Pharmacokinetic study of the oral fluorouracil antitumor agent S‐1 in patients with impaired renal function

Although dose reduction of S‐1 is recommended for patients with impaired renal function, dose modification for such patients has not been prospectively evaluated. The aim of the present study was to investigate the pharmacokinetic parameters of 5‐fluorouracil, 5‐chloro‐2,4 dihydroxypyridine and oteracil potassium, and to review the recommended dose modification of S‐1 in patients with renal impairment. We classified patients receiving S‐1 into 4 groups according to their renal function, as measured using the Japanese estimated glomerular filtration rate (eGFR) equation. The daily S‐1 dose was adjusted based on the patient's eGFR and body surface area. Blood samples were collected for pharmacokinetic analysis. A total of 33 patients were enrolled and classified into 4 groups as follows: 10 patients in cohort 1 (eGFR ≥ 80 mL/min/1.73 m²), 10 patients in cohort 2 (eGFR = 50‐79 mL/min/1.73 m²), 10 patients in cohort 3 (eGFR = 30‐49 mL/min/1.73 m²), and 3 patients in cohort 4 (eGFR < 30 mL/min/1.73 m²). Those in cohorts 3 and 4 treated with an adjusted dose of S‐1 showed a similar area under the curve for 5‐fluorouracil (941.9 ± 275.6 and 1043.5 ± 224.8 ng/mL, respectively) compared with cohort 2 (1034.9 ± 414.3 ng/mL). Notably, while there was a statistically significant difference between cohort 1 (689.6 ± 208.8 ng/mL) and 2 (P = 0.0474) treated with an equal dose of S‐1, there was no significant difference observed in the toxicity profiles of the cohorts. In conclusion, dose adjustment of S‐1 in patients with impaired renal function using eGFR is appropriate and safe.     

Case of autoimmune neutropenia with severe marginal periodontitis

Early onset periodontitis is rarely seen in infants, though often leads to an acute and serious clinical course when encountered in such patients. Autoimmune neutropenia presents systemic and dental symptoms, as depressed resistance to bacterial infection is caused by a disorder that reduces the number of neutrophils. This disease can result in not only gingival inflammation but also destruction of periodontal tissues, such as attachment loss, alveolar bone absorption, and early tooth loss in primary as well as mixed dentition. Here, we report treatment of a child with marginal periodontitis from the age of 3 years–7 years 9 months. No systemic manifestations were noted until 3 years of age, thus the patient had never received a detailed examination or medication related to the disease. Following examinations at our department, we referred the patient to a pediatrician at our university hospital for possible systemic disease, who made a diagnosis of autoimmune neutropenia. Although administration of antibiotics and professional dental care were continued, neutrophil count was not increased and progressive periodontal destruction was observed. Extraction of teeth with poor prognosis was performed and a prosthetic strategy for the missing teeth developed. It is important to recognize that periodontitis along with autoimmune neutropenia can appear in infants, even though the incidence is quite low. Early detection and early treatment of this disease is necessary for delaying progression of periodontitis and optimal occlusal induction of permanent teeth.     

Experimental study on the optimal size of the tricuspid valve annular area on annuloplasty

The optimal size of tricuspid valve annular area (TVAA) by annuloplasty for tricuspid regurgitation remains controversial. Recently, we developed a new measuring system which permits to do real-time measurement of tricuspid valve annular area in anesthetized dogs. Using this system, we studied the optimal size of TVAA by annuloplasty. After the right atrial incision, a metal thread which functions as a sense loop of the electromagnetic fields was stitched along the tricuspid valve annulus (visible juncture of the valve leaflets and the cardiac wall). The drive coil assembly was placed perpendicular to the extension of the long axis of the heart and was directed toward the tricuspid valve region. During control conditions, the maximum TVAA appeared at the onset of ventricular systole. The minimum TVAA appeared during the early ventricular diastolic phase which included the ventricular isovolumic relaxation phase. The maximum TVAA varied in five dogs between 2.2 cm2 and 3.1 cm2, the minimum TVAA also varied between 1.8 cm2 and 2.5 cm2: During regular sinus rhythm, a decrease of TVAA during one cardiac cycle ranged between 11.9% and 22.4% of the maximum size. When TVAA was not decreased by annuloplasty to the minimum area which was observed during cardiac cycle in the control state, the cardiac output and the right atrial pressure remained unchanged, because the ventricular filling was not obstructed. On the other hand, when TVAA was decreased smaller than this minimum area, the cardiac output decreased and the right atrial pressure rose.(ABSTRACT TRUNCATED AT 250 WORDS)     

