Evaluation of resectability after neoadjuvant chemotherapy for primary non-resectable colorectal liver metastases: A multicenter study.

BACKGROUND/AIM: The Kyushu Study Group of Clinical Cancer (KSCC) previously reported the safety and efficacy of neoadjuvant chemotherapy with mFOLFOX6 + bevacizumab for H2/H3 liver metastases of colorectal cancer. The aim of the current study was to evaluate the resectability of these metastases before and after chemotherapy as determined by independent liver surgeons. METHODS: Between May 2008 and April 2010, 40 patients were registered in a multicenter phase 2 trial of neoadjuvant chemotherapy (KSCC 0802). In Study 1, 5 independent liver surgeons from five different KSCC centers evaluated the resectability of liver metastases of colorectal cancer based on imaging studies performed before and after chemotherapy. Each surgeon was blinded to the other surgeons' evaluations. In addition, no information about the patients' characteristics was provided. In Study 2, 3 surgeons evaluated the resectability of these lesions based on imaging studies with discussion with each other, with the surgeons being provided with information on the patients' characteristics. RESULTS: In Study 1, 13 patients (36.1%) were evaluated to be resectable at baseline, whereas 17 patients (47.2%) were evaluated to be resectable after chemotherapy. In Study 2, 4 patients (11.1%) were evaluated to be resectable at baseline, compared to 23 patients (63.9%) after chemotherapy. CONCLUSION: Neoadjuvant chemotherapy with mFOLFOX6 + bevacizumab was confirmed to increase the resectability of non-resectable liver metastases of colorectal cancer according to the independent assessments of surgeons.

Effects of amlodipine and valsartan on vascular damage and ambulatory blood pressure in untreated hypertensive patients.

The present study was performed to compare the long-term effects of 24-h ambulatory blood pressure (BP) control with amlodipine versus valsartan on vascular damage in untreated hypertensive patients. Amlodipine and valsartan have benefits on cardiovascular mortality and morbidity in hypertensive patients. Although ambulatory BP is associated with severity of target-organ damage in hypertensive patients, beneficial effects of ambulatory BP control with amlodipine versus valsartan on vascular damage have not been compared. Pulse wave velocity (PWV), intima-media thickness (IMT) of the carotid arteries, urinary albumin excretion (UAE) and 24-h ambulatory BP were determined in 100 untreated hypertensive patients before and 12 months after the start of antihypertensive therapy with amlodipine or valsartan. Amlodipine and valsartan decreased ambulatory BP similarly, but the variability of 24-h and daytime ambulatory systolic BP was significantly reduced by amlodipine but not by valsartan. The reduced variability of ambulatory systolic BP caused by amlodipine significantly contributed to the improvement of PWV, although both drugs decreased PWV similarly. Carotid IMT was unaffected by treatment with either drug. Valsartan significantly decreased UAE independently of its depressor effect, but amlodipine had no effect on UAE. These results suggest that the 24-h control of ambulatory BP with amlodipine had functionally improved the stiffened arteries of hypertensive patients by the end of 12 months of treatment, in part through reducing BP variability, whereas ambulatory BP control with valsartan decreased the arterial stiffness to the same degree as amlodipine without affecting BP variability maybe through some pleiotropic effects.

Increased expression of cyclooxygenase-2 in the renal cortex of human prorenin receptor gene-transgenic rats.

