrohepatic inferior vena cava in some patients. However, when the case is complicated by chronic nephropathy or simultaneous nephrectomy is required, venovenous bypass should be performed.
Abstract: BACKGROUND: The impact of the use of preoperative portal vein embolization (PVE) on long-term survival after surgery was evaluated by retrospective analysis of prognostic factors in patients with advanced-stage hepatocellular carcinoma (HCC) who had undergone hepatic resection with or without PVE. METHODS: The portal embolization group (Group P) consisted of 26 patients who had undergone major hepatectomy (more extensive than right hepatectomy) with PVE, and the nonembolized group (Group N) consisted of 43 patients who had undergone major hepatectomy without PVE. All patients were diagnosed with advanced HCC graded as Stage III or IV according to the International Union Against Cancer TNM classification system. Patient survival rates, recurrence rates, and recurrence sites after surgery in the two groups were evaluated and compared. RESULTS: The 1-year, 3-year, and 5-year cumulative disease specific survival rates in patients with TNM Stage III HCC, respectively, were 96.0%, 64.4%, and 52.7% in Group N and 92.9%, 57.1%, and 45.7% in Group P, whereas the corresponding values in patients with Stage IV HCC were 53.5%, 40.1%, and 26.8% in Group N and 63.5%, 50.8%, and 19.1% in Group P. There were no statistically significant differences in survival rates between Group P and Group N. Multivariate analysis showed that PVE was not a significant prognostic factor. The 1-year, 3-year, and 5-year cumulative recurrence rates for patients with both stages of disease combined were 44.1%, 80.2%, and 86.8% in Group N, respectively, and 39.9%, 72.2%, and 72.2% in Group P, respectively, with no statistically significant differences between the two groups. To date, 35 patients in Group N and 16 patients in Group P have had tumor recurrences in the liver remnant; of these, 27 patients in Group N and 12 patients in Group P had multiple recurrence foci in the liver remnant. No significant difference was seen between the two groups; however, 10 of 16 patients in Group P (62.5%) had remote organ metastasis in addition to recurrence in the liver remnant compared with only 6 of 35 patients in Group N (17.1%): This difference was significant statistically (P = 0.012). CONCLUSIONS: PVE during major hepatic resection neither improves nor worsens long-term prognosis but allows resection in a patient group that, otherwise, is considered as unresectable. Remote metastasis involving the lung, bone, or stomach was seen more frequently postoperatively in Group P compared with Group N, raising a possibly important issue regarding the use of this approach for the treatment of patients with hepatic malignancies, especially HCC.
Abstract: The extent of cancerous invasion of the inferior vena cava (IVC) determined from resected liver cancer was examined pathologically. Ten patients presenting with liver cancer (metastatic liver cancer, five patients; hepatocellular carcinoma, three; and cholangiocellular carcinoma, two) were diagnosed with positive IVC invasion using preoperative imaging techniques of extracorporeal ultrasonography, computed tomography, magnetic resonance imaging, and vena cavography. The diagnostic criterion for positive IVC invasion by preoperative imaging was longitudinal IVC compression measuring over 50 mm, or transverse IVC compression extending to more than half the circumference of the IVC, or the presence of lesions protruding into the IVC lumen, or the presence of developed collateral veins. All patients underwent combined resection of the IVC. However, pathology results revealed that four of the ten patients had no cancerous invasion of the IVC, and that the extent of invasion along both the longitudinal and transverse axes of the IVC was much smaller than the compression shown by imaging results. We believe that detailed preoperative assessment, using a more precise imaging technique, as well as further intraoperative examination, is required to predict the full pathological extent of cancerous invasion of the IVC.
