Phase III randomised controlled trial of neoadjuvant chemotherapy plus radical surgery vs radical surgery alone for stages IB2, IIA2, and IIB cervical cancer: a Japan Clinical Oncology Group trial (JCOG 0102).

BACKGROUND: A phase III trial was conducted to determine whether neoadjuvant chemotherapy (NACT) before radical surgery (RS) improves overall survival. METHODS: Patients with stage IB2, IIA2, or IIB squamous cell carcinoma of the uterine cervix were randomly assigned to receive either BOMP (bleomycin 7 mg days 1-5, vincristine 0.7 mg m(-2) day 5, mitomycin 7 mg m(-2) day 5, cisplatin 14 mg m(-2) days 1-5, every 3 weeks for 2 to 4 cycles) plus RS (NACT group) or RS alone (RS group). Patients with pathological high-risk factors received postoperative radiotherapy (RT). The primary end point was overall survival. RESULTS: A total of 134 patients were randomly assigned to treatment. This study was prematurely terminated at the first planned interim analysis because overall survival in the NACT group was inferior to that in the RS group. Patients who received postoperative RT were significantly lower in the NACT group (58%) than in the RS group (80%; P=0.015). The 5-year overall survival was 70.0% in the NACT group and 74.4% in the RS group (P=0.85). CONCLUSION: Neoadjuvant chemotherapy with BOMP regimen before RS did not improve overall survival, but reduced the number of patients who received postoperative RT.

3-D fractal tumor growth of epithelial ovarian cancer.

PURPOSE: A fractal is a shape made of parts similar to the whole. Our objective was to determine whether surface growth patterns in malignant epithelial ovarian tumors are 3-D fractal, and if the mean fractal dimension differs according to histologic types. METHODS: After the images of photographs of 139 resected malignant epithelial ovarian tumors were digitized, the fractal dimensions of surface of solid portions were measured using 3-D fractal analysis software. RESULTS: The mean fractal dimensions of the surface of a solid area of tumor in serous, mucinous, endometrioid, and clear cell adenocarcinoma were 2.320, 2.224, 2.229, and 2.298, respectively. Those of serous and mucinous cystadenoma of low malignant potential (LMP) were 2.398 and 2.282, respectively. These values were significantly greater than the topological dimension of a surface (= 2). The mean fractal dimensions of a solid area of tumor inside the cyst for serous, mucinous, endometrioid, and clear cell carcinoma were 2.347, 2.223, 2.228, and 2.310, respectively. The values for serous and mucinous cystadenoma of LMP were 2.398 and 2.282, respectively. CONCLUSION: This study shows that the surface of a solid area of malignant epithelial ovarian tumors has a 3-D fractal structure, and the mean fractal dimension may differ according to histologic types.

PTEN mutation located only outside exons 5, 6, and 7 is an independent predictor of favorable survival in endometrial carcinomas.

Although the prognostic impact of PTEN mutation in endometrial carcinoma is beginning to be analyzed, the prognostic significance of mutated PTEN exons has not ever been described. Sixty-seven endometrial carcinomas were analyzed for PTEN mutations using single-strand conformation polymorphism analysis and DNA sequencing. First, survival rates were compared according to PTEN status and mutated PTEN exons. Subsequently, univariate and multivariate analyses of various favorable prognostic factors for survival were conducted. The associations between PTEN mutation and clinicopathological features were also statistically evaluated. PTEN mutations were detected in 37 of 67 (55%) specimens. Among 47 mutations, frameshifts (57%) and mutations in exon 8 (38%) were most frequent. In univariate analysis, a factor of PTEN mutation only outside exons 5-7 was associated with significantly better survival (P = 0.02), although mutation in any exon of PTEN was not (P = 0.33). Subsequent multivariate analysis revealed that factors of mutation only outside exons 5-7 of PTEN, stage I/II, and G1 were significant and independent prognostic indicators for favorable survival (P = 0.004, 0.004, and 0.0006, respectively). In the subset of advanced-stage disease, mutation only outside exons 5-7 was associated with a trend toward better survival (P = 0.13). No significant correlation was observed between PTEN mutation and estrogen-related clinicopathological features. In conclusion, we find that PTEN mutation located only outside exons 5-7 is a significant and independent positive prognostic indicator for survival. The current observation has prognostic and therapeutic implications for the management of patients with endometrial carcinoma.

