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.

Anti-annexin A5 antibodies in reproductive failures in relation to antiphospholipid antibodies and phosphatidylserine.

PROBLEM: The presence of IgG anti-annexin A5 (IgGalphaA5) and/or antiphospholipid antibodies (aPL) are risk factors associated with recurrent spontaneous abortion. Problems are whether IgA antiannexin A5 (IgAalphaA5) is pathogenic, and how IgGalphaA5 works. METHOD OF STUDY: Blood samples from 238 patients with early recurrent spontaneous abortion, 48 patients with recurrent in vitro fertilization-embryo transfer failure, 179 non-pregnant women and 120 pregnant controls were tested for IgAalphaA5 by enzyme-linked immunosorbent assay. We also determined if IgGalphaA5 appeared coincident with aPL. The antigenic epitope(s) recognized by IgGalphaA5 was investigated. RESULTS: We observed no difference between patients and controls for IgAalphaA5. The prevalence of IgGalphaA5 was not different statistically between patient samples with or without aPL. Patient IgGalphaA5 bound annexin A5 when the latter was free/unbound but not when annexin A5 was associated with phospholipid. CONCLUSIONS: The IgAalphaA5 does not appear to be pathogenic. IgGalphaA5 works to make a complex with annexin A5 without relation to aPLs, which may reduce annexin A5 available for binding to trophoblast.

Effects of losartan on blood pressure and humoral factors in a patient who suffered from anaphylactoid reactions when treated with ACE inhibitors during LDL apheresis.

In a patient who was taking an angiotensin-converting-enzyme inhibitor, low-density lipoprotein (LDL) apheresis with dextran-sulfate cellulose provoked hypotension accompanied by lacrimation and blurred vision. Hypotension was eliminated by changing the anticoagulant from heparin to a protease inhibitor, nafamostat mesilate. A study was undertaken to clarify whether an antagonist of angiotensin type 1-receptor, losartan, could be safely used in the same patient during LDL apheresis treatment. Blood pressure and humoral factors were compared between the apheresis sessions with losartan and those without. Although angiotensin II and bradykinin plasma levels during LDL apheresis were significantly greater with losartan than without, blood pressure reduction by losartan was mild and unpleasant symptoms were not induced. Losartan was thus safely used for this patient during treatment by LDL apheresis. The greater rise in bradykinin levels during apheresis with losartan might be ascribable to angiotensin type 2-receptor stimulation.

Renal macrostructure and cortical circulation in hypertension assessed by dynamic computed tomography.

The aim of this study was to assess the macrostructure of the kidney and the grade of heterogeneity in renal cortical circulation in the early stages of essential hypertension. The subjects consisted of 84 patients (<50 years old) who underwent dynamic computed tomography (CT) because of various abdominal diseases and who had no serious hemodynamic abnormalities. The volumes of the whole kidney, cortex, and medulla were measured with the program installed in the CT instrument. In dynamic CT under appropriate conditions, the CT number of each pixel (image element) reflects the blood volume in the pixel. The means and standard deviations were calculated from the CT numbers within the renal cortex. The coefficient of variation (CV) of CT numbers was used as the index of the heterogeneity of renal cortical circulation. The volume ratio of cortex/medulla was significantly (P < .01) smaller in the hypertensive patients (0.80 +/- 0.03 (mean +/- SE)) than in the normotensive subjects (0.92 +/- 0.03). The CV was significantly (P < .01) greater in the hypertensives (n = 23, 0.124 +/- 0.008) than in the normotensives (n = 61, 0.106 +/- 0.003). There was a significant correlation (r = -0.391, P < .001) between the CV of CT numbers and the volume ratio of cortex/medulla, and the relationship between the two variables was independent of other variables. These results suggest that the heterogeneity of renal cortical circulation is increased in the early stages of essential hypertension and is related to changes in renal macrostructure.

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.