Increased macula densa cyclooxygenase-2 (COX-2) is observed in diabetic rats and may contribute to hyperfiltration states. However, the signals mediating increased COX-2 expression in diabetic rats remain undetermined. We recently found that non-proteolytic activation of prorenin by site-specific binding proteins, such as prorenin receptor, plays a pivotal role in the development of diabetic nephropathy. The present study was designed to determine the contribution of prorenin receptor to renal cortical COX-2 expression. The COX-2 mRNA and protein levels of six 4-week-old male wild-type rats and six human prorenin receptor gene-transgenic (hProRenRcTg) rats were measured by real-time polymerase chain reaction methods, Western blotting, and immunohistochemistry, and compared. There were no differences between the two groups in arterial pressure measured by telemetry, urinary sodium excretion, or renal levels of rat prorenin receptor mRNA. The renal cortical COX-2 mRNA levels of the hProRenRcTg rats were significantly higher than those of the wild-type rats, and the renal cortical COX-2 protein levels were also higher in hProRenRcTg rats than in the wild-type rats. Immunohistochemical analysis revealed that COX-2 immunostaining was predominantly present in the macula densa cells, and significantly more COX-2-positive cells were present in the hProRenRcTg rats than in the wild-type rats. In addition, COX-2 inhibition with NS398 significantly decreased renal cortical blood flow in the hProRenRcTg rats but not in the wild-type rats. These results strongly suggest that human prorenin receptor directly or indirectly contributes to the regulation of renal cortical COX-2 expression.

Ambulatory blood pressure variability and brachial-ankle pulse wave velocity in untreated hypertensive patients.

Blood pressure (BP) variability is estimated as the standard deviation of 24-h ambulatory BP. The present study was performed to determine the effect of the mean 24-h ambulatory BP values and standard deviations on arterial wall stiffness assessed by brachial-ankle pulse wave velocity (baPWV). Brachial-ankle pulse wave velocity, carotid intima-media thickness (IMT), urinary albumin excretion (UAE) and 24-h ambulatory BP were measured before the start of antihypertensive therapy in 203 newly diagnosed hypertensive patients (53.3+/-0.7 years old; clinic systolic/diastolic BP: 154+/-1/98+/-1 mm Hg), and univariate and multivariate regression analyses of these clinical and biological parameters were performed. Univariate regression analyses revealed a significant association between mean baPWV values and the standard deviations of ambulatory systolic/diastolic BP. Mean ambulatory systolic/diastolic BP values were also associated with UAE, and the standard deviations of ambulatory systolic BP were associated with maximum carotid IMT. Quintile analyses showed that patients with a mean 24-h ambulatory mean BP value and standard deviation below 110 and 20 mm Hg, respectively, had the lowest baPWV. Moreover, the multivariate regression analyses confirmed a significant correlation between baPWV and the standard deviation of 24-h ambulatory systolic BP. In conclusion, untreated hypertensive patients with a higher 24-h ambulatory systolic BP variability had stiffer arterial walls. Ambulatory systolic BP variability may be involved in stiffening of the arteries of hypertensive patients.

Gastrointestinal tract perforation: CT diagnosis of presence, site, and cause.

Gastrointestinal tract perforation is an emergent condition that requires prompt surgery. Diagnosis largely depends on imaging examinations, and correct diagnosis of the presence, level, and cause of perforation is essential for appropriate management and surgical planning. Plain radiography remains the first imaging study and may be followed by intraluminal contrast examination; however, the high clinical efficacy of computed tomographic examination in this field has been well recognized. The advent of spiral and multidetector-row computed tomographic scanners has enabled examination of the entire abdomen in a single breath-hold by using thin-slice sections that allow precise assessment of pathology in the alimentary tract. Extraluminal air that is too small to be detected by conventional radiography can be demonstrated by computed tomography. Indirect findings of bowel perforation such as phlegmon, abscess, peritoneal fluid, or an extraluminal foreign body can also be demonstrated. Gastrointestinal mural pathology and associated adjacent inflammation are precisely assessed with thin-section images and multiplanar reformations that aid in the assessment of the site and cause of perforation.

[Arterial infusion therapy with implantable port for inoperable hepatobiliary tumors].

