Experimental venous thrombi: MRI characteristics with histopathological correlation.

OBJECTIVES: The purpose of this study was to evaluate the MRI characteristics of venous thrombus over set time thresholds with histopathological correlation in a porcine model. METHODS: Inferior vena cava thrombi were induced in 12 pigs. MRI was performed in three pigs 2 h, 1 day, 3 days and 2 weeks after thrombus induction. RESULTS: The MRI characteristics were analysed in correlation with histopathological findings. The thrombi after 2 hours, which consisted of red blood cells (RBCs), showed isointensity on T(1 )weighted images (T(1)WIs) and hyperintensity on both T(2 )weighted images (T(2)WIs) and diffusion-weighted images (DWIs). The mean apparent diffusion coefficient (ADC) value was 1.93 × 10(-3) mm(2) s(-1). The thrombi after Day 1, which consisted of RBCs and migrating neutrophils at the periphery, showed isointensity on T(1)WIs, slight hyperintensity on T(2)WIs and hypointensity on DWIs. The mean ADC value was 1.62 × 10(-3) mm(2) s(-1) [corrected]. The thrombi after Day 3, which consisted of RBCs and peripheral inflammatory cells including macrophages, showed isointensity with peripheral hyperintense regions on T(1)WIs and hypointensity on both T(2)WIs and DWIs. The mean ADC value was 1.67 × 10(-3) mm(2) s(-1). After 2 weeks, the thrombi, which revealed RBC lysis surrounded by granulation tissues, showed isointensity on T(1)WIs and hyperintensity on T(2)WIs and DWIs. The mean ADC value was 2.48 × 10(-3) mm(2) s(-1). CONCLUSION: The temporal MRI characteristics seemed to be related to chemical and physical changes in RBC and organisation of granulation tissues. Free radicals generated by macrophages might also be related to some extent.

The proposal of noninvasive quantitative diagnostic method of the atherosclerosis and the clarification of organ correlation of atherosclerosis and oxygen metabolism.

The proposal of noninvasive diagnostic method of mechanical degradation of vascular wall is clinically useful and it will be correlated with noninvasive diagnostic method of atherosclerosis. Supersonic Doppler effect sensor has been used to measure blood flow velocity as a noninvasive measuring method. However, it is remain problem whether the output from the Doppler effect sensor really detects the pure blood flow velocity. Theoretically, when the Doppler effect sensor is set perpendicular to the blood flow direction, that is, perpendicular to the blood vessel, the output will correspond to the expansion velocity of blood vessel wall, because it detect the frequency of Doppler shifted supersonic scattered from vascular wall. Previously, on the basis of this concept, using Doppler effect sensor, we showed this method can really detect the deformation velocity of blood vessel wall and it correlates the degradation of elastic property of blood vessel. Furthermore, using this proposed measuring method, atherosclerosis is found to progress correspondingly with the visco-elastic degradation of vascular wall. In this paper, on the basis of our proposed method, the quantitative noninvasive estimation method of the degradation of vascular wall and the progressive degree of atherosclerosis by unique parameter has been proposed. Using this method, the degradation of vascular wall is correlated to the oxygen metabolic function of blood vessel corresponding to the function of oxygen transportation and progression of atherosclerosis. Furthermore, the organ correlation on the atherosclerosis between lower limb and carotid is investigated by this proposed method.

Phase I and pharmacokinetic study of carboplatin and paclitaxel with a biweekly schedule in patients with advanced non-small-cell lung cancer.

PURPOSE: A phase I study was conducted to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of carboplatin in combination with paclitaxel using a biweekly schedule in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: The pharmacokinetics of paclitaxel were determined preliminarily in some patients. The criteria for eligibility for study entry included histologically and/or cytologically confirmed NSCLC (stage IIIb or IV), no prior treatment, and measurable disease. Paclitaxel was given in combination with a fixed dose of carboplatin at an area under the concentration-time curve (AUC) of 3 mg/ml x min, every 2 weeks. The starting dose of paclitaxel was 100 mg/m(2), and the dose was increased in increments of 20 mg/m(2). Three to six patients were allocated to each dose level. RESULTS: A total of 19 patients (11 male and 8 female) with a median age of 61 years (range 43-74 years) and a median ECOG performance status of 0 (range 0-1) were enrolled. The MTD of paclitaxel proved to be 160 mg/m(2), and the DLT was neutropenia, which improved well following treatment with G-CSF. Gastrointestinal toxicity was well tolerated. Of 17 patients who received four cycles or more, 7 (41%; 95% confidence interval 18.4-67.1%) responded to this combination therapy. The pharmacokinetics of paclitaxel did not differ from published data. CONCLUSIONS: The recommended dose for phase II study is paclitaxel 140 mg/m(2) with a carboplatin AUC of 3 mg/ml.min. This biweekly regimen is highly effective and acceptable, and the present data indicate that the regimen may be suitable for use on an outpatient basis.

