Significance of histologic pattern of carcinoma and sarcoma components on survival outcomes of uterine carcinosarcoma.

BACKGROUND: To examine the effect of the histology of carcinoma and sarcoma components on survival outcome of uterine carcinosarcoma. PATIENTS AND METHODS: A multicenter retrospective study was conducted to examine uterine carcinosarcoma cases that underwent primary surgical staging. Archived slides were examined and histologic patterns were grouped based on carcinoma (low-grade versus high-grade) and sarcoma (homologous versus heterologous) components, correlating to clinico-pathological demographics and outcomes. RESULTS: Among 1192 cases identified, 906 cases were evaluated for histologic patterns (carcinoma/sarcoma) with high-grade/homologous (40.8%) being the most common type followed by high-grade/heterologous (30.9%), low-grade/homologous (18.0%), and low-grade/heterologous (10.3%). On multivariate analysis, high-grade/heterologous (5-year rate, 34.0%, P = 0.024) and high-grade/homologous (45.8%, P = 0.017) but not low-grade/heterologous (50.6%, P = 0.089) were independently associated with decreased progression-free survival (PFS) compared with low-grade/homologous (60.3%). In addition, older age, residual disease at surgery, large tumor, sarcoma dominance, deep myometrial invasion, lymphovascular space invasion, and advanced-stage disease were independently associated with decreased PFS (all, P < 0.01). Both postoperative chemotherapy (5-year rates, 48.6% versus 39.0%, P < 0.001) and radiotherapy (50.1% versus 44.1%, P = 0.007) were significantly associated with improved PFS in univariate analysis. However, on multivariate analysis, only postoperative chemotherapy remained an independent predictor for improved PFS [hazard ratio (HR) 0.34, 95% confidence interval (CI) 0.27-0.43, P < 0.001]. On univariate analysis, significant treatment benefits for PFS were seen with ifosfamide for low-grade carcinoma (82.0% versus 49.8%, P = 0.001), platinum for high-grade carcinoma (46.9% versus 32.4%, P = 0.034) and homologous sarcoma (53.1% versus 38.2%, P = 0.017), and anthracycline for heterologous sarcoma (66.2% versus 39.3%, P = 0.005). Conversely, platinum, taxane, and anthracycline for low-grade carcinoma, and anthracycline for homologous sarcoma had no effect on PFS compared with non-chemotherapy group (all, P > 0.05). On multivariate analysis, ifosfamide for low-grade/homologous (HR 0.21, 95% CI 0.07-0.63, P = 0.005), platinum for high-grade/homologous (HR 0.36, 95% CI 0.22-0.60, P < 0.001), and anthracycline for high-grade/heterologous (HR 0.30, 95% CI 0.14-0.62, P = 0.001) remained independent predictors for improved PFS. Analyses of 1096 metastatic sites showed that carcinoma components tended to spread lymphatically, while sarcoma components tended to spread loco-regionally (P < 0.001). CONCLUSION: Characterization of histologic pattern provides valuable information in the management of uterine carcinosarcoma.

F-18 fluorodeoxyglucose uptake in leiomyomatous uterus.

Leiomyomas of uterus are common disease in gynecology. It is important to differentiate leiomyoma from leiomyosarcoma at the decision of treatment methods, especially in the case of the conservative treatment for uterine leiomyoma. But the exact diagnosis of benign leiomyoma is often difficult due to the degeneration of myoma by imaging modalities including magnetic resonance imaging. Recently, whole-body positron emission tomography (PET) using F-18 fluorodeoxyglucose (FDG) has been used for a diagnosis of malignant tumors. There is a growing body of evidence for the use of FDG in differentiating malignant from benign disease. But optimal utilization in gynecology remains unclear. Our case represents increased uptake of FDG in myomatous uterus, which is pathologically confirmed benign leiomyoma by the hysterectomy. Immunohistochemical analysis of glucose transporter-1 showed positive in endometrial tissue and negative in leiomyoma. Our case indicates that myomatous uterus in premenopausal women shows the potential pitfall of a positive result of FDG-PET.