Abstract: Serum hyaluronate can be used as an index of hepatic sinusoidal endothelial cell function. This study was designed to evaluate its application as a predictor of liver failure after major hepatectomy. Thirty-six patients who underwent right liver lobectomy after percutaneous transhepatic right branch portal vein embolization were divided into two groups based on their postoperative clinical course (groups 1 and 2, with and without postoperative liver failure, n = 6 and n = 30, respectively). We serially measured serum hyaluronate levels using a sandwich binding protein assay system before and after hepatectomy and determined relations with progression of the underlying chronic liver disorder, portal venous pressure, and liver growth of the left lobe after portal embolization. Serum hyaluronate levels were significantly elevated, in line with the degree of severity of the underlying chronic liver disorder, and correlated well with the portal venous pressure and the hypertrophic ratio of the left lobe subsequent to portal embolization. Serum hyaluronate levels in group 1 were significantly higher than those in group 2 before surgery and increased steeply during the early period after hepatectomy. These results suggest that the serum hyaluronate reflects the hepatic functional reserve, and serial measurement of this parameter after hepatectomy can serve as a simple indicator for early detection of posthepatectomy liver failure.
Abstract: BACKGROUND: Preoperative portal vein embolization successfully reduces the incidence of postoperative hepatic failure in which endotoxin is postulated to be involved. To identify the mechanism of this preventive effect, the relationship of endotoxin-induced liver injury with tumour necrosis factor (TNF) alpha and nitric oxide production in the peripheral blood, liver and spleen of rats subjected to preoperative portal vein branch ligation (PVL) was compared with that in rats undergoing sham operation. METHODS: Rats with PVL and those that underwent sham operation were subjected to resection of ligated liver lobes (PVL-Hx rats) and two-thirds hepatectomy (noPVL-Hx rats) respectively at day 5, followed by intravenous administration of endotoxin 200 microgram/kg body-weight at day 7. At various time intervals after endotoxin injection, the peripheral blood, liver and spleen tissues were harvested and analysed for TNF-alpha and nitric oxide production. RESULTS: The survival rates of noPVL-Hx and PVL-Hx rats at 48 h after endotoxin administration were 40 and 100 per cent respectively. The former rats showed more extensive liver injury as represented by higher serum aminotransferase and hyaluronate levels than the latter. Plasma concentrations of TNF-alpha at 1.5 h after endotoxin treatment were significantly higher in noPVL-Hx rats (mean(s.e.m.) 22 125(2175) pg/ml; n = 6) than PVL-Hx rats (8344(4076) pg/ml; n = 6) (P < 0.01). Consistent with this, expression of TNF-alpha messenger RNA in the liver and spleen was suppressed in PVL-Hx rats. In two-thirds hepatectomized rats, plasma TNF-alpha concentrations after endotoxin administration at 1, 2 and 3 days (14 350(2186), 26 375(2478) and 23 000(3745) pg/ml respectively; n = 6 each) were significantly higher than that before operation (9067(1559) pg/ml; n = 6) (P < 0.05), whereas those at 5 and 7 days (10 102(3616) and 8580(1427) pg/ml respectively; n = 6 each) showed no significant increase. Furthermore, nitric oxide production in peripheral blood and liver was suppressed by preoperative PVL. CONCLUSION: Prevention of endotoxin-induced liver failure by preoperative PVL is associated with reduced production of TNF-alpha in the later phase of liver regeneration.
Abstract: A total of 18 patients (13: colon cancer, 5: gastric cancer) with multiple liver metastases (H3) underwent hepatic arterial infusion chemotherapy (HAI) using an implanted arterial port with portable syringe pumps in our outpatient clinic. Clinical perspective: overall response rate was 22.2% (CR: 1 case, PR: 3 cases (1 case: hepatectomy after HAI), NC: 12 cases, PD: 2 cases), however, 7 of 12 cases of NC were long NC (more than 6 months). No major complications with HAI were experienced. Patient Perspective: After HAI in our outpatient clinic, the 50% survival was 341 days, 50% hospital free days were 319 days and home stay rate was 92.9%. Societal Perspective: cost and hospital stay days were significantly reduced. Home anti-cancer chemotherapy using HAI for gastrointestinal cancer patients with multiple liver metastases was safe and efficient from the viewpoint of medical outcomes.