Phase I study of irinotecan and cisplatin with concurrent split-course radiotherapy in limited-disease small-cell lung cancer.

We conducted a phase I study of irinotecan (CPT-11) and cisplatin with concurrent split-course radiotherapy in limited-disease small-cell lung cancer (LD-SCLC). This study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of this therapy. Four chemotherapy cycles of CPT-11 (days 1, 8 and 15) and cisplatin (day 1) were repeated every 28 days. Radiotherapy of 2 Gy/day commenced on day 2 of each chemotherapy cycle with 20 Gy administered from the first to the third cycles (a total of 60 Gy). 17 patients were enrolled at three dose levels (CPT-11/cisplatin: 40/60, 50/60 and 60/60 mg/m(2)), and 16 were evaluable for toxicity and outcome. 2 of 4 patients at 60/60 mg/m(2) refused continuation of therapy because of general fatigue, and the relative dose intensity of CPT-11 at 50/60 mg/m(2) was approximately 50%. These levels were considered as the MTD. Tumour responses included four complete responses (CR), 11 partial responses (PR) and one no change (NC), and the overall response rate was 93.8% (95% confidence interval: (CI) 71.7-98.9%). This combined modality is tolerable, and CPT-11/cisplatin of 40/60 mg/m(2) in this modality is recommended for phase II study.

Phase I study of irinotecan and cisplatin with concurrent split-course radiotherapy in unresectable and locally advanced non-small cell lung cancer.

We conducted a phase I study of irinotecan (CPT-11) and cisplatin with concurrent split-course radiotherapy in locally advanced stage III non-small cell lung cancer (NSCLC). This study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of this therapy. Two chemotherapy cycles of CPT-11 (days 1, 8 and 15) and cisplatin (day 1) were repeated with a 28-day interval. Radiotherapy of 2 Gy/day commenced on day 2 of each chemotherapy cycle, with 24 Gy and 36 Gy administered for the first and second cycle, respectively. 24 eligible patients were enrolled at five dose levels (CPT-11/cisplatin: 40/60, 50/60, 60/60, 60/70 and 60/80 mg/m(2)), and 23 patients were evaluated for toxicity and clinical outcome. Only 1 patient experienced a DLT with neutropenia and diarrhoea at 60/60 mg/m(2). Dose escalation was limited to 60/80 mg/m(2) which was the recommended dose for CPT-11/cisplatin alone in NSCLC. Tumour responses included one complete response (CR), 15 partial response (PR), and 7 no change (NC), and the overall response rate was 69.6% (95% confidence interval (CI) 47.1-86.8%). This combined modality is tolerable, and CPT-11/cisplatin of 60/80 mg/m(2) in this modality is recommended for phase II study.

Monosaccharide composition of sweetpotato fiber and cell wall polysaccharides from sweetpotato, cassava, and potato analyzed by the high-performance anion exchange chromatography with pulsed amperometric detection method.

The cell wall materials (CWMs) from sweetpotato (Ipomoea batatas cv. Kokei 14), cassava (Manihot esculenta), and potato (Solanum tuberosum cv. Danshaku) and commercial sweetpotato fiber as well as their polysaccharide fractions were analyzed for sugar composition by the high-performance anion exchange chromatography with pulsed amperometric detection (HPAEC-PAD) method. The separation of arabinose and rhamnose, and xylose and mannose, by this method has been improved using a CarboPac PA 10 column. Pretreatment of the CWMs and cellulose fractions with 12 M H(2)SO(4) was required for complete hydrolysis to occur. Commercial sweetpotato fiber was found to be mainly composed of glucose (88.4%), but small amounts of other sugars were also detected. Among the root crops, sweetpotato CWM had the highest amount of pectin and galacturonic acid. Fucose was detected only in cassava CWM and its hemicellulose fraction, while galactose was present in the highest amount in potato CWM. Among the polysaccharide fractions, it was only in the hemicellulose fraction where significant differences in the sugar composition, especially in the galactose content, were observed among the root crops.

Intra-uterine physical growth in schizophrenia: evidence confirming excess of premature birth.