PURPOSE: To assess the clinical utility of arterial infusion therapy with implantable port for inoperable malignant hepatobiliary tumors. MATERIALS AND METHODS: Twenty-seven patients with advanced hepatobiliary tumors (M:F = 14:13, mean age 63.6, 11 cases with metastases from colon cancer, 4 cases from gastric cancer, 5 cases with gallbladder cancer, 3 cases with cholangiocarcinoma, 2 cases with cholangiocellularcarcinoma, 1 case with hepatocellular carcinoma and 1 with pancreatic cancer) were treated with arterial infusion ports which were placed via left subclavian artery or femoral artery. The regimens used were FEM for 5 cases, EEP for 2 cases and FP for 20 cases. RESULTS: Overall mean survival date was 241.8 days. The numbers of cases with CR, PR, NC and PD were 1, 6, 10 and 10, respectively, and the effective rate was 25.9%. Mean survivals of cases with cholangiocellularcarcinoma, metastases from gastric cancer and colon cancer were 715 days, 324.3 days and 245.9 days, respectively. Severe gastrointestinal side effects (> grade 3) were not observed. Serious bone marrow suppressions were frequently observed with FEM and EEP, but were rare with FP (10%). DISCUSSION: Arterial infusion therapy with implantable port is clinically useful for advanced cholangiocancer and metastases from the gastrointestinal system. This system contributes to the quality of life of patients, since the infusion procedure is simple and can be archived in the outpatient clinics.

[Experience of 7 cases with home parenteral nutrition in our hospital].

We have experienced 7 patients with home parenteral nutrition (HPN), (including 3 failure cases). Four were benign disease and 3 were malignant. The HPN was given for 0 to 316 days. In 3 cases, we could not allow them to leave the hospital. All 3 cases involved malignant disease. The catheter was removed in only 1 case because of infection. Technical complications due to catheterization or catheter maintenance were not found in the other 6 cases. For successful management of HPN, the following 3 points are necessary for patients, family or doctors. 1) Patients and their family must understand their disease and condition. 2) Patients and their family have great hopes of spending their final days at home. 3) Doctors should have more concern for HPN.

High serum alpha-fetoprotein concentration associated with pseudoinfarction of a cirrhotic liver: report of a case.

We report herein the case of a 65-year-old man with cirrhosis of the liver in whom a portal vein thrombus was found to be the cause of a marked elevation in serum alpha-fetoprotein (AFP). The patient presented with fever and abdominal pain, and a diagnostic work-up revealed a liver mass and an increased serum AFP concentration of 91,000 ng/ml. The mass gradually regressed, and the AFP concentration simultaneously decreased to 163 ng/ml. However, because hepatocellular carcinoma (HCC) could not be ruled out, a partial hepatectomy was performed. Histological examination of the resected specimen revealed a thrombus of the portal vein surrounded by the fibrosis associated with liver cirrhosis, but no neoplastic lesion was found. Thus, portal thrombus associated with liver cirrhosis might induce an extremely high level of AFP production.

Autoxidation of human hemoglobin: kinetic analysis of the pH-profile.

The autoxidation reaction of human hemoglobin A was studied over the pH range of 5.3-10.4 in 0.1 M buffer at 37 degrees C. In the first-order plot, hemoglobin showed a biphasic reaction, which consisted of a rapid initial reaction and was followed by a slower second phase in the acidic or neutral pH range (5.3-8). However, this difference decreased with increase of pH of the solution and only a single-phase reaction was observed in alkali solutions above pH 8. For the kinetic analysis of the time course of the reaction, computer fitting was made to obtain curves as a function of time by a non-linear least squares method using a biphasic first-order equation with rate constants of kf and ks for the initial fast component reaction and for the slower second reaction, respectively. The parameter of the molar fraction (P) with a rate constant of kf was computed in the range of 0.45-0.55, which means that hemoglobin was autoxidized with half of the component via the reaction process with the initial rapid rate (kf) and the other half via the reaction with the following slower rate (ks). kf and ks thus obtained versus pH plot also indicated that (1) both rate constants increase markedly with increase in hydrogen ion concentrations, but (2) when pH > 8, kf becomes equal to ks with P = 1.0, and (3) there appears a rate minimum at pH 8-8.5, followed by a considerable elevation of the rate with increase in hydroxyl ion concentration. In order to examine these complicated pH-profiles, some mechanistic models were proposed for the autoxidation reaction of hemoglobin. Fitting of their rate equations as a function of pH was examined for the experimental rate constants kf and ks versus pH plot by the least squares method with use of a computer. Both pH-profiles could be best explained by the "acid-base catalyzed model." This revealed not only the catalytic role of hydrogen ions but also the involvement of hydroxyl ions and water molecules in the autoxidation reaction of human hemoglobin.