Abstract: BACKGROUND: Prostaglandin E1 (PGE1) has protective effects experimentally and clinically in individual models of hepatic ischaemia-reperfusion injury and of partial hepatectomy. The present study investigated the effects of intraportal administration of PGE1 on hepatic blood flow, systemic arterial pressure and long-term animal survival after 60 min of total liver ischaemia followed by 70 per cent partial hepatectomy in rats. METHODS: Total liver ischaemia was induced by occluding the hepatoduodenal ligament for 60 min. PGE1 0.5 microg per kg per min was infused intraportally for 15 min before inducing ischaemia and for 120 min after ischaemia in the treatment group. Normal saline was infused in the control group. During ischaemia 70 per cent partial hepatectomy was performed. Portal venous flow (PVF), peripheral tissue blood flow (PTBF) and hepatic artery flow were measured before and after ischaemia. Serum biochemical analysis was carried out at 1, 3 and 24 h, and 7 and 14 days; and liver histology at 1 and 24 h, and 7 days after reperfusion. Survival was followed for 1 year. RESULTS: Intraportal infusion of PGE1 significantly improved PVF and PTBF without affecting the systemic arterial pressure. Long-term survival was significantly higher in the PGE1 group. Serum aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase levels decreased significantly, and 2-h bile flow was significantly improved, in the PGE1 group. Histological examination revealed significant portal venous congestion, sinusoidal congestion, fatty degeneration and tissue necrosis 24 h and 7 days after reperfusion in the control group. CONCLUSION: PGE1 has a protective effect against liver damage when the liver is injured by warm ischaemia and reperfusion followed by partial resection.
Abstract: We describe herein the case of a 21-year-old woman in whom Castleman disease of the pararenal retroperitoneum was successfully resected. The patient was referred to our hospital from another hospital for investigation of a retroperitoneal mass in the right middle abdomen. Ultrasonography, computed tomography, and magnetic resonance imaging demonstrated a large retroperitoneal mass with heterogeneous imaging characteristics. An aortogram showed arterial feeding to this mass from a few lumbar arteries. Although a definitive preoperative diagnosis could not be made, surgical excision was performed and histopathological examination confirmed a diagnosis of the hyaline type of Castleman disease. The patient had an uneventful postoperative course and was discharged 14 days after her operation. She now leads an active social life without any signs of sequelae or recurrence 14 months later. To the best of our knowledge, only 2% (6/315) of all reported cases of Castleman disease have been located in the pararenal and retroperitoneal area.
Abstract: We report, herein, on the first case of a mesenteric desmoid tumor with multiple peritoneal dissemination. A 73 year-old Japanese woman, who had a history of uterine cancer that was treated with hysterectomy followed by a high dose of irradiation 25 years ago, had an unknown stenosis of the sigmoid colon, which was treated with partial resection of the stenosed colon 6 years ago, and then resulted in multiple small bowel obstructions due to the recurrence of mesenteric desmoids. The clinical behavior of this tumor is considered to be unpredictable. We emphasize that mesenteric desmoid tumors should be considered as one of the causes of stenosis of the colon and small bowel, and patients should receive careful follow-up after unknown stenosis.
Abstract: The development of oxygen-sensitive paramagnetic materials is being pursued actively because of their potential applications in in vivo EPR oximetry. Among these materials, several charcoals and carbohydrate chars are of special interest because of their desirable EPR properties: high sensitivity of the EPR linewidth to the partial pressure of oxygen, simple EPR spectra, and high spin density. Their potential use in humans, however, is limited by the need to demonstrate that they will not lead to deleterious effects. A strategy was used to optimize the biocompatibility of the oxygen-sensitive materials by decreasing the size of the particles and coating them with suspending or surfactive agents such as arabic gum, poloxamer (Pluriol 6800), and polyvinylpyrrolidone. The coated particles of a carbohydrate char and fusinite were characterized in vitro for their size, stability, and pO2 sensitivity. The feasibility of performing pO2 measurement was examined in vivo by inducing ischemia in the gastrocnemius muscle of mice. The use of arabic gum for coating the fusinite particles preserved the pO2 sensitivity in vivo, whereas the other surfactive agents led to a loss of the pO2 sensitivity in vivo. Small particles of fusinite coated by arabic gum and intravenously administered to mice accumulated in the liver, whereas the uncoated fusinite was toxic when injected intravenously due to the large size and aggregation of the particles. Histological studies performed up to 6 months after the injection in muscles of mice did not indicate any toxicity from the materials used in the present study.