Whole-body positron emission tomography with F-18 fluorodeoxyglucose for the detection of recurrence in uterine sarcomas.

We evaluated the usefulness of whole-body positron emission tomography (PET) using F-18 fluorodeoxyglucose (FDG-PET) for the detection of recurrence in follow-up patients after primary treatment of uterine sarcoma. Eight patients with pathologically proven uterine sarcoma underwent FDG-PET, computed tomography (CT), and ultrasonography (US). Final diagnoses of recurrence were established in five cases (three carcinosarcomas and two leiomyosarcomas). PET revealed recurrent sites in the intraperitoneum, liver, lung, bone, and retroperitoneal lymph nodes. However, the minimum size of the tumor detected by PET depended on the sites of recurrence. CT and US images showed two false-negative cases of intraperitoneal tumors. PET was able to detect a solitary small intraperitoneal tumor, which was very difficult to detect by CT and US. Positive PET findings did not affect the prognosis in three of the five recurrent patients; however, the remaining two patients consequently underwent the combination therapy consisting of surgery and chemotherapy and survived for more than 1 year after the positive FDG-PET results. Application of PET imaging for the early detection of recurrent sites was useful for the decision of treatment strategy for patients with recurrent uterine sarcoma.

Whole-body positron emission tomography and tumor marker CA125 for detection of recurrence in epithelial ovarian cancer.

We evaluated the clinical role of the combination of positron emission tomography (PET) with F-18 fluorodeoxyglucose (FDG) and tumor marker CA125, in the detection of recurrence after initial therapy for epithelial ovarian cancer. The indication is the cases that cannot be confirmed the recurrence by conventional imaging modalities. Ninety patients underwent PET and computed tomography, including the measurement of specific tumor markers. FDG-PET confirmed recurrence in 46 patients (51%), and the recurrent site was confirmed by PET alone in 17 (37%). PET had high sensitivity for detecting both intraperitoneal and retroperitoneal metastases (93.9 and 92.9%, respectively). PET imaging was able to detect normal-sized metastases in the lymph nodes in 14 (50%) of the 28 patients with retroperitoneal metastasis. PET could show 87.5% positive rate of recurrent patients with asymptomatic rise of CA125 who had no sign of recurrence by conventional imaging methods. Of the 46 recurrent patients, 41 (89%) had specific elevated titers of CA125 at the first treatment. PET imaging was able to detect recurrence at relatively low titers (a median 68 U/mL) of CA125. In 8 (19.5%) of these 41 patients, recurrence with normal CA125 levels could be confirmed only by PET. The sensitivity of the combination of PET and CA125 was 97.8% with only one false-negative case. The combination of FDG-PET and CA125 titer is useful for the accurate detection of recurrence.

Acute changes in plasma levels of hepatocyte growth factor during low-density lipoprotein apheresis.

Hepatocyte growth factor (HGF) is a mesenchyme-derived pleiotropic factor, and angiogenesis is included in a variety of its functional effects. HGF levels were measured in 5 sessions of low-density lipoprotein (LDL) apheresis in 3 patients with severe hypercholesterolemia. Blood was collected at the start (T0) and at 1,000 ml (T1), 2,000 ml (T2), and 3,000 ml (T3) plasma treatments. During LDL apheresis, HGF levels increased from 1.59 +/- 0.78 (mean +/- SE, n = 5) ng/ml at T0 to 6.64 +/- 0.97 at T1, 6.28 +/- 0.97 at T2, and 5.20 +/- 0.94 at T3. In one apheresis session, HGF increased immediately at the 100 ml plasma treatment stage. HGF was adsorbed completely by a dextran-sulfate (DS) column. Despite the adsorption by the DS column, HGF in the patient blood increased to the levels with functional effects. The improvement of ischemic symptoms due to LDL apheresis may be related to the angiogenic activities of HGF.

Effects of losartan on low-density lipoprotein apheresis.

