Application of Akaike's information criterion (AIC) in the evaluation of linear pharmacokinetic equations

According to linear pharmacokinetics, the time course of plasma concentration of a drug, C_p,is expressed by a sum of exponential functions, C_p= _i=1 ⁿ a_i .This article describes a statistical technique to estimate the number of exponential terms, n,for the time course of drug by the application of Akaike's information criterion (AIC). Plasma concentrations of ethoxybenzamide, sulfisoxazole, bishydroxycoumarin, and diazepam measured following bolus intravenous injection were used as clinical examples for this method. Selection of models is compared between the AIC method and an Ftest method at significance levels of 5% and 1%.     

Adolescent smoking behavior in Japan, 1996.

We conducted second nationwide survey on smoking behavior among Japanese high school students. The survey was a cross-sectional sampling survey. The survey's targets were junior and senior high schools throughout Japan. Sample schools were selected by stratified cluster sampling. Self-administered anonymous questionnaires were sent to sample schools for all students to fill out. 65.6% of the junior high schools and 67.0% of the senior high schools were responded to this survey. A total of 117,325 students responded and 115,814 questionnaires were subjected to analysis. 7.5% of boys and 3.8% of girls in the 1st grade of junior high school were classified as current smokers, compared with 36.9% of boys and 15.6% of girls in 3rd grade of senior high school. Less than 1% of boys and girls in the 1st grade of junior high school were classified as daily smokers, this figure increased markedly by the 3rd grade of senior high school to reach 25.4% of boys and 7.1% of girls. Of students in the 3rd grade of senior high school, 21.2% of boys and 9.9% of girls had tried smoking before 13 year of age. Cigarette consumption also increased with age, although the proportion of those smoking 20 or more cigarettes per day did not. The major source for cigarettes among current smokers was vending machines. This survey revealed that smoking prevalence among Japanese high school students has already reached quite high level. Comprehensive energetic measures for control minor smoking are necessary in Japan.     

Overexpression of collagen XVIII is associated with poor outcome and elevated levels of circulating serum endostatin in non-small cell lung cancer.

PURPOSE: The aim of this study was to determine whether collagen XVIII expression is correlated with circulating serum endostatin and whether this has any prognostic value in patients with non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Serum endostatin levels were measured quantitatively by a competitive enzyme immunoassay, and collagen XVIII expression in tumor tissue was investigated with an immunohistochemical method in a series of 94 patients who underwent surgery for NSCLC. RESULTS: Sixty cases (63.8%) had positive immunohistochemical staining with anticollagen XVIII polyclonal antibodies, including strongly positive staining in 11 (11.7%) cases. The mean (+/- SD) serum endostatin level was 41.6 +/- 34.4 ng/ml in the patient group and 16.3 +/- 10.3 ng/ml in the control group (P < 0.0001). The 11 cases who were strongly collagen XVIII-positive had significantly higher serum endostatin levels than the cases who were negative or weakly positive (P = 0.0297). The 5-year survival rates of negative, weakly positive, and strongly positive patients were 77.8%, 56.9%, and 43.8%, respectively. The cases with strongly positive collagen XVIII expression had a significantly poorer outcome than cases with negative expression (P = 0.0027). A multivariate analysis with Cox proportional hazards model for disease-specific survival revealed that expression of collagen XVIII (strongly positive versus negative; weakly positive versus negative), tumor classification, and regional lymph node classification were independent prognostic factors. CONCLUSIONS: Our results suggest that expression of collagen XVIII in tumor tissue is strongly associated with a poorer outcome in NSCLC and correlates with elevated levels of circulating serum endostatin.     

Tumor lysis syndrome in widely metastatic small-cell lung cancer

Tumor lysis syndrome is a rare complication of nonhematologic malignancies that results from massive necrosis of neoplastic cells after chemotherapy. This syndrome consists of life-threatening metabolic derangements, including severe hyperphosphatemia, hyperkalemia, hyperuricemia, and hypocalcemia, and may result in renal failure and death if not recognized early and treated appropriately. We report a case of tumor lysis syndrome after induction chemotherapy in a patient with widely metastatic smallcell lung cancer. This case emphasizes the importance of awareness and early treatment of this syndrome.     

Seven-year survivor with malignant melanoma of the anus without radical surgery

We report a case of a long-term survivor with malignant melanoma of the anus who did not undergo radical surgery. A 71-year-old woman who presented with anal bleeding and anal tumor underwent an excisional biopsy in September 1985. The biopsy specimen was a lobulated, polypoid, pigmented mass 2 cm in diameter, that had been located on the anterior wall of the anus. A satellite nodule 7 mm in diameter was found on the left wall of the anus at the level of the dentate line. Both tumors were histologically diagnosed as malignant melanoma. The primary tumor was 6 mm thick. Melanoma cells were present microscopically at the cut end of the rectum. Because of her history of ischemic heart disease, the patient rejected our recommendation that she undergo radical surgery, and received 10 courses of carboplatin 20 mg intramuscularly and OK-432 10 K.E. (Klinische Einheit) intradermally every week. A single, pigmented metastatic inguinal lymph node developed and was excised in June 1987. A recurrent tumor was detected in the rectum in October 1992, so again we recommended radical surgery. The patient rejected radical surgery again, and received 12 courses of carboplatin 10 mg intramuscularly every 2 weeks. She died of disease at home in July 1993 after surviving for 7 years and 10 months. An autopsy was not performed. This case shows that local excision of the primary lesion may be appropriate to preserve the quality of life of patients with early-stage malignant melanoma of the anus.     