Abstract: Tumor reoxygenation after irradiation may contribute to a tumor's response to subsequent doses of radiation. The timing of reoxygenation in RIF-1 murine tumors was determined using electron paramagnetic resonance (EPR) oximetry with intratumoral implantation of an oxygen-sensitive paramagnetic material (India ink) to monitor the pO2 in individual murine tumors before, during and after three different irradiation schemes. Radiation was given as a single 20-Gy dose or was split into two 10-Gy doses where the second dose of radiation was delivered at the minimum postirradiation tumor pO2 (24-h interval, hypoxic group) or where the second dose of radiation was delivered after reoxygenation had occurred (72-h interval, oxygenated group). The end point for tumor response was time taken to reach double the volume at the time of treatment. There were significantly longer tumor doubling times in the oxygenated compared to the hypoxic group, indicating that the measured changes in pO2 reflected changes in tumor radiosensitivity. A 24-h interval between doses resulted in a delay of reoxygenation in the tumors, while a 72-h interval resulted in a second cycle of hypoxia/reoxygenation. Our results suggest that repeated direct measurements of pO2 in tumors by EPR oximetry could be useful in timing radiation doses to achieve improved local control of tumors.
Abstract: This paper describes the characteristics of a new oxygen sensitive, paramagnetic material that has some significant advantages for measurements of tissue pO2 by in vivo EPR. This paramagnetic component of Welsh coal, termed "gloxy" was found to have valuable EPR features that allow accurate measurement of low oxygen tensions in vivo; these include large oxygen-dependent changes in linewidth, a high number of paramagnetic spin centers (resulting in high signal amplitude), and stability in tissue allowing repeated pO2 measurements to be made in vivo with high precision. Renal pO2 was measured deep in the medulla region of isolated perfused kidneys and found to be lower than that in the cortex (1.7 +/- 0.05 and 7.1 +/- 0.3 mm Hg, respectively). The quality of the EPR signal obtained from the renal outer medulla and also from tumors in mice was such that the pO2 measurements were obtained with a precision of +/-3% of the measured pO2 (Kidney: 1.7 +/- 0.05 mmHg; Tumor: 1.37 +/- 0.04 mmHg). In vitro tests on the viability of cells and in vivo studies using Gloxy demonstrate the stability and inertness of this oxygen-sensitive material.
Abstract: Early degeneration of cartilage is accompanied by a loss of proteoglycans and consequent changes in the content of water. Conventional magnetic resonance imaging (MRI) cannot reliably detect this change, since the relaxation properties of the cartilage are dominated by its collagen content. The applicability of a positively charged nitroxide as an MRI contrast agent in detection of the content of the negatively charged proteoglycans within the cartilage was investigated. The results from both MRI and electron paramagnetic resonance (EPR) spectroscopy indicate that the accumulation of the contrast agent reflects the amount of proteoglycans within the cartilage, presumably due to the electrostatic interactions between the negatively charged proteoglycans and the positively charged nitroxide. Such a contrast agent could be useful in the detection and study of early stages of the degeneration of joints.
Abstract: Electron Paramagnetic Resonance (EPR) oximetry was used to measure tissue oxygen tension (pO2-partial pressure of oxygen) simultaneously in the kidney cortex and outer medulla in vivo in mice. pO2 in the cortex region was higher compared to that in the outer medulla. An intravenous injection of endotoxin resulted in a sharp drop in pO2 in the cortex and an increase in the medulla region, resulting in a transient period of equal pO2 in both regions. In control kidneys, functional Magnetic Resonance (MR) images showed the cortex region to have high signal intensity (T2*-weighted images), indicating that this region was well supplied with oxygenated hemoglobin, whereas the outer medulla showed low signal intensity. After administration of endotoxin, we observed an immediate increase in signal intensity in the outer medulla region, reflecting an increased level of oxygenated blood in this region. Pretreatment of mice with NG-monomethyl-L-arginine prevented both the changes in tissue pO2 and distribution of oxygenated hemoglobin, suggesting that localized production of nitric oxide has a critical role to play in renal medullary hemodynamics. In combining in vivo EPR with MR images of kidneys, we demonstrate the usefulness of these techniques for monitoring renal pO2 and changes in the distribution of oxygen.