The negative charges of dextran sulfate cellulose (DSC) used for low-density lipoprotein (LDL) apheresis activate the intrinsic coagulation pathway, accompanied by bradykinin production. This study was undertaken to see whether an antagonist of angiotensin receptor (AT1), losartan, could be safely used in a patient treated by DSC-LDL apheresis. Losartan (50 mg/day) was given to a patient with coronary heart disease who had been treated by DSC-LDL apheresis and had experienced an anaphylactoid reaction by administration of an angiotensin converting enzyme inhibitor. The effects of losartan on blood pressures and humoral factors were examined by comparing these parameters between apheresis with and without losartan. Blood pressures and plasma levels of bradykinin, renin, and aldosterone were measured before and at 1,000, 2,000, and 3,000 ml of plasma treatment. Bradykinin levels during LDL apheresis tended to be higher with losartan than without losartan (without versus with, 529 +/- 121 [n = 4, mean +/- SE] pg/ml vs. 1,058 +/- 49 at the 2,000 ml stage, p < 0.01). The rise of plasma renin activity with losartan (221 +/- 26% at the 3,000 ml stage) was significantly greater than that without losartan (144 +/- 2.4%). Mean blood pressure decreased by 7% during apheresis with losartan, but blood pressure reduction was not accompanied by any complaints. These results suggest that AT1 receptor antagonists are safely used in patients treated by DSC-LDL apheresis.

Uptake of doxorubicin by cultured kidney epithelial cells LLC-PK1.

The renal handling of doxorubicin (DXR) was investigated using a kidney epithelial cell line, LLC-PK1. The uptake of DXR by LLC-PK1 cells cultured on plastic dishes was shown to be temperature and concentration dependent. The initial uptake of DXR was slightly saturable. The Km and Vmax of the saturable component were calculated to be 20.2 microM, and 0.355 nmol/mg protein/10 min, respectively. The release of DXR from LLC-PK1 cells was very slow at 37 degrees C and almost negligible at 4 degrees C, indicating that most of the DXR in the cells irreversibly binds to cellular constituents and that only a slight amount of unbound DXR participates in the efflux out of the cells. DXR uptake at 37 degrees C was significantly decreased in the presence of 2,4-dinitrophenol. However, organic cations and aminoglycoside antibiotics, such as tetraethylammonium, N1-methylnicotinamide, guanidine, gentamicin and neomycin, did not inhibit DXR uptake, suggesting that a process distinct from the organic cation transport system and absorptive endocytosis might be involved in the uptake of DXR by LLC-PK1 cells.

Does binding of ouabain to human alpha1-subunit of Na+, K+-ATPase affect the ATPase activity of adjacent rat alpha1-subunit?

To ascertain whether ouabain binding to human alpha1-subunit influences coexpression of rat alpha1-subunit, the ouabain-sensitive profiles of Na+,K+-ATPase activity and 86Rb+ uptake activity and ouabain binding capacity were measured in HeLa cells stably expressing rat alpha1-subunit. The ouabain-sensitive profile of ATPase and 86Rb+ uptake activity seemed to be the sum of two components, one with high and one with low apparent affinity to ouabain, which were similar to that observed in HeLa and NRK-52E cells derived from human and rat, respectively. The ATPase activity with low sensitivity to ouabain increased in simple proportion to the amount of the rat alpha1 mRNA derived from transfected cDNA, which was determined by the reverse transcription-polymerase chain reaction method. The turnover number of the human Na+,K+-ATPase activity obtained from the ratio of the Na+,K+-ATPase activity to the ouabain binding capacity is about 150/sec. The expression of the rat alpha1-subunit had no effect on the turnover numbers of the Na+,K+-ATPase activity with high affinity to ouabain estimated from the ouabain binding capacity as the active site concentration. These results suggested that the ouabain bound to human alpha1-subunit did not inhibit the ATPase activity of the coexpressing rat alpha1 in these cells.

[The transport of enoxacin in cultured kidney epithelial cells LLC-PK1].

