Pharmacokinetic Characteristics of 5-Fluorouracil and Mitomycin C in Intraperitoneal Chemotherapy

Abstract— Eight patients with malignancies confined to the peritoneal space participated in this study. Five hundred milligrams 5-fluorouracil or 10 mg mitomycin C was diluted in 1 L saline. The mixed solution was injected intraperitoneally through the semi-permanent peritoneal catheter. Blood and peritoneal fluid were collected after injection. 5-Fluorouracil concentrations in the peritoneal fluid were 1000 times those in serum, while mitomycin C concentrations were 100 times those in serum. Areas under the concentration vs time curve (AUC) were calculated by the trapezoidal method with extrapolation to infinity. The ratio of peritoneal fluid AUC to serum AUC was about 1400 for 5-fluorouracil and 80 for mitomycin C. Patterns for the absorption and elimination from systemic circulation were similar for both compounds. Drug concentrations in the peritoneal fluid and serum were analysed according to the compartment model. The half-life in the peritoneal fluid (t½_p) and the rate constant from the peritoneal fluid to the systemic circulation (k_a) were nearly equal for both 5-fluorouracil and mitomycin C (t½_p, 1·0 h for 5-fluorouracil and 1·3 h for mitomycin C; k_a 0·71 h^?1 for 5-fluorouracil and 0·68 h^?1 for mitomycin C), although the apparent volume of distribution (Vd_s/F) and clearance in the peritoneal cavity (CL_p) for mitomycin C (78 Lm^?2 and 1.8 L h^?1 m^?2) were about twice the values for 5-fluorouracil (149 L m^?2 and 0·8 L h^?1 m^?2).     

Transplacental Initiation of Liver, Lung, Neurogenic, and Connective Tissue Tumors by N-Nitroso Compounds in Mice

Transplacental Initiation of Liver, Lung, Neurogenic, and ConnectiveTissue Tumors by N-Nitroso Compounds in Mice. ANDERSON, L. M.,HAGIWARA, A., KOVATCH, R. M., REHM, S., AND RICE, J. M. (1989).Fundam. Appl Toxicol. 12, 604–620. Epidemiological studieshave implicated nitroso compounds as possible causative agentsfor human childhood cancers, including those of neurogenic origin.Published evidence from animal models, which is reviewed inthis report, indicates that capacity for metabolic activationof nitrosamines is limited in rodent fetuses and that nitrosaminesare correspondingly weak transplacental carcinogens. The C3Hmouse fetus, however, has both moderate capability for activationof N-nitrosodimethylamine (NDMA) and proven susceptibility totransplacental causation of neurogenic tumors by a nitrosourea.We tested whether NDMA could act as a transplacental carcinogenin the C3H mouse, and whether it or N-nitrosodiethylamine (NDEA)would initiate neurogenic tumors. N-Nitrosoethylurea (NEU) servedas positive control. C3H/HeNCr MTV^– pregnant mice weretreated ip on Gestation Day 16 or 19 with NDMA (0.1 mmol, 7.4mg/kg, maximum nonfetotoxic dose), NDEA (0.5 mmol, 51 mg/kg),or NEU (0.4 mmol, 47 mg/kg). NDMA had significant transplacentalcarcinogenic effects, resulting in an increase in percentagefemale offspring with hepatocellular carcinomas and in averagenumber of liver tumors after treatment on either gestationalday, compared with controls. In the males there was a significantincrease in numbers of liver tumors and carcinomas followingDay 19 exposure. An increase in incidence of histiocytic andundifferentiated sarcomas was also of statistical significance.There was no change in num ber of pulmonary tumors. One intracranialschwannoma resulted. NDEA had no effect when given on GestationDay 16, but caused a significant increase in liver and lungtumor numbers in both sexes when treatment was on Day 19. NELlinduced the expected high incidence of lung tumors, significantlyincreased liver tumor incidence in females (Day 19 exposure),and produced schwannomas in 14 and 35% of the offspring afterDays 16 or 19 treatment, respectively. The results show thatNDMA at even a low dose had significant transplacental carcinogenic effects, including one schwannoma, which was most unlikelyto have occurred spontaneously. However, this single neurogenictumor contrasts with the absence of similar neoplasms in miceexposed transplacentally to NDEA, in view of the generally greaterefficiency of ethylat ing agents as carcinogens for the nervoussystem in rodents. These data thus neither conclusively supportnor refute the hypothesis that nitrosamines may initiate neurogenictumors in fetuses.     

Adrenal metastasis from renal cell carcinoma: Significance of adrenalectomy

BACKGROUND: The present study examined adrenal metastasis resulting from renal cell carcinoma (RCC), with the aim of assessing the need for routine ipsilateral adrenalectomy during radical nephrectomy. METHODS: Ipsilateral and contralateral adrenal metastases were investigated in 256 patients with RCC who had undergone radical nephrectomy from 1977 to 1996 at the Tohoku University School of Medicine. RESULTS: Twelve of the 256 patients (4.7%) had adrenal metastasis. Ten of these 12 patients had progressed to disseminated disease with very poor prognosis. Two patients who had solitary adrenal metastases remained disease-free for 21 and 7 years. Four patients showed metastases to the contralateral adrenal gland. Adrenal metastases in seven of 12 patients were identified by pre- or postoperative computed tomography (CT), and in another five macroscopically during surgery. CONCLUSIONS: Adrenalectomy was regarded as a possible curative treatment for patients with solitary adrenal metastasis. However, the incidence of this kind of metastasis was minimal and contralateral adrenal metastases may occur in RCC cases. We therefore believe that adrenalectomy should only be performed if radiographic evidence reveals metastases in the adrenal gland or if gross disease is present at the time of nephrectomy.     