Abstract: With the use of India ink and lithium phthalocyanine (LiPc) as electron paramagnetic resonance (EPR) oximetry probes, the PO2 of the liver was investigated in mice. Because India ink was taken up by the Kupffer cells of the liver, the EPR signal of the India ink reflected the average PO2 in phagocytic vesicles of these cells. The mean value of PO2 in the Kupffer cells measured by India ink was 15.3 +/- 4.4 Torr in unanesthetized animals. LiPc was administered as a macroscopic crystal and therefore reflected the PO2 of the overall liver. The PO2 measured by LiPc was 23.4 +/- 4.4 Torr, which is consistent with the median value of 23.5 Torr reported previously with the use of an oxygen electrode. Anesthesia (injection of 60 mg/kg ip pentobarbital sodium) decreased the average PO2 in both Kupffer cells and the overall liver. The effects of perturbing the blood flow were studied by reversible blockage of the portal vein and hepatic artery in anesthetized mice; the PO2 in both Kupffer cells (measured with India ink) and in overall liver (measured with LiPc) decreased with obstruction of the blood flow and returned toward normal with reperfusion. These results indicate that the PO2 in different locations in the liver can be significantly different under both normal conditions and after perturbation by either anesthesia or ischemia. These results also demonstrate that EPR oximetry can provide sensitive measurements of PO2 in the liver in vivo under various conditions.
Abstract: Relative perfusion, pO2, and bioreduction were measured simultaneously in vivo in tissues in mice by following changes in the intensity and shape of the EPR spectra of nitroxides injected directly into the tissues, using low frequency (1.1 GHz) localized EPR spectroscopy. Using normal and blood flow restricted gastrocnemius muscles it was shown that the decrease of the EPR signals of the nitroxides in tissues was due principally to perfusion, which redistributed the nitroxides. Changes in pO2 were reflected by changes of the linewidth; only a perdeuterated nitroxide with a narrow line was an adequate indicator for this parameter. This technique was applied experimental murine tumors (MTG-B and RIF-1) to determine the perfusion and pO2 in these relatively hypoxic model tumor systems. Using the paramagnetic properties of the nitroxides to enhance T1-weighted MR images, heterogeneity in perfusion in individual tumors was demonstrated
Abstract: Detection of Cr(V) in the reduction of Cr(VI) by whole live mice and its characterization were carried out by low frequency electron paramagnetic resonance (EPR). Intravenous injection of Cr(VI) to mice generated Cr(V). The Cr(V) was found predominantly in the liver with a small amount in the blood. Liver homogenates from Cr(VI) treated mice generated essentially the same Cr(V) spectrum as that obtained from the whole live mice. This Cr(V) species was identified to be a Cr(V)-nicotinamide adenine dinucleotide (NAD) (P)H complex with an oxygen bond to Cr(V). Pretreatment of the mice with ascorbic acid and glutathione reduced the Cr(V) formation, while pretreatment with reduced nicotinamide adenine dinucleotide (NADH) enhanced it. Metal chelators, ethylenediaminetetraacetic acid (EDTA), 1,10-phenanthroline, and diethylenetriaminepentaacetic acid (DTPA) inhibited the intensity of the Cr(V) signal. The results suggest that Cr(V) generated in the whole body of a live animal is a Cr(V)-NAD(P)H complex and NAD(P)H/flavoenzymes and not glutathione or ascorbate as the major one-electron Cr(VI) reductant responsible for observed formation of Cr(V)-NAD(P)H complex in vivo.