In this study, the transport of enoxacin (ENX) was investigated in a LLC-PK1 kidney epithelial cell line. The uptake of ENX by LLC-PK1 monolayers cultured in plastic dishes was shown to be temperature-dependent and concentration-dependent. Cimetidine and guanidine inhibited the uptake of ENX, whereas TEA and NMN did not. The basolateral to apical flux of ENX across LLC-PK1 monolayers cultured on permeable supports was about two times larger than the apical to basolateral flux. The basolateral to apical flux of ENX was remarkably inhibited by guanidine, whereas it was not inhibited by TEA, NMN and cimetidine. The apical to basolateral flux of ENX was inhibited by cimetidine and guanidine, whereas it was not inhibited by TEA and NMN.

Transcriptional regulation of the vimentin-encoding gene in mouse myeloid leukemia M1 cells.

To investigate the regulatory mechanisms controlling expression of the vimentin-encoding gene (Vim) during mouse myeloid leukemia M1 cell differentiation, mouse Vim was cloned and the transcriptional activity of its 5' promoter region was analysed by chloramphenicol acetyltransferase (CAT) assay. Analyses of various deletion mutants revealed that a 188-bp fragment of the proximal Vim promoter (pVim) was sufficient for effective transcription in M1 cells. This 188-bp sequence is highly conserved between mouse, hamster and human. Further deletion analyses revealed that a minimum promoter element (-44 to +26) is essential for basic promoter function and could respond to cell differentiation. Detailed analyses of mutant and chimeric pVim constructs defined a CCAAT box at -89 to -84 to be an essential positive regulatory element. A G+C-rich element between the CCAAT and TATA boxes was found to act as a strong negative regulatory element in Vim transcription.

Effects of age on c-fos and c-myc gene expression in response to hemodynamic stress in isolated, perfused rat hearts.

Using an ex vivo model we examined whether the age-associated modulation of proto-oncogene expression was due to the aging of the heart per se. In the two age groups of Wistar rats (2 and 18 months), expression of c-fos and c-myc genes was determined in isolated, isovolumically contracting hearts (balloon in the left ventricle) perfused with Tyrode's solution containing bovine serum and red blood cells. In both age groups, a c-fos signal was detected at 30 min, increased further at 60 min, and declined at 120 min, while the c-myc signal was detected at 60 min and increased for a further 120 min after initiation of perfusion at 25 mmHg of end-diastolic pressure (EDP). The expression of these genes by 60 min of relatively mild hemodynamic stress was depressed in old hearts compared to that in young hearts (c-fos at 0 (P < 0.05), 5 (P < 0.05) and 15 mmHg of EDP (P < 0.01); c-myc at 5 (P < 0.05) and 15 mmHg (P < 0.05)). The age-associated differences in the expression of these genes were smaller under severe hemodynamic stress (25 mmHg of EDP). Peak systolic and diastolic wall stress calculated from left ventricular pressure, cavity volume and muscle weight were similar in the two age groups. Thus, aging diminishes the expression of proto-oncogenes and seems to elevate the threshold at which hemodynamic stress to the heart results in a response at the gene level. The age-associated modulation is caused by aging of the heart per se.

Trophoblast-specific transcription from the mouse placental lactogen-I gene promoter.

We have isolated the gene encoding mouse placental lactogen-I and characterized the promoter region of this gene by transient and stable transfection. Promoter sequences extending 274 basepairs (bp) up-stream from the start site of transcription contain all of the elements necessary for maximal expression upon transient transfection into the rat choriocarcinoma Rcho-1 cell line; these Rcho-1 cultures contain both proliferative trophoblast stem cells and terminally differentiated trophoblast giant cells. In stably transfected cell lines, expression from this promoter increases as the percentage of differentiated cells in the culture increases. In contrast to these results in trophoblast cells, the 274-bp promoter as well as a promoter region extending 2700 bp up-stream of the transcriptional start site are unable to drive transcription in a variety of other cell types. Mutational and protein binding analyses indicate that two AP-1 sites are required for maximal expression in Rcho-1 cells, and that the composition of the AP-1 transcription factor may vary as differentiation in the cell culture increases. In addition to these two AP-1 sites, at least one other element appears to be critical for promoter activity in trophoblast cells.

Placental-specific expression from the mouse placental lactogen II gene promoter.

