The relationship between partial pressure of oxygen and perfusion in two murine tumors after X-ray irradiation: a combined gadopentetate dimeglumine dynamic magnetic resonance imaging and in vivo electron paramagnetic resonance oximetry study.

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.

Changes of oxygen tension in experimental tumors after a single dose of X-ray irradiation.

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.

Endotoxin-induced changes in intrarenal pO2, measured by in vivo electron paramagnetic resonance oximetry and magnetic resonance imaging.

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.

Effect on regrowth delay in a murine tumor of scheduling split-dose irradiation based on direct pO2 measurements by electron paramagnetic resonance oximetry.

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.

The pO2 in a murine tumor after irradiation: an in vivo electron paramagnetic resonance oximetry study.

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.

Measurement of PO2 in liver using EPR oximetry.

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.

Use of multislice helical computed tomography cholangiography in the diagnosis of biliary disease.

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.

Low frequency electron paramagnetic resonance investigation on metabolism of chromium (VI) by whole live mice.

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.

Recurrent mesenteric desmoid tumors with multiple peritoneal dissemination: a case report and review of desmoid in Japan.

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.

Retrohepatic vena cava replacement of hepatic malignancies without using total hepatic vascular exclusion or extracorporeal bypass.

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.

[Outcomes of home anti-cancer chemotherapy--estimation of hepatic arterial infusion chemotherapy for patients with multiple liver metastases].

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.

Novel diarylsulphide derivatives as potential cytotoxic agents.

A series of diarylsulphides bearing amino, acetamido, sulphonamido, benzamido or arylideneamino synthons have been synthesized and evaluated for their antimicrobial and cytotoxic activities. Some of the tested compounds proved to possess a remarkable activity. The detailed synthesis, spectroscopic and biological data are reported.

Phase I/II study of intraperitoneal docetaxel plus S-1 for the gastric cancer patients with peritoneal carcinomatosis.

PURPOSE: We designed a phase I/II trial of intraperitoneal (IP) docetaxel plus S-1 to determine the maximum tolerated dose (MTD) and recommended dose (RD) and to evaluate its efficacy and safety in gastric cancer patients with peritoneal carcinomatosis (PC). METHODS: Patients with PC confirmed by laparoscopy or laparotomy received IP docetaxel on days 1 and 15 and S-1 (80 mg/m(2)) on days 1-14 every 4 weeks. RESULTS: In the phase I part (n = 12), each cohort received escalating doses of docetaxel (35-50 mg/m(2)); the MTD was determined to be 50 mg/m(2) and the RD was determined to be 45 mg/m(2). Dose-limiting toxicities included grade 3 febrile neutropenia and grade 3 diarrhea. In the phase II part (n = 27), the median number of courses was 4 (range 2-11). The 1-year overall survival (OS) rate was 70 % (95 % confidence interval 53-87 %). The overall response rate was 22 % and peritoneal cytology turned negative in 18 of 22 (81 %) patients. The most frequent grade 3/4 toxicities included anorexia (19 %), neutropenia (7 %), and leukopenia (7 %). CONCLUSION: IP docetaxel plus S-1 is active and safety in gastric cancer patients with PC.

Association between cardiac function and pulmonary function in hypertensive patients.

OBJECTIVE: This study examined the association between cardiac function and pulmonary function in hypertensive patients. METHODS: Hypertensive patients without overt cardiovascular disease were enrolled (n=43; mean±SD age 71±9 years). Pulmonary function was measured by the percentage of predicted forced vital capacity (%FVC) and the ratio of 1 s forced expiratory volume (FEV1) to FVC (FEV1/FVC ratio). Left ventricular ejection fraction (LVEF) and the ratio of peak early diastolic transmitral flow (E) to peak early diastolic mitral annular velocity (e') (E/e' ratio) were assessed using echocardiography. RESULTS: Multiple linear regression analysis revealed that E/e' was independently associated with %FVC and that LVEF was independently associated with FEV1/FVC ratio. Both LVEF and FEV1/FVC ratio were significantly lower in hypertensive former or current smokers than in hypertensive never smokers. CONCLUSIONS: Subclinical cardiac dysfunction was independently associated with reduced pulmonary function in hypertensive patients. Hypertensive patients with decreased pulmonary function may need preventive care to prevent the progression of heart failure.

Differences in left ventricular diastolic dysfunction between eccentric and concentric left ventricular hypertrophy in hypertensive patients with preserved systolic function.

Left ventricular (LV) hypertrophy (LVH) may be eccentric or concentric (2 × LV posterior wall thickness relative to LV end-diastolic dimension ≤ 0.42 or > 0.42, respectively). The LV diastolic function between age-matched hypertensive patients with eccentric and concentric LVH was compared in the present study. Echocardiography was used to measure LV mass index (LV mass/body surface area; LVMI) as an index of LVH. LV diastolic function was assessed by measurements of peak early transmitral flow velocity (E)/peak late transmitral flow velocity (A) (the E/A ratio), peak early diastolic mitral annular velocity (e') and the E/e' ratio. Although LVMI, E/A and e' did not differ between the two groups, E/e' was significantly higher (worse) in patients with concentric LVH (13.4 ± 5.4) than in those with eccentric LVH (11.1 ± 3.6). Among hypertensive patients with LVH, those with concentric LVH may, therefore, have more severe LV diastolic dysfunction than those with eccentric LVH even if their LVMIs, which reflect the degree of LVH, are similar.

Aortic root dilatation as a marker of subclinical left ventricular diastolic dysfunction in patients with cardiovascular risk factors.

Consensus is lacking about the clinical importance of aortic root dilatation in assessment of the risk of cardiovascular disease. In this study, correlations between aortic root diameter and echocardiographic features of left ventricular (LV) diastolic function were investigated in 333 patients with at least one cardiovascular risk factor (hypertension, diabetes or dyslipidaemia) and preserved LV systolic function. Aortic root diameter was measured by M-mode echocardiography, and LV diastolic function was evaluated by measuring the peak velocity of early (E) and late (A) diastolic transmitral blood flow and peak early diastolic mitral annular velocity (E') by Doppler echocardiography. Linear regression analysis showed that, in men, age was not related to aortic root diameter but hypertension and LV hypertrophy were, whereas the converse was true in women. The parameters E, E/A ratio and E', were related to aortic root diameter in both sexes. Stepwise multiple regression analysis confirmed that E in women and E' in men were independently associated with aortic root diameter. It is concluded that aortic root dilatation might be a useful marker of subclinical LV diastolic dysfunction. Patients with preserved systolic function showing aortic root dilatation should, therefore, be given preventative therapy against LV diastolic heart failure.