Abstract: Changes of partial pressure of oxygen (pO2) and blood perfusion were studied in MTG-B and RIF-1 tumors (n = 5 each) before and after a single 20-Gy dose of X-ray irradiation. Using electron paramagnetic resonance oximetry, we have observed an initial fast decrease of pO2 after irradiation, followed by a slow increase. The time course of these changes was faster in the MTG-B tumors than in the RIF-1 tumors. Gadopentetate dimeglumine (Gd-DTPA) dynamic magnetic resonance imaging studies showed a reduction in uptake of Gd-DTPA at the time of minimum pO2 and a recovery at the time of maximum pO2 in each tumor. Previous work indicates that there is microscopic heterogeneity in tumors, with well-vascularized "capillary regions" being closer to capillaries than poorly vascularized "noncapillary regions." We propose a two-component (slow and fast) model of Gd-DTPA uptake that is designed to quantify the kinetics of these two compartments by analyzing the total tumor uptake kinetics without having to identify specific regions of interest. Total perfusion in the tumors was greatly reduced at the time of minimum oxygenation, and the volume of the slow component increased after irradiation. We conclude that a decrease in blood perfusion is one of the main causes of the decline in pO2 observed after irradiation.
Abstract: Electron paramagnetic resonance oximetry was used to measure the partial pressure of oxygen (pO2) in two types of tumor in vivo in C3H/HeJ mice. The pO2 in MTG-B (high hypoxic fraction) and RIF-1 (low hypoxic fraction) tumors was monitored prior to and at several time points after a single dose of X-ray irradiation (up to 7 days after treatment). Initial values of pO2 in RIF-1 (8.7 +/- 1.1 mm Hg; n = 14) were higher than that of pO2 in MTG-B (3.3 +/- 0.5 mm Hg; n = 19). The pO2 in both types of unirradiated tumors decreased slowly with tumor growth. Irradiation of tumors had a two-phase effect on pO2: an initial sharp decrease in pO2, followed by slow reoxygenation. After a 20-Gy radiation dose, the pO2 was 2.2 +/- 0.5 mm Hg at 6 h [significantly lower (P < 0.0001) than in control] and 3.2 +/- 0.5 mm Hg at 48 h [significantly higher (P < 0.02) than in control] in MTG-B, and 5.4 +/- 1.2 mm Hg at 24 h and 8.2 +/- 1.0 mm Hg at 72 h in RIF-1. The time course for these changes in pO2 was found to be independent of the doses in use in this study (10, 20, and 40 Gy). The occurrence of radiation-induced changes in pO2 and the different time courses of these changes suggest that repeated monitoring of pO2 in tumors during treatment could be used to enhance the efficacy of clinical treatments.
Abstract: Recent advances in electron paramagnetic resonance (EPR) oximetry have established the use of the particulate materials fusinite and lithium phthalocyanine (LiPc) as probes for measurement of oxygen tensions in tissues in vivo with a sensitivity and accuracy that is relevant for studying pathophysiological processes. India ink, another potentially very useful new probe for EPR oximetry, shares the critical properties of fusinite and LiPc and has the additional advantage of already having been widely used clinically with no apparent toxicity. The line width is particularly sensitive to changes in oxygen tension of less than 30 mmHg; in this range the line broadening/unit of pO2 is much greater than that of fusinite and LiPc. Over the range of biological conditions that can occur in vivo, the response of the EPR spectrum of India ink to pO2 is independent of pH, oxidants, reductants, and the nature of the medium. In this paper we describe the relevant properties of India ink and its use to measure pO2 in vivo in experimental animals and a human subject.
Abstract: A recent note from our laboratory reported that L-band (1.2 GHz) electron paramagnetic resonance spectroscopy can be utilized in detecting the formation of Cr(V) intermediates from chromate-treated whole mice. Since Cr(V) is thought to be one of the key species in the mechanism of chromate's toxicity, we carried out additional measurements with improved sensitivity. The new spectra show partially resolved hyperfine structure from protons that suggests that the Cr(V) ion is ligated to NAD(P)H moieties via oxygens. Using laboratory-synthesized Cr(V) (K3CrO8) as a standard, the yield of Cr(V) formation was estimated to be 153 +/- 12 nmol after intravenous injection of 100 microliters of 100 mM sodium dichromate into mice. Pretreatment of the mice with ascorbic acid and glutathione significantly reduced the Cr(V) formation yield in a dose-related manner, while pretreatment with NADH had the opposite effect. Injection of ascorbic acid also had the effect of enhancing the rate of Cr(V) disappearance in vivo. By comparing these results with in vitro results utilizing L-band as well as X-band (9.6 GHz) measurements, we conclude that L-band spectroscopy can indeed be effectively utilized for following the metabolism of Cr(V) in live mice and that Cr(V) formation can be controlled by utilizing cellular antioxidants in vivo.