Small polydisperse low density lipoproteins in familial hyperalphalipoproteinemia with complete deficiency of cholesteryl ester transfer activity.

Lipoprotein abnormalities were analyzed in 3 cases of marked hyperalphalipoproteinemia caused by complete deficiency of cholesteryl ester transfer activity. The probands were all men, aged 34, 43 and 48 years, respectively. The serum high density lipoprotein (HDL)-cholesterol levels of these patients were higher than 150 mg/dl (157-254 mg/dl), while serum total cholesterol levels ranged from 227 to 360 mg/dl. Sequential flotation-ultracentrifugation analysis disclosed that low density lipoprotein (LDL)-cholesterol was slightly decreased and that cholesteryl ester accumulated solely in the HDL2 fraction, which was also enriched with apolipoprotein E. Cholesteryl ester transfer activity was completely absent in all of these cases. High-performance liquid chromatography showed a decrease of LDL particle size in combination with a marked enlargement of HDL particle size. Analytical ultracentrifugation disclosed heterogeneity of LDL with the presence of small LDL subpopulations. We conclude that hyperalphalipoproteinemia due to complete deficiency of cholesteryl ester transfer activity is characterized by the presence of both small polydisperse LDL and markedly large HDL enriched with cholesteryl ester and apolipoprotein E.

Enhanced oncogenicity of human papillomavirus type 16 (HPV16) variants in Japanese population.

To investigate whether HPV16 E6 variants carry an elevated risk for cervical cancer in Japanese population, we investigated the E6 sequence variation in 40 cervical intraepithelial neoplasias (CINs) I-III and 43 invasive cervical cancers (ICCs), all positive for HPV16. HPV16 E6 variants were frequently found in ICCs than in CINs (88 vs. 65%, P=0.01). The E6 D25E, a rare variant in Western countries, was most frequently observed in ICC (44%). CIN I/II lesions with HPV16 variants were less likely to regress than those with HPV16 prototype (P=0.048). The finding that HPV16 E6 variants represent a significant risk factor is common between Western and Japanese women despite the different distribution of each variant.

Analysis of E6 variants of human papillomavirus type 33, 52 and 58 in Japanese women with cervical intraepithelial neoplasia/cervical cancer in relation to their oncogenic potential.

The variation of the E6 region of human papillomavirus type 16 (HPV16) is associated with a high risk for cervical carcinogenesis. To see whether the same is the case with HPV33, 52 and 58, known to have high homology with HPV16, we analyzed the E6 sequence variation of these HPVs in 107 Japanese women with cervical intraepithelial neoplasia (CIN) or invasive cervical cancer (ICC): 20 HPV33-positive, 46 HPV52-positive and 41 HPV58-positive cases. HPV33 variants were more frequently observed in CINs I/II than in CIN III/ICCs (71% (5/7) versus 15% (2/13), P=0.02). In HPV52-positive cases, a single E6 variant was detected in 98% of the cases, whereas the prototype accounted for 98% of HPV58-positive cases. In summary, the distribution of E6 variants is different among HPV types tested, suggesting a link between E6 variation and oncogenic potential being type-specific.

Effects of ketanserin tartrate on serum lipids in patients with essential hypertension.