Revision of the theory of phototropism in plants: a new interpretation of a classical experiment.

Went's classical experiment on the diffusion of auxin activity from unilaterally illuminated oat coleoptile tips (Went 1928), was repeated as precisely as possible. In agreement with Went's data with theAvena curvature assay, the agar blocks from the illuminated side of oat (Avena sativa L. cv. Victory) coleoptile tips had, on an average, 38% of the auxin activity of those from the shaded side. However, determination of the absolute amounts of indole-3-acetic acid (IAA) in the agar blocks, using a physicochemical assay following purification, showed that the IAA was evenly distributed in the blocks from the illuminated and shaded sides. In the blocks from the shaded and dark-control halves the amounts of IAA were 2.5 times higher than the auxin activity measured by theAvena curvature test, and in those from the illuminated half even 7 times higher. Chromatography of the diffusates prior to theAvena curvature test demonstrated that the amounts of two growth inhibitors, especially of the more polar one, were significantly higher in the agar blocks from the illuminated side than in those from the shaded side and the dark control. These results show that the basic experiment from which the Cholodny-Went theory was derived, does not justify this theory. The data rather indicate that phototropism is caused by the light-induced, local accumulation of growth inhibitors against a background of even auxin distribution, the diffusion of auxin being unaffected.

Phototropism in Hypocotyls of Radish: IV. Flank Growth and Lateral Distribution of cis- and trans-Raphanusanins in the First Positive Phototropic Curvature.

The first positive phototropic curvature induced by a pulse of unilateral white irradiation (0.1 watt per square meter, 30 seconds) of etiolated and de-etiolated Sakurajima radish (Raphanus sativus var hortensis f. gigantissimus Makino) hypocotyls was analyzed in terms of differential growth and growth inhibitor contents of the hypocotyls. In both etiolated and de-etiolated hypocotyls, the growth rates at the lighted sides were suppressed whereas those at the shaded ones showed no change. De-etiolation treatment induced a larger difference between the growth rates at the lighted and shaded sides of the hypocotyls, resulting in a larger curvature of de-etiolated seedlings than of etiolated ones. The contents of growth inhibitors, cis- and trans-raphanusanins, increased in the lighted but not in the shaded halves of the hypocotyls of etiolated seedlings. In de-etiolated seedlings, the two inhibitors increased due to the de-etiolation treatment. When de-etiolated seedlings were exposed to a pulse of unilateral irradiation the level of the two inhibitors remained high along the lighted side for 1 h following the light pulse, whereas at the shaded side the contents of the inhibitors abruptly decreased upon transfer to the dark, the difference between their amounts in the lighted and shaded sides being larger than in etiolated seedlings. Another growth inhibitor, raphanusamide, did not respond to the phototropic stimulus, although its amounts increased by the de-etiolation treatment. These data suggest that cis- and trans-raphanusanins are involved in the first positive phototropic response of radish hypocotyls, and that de-etiolation magnifies the phototropic response through induction of a larger lateral gradient of the raphanusanins in the hypocotyls by the phototropic stimulus.

Enhancement of leucine-induced insulin secretion by somatostatin antiserum pretreatment.

Insulin secretion induced by leucine and leucine plus glucose from rat pancreatic islets was enhanced by prior treatment with somatostatin antiserum as compared with normal rabbit serum in vitro. The results provide evidence that somatostatin plays an important role in insulin secretion in rats.