The gene for mouse placental lactogen II (mPL-II) has been isolated and characterized. This gene contains five exons, with a transcription start site 59 nucleotides upstream of the translation initiation ATG. Introduction of a DNA construct containing 2.7 kilobases of sequence upstream of the mPL-II transcription initiation site directed the synthesis of a linked coding region for the simian virus 40 large and small tumor antigens in placental trophoblast giant cells of transgenic mice. The pattern of simian virus 40 transgene expression in the placenta was indistinguishable from that of the endogenous mPL-II gene. In contrast, the first 569 base pairs upstream of the transcription start site proved insufficient to direct placental expression. Thus, one or more elements required for placental trophoblast giant cell expression have been localized to a region between -2700 and -569 of the mPL-II gene.

[Acute lymphocytic leukemia having surface phenotype of CD 2 and NKH-1 with rapid clinical course].

Abnormal expansion of large granular lymphocytes (LGLs) was observed in peripheral blood and bone marrow in a 28-year-old man. He had general lymphadenopathy and splenomegaly. Surface phenotypical analysis of LGLs showed that these LGLs express CD 2, Ia and NKH-1 but not express CD 3, CD 4, CD 8 and Leu 7. Cytochemical analysis of these LGLs revealed positive acid phosphatase and beta-glucuronidase reaction but negative alpha-naphthyl acetate esterase reaction. These LGLs showed very weak NK activity against only MOLT-4 but showed no cytotoxic activity against K 562. An beta-receptor gene rearrangement of human T-cell receptor was not found by Southern blot analysis. Rapid and fetal clinical course with the results of theses analytical studies showed that this case is highly suggestive of acute leukemia of LGLs which is committed to NK cell lineage.

Role of adrenergic receptor systems in canine left ventricular hypertrophy.

Although the sympathetic nervous system and catecholamines have been postulated to play an important role in the development of myocardial hypertrophy, the precise mechanism is still ill-defined. We therefore investigated myocardial norepinephrine and the adrenergic receptor systems in two experimental canine models for cardiac hypertrophy; in 12 dogs with surgical cardiac denervation, and in 12 dogs with chronic infusion of a subhypertensive dose of norepinephrine at a rate of 0.04 mg/kg/day. After two months both models induced myocardial hypertrophy, indicated by significant increases in the heart weight, left ventricular wall thickness and cell diameter, as compared with 14 sham-operated control dogs. Cardiac denervation remarkably depleted myocardial norepinephrine while plasma norepinephrine remained unchanged. Both alpha 1- and beta-receptors were up-regulated, with Bmax increasing by 124% and 49%, respectively. The decrease in myocardial cyclic AMP content was relatively small as compared with the marked depletion in myocardial norepinephrine, probably compensated by augmentation of beta-receptor system activity. Chronic norepinephrine infusion also reduced myocardial norepinephrine content possibly due to stimulation of presynaptic alpha 2-receptor inhibiting norepinephrine synthesis and release. The number of alpha 1- and beta-receptors also increased by 97% and 30%, respectively, while myocardial cyclic AMP content remained unchanged. These observations indicate that neither direct stimulation of norepinephrine on the myocardial cell nor increased cyclic AMP is the mechanism for cardiac hypertrophy. A greater increase in the alpha 1-receptor, rather than in the beta-receptors, in both models implies that a disproportional augmentation of the alpha 1-receptor system may play an important role in the development of myocardial hypertrophy.

[Hypertrophic cardiomyopathy with left ventricular dilatation].