Several antihypertensive agents such as thiazide diuretics and some beta-blockers have recently been shown to adversely affect lipid metabolism. Moreover, there is a growing suspicion that the adverse effect on plasma lipids might outweigh the favourable effect of lowering blood pressure. The effect of ketanserin tartrate (20 to 60 mg daily), a new antihypertensive drug, on blood lipids was evaluated in a 12-week non-comparative clinical trial in 34 patients with mild or moderate hypertension. Ketanserin reduced systolic and diastolic blood pressure by 12.2 and 9.8%, respectively, without altering heart rates. Total cholesterol and low density lipoprotein (LDL)-cholesterol levels in the fasting plasma were observed to decrease significantly by 6.3 and 8.8% respectively, whereas mean triglyceride and high density lipoprotein (HDL)-cholesterol remained almost unchanged. These changes were consistent irrespective of their initial values. Significant decrease in apolipoprotein B and E was also observed. Apolipoprotein A-I, A-II, C-II and C-III were not altered significantly. It is speculated that ketanserin affects mainly LDL-cholesterol. Based on these findings, ketanserin is considered to have a potentially beneficial effect on coronary risk profile and should be given full consideration when drug therapy is selected for patients with mild to moderate hypertension.

Chemical stimulation of the locus coeruleus: inhibitory effects on hemodynamics and renal sympathetic nerve activity.

We examined the role of the locus coeruleus (LC) in the regulation of the hemodynamics and sympathetic nerve activity in anesthetized rats. Unilateral microinjection into the LC of the excitatory amino acid, L-glutamate (Glu), elicited dose-dependent decreases in arterial pressure (AP) and heart rate (HR). The bradycardic response was partially attenuated after intravenous injection of atropine sulfate, but the greater part of this response still remained. Interruption of the ascending projections of the LC by midbrain transection did not affect the depressor and bradycardic responses elicited by chemical stimulation. The renal sympathetic nerve activity showed transient but strong inhibition with this stimulation. Cardiac output was measured using an electromagnetic flowmeter implanted in the ascending aorta. The stroke volume and total peripheral resistance (TPR) were calculated. Microinjection of Glu elicited a significant decrease in TPR and slight decreases in cardiac output and stroke volume. Microinjection of the inhibitory amino acid, gamma-aminobutyric acid (GABA), or the alpha 2-adrenergic agonist, clonidine, exerted no effect on AP and HR. The present results therefore suggest that: (1) the LC neurons have an inhibitory influence on the sympathetic nervous system, and stimulation of these neurons can elicit depressor and bradycardic responses; (2) the depressor response was produced predominantly as a result of a decrease in vascular resistance, rather than a decrease in cardiac output; (3) these inhibitory responses may be provided not via the ascending projections of the LC; and (4) the LC neurons do not have a tonic influence on the cardiovascular system.

Differential regional hemodynamic changes produced by L-glutamate stimulation of the locus coeruleus.

The locus coeruleus (LC) exerts an inhibitory influence on the cardiovascular system. Microinjection of the excitatory amino acid, L-glutamate, into the LC elicits a decrease in arterial pressure as a result of a decrease in total peripheral resistance (TPR). The aim of the present study was to examine the role of the LC in the regulation of the regional hemodynamics. Employing anesthetized rats, the blood flow to the renal, mesenteric and hind-limb vascular beds was measured with an electromagnetic flowmeter. The changes in regional blood flow and vascular resistance evoked by chemical stimulation of the LC were examined separately in each region. During the depressor response elicited by LC stimulation, the hind-limb and renal vascular resistance was significantly decreased, while the mesenteric resistance was unchanged. The vasodilatation appeared to be more prominent in the hind-limb muscle than in the systemic circulation. Renal nerve denervation attenuated the decrease in renal vascular resistance elicited by LC stimulation. However, a small part of this response still remained in the denervated kidney. The present results suggest therefore that: (1) LC neurons exert differential hemodynamic effects on the hind-limb muscle, renal and mesenteric vascular beds; (2) the largest contribution to the decrease in TPR is related to vasodilatation in the hind-limb muscles; and (3) the renal vasodilation elicited by LC stimulation is not mediated solely by the renal innervation.

Altered basal firing pattern and postactivation inhibition of locus coeruleus neurons in spontaneously hypertensive rats.