Abstract: Using electron paramagnetic resonance (EPR) oximetry with the oxygen-sensitive paramagnetic material, fusinite, we have measured the partial pressure of oxygen (pO2) in the mouse mammary adenocarcinoma MTG-B. The average pO2 in untreated tumors was low (about 5 mm Hg) and decreased with tumor growth. Magnetic resonance imaging and histological examination were used to localize the position of the fusinite with respect to tumor margins and vascularization. The pO2 was generally higher in the periphery than in the center of the tumors, but there was considerable variation among tumors both during normal growth and after radiation treatment. After a single 20-Gy dose, a characteristic pattern of change in tumor pO2 was observed. In irradiated tumors, there was an initial reduction in pO2 (minimum occurred 6 h postirradiation) which was followed by a transient increase in pO2 to levels higher than the preirradiation pO2 (maximum occurred 48 h postirradiation). This work demonstrates postirradiation changes in pO2 of potential radiobiological significance. Compared to other oxygen assessment techniques, EPR oximetry is very useful because it can assess pO2 in the same region of the tumor over the course of tumor growth and during response to treatment. Thus EPR could be used to identify potentially radioresistant tumors as well as to identify tumors with slow reoxygenation.
Abstract: The partial pressure of oxygen (pO2) of the liver in vivo in unanesthetized mice was determined using electron paramagnetic resonance (EPR) oximetry with India ink. The EPR spectra were obtained using a low-frequency (1.2 GHz) EPR spectrometer with a loop gap cavity resonator. The line width of the India ink used in this experiment was reversibly broadened by oxygen and was particularly sensitive to pO2 below 30 torr. After the administration of India ink into the tail vein, the India ink particles were taken up mainly by Kupffer cells in the liver and in part by phagocytes in the spleen. The pO2 measured in the normal liver was about 14 torr and was constant for the 2-week experimental period. The pO2 decreased when measured at 1, 2, and 6 days after treatment with hepatotoxin (carbon tetrachloride (CCl4)); within 2 weeks, it returned almost to the initial level. Measurements by EPR at sacrifice of controls and CCl4-treated mice indicated that more than 90% of the India ink went to the liver; the spleen contained 4.7% of total amount in control mice and 8.8% in CCl4-treated mice when measured 2 weeks after the treatment. These data indicate the usefulness of India ink for measuring the pO2 of the liver in vivo and that the pO2 in the Kupffer cells is decreased when the liver is damaged by CCl4.
Abstract: Using a material that already is in widespread use in humans, India ink, the first EPR measurements in a human have been made, using the India ink in a pre-existing tattoo. The EPR spectra of India ink are very sensitive to the partial pressure of oxygen (pO2), thereby making it feasible to use this approach to measure pO2 in tissues in patients. This potentially provides a means to measure this parameter directly with a sensitivity, accuracy, and repeatability that have not been available previously, and thereby to be able to individualize and guide treatment of diseases such as cancer and peripheral vascular insufficiency.
Abstract: The effects of fusinite, a new agent for the measurement of the concentration of oxygen in vivo by EPR, on MRI images have been studied. There was little effect on spin-echo T1-weighted images, but the fusinite resulted in large effects on T2-weighted images. Especially large effects could be observed when using spoiled gradient echo sequences (SPGR). The observed measurements of oxygen by EPR corresponded to the relative vascularity at the site of the fusinite both histologically and by MRI studies of vascularity using Gd-DTPA as a contrast agent. We conclude that by using the effects of fusinite on magnetic susceptibility, it can be located accurately and noninvasively with MRI and thereby the value of the use of fusinite to measure concentration of oxygen in vivo is enhanced.