BACKGROUND: Many studies have suggested a possible aetiological role for obstetric complications in the development of schizophrenia. We focused on prenatal physical growth in schizophrenia, a contentious issue in the literature. METHODS: We compared gestational age at birth, birth weight (BW) and birth head circumference (BHC) between 312 schizophrenics and 517 controls, and between 187 schizophrenics and their matched healthy siblings. Information on obstetric histories was obtained from the Maternal and Child Health Handbooks (i.e. contemporaneous records). RESULTS: Gestational age at birth was significantly earlier in the schizophrenics than in the controls (P = 0.017). Pre-term birth (gestational age of 36 weeks or less) was more common in schizophrenics than in controls (8.0% v. 3.4%, P = 0.005, odds ratio 2.5). Low BW (2500 g or less) was more frequent in schizophrenics than in controls (9.6% v. 4.6%, P = 0.005, odds ratio 2.2). The schizophrenics had significantly lighter BW (P = 0.0003) and tended to have smaller BHC (P = 0.081) compared with controls. However, multiple regression analysis showed that there was no significant difference in BW or BHC between the schizophrenics and controls when gestational age and maternal weight were controlled. There was no significant difference in BW or BHC between schizophrenics and their siblings, although the schizophrenics tended to be born at earlier gestational age than their siblings. CONCLUSIONS: Our results suggest that prematurity at birth is associated with a risk of developing schizophrenia in adulthood. When gestational age and maternal body weight were allowed for, there was no evidence that schizophrenics tend to have lower mean BW or smaller BHC.

[Clinical features and outcome of pneumonia in patients with lung cancer].

We reviewed our experience with pneumonia in patients with lung cancer over a 14-year period at Kurume University Hospital. We examined the clinical features and significance of pathogenic microbes isolated from sputum in patients with lung cancer complicated by pneumonia. Many investigators have noted that patients with squamous cell lung cancer tend to contract pneumonia more readily than patients with cancers of other histopathological types. Our review, however, disclosed no significant differences among histopathological types. Bacteriological examinations of sputum revealed the frequent involvement of Staphylococcus aureus, Enterococcus faecalis, and various gram-negative organisms (e.g., Pseudomonas, Acinetobacter, Enterobacter, and Klebsiella species) that are known to be causative agents of hospital-acquired infection. Beta-lactam and CLDM were less effective. Carbapenem used alone as the second regimen of treatment for lung cancer patients with pneumonia was found to be as effective as combination therapy with beta-lactam and aminoglycoside. However, more detailed investigations (e.g., randomized prospective studies) will be needed to identify suitable antibiotics against pneumonia in patients with lung cancer. We concluded that it will be necessary to evaluate the clinical features and outcome of pneumonia in lung cancer patients in order to provide more effective treatment.

Phase I study of a combination of irinotecan and ifosfamide in advanced primary lung cancer.

We sought to investigate cisplatin-free chemotherapy for patients with primary lung cancer. We therefore conducted a Phase II study to identify; a) the maximum tolerated dose (MTD) of irinotecan (CPT-11) given with a fixed dose of ifosfamide (IFM), and b) the principal toxic effects associated with this regimen in a Phase I study. A total of 27 patients with previously treated or untreated primary lung cancer received CPT-11 on days 1, 8 and 15 in combination with a fixed dose of IFM, 1.5 g/m2/day, on days 1 through 3, given every 4 weeks. The starting dose of CPT-11 was 30 mg/m2, which was increased by amounts of 10 mg/m2. Four patients were assigned to different dosage levels, and drug toxicity was evaluated for the first 2 cycles. The MTD of CPT-11 was 90 mg/m2, with leukopenia being the dose-limiting effect. The response rate was 43% (6/14; 1 complete response) in non-small cell lung cancer, and 78% (7/9; no complete response) in small cell lung cancer. The recommended dose of CPT-11 for a Phase II study is thus 80 mg/m2 on days 1, 8 and 15 with IFM 1.5 g/m2 given on days 1 through 3. This regimen appears particularly encouraging, because of its low toxicity. Phase II trials of the combination are indicated.

Prognostic significance of febrile episodes in lung cancer patients receiving chemotherapy.