We compared the spontaneous unit activity and inhibition of impulse activity following antidromic activation (postactivation inhibition, PAI) of locus coeruleus (LC) neurons in spontaneously hypertensive rats (SHR) with those of LC neurons in Wistar-Kyoto rats (WKY). Spontaneous spikes of the LC were analyzed by interspike time histograms. The basal unit activity and variation coefficient of the interspike interval were decreased in SHR. The duration of the PAI which was yielded by antidromic activation from the dorsal noradrenergic bundle was shortened in SHR. These findings suggest that SHR LC neurons possess an altered basal firing pattern and inhibitory mechanism.

A personal diffusive sampler for occupational acetone vapor exposure monitoring.

A commercially produced badge-type personal sampler, with water as absorbent and originally designed for monitoring of formaldehyde, was investigated for possible application to monitoring of occupational exposure to acetone, one of the hydrophilic solvents which cannot be monitored so far with activated carbon cloth-equipped diffusive samplers. Under the experimental condition of exposure at constant acetone concentration, the amount of acetone absorbed was proportional to the acetone exposure concentration up to 1500 ppm and duration of exposure for up to 8 h. Inter-sampler variation became wider, however, at 8 h of exposure to 1500 ppm acetone. Loss of acetone in the absorbent water due to spontaneous desorption became significant at 6 h after acetone impregnation of absorbent water. In practice, therefore, limitation of the duration of exposure up to 4 h is recommended.

Urinalysis vs. blood analysis, as a tool for biological monitoring of solvent exposure.

Blood and urine samples were collected at the end of an 8-h workshift from 30 male workers exposed to a mixture of n-hexane, ethyl acetate and toluene (each being about 2 ppm as geometric means) and also from 20 nonexposed male workers. Blood samples were analyzed for n-hexane and toluene, and urine samples were analyzed for n-hexane, toluene, 2,5-hexanedione (both with and without hydrolysis) and hippuric acid. Based on the correlation between biological exposure indicators and solvent concentrations in air, sensitivity as an exposure indicator was compared between solvents in blood and solvents or metabolites in urine in terms of the lowest solvent concentration at which the exposed subjects can be statistically separated from the nonexposed. Both n-hexane and toluene in blood were sensitive enough to detect the exposure at 6.1 ppm and 1.4 ppm, respectively. n-Hexane exposure below 2 ppm was detectable also by urinalysis for 2,5-hexadione without hydrolysis. Urinary hippuric acid, however, failed to detect low toluene exposure under the conditions studied. Of additional interest is the fact that toluene in urine correlated significantly with toluene in air, which apparently deserves further study for confirmation.

Curvi-linear relation between acetone in breathing zone air and acetone in urine among workers exposed to acetone vapor.

An occupational health study was conducted on 45 acetone-exposed male workers in combination with 343 non-exposed men to examine the quantitative relationship between the intensity of acetone vapor exposure and the concentration of acetone in urine. The time-weighted average acetone concentrations were measured by means of diffusive samplers with water as absorbent, whereas urine samples were collected at the end of the shift as well as before the shift on the next morning. Acetone concentration in shift-end urine did not increase when the workers were exposed to acetone up to approx. 15 ppm, and this was followed by a gradual increase at a higher atmospheric acetone concentration, in a manner dependent to acetone vapor concentration. The comparison in acetone concentrations between the urine samples collected at the shift-end and those before the shift of the next morning showed that the levels in two sets of samples were the same among those exposed to 15 or less ppm acetone, whereas acetone in the shift-end samples was significantly higher than the counterpart levels in the pre-shift samples among those exposed to acetone at more than 15 ppm.

In vitro hydrolysis of methyl acetate, a limitation in application of head-space gas-chromatography in biological monitoring of exposure.

Stoichiometric conversion of methyl acetate to methanol in vitro was detected when methyl acetate was incubated with blood for 2 to 8 h. The velocity of the reaction was so fast that almost all of methyl acetate disappeared in 8 h. The methanol formation was further confirmed by means of gas-chromatography-mass spectrometry. The capacity to hydrolyze methyl acetate was evenly distributed in cellular and noncellular fractions of blood, but not in urine. The significance of the observation is discussed in relation to biological monitoring of exposure to industrial ester solvents by means of head-space gas-chromatography of blood samples.