There is increasing interest in the notion that some patients with hypertrophic cardiomyopathy (HCM) progress to morphological and functional manifestations similar to those of dilated cardiomyopathy (DCM). From 165 consecutive patients with HCM, 20 patients with left ventricular dilatation (left ventricular end-diastolic diameter greater than or equal to 50 mm) were selected and designated as dilated HCM. The diagnosis of HCM was established in these patients either by detection of the classical form of HCM in family members, with 2-dimensional echocardiographic evidence of asymmetric septal hypertrophy (ASH; septal thickness greater than or equal to 15 mm and a ratio of septal to posterior wall thickness greater than or equal to 1.3); or by demonstrating myocardial fiber disarray in autopsy or biopsy samples. The clinical manifestations of these patients with dilated HCM were then compared with those of other forms of HCM without left ventricular dilatation; 1) 40 patients with hypertrophic obstructive cardiomyopathy (HOCM) who had resting intraventricular pressure gradients of 20 mmHg or more, 2) 80 patients with non-obstructive HCM, each of whom had ASH of the entire ventricular septum (typical ASH), and 3) 25 non-obstructive patients whose hypertrophy was localized to the apical region of the ventricular septum (apical ASH). Patients having apical hypertrophy with a spade-like configuration on the left ventriculogram were excluded from the study. Compared with HOCM and typical ASH groups, the patients with dilated HCM had family histories of significantly more frequent HCM and less frequent hypertension. The patients with dilated HCM also had significantly less fractional shortening (FS), decreased interventricular septal thickness, greater left ventricular end-diastolic pressure (LVEDP), and left ventricular dilatation. During the follow-up period (average: 3.5 years), seven patients (35%) with dilated HCM died; five from congestive heart failure (CHF), one suddenly, and one three days following mitral valve replacement. The other five patients had CHF at the time of their follow-up examination. The patients with apical ASH had clinical features similar to those of dilated HCM; a higher familial frequency, less marked septal hypertrophy, and higher LVEDP. They tended to develop left ventricular dilatation, associated with reduced fractional shortening, although left ventricular diameter at end-diastole did not exceed 50 mm. These findings suggested that dilated HCM is not a rare condition. It is observed in 12% of consecutive patients with HCM.(ABSTRACT TRUNCATED AT 400 WORDS)

Elicited antibody nature of human monoclonal protein with anti-streptolysin O activity--analysis with monoclonal anti-idiotype antibody.

Sera from 7 patients with multiple myeloma having antistreptolysin O (ASO) activity in high titers were detected by a streptolysin O (SLO) inhibition assay. However, activity was in low titer when assayed by a passive agglutination assay. The discrepancy between these 2 assays raised some doubts as to whether these monoclonal proteins (M.protein) bond to SLO in the same manner as elicited antibodies. Immunochemical analysis and idiotope analysis using monoclonal antibody to one of these M.proteins strongly suggest that M.protein with ASO activity bind to SLO in a manner similar to elicited antibody. The discrepancy between the 2 assays might be due to differences in the antigenic structure of different forms of the SLO molecule.

Effect of 1,4-dimorpholino-7-(4-hydroxyphenyl)pyrido[3,4-d]) pyridazine [DS-511(4'-OH)] on the transepithelial transport of sodium and water and the permeability to urea in the toad urinary bladder.

To elucidate the mechanism of the inhibitory action of 1,4-dimorpholino-7-phenylpyrido[3,4-d]pyridazine (DS-511) on water and sodium reabsorption at the renal tubules, the effect of DS-511 (4'-OH), which is similar in diuretic effect to but more water-soluble than DS-511, on the transepithelial transport of sodium and water and permeability to urea was studied in isolated toad urinary bladder. Application of DS-511(4'-OH) at concentrations above 2 x 10(-4) mol/l to the serosal side of the bladder depressed the transepithelial potential difference, short circuit current (SCC), and membrane conductance as well as the increased response of the SCC to arginine vasopressin (AVP) and cyclic AMP. The effect of DS-511 (4'-OH) applied to the mucosal side was delayed in onset and less pronounced. Neither serosal nor mucosal 10(-3) mol/l DS-511(4'-OH) depressed the increased response of the SCC to amphotericin B. 2 x 10(-4) mol/l DS-511 (4'-OH) applied to the serosal side did not affect osmotic water flow, but potentiated the increase in water flow caused by AVP. Basal urea permeability as well as the increase in urea permeability caused by AVP were depressed by serosal 10(-3) mol/l DS-511 (4'-OH). The results show that DS-511(4'-OH) has two actions, the depression of the transepithelial transport of sodium and urea, and the potentiation of the increased water permeability caused by AVP.