The prognostic significance of neutropenic fever in lung cancer patients receiving chemotherapy with or without radiotherapy was investigated. Male patients and patients with squamous cell lung cancer had a higher incidence of febrile episodes than female patients and patients with other cell types, but the differences were not significant. Patients with a poor performance status had a significantly higher incidence of febrile episodes. An indwelling central venous catheter was an important risk factor for febrile episodes, indicating that bacteremia was one of the major causes of fever. The median survival time of the patients who developed febrile episodes during chemotherapy was significantly shorter than that of patients without fever (6.1 vs 12.0 months), whether or not cases of early death within 3 months were excluded (8.9 vs 13.1 months). The prevention of infectious complications during anticancer treatment by the use of rh G-CSF and the early initiation of antimicrobial chemotherapy, although the results are inconclusive, may be worthwhile.

Cyfra 21-1 as a marker of lung cancer.

The utility of cytokeratin fragment (Cyfra) 21-1, a new tumor marker, was investigated in 100 patients with lung cancer. Sandwich enzyme immunoassay detected Cyfra 21-1 in the sera of 60% of patients. Sensitivity of this marker was especially high (86.4%) for squamous cell carcinoma, exceeding that of a similar marker, squamous cell carcinoma antigen (SCC, 54.5%). In contrast, sensitivity of Cyfra 21-1 was relatively low for adenocarcinoma (52.6%) and for small cell carcinoma (50%). We conclude that Cyfra 21-1 is of value in diagnosis of lung cancer, particularly squamous cell carcinoma.

Diagnostic features and therapeutic outcome of erosive and ulcerous endobronchial tuberculosis.

SETTING AND OBJECTIVE: Erosive and ulcerous endobronchial tuberculosis (EBTB) is distinct from pulmonary tuberculosis in some aspects. We evaluated the clinical features of 56 patients (26 males and 30 females) with EBTB to characterize the clinical features of the disease. RESULTS: The chief complaint in 70% of patients was intractable cough, particularly in those with tracheal tuberculosis. The predominant radiological features were patchy bi-apical infiltrates of variable intensity without cavitation; for six patients, however, plain radiographs revealed no abnormalities. The ulcerous lesions could be classified into three stages: active, healing and scarring. Furthermore, we divided scarring stage into two subtypes, polypoid and non-polypoid. Most of the patients were treated with isoniazid, rifampin, and streptomycin (SM) or ethambutol. Approximately one-third of the patients, not randomly selected, were treated with aerosolized SM and corticosteroids in addition to conventional oral therapy. CONCLUSION: EBTB involves typical clinical and radiographic features. In this uncontrolled series, it was our impression that the period of time to healing of ulcerous lesions seemed to be shorter in those treated with aerosol therapy including streptomycin and corticosteroids.

[Inflammatory reactions and microorganisms cultured from sputum and blood in association with terminal stage infection of patients with lung cancer].

We reviewed our experience with terminal stage infections in patients with lung cancer over an 11 year period at Kurume University Hospital. In patients with end-stage lung cancer, the infection is common and a mortal disease. We examined the clinical features and significance of pathogenic microbes isolated from sputum and blood in patients with lung cancer during their last month. Bacteriological examinations from blood done frequently in patients with episodes of fever revealed that bacteremia was one of the most important disease in terminal stage infection. In the blood cultures from the 22 patients various species of pathogenic microbes were recovered, and nine of which were fungi; five Candida albicans, three Candida tropicalis and one Candida parapsilosis. The major species of bacteria isolated from sputum were Staphylococcus aureus, including methicillin-resistant strain, and Gram-negative bacilli; P. aeruginasa, A. calcoaceticus, K. pneumoniae and E. cloacae, which are known to be frequently involved in hospital-acquired infections. However, S. pneumoniae and H. influenzae which were well known to be microbes of respiratory infections were rare. We concluded that we had to reveal the feature of terminal stage infection in order to reduce the fee for medical treatment and improve the QOL of patients with terminal stage lung cancer.

Detection of MAGE-4 protein in sera of lung cancer patients.

We investigated the level of MAGE-4 protein in sera of patients with primary lung cancer to understand better the biological roles of the MAGE proteins. MAGE-4 protein was detected as a non-degraded form in both the supernatant of a MAGE-4+ tumor cell line and in a patient's serum. Serum level of the MAGE-4 protein in lung cancer patients (n=100, mean=1.17 ng/ml) was significantly higher than that in either patients with benign pulmonary diseases (n=80, 0.33 ng/ml) or healthy donors (n=68, 0.32 ng/ml). It was higher than the cutoff level (1.15 ng/ml) in 34 of 100 cancer patients, but not in anyone in the other groups.

Detection of the circulating lung cancer marker LCAP with a new monoclonal antibody TRD-L1.