Scintigraphic detection of recurrence of medullary thyroid cancer

A case of recurrent medullary thyroid cancer (MTC) was evaluated with¹²³I-MIBG,^99mTc(V)-dimercaptosuccinic acid (DMSA), and²⁰¹Tl scintigraphy. This patient had been operated on for MTC in the right thyroid. Recently a left neck mass was noticed, and was suspected of being a. recurrence of MTC based on increased plasma calcitonin (CT) and carcinoembryonic antigen (CEA). He was operated on for the neck mass which revealed MTC, and papillary thyroid cancer was incidentally found in the left thyroid, but the CT and CEA levels remained high, and remaining MTC tumor was suspected. But the location of the tumor was unknown. Although^99mTc(V)-DMSA scintigraphy is generally believed to be superior in sensitivity to¹²³I-MIBG scintigraphy, it did not demonstrate the tumor site but²⁰¹Tl and¹²³I-MIBG did. Furthermore,¹²³I-MEBG scintigraphy has greater specificity for tumors which arise in the neural crest. Judging from the results of this case and cases reported in the literatures, both¹²³I-MIBG and^99mTc(V)-DMSA should be performed in the detection of recurrent MTC.     

Research review: DNA polymerases as molecular markers of the regenerating capacity of hepatocytes

Hepatocyte regeneration has been widely investigated, with the mitotic index and the incorporation of [³H]thymidine being used as regeneration markers. We focused on the induction of DNA replication enzymes, particularly DNA polymerases (pol) α, δ, and ε. Using rat models, we have shown that the activity of pol α in crude liver extract well represents the regenerating capacity of hepatocytes. Using pol α as an indicator, we analyzed liver regeneration in rat models under various conditions: obstructive jaundice, external or internal biliary drainage, and the obstruction of portal vein branches. It has been revealed that the ligation of the common bile duct alone induces a certain amount of hepatocyte proliferation. It was striking that external biliary drainage suppressed regeneration capacity in cholestatic rat liver after partial hepatectomy. The strong regeneration in nonligated lobes induced by portal branch ligation was similar to the liver regeneration seen after partial hepatectomy with respect to the induction of DNA polymerases. Taken together, the aspects of DNA replication, particularly the induction of DNA polymerases, may contribute to shedding new light on the regeneration of human liver. This work was supported in part by a Grant-in-Aid for General Scientific Research and for Cancer Research from the Ministry of Education, Science and Culture, Japan, and by grants from the Uehara Memorial Foundation     

Early and midterm results of the arterial switch operation for transposition of the great arteries in Japan

A total of 267 infants and children who underwent the arterial switch operation for transposition of the great arteries in the 6 years before Jan. 1, 1988 in six main Japanese institutions were entered into this review. The current status of patients surviving more than 1 year after the operation were evaluated along with early operative results. One hundred forty-six patients had an intact ventricular septum, 103 had a significant ventricular septal defect, and 18 had so-called Taussig-Bing anomaly of the transposition type. Eighteen patients were less than 28 days of age, 73 were 1 to 5 months of age, and 176 were older than 6 months of age at the time of operation. The overall mortality rate was 35% in the first 3 years and 12% in the more recent 3 years. There was a significant difference between the overall mortality rate of primary and two-stage repair (22% versus 10%, p = 0.047) in patients with intact ventricular septum. The overall mortality rate in patients with type B or C coronary arteries of Yacoub, and Radley-Smith's classification was significantly higher than that of other types of arteries (86% versus 18%, p = 0.0001). A total of 156 patients survived more than 1 year after the operation, and 44 children (28%) were noted to have supravalvular pulmonary stenosis (greater than 20 mm Hg). This complication was more common in patients operated on in the newborn period. Trivial or mild aortic regurgitation was noted in 29 patients (19%) and was more common in patients with two-stage than with primary repair (24% versus 14%). Aortic regurgitation was significantly more prevalent in patients in whom coronary arteries were implanted into slits or U-shaped defects than in those whose arteries were implanted into punched-out holes made on the pulmonary root (28% versus 8%, p = 0.049). Normal sinus rhythm was present in 97% of 154 patients and left ventricular ejection fraction was within the normal range in 97% of 115 patients at catheterization 1 to 5 months after the operation.     

Off-pump resection of a coronary arterial fistula using the Harmonic Scalpel

Off-pump surgery was performed in a patient with post-infarction angina complicated with aneurysmal coronary-pulmonary arterial fistula. Epicardial echocardiography localized the artery feeding the fistula in the myocardium, which had not been revealed by visual inspection, palpation, or transesophageal echocardiography. The patient underwent off-pump coronary artery bypass grafting concomitant with aneurysmectomy. The feeding arteries were dissected easily using a Harmonic Scalpel and ligated. The flow in the aneurysm disappeared immediately and aneurysmectomy was performed without bleeding.