Effects of thyroxine and cold exposure on hypothalamic TRH levels in rats with various pituitary-thyroid states.

The hypothalamic content and concentration of thyrotropin-releasing hormone (TRH) were determined by radioimmunoassay in normal, thyroidectomized, hypophysectomized and cold-exposed rats with or without thyroxine. In normal animals, the single administration of thyroxine (1,5 and 20 microgram/100 g B.W.) altered neither the content nor the concentration of TRH in the hypothalamus. However, seven days' administration of this hormone resulted in the dose-dependent increase in the hypothalamic TRH levels. In thyroidectomized rats the hypothalamic TRH levels were slightly reduced in spite of the marked increase of plasma TSH levels and decrease of pituitary TSH levels. In the animals given thyroxine (10 microgram/100 g B.W.) for 7 days in addition to thyroidectomy, however, the TRH levels exceeded that in the animals which underwent throidectomy alone. The hypothalamic TRH levels were markedly reduced in hypophysectomized rats. Conversely, in hypophysectomized rats given 7 days' thyroxine (1 and 5 microgram/100 g B.W.), the levels were increased dose-dependently. In cold-exposed rats, the plasma TSH levels roughly doubled, but the TRH levels remained unchanged. These findings strongly suggest that the feedback site of thyroxine extends not only to the pituitary gland but also to the hypothalamus, and that thyroxine has an increasing effect of the hypothalamic TRH level, though the mechanism(s) remain to be clarified.

Physiologic role of somatostatin. Insulin release from rat islets treated by somatostatin antiserum.

In order to clarify the physiologic role of somatostatin in insulin release, rat pancreatic islets treated by somatostatin antiserum were incubated in media containing various concentrations of glucose. Insulin release from antiserum-treated islets was significantly elevated above that from nontreated ones at 3.3 and 8.3 mM glucose, while the former was not different from the latter at 16.7 mM glucose. It is suggested that somatostatin plays an important role in the regulation of insulin release in the physiologic range of glucose concentration.

A method for the deductive and unique determination of the values of three parameters involved in fractional functions applicable to relaxation kinetics.

A novel method is proposed to determine deductively and uniquely the values of three parameters, a, b, and c in a fractional function of the form, y=a+bx/(c+x) where x and y are experimentally obtainable variables. This type of equation is frequently encountered in chemistry and biochemistry involving relaxation kinetics. The method of least squares with the Taylor expansion is employed for direct curve fitting of observed data to the fractional function. Approximate values of the parameters, which are always necessary prior to commending the above procedure, can be obtained by the method of rearrangement after canceling the denominator of fractional functions. This procedure is very simple, but very effective for estimating provisional values of the parameters. Deductive and unique determination of the parameters involved in the fractional function shown above can be accomplished for the first time by the combination of these two procedures. This method is extended to include the analysis of relaxation kinetic data such as those of temperature-jump method where the determination of equilibrium concentrations of reactants in addition to the three parameters is also necessary.

Determination of the best-fit values of kinetic parameters of the Michaelis-Menten equation by the method of least squares with the Taylor expansion.

The best-fit values of the Michaelis constant (Km) and the maximum velocity (V) in the Michaelis-Menten equation can be obtained by the method of least squares with the Taylor expansion for the sum of squares of the absolute residual, i.e., the difference between the observed velocity and the corresponding velocity by calculation. This method makes it possible to determine the values of Km and V not in a trial-and-error manner but in a deductive and unique manner after some iterative procedures starting from arbitrary approximate values of Km and V. These values can be said to be uniquely determined for a set of data as the finally converged values are no longer dependent upon the initial approximate values of Km and V. It is also very important to obtain initial approximate values of parameters for the application of the method described above. A simple method is proposed to estimate the approximate values of parameters involved in fractional functions. The method of rearrangement after canceling of denominator of a fractional function can be utilized to obtain approximate values, not only for cases of two unknown parameters such as the Michaelis-Menten equation, but also for cases with more than two unknowns.