(2-Carbamoylethyl)bis(dimethylglyoximato-N, N')

The 2-carbamoylethyl and 2-(methylcarbamoyl)ethyl groups in the title cobaloxime complexes, [Co(C(4)H(7)N(2)O(2))(2)(C(3)H(6)NO)(C(12)H(13)N)].C(2)H(6)O and [Co(C(4)H(7)N(2)O(2))(2)(C(4)H(8)NO)(C(10)H(13)NO(2))], were isomerized to 1-carbamoylethyl and 1-(methylcarbamoyl)ethyl groups, respectively, on exposure to visible light in the solid state. Although both the crystal structures and the intermolecular hydrogen bonds are different in the two crystals, similar reaction rates were observed.

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.

Physical and biological properties of cationic triesters of phosphatidylcholine.

The properties of a new class of phospholipids, alkyl phosphocholine triesters, are described. These compounds were prepared from phosphatidylcholines through substitution of the phosphate oxygen by reaction with alkyl trifluoromethylsulfonates. Their unusual behavior is ascribed to their net positive charge and absence of intermolecular hydrogen bonding. The O-ethyl, unsaturated derivatives hydrated to generate large, unilamellar liposomes. The phase transition temperature of the saturated derivatives is very similar to that of the precursor phosphatidylcholine and quite insensitive to ionic strength. The dissociation of single molecules from bilayers is unusually facile, as revealed by the surface activity of aqueous liposome dispersions. Vesicles of cationic phospholipids fused with vesicles of anionic lipids. Liquid crystalline cationic phospholipids such as 1, 2-dioleoyl-sn-glycero-3-ethylphosphocholine triflate formed normal lipid bilayers in aqueous phases that interacted with short, linear DNA and supercoiled plasmid DNA to form a sandwich-structured complex in which bilayers were separated by strands of DNA. DNA in a 1:1 (mol) complex with cationic lipid was shielded from the aqueous phase, but was released by neutralizing the cationic charge with anionic lipid. DNA-lipid complexes transfected DNA into cells very effectively. Transfection efficiency depended upon the form of the lipid dispersion used to generate DNA-lipid complexes; in the case of the O-ethyl derivative described here, large vesicle preparations in the liquid crystalline phase were most effective.

The new-concept full-face-type helmet with removable cheek pads.

BACKGROUND: The American College of Surgeons proposed a method of removing helmets. But the problem with full-face-type helmets is that their shape makes them difficult to remove. METHODS: A dummy doll was fixed to a smooth bed surface in the supine position, and a full-face-type helmet with a hook attached to the vertex was placed on the doll's head. A spring balance was attached to the hook, traction was applied to the helmet through the spring balance, and the maximum tension needed to completely remove the helmet was measured. RESULTS: A tension of 13.2 +/- 1.8 kg was found. But when cheek pads were removed, the tension required to remove the helmet was 1.7 +/- 0.2 kg. CONCLUSION: We devised a full-face-type helmet that uses removable cheek pads so that helmet removal can be performed safely by removing only the cheek pads in the event of an accident.

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.

Travelling Wave Solutions for the Spread of Farmers into a Region Occupied by Hunter-Gatherers

The geographical spread of an initially localized population of farmers into a region occupied by hunter-gatherers is modelled as a reaction-diffusion process in an infinite linear habitat. Hunter-gatherers who come in contact with farmers are converted at rate e. Growth of initial farmers, converted farmers, and hunter-gatherers is logistic with intrinsic rates rf, rc, and r h. The carrying capacities of all farmers (i.e., initial and converted farmers combined) and hunter-gatherers are K and L. Individuals migrate at random, where the diffusion constant, D, is the same for all three groups. Under the above assumptions, we deduce the conditions under which wavefronts of initial or converted farmers are generated. Numerical work suggests that a travelling wave solution of constant shape always exists, comprising an advancing wavefront of all farmers and a retreating wavefront of hunter-gatherers. Linear analysis in phase space suggests that the speed is given by 2(Drf)1/2 or 2[D(r c+eL)]1/2, whichever is greater. The composition of the expanding distribution of all farmers appears to depend on the relative magnitude of rf versus rc+eL and of eK versus rh. A wavefront of initial farmers is not generated if rfrh. On the other hand, a wavefront of initial farmers is