Acute hepatitis C transmitted by needlestick accident despite short duration interferon treatment

Hepatitis C virus (HCV) transmission by needlestick accidents involving hospital employees has become an important problem. The present report is of a case of acute hepatitis C that developed after a needlestick injury, despite short duration interferon treatment performed just after the accident in a trial effort to prevent HCV transmission. Nosocomial infection of HCV in medical employees is reviewed, and the current prospects for protecting them from HCV transmission after needlestick accident are discussed.     

Antibody response to E2/NS1 hepatitis C virus protein in patients with acute hepatitis C

Antibody response to the E2/NS1 protein of the hepatitis C virus (HCV) was studied in 26 patients with post-transfusion acute hepatitis C. Second-generation HCV (HCV-2) antibody, E2/NS1 antibody and HCV-RNA were measured in serial serum samples taken within 1 month and 3, 6 and 12 months after the onset of acute hepatitis C. The HCV genotype was also tested to study its clinical significance. Of 26 patients, eight showed normalization of alanine aminotransferase (ALT) and clearance of HCV-RNA (resolved group). In the remaining 18 patients, HCV viraemia and ALT abnormality (except one patient) continued for more than 3 years (unresolved group). Both HCV-2 and E2/NS1 antibodies were positive at least once in all patients. The prevalence of E2/NS1 antibody was significantly (P < 0.05) higher in the resolved group (88%) than in the unresolved group (39%) in the period within 1 month of onset; the prevalence was similar between the two groups thereafter. The prevalence of HCV-2 antibody did not differ between the two groups at any point. The HCV genotype was not related to the chronicity of acute hepatitis C. In conclusion, the E2/NS1 antibody appeared in all patients with acute hepatitis C and was associated with the clearance of HCV.     

Oncological outcome of retroperitoneoscopic nephroureterectomy for upper urinary tract transitional cell carcinoma

OBJECTIVE: To report the oncological outcome of retroperitoneoscopic nephroureterectomy (RNU) with bladder cuff excision for upper urinary tract transitional cell carcinoma (TCC), and to compare the outcome with that of the traditional open nephroureterectomy (ONU). PATIENTS AND METHODS: From January 2001, 48 patients with upper urinary tract TCC were enrolled in the study; 25 had RNU and 23 had ONU. Oncological parameters (disease-free survival and disease-specific survival) were calculated from the time of surgery to the date of last follow up and were analysed by the Kaplan-Meier method. RESULTS: Mean follow up was 24.3 months in the RNU group, significantly shorter than in the ONU group. Bladder recurrence was identified in two patients with grade 3 pathological stage pT3, one patient with grade 3 stage pT2 disease and two patients with grade 2 stage pT2 disease. Multiple organ metastases in the lung, liver and lymph nodes were associated with bladder recurrence in two cases (grade 2 stage pT3, and grade 3 stage pT3). The recurrence rate was 20% (5 of 25 cases) and mean time to recurrence was 9.5 months. In the ONU group, bladder recurrence and metastases developed in four and three patients, respectively. The recurrence rate was 17% (4 of 23 cases) and mean time to recurrence was 23.4 months. No significant difference was detected in the disease-free survival rate and cancer-specific survival rate between the two groups (P=0.759 and P=0.866, respectively). CONCLUSION: The oncological outcome of RNU appears to be equivalent to that of ONU. Moreover, long-term follow up is necessary to evaluate the oncological outcome in comparison to ONU.     

Three-dimensional structure of human insulin-like growth factor-I (IGF-I) determined by 1H-NMR and distance geometry

The three-dimensional structure of human insulin-like growth factor-I has been determined through a combination of NMR measurements and distance geometry calculations. A total of 320 interatomic distance constraints, including 12 related to the disulfide bridges, were used in these calculations. The resulting structure is characterized by the presence of three helical rods corresponding to the sequence regions, Ala8-Cys18, Gly42-Cys48 and Leu54-Cys61. Furthermore, a turn structure and an extended structure exist in the Gly19-Gly22 and Phe23-Asn26 regions, respectively. Neglecting the N- and C-termini, with their expectedly high degree of mobility as well as a fluctuating C-domain, the r.m.s.d. value is 1.9 Å for backbone atoms. Those of the three α-helical regions are 1.0, 0.9 and 0.8 Å, respectively, 1.8 Å being that for the total backbone atoms participating in the formation of these three helices, showing the good convergence of their spatial arrangements. The overall structure obtained here shows that the human IGF-I molecule folds into a spatial structure very similar to that of insulin in an aqueous solution.     

Hand-assisted retroperitoneoscopic radical nephrectomy: Initial experience

OBJECTIVES: To report our initial experience of hand-assisted retroperitoneoscopic radical nephrectomy for stage T1 renal tumors. METHODS: The clinical data on 22 consecutive patients who had undergone hand-assisted retroperitoneoscopic radical nephrectomy and 22 who had undergone open radical nephrectomy were reviewed. The operation was performed with a hand placed retroperitoneally through a pararectal longitudal 7-7.5 cm incision using a LAP DISC. RESULTS: The total operating time was between 2.3 and 5.8 h (mean: 3.4 h). The estimated blood loss was between 15 and 650 mL (mean: 170 mL). The complication rate was 9% (2/22). No conversions to open procedure occurred. In comparison to open radical nephrectomy, the operating time was similar (3.4 vs 3.9 h) whereas the estimated blood loss was significantly less in this procedure (170 vs 495 mL). During the convalescence period the patients revealed significantly less postoperative pain, shorter intervals to resuming oral intake and more rapid return to normal activities compared to the open radical nephrectomy patients. CONCLUSION: Hand-assisted retroperitoneoscopic radical nephrectomy is an effective and safe procedure for T1 renal tumors.