Lung Cancer Associated Protein (LCAP) is a high molecular weight glycoprotein defined by the monoclonal antibody (MAb) DF-L1 prepared against a primary adenocarcinoma of the lung. Previous studies have demonstrated that LCAP circulates at elevated levels in patients with lung cancer. However, a suitable assay for monitoring LCAP levels has not been available. The present work describes the development of a double-determinant LCAP assay using MAb TRD-L1 as the capture antibody and MAb DF-L1 as the tracer. In 60 normal subjects, the mean LCAP level was 4.8 U/ml with 2 (3.3%) subjects having values > 12 U/ml (mean + 2SDS). By contrast, 37 of 67 (55.2%) patients with lung cancer had LCAP levels > 12 U/ml. Moreover, only 14 of 203 (6.9%) patients with benign lung disease had elevated levels. LCAP levels were most commonly elevated (62.7%) in patients with adenocarcinoma of the lung and with advanced disease. These results indicate that LCAP as detected by MAb TRD-L1 is a potentially useful marker for the evaluation of patients with lung cancer.

[Phase II study of combination chemotherapy with cisplatin, carboplatin and etoposide (CPVP) in unresectable non-small cell lung cancer: analysis of survival time and prognostic factors].

Phase II study of combination chemotherapy with cisplatin, carboplatin and etoposide (CPVP) was conducted in 46 patients with unresectable non-small cell lung cancer. In the previous paper, we showed that CPVP produced a satisfactory response rate without major toxicities. In the present paper, survival time and prognostic factors were analyzed. The median survival time (MST), 1- and 2-year survival of 46 patients (III A4, III B15, IV 27) were 14.1 months, 57.0% and 18.2%, respectively. In prognostic analysis, responders survived significantly longer than non-responders (MST: 15.8 vs 11.0 months, p < 0.05). Large cell carcinoma and stage IV have proven to be indicators of poor prognosis. Females and patients less than 60 years old tended to do better. With regard to the relationship between the time from initiation of treatment to response and survival time, late responders (response after 3 or 4 courses) survived significantly (p < 0.05) longer than early responders (response after 1 or 2 courses). The CPVP regimen is not only practical, but also very effective. It deserves further study to reveal its advantages compared to the other platinum compound containing regimens.

Phase I/II study of combination chemotherapy with cisplatin, carboplatin and etoposide in small cell lung cancer.

A Phase I/II study of combination chemotherapy with cisplatin (CDDP), carboplatin (CBDCA) and etoposide (VP-16) (CPVP) was conducted in patients with small cell lung cancer. The dose level of etoposide was fixed at 100 mg/m2, while the doses of CDDP and CBDCA administered at each of the four steps were 50/200, 60/200, 60/250 and 70/250 mg/m2, respectively. Nine patients were allocated to each step dose group. Adverse effects were evaluated during the first two courses to establish the maximum tolerated dose (MTD). As a result, the step 3 doses turned out to be the MTD. The dose-limiting factor was hematotoxicity. Gastrointestinal toxicity was also present, but was tolerated. The overall response rate in patients with measurable or evaluable lesions was 91%. In 22 chemotherapy-naive patients, the median survival time was 16.6 months. These results suggest that the recommended dose is step 2, and that the CPVP regimen might be both more tolerable and more effective than the standard PVP regimen. Based on the above findings, CPVP therapy warrants further study in Phase II and III trials.

[Phase I/II study of a combination regimen composed of cisplatin, carboplatin and etoposide against small cell lung cancer].

Phase I/II study of combination regimen composed of cisplatin (CDDP), carboplatin (CBDCA) and etoposide (VP-16) [CPVP] was conducted for small cell lung cancer. The dose level of VP-16 was fixed at 100 mg/m2, while the dosages of CDDP and CBDCA administered at each of the 4 steps were 50/200, 60/200, 60/250 and 70/250 mg/m2, respectively. Nine patients were allocated to each step dose group. Toxicities were evaluated in the first 2 courses to determine the maximum tolerated dose (MTD). As a result, step 3 dosages proved to be MTD, and the dose limiting factor (DLF) was hematotoxicity, but gastro-intestinal toxicity was tolerated. The response (CR+PR) was found in 21 out of 23 patients with evaluable lesions (91%). In the 22 patients who had not received pretreatment, median survival time (M ST) was 16.4 months. These results suggest that the recommended dose is step 2, and that the CPVP regimen is both more tolerable and more effective than the standard regimen. The CPVP regimen warrants further study in phase III trials.