Lipoprotein(a) levels in the nephrotic syndrome.

We investigated serum lipoprotein(a) [Lp(a)] levels in 20 patients with the nephrotic syndrome. Lp(a) levels in the nephrotic syndrome patients were significantly higher than those in a control group (30.4 +/- 22.5 vs 10.4 +/- 17.7 mg/dl). Overall, the serum Lp(a) and lipid levels showed no relationship, but on an individual basis the serum Lp(a) level varied with the serum levels of total cholesterol and low density lipoprotein cholesterol in the nephrotic syndrome patients. Our findings suggest that a decrease in serum albumin led to increased hepatic Lp(a) synthesis. It is well known that thrombotic disease supervenes on hypercoagulability in the nephrotic syndrome, so the determination of Lp(a) levels in these patients may provide information which is useful for preventing thrombotic complications.

Prevalence of ovarian endometriosis in epithelial ovarian cancer.

OBJECTIVE: The objective of this study was to examine the occurrence of ovarian endometriosis in epithelial ovarian cancer in Japan. METHOD: The presence of ovarian endometriosis was determined by reviewing the sections of resected specimens in 172 epithelial ovarian cancers. RESULTS: The incidence of ovarian endometriosis in ovarian cancer (14.5%) was higher than that in Western countries. The rank order of incidence of endometriosis in each histologic type was clear cell (40.6%)>endometrioid (23.1%)>serous (8.7%)>mucinous (2.9%). The incidence in serous type was higher when compared with that reported in Western countries. The higher incidence of endometriosis in Japan can be explained by a greater proportion of clear cell type, comprising 18.6% of all the cases and a higher incidence of endometriosis in the serous type. CONCLUSION: The association of ovarian endometriosis with epithelial ovarian cancer was more frequently found in Japan.

Types of organic solvents used in workplaces and work environment conditions with special references to reproducibility of work environment classification.

A survey of solvent was conducted for 196 unit work areas in 95 plants in 1994 to 1996 in Hiroshima Prefecture, Japan. The survey had been repeated every 6 months (i.e., twice a year) during the 3-year period. Sampling and analysis of the solvent vapors were carried out after national protocols set by the regulation. Toluene was most frequently detected regardless of the type of solvent work (except for degreasing), whereas the second- and the third-most common solvents varied depending on the type of solvent works. Among chlorinated hydrocarbon solvents for degreasing, dichloromethane was most widely used. Solvent concentrations were generally low as none of the median concentrations exceeded corresponding Administrative Control Levels set by the regulation, either individually or even when the assumption of additiveness was applied. Among the 1176 cases analyzed, 80% of the unit work areas were evaluated as adequate (i.e., classified as Class I). Furthermore, about 57% stayed in Class I throughout the 3 years, suggesting that solvent exposure conditions were generally quite stable. In regulatory evaluation by classification, A-sampling was decisive in most cases, whereas the role of B-sampling was limited.

Absence of mutagenicity in peripheral lymphocytes of workers occupationally exposed to methyl methacrylate.

Chromosome aberration rates and sister chromatid exchange frequency were examined in the peripheral lymphocytes of 38 male workers who were engaged in organic glass production and exposed to methyl methacrylate (MMA) vapors at the concentrations of 0.9 ppm to 71.9 ppm. The results were compared with the findings in the concurrent nonexposed male subjects. Comparison of the exposed group with the nonexposed controls showed that there were no exposure-related changes in chromosome aberration rate. SCE frequency was higher in the exposed group than in the controls, but this was considered to be due to higher ages of the former group than that of the latter. In fact, selection of nonsmokers and further classification of the exposed nonsmokers into two groups of those with exposure below and above a median MMA concentration (ca. 4 ppm) failed to show any difference among the three nonsmoking groups in cytogenetic parameters, or any dose-dependency. The present results, although in a limited number of subjects, indicate that occupational methyl methacrylate exposure under the conditions studied is not associated with mutagenicity. This conclusion confirms the absence of mutagenicity of methyl methacrylate in humans, and is in general agreement with a majority of the results of studies on mutagenicity in vitro, animal carcinogenicity and occupational cancer epidemiology of methyl methacrylate.