A Proposal for a New Histological Classification Scheme for Predicting Short-term Tumor Recurrence and Death in Patients with Invasive Ductal Carcinoma of the Breast

Tumor recurrence rate (TRR) and mortality rate (MR) of invasive ductal carcinoma (IDC) of the breast in short-term follow-up are relatively low. Nevertheless, it is extremely important to identify patients at risk of early recurrence or death after surgery. The aim of this study was to establish a new histological prognostic classification scheme for IDC in order accurately to predict the short-term outcome. The following histological parameters were analyzed in 201 IDCs: 1) tumor size, 2) structural atypia, 3) nuclear atypia, 4) number of mitotic figures, 5) fibrotic focus (FF), 6) vascular invasion, 7) tumor necrosis, 8) skin invasion, 9) muscle invasion, 10) nodal status and 11) extramammary fat invasion. Multivariate analysis showed that nuclear atypia, presence of FF, and the invasive length of fat invasion (ILFI) were the most important histological parameters correlated with TRR or MR of IDCs. Accordingly, a new histological classification based on nuclear atypia, FF and ILFI (Nucleus-Fibrotic focus-Fat invasion, NFF) was devised. Comparative studies were performed with the following existing prognostic classifications: 1) histological grade, 2) modified Scarff-Bloom-Richardson histological grade, 3) prognostic index and 4) pathological TNM (pTNM) stage classifications. Patient grouping defined by NFF classification significantly correlated with tumor recurrence or death of IDCs in all cases, cases at stages I and II, those without lymph node metastasis and those who were estrogen receptor (ER)-positive after adjustment for the other four classifications, using multivariate analysis. NFF classification appeared superior to existing prognostic classifications for the accurate prediction of the short-term outcome for patients with IDCs in low risk groups.     

Induction of Squamous Cell Carcinomas in the Salivary Glands of Rats by Potassium Iodide

In a 2-year carcinogenicity study of potassium iodide (KI) in F344/DuCrj rats, squamous cell carcinomas (SCCs) were observed in the salivary glands of 4/40 males and 3/40 females receiving 1000 ppm KI in the drinking water. Ductular proliferation with lobular atrophy was observed at high incidence in the submandibular glands of the high-dose animals, and squamous metaplasia was frequently evident within the proliferative ductules and the larger interlobular ducts. A transition from metaplasia to SCC was apparent. The results suggest that squamous metaplasia in proliferative ductules, occurring secondarily to lobular impairment induced by KI, may develop into SCCs via a non-genotoxic, proliferation-dependent mechanism.     

Relevance of a New Impedance Matching, or Subtrap, Method for the Reduction of Pain During Hyperthermia

Capacitive heating is widely used in hyperthermic treatment of human malignancies. However, the pain on the body surface or thermoesthesia in the subcutaneous fatty layer may prevent an elevation of temperature in the tumors. Impedance matching is improved by a subtrap method entailing the application of two copper plates (10×850×0.06 mm) as a subtrap circuit to each of two capacitive electrodes. In a clinical trial the Tmax, Tave, Tmin for the subtrap method were all higher in comparison with those for the conventional technique (42.5±0.7°C, 41.9±1.0°C, 41.3±1.1°C vs. 41.1±1.5°C, 40.6±1.3°C, 40.0±1.3°C). Although the maximal radiofrequency (RF) power applied to patients was higher with the subtrap method (875±189 W vs. 763±200 W), the incidence of surface pain was reduced dramatically. It is concluded that the subtrap method substantially improves the RF capacitive heating of deep-seated tumors.     

Radioresponse of Thymomas Verified with Histologic Response

Patterns of radiologic response of 10 thymomas treated by preoperative radiotherapy (RT) (18-20 Gy/2 weeks) were determined in conjunction with histologic response. Changes in tumor volume were evaluated with CT scans obtained 5 to 36 days before and 14 to 24 days after the initiation of RT and before surgery. The extent of tumor volume reduction (TR) varied widely (40-78%), while the mean daily volume decrement expressed as a percentage of the pre-RT tumor volume correlated significantly with the pre-RT tumor volume. Histologically, the tumors, all of which were resected 17 to 33 days after RT initiation, generally consisted of predominant fibrous tissues, rare necrotic foci, and few epithelial cells. The TR did not correlate with pre-RT tumor volume, observation period, histologic subtype, or quantity of remaining epithelial cells. The TR of thymomas does not predict RT impact on tumor cells but does reflect the quantity of inherent tumor stroma.