[Usefulness and safety of dobutamine stress thallium myocardial scintigraphy].

Pharmaceutical stress test is performed for diagnosis of coronary artery disease in patients who can not perform exercise test. We studied whether high dose dobutamine stress test is useful and safe. Subjects consisted of 133 patients (pts) in doubutamine stress test and 45 pts in exercise test. Dobutamine stress test was initiated by 10 micrograms/kg/min, followed by 10 micrograms/kg/min increment every 3 minutes. Maximal doubutamine dose was 40 micrograms/kg/min for 3 minutes. Endpoints of dobutamine stress were as follows: ST depression equal to or more than (> or =) 0.2 mV: 30 pts, > or = 75% predictive maximum heart rate: 20 pts, > or = 20 mmHg systolic blood pressure fallen: 10 pts, 40 micrograms/kg/min for 3 minutes: 10 pts, chest pain: 7 pts, pressure rate product (PRP) > or = 25,000: 1 patient. Side effects of dobutamine stress test were as follows: palpitation: 52%, arrhythmia: 13%, angina and dyspnea: 7%, headache: 6%. These symptoms were disappeared within 2 minutes. One patient, who performed dobutamine test 2 day after PTCA, had myocardial infarction. At peak of dobutamine stress test, systolic blood pressure, heart rate and PRP were increased similar to exercise test. However, diastolic blood pressure was not changed. The concentration at peak of dobutamine was 25.5 +/- 7.8 micrograms/kg/min. The duration of dobutamine stress test was 7.3 +/- 2.3 minutes. The 65 patients (49%) need more than 20 micrograms/kg/min of dobutamine which was maximal loading dose in previous reports. For diagnosis of coronary artery disease, sensitivity was 91% (31/34) and specificity was 70% (7/10). From these data, high dose dobutamine stress test is useful and relatively safe stress method for diagnosis of coronary disease. This stress test would be performed in patients who can not perform exercise test.

[Usefulness of electrocardiogram gated 99mTc-methoxy isobutyl isonitrile (MIBI) single photon emission computed tomography for detection of wall motion abnormality of left ventricle].

We evaluated whether the newly developed perfusion imaging agent "99mTc-methoxy isobutyl isonitrile (MIBI)" has a possibility to detect wall motion abnormality of left ventricle. Electrocardiogram (ECG) gated single photon emission computed tomography (SPECT) was performed in 6 patients with myocardial infarction (anterior: 3 and inferior: 3). Apical and basal short axis images were selected from each patient and circumferential analysis was performed on end-diastolic (ED) and end-systolic (ES) images respectively. Count in end-diastole (EDC) and count in end-systole (ESC) were obtained, then % (ESC-EDC) and (ESC-EDC)/EDC were calculated. Wall motion of left ventricle was evaluated by either ultrasonic cardiogram or left ventriculography. Left ventricle was divided into anterior, septal, posterior and lateral areas and then each area was divided into apical and basal segments (finally the heart was divided into 8 segments). Of 48 segments, 33 segments showed normal wall motion and 15 segments showed abnormal wall motion: hypokinesis, akinesis and dyskinesis. % (ESC-EDC) was 74.39 +/- 16.85% in segment of normal wall motion and 33.27 +/- 23.56% in segment of abnormal wall motion (p < 0.001). (ESC-EDC)/EDC was 48.67 +/- 13.35% in segment of normal wall motion and 23.33 +/- 18.83% in segment of abnormal wall motion (p < 0.001). From these data, lower limit of % (ESC-EDC) and (ESC-EDC)/EDC in normal wall motion was defined as 40 and 22 respectively: mean -2SD of normal wall motion. Sensitivity of diagnosis of abnormal wall motion was 73% in % (ESC-EDC) and 60% in (ESC-EDC)/EDC (n.s.). Specificity was 94% and 97% (n.s.).(ABSTRACT TRUNCATED AT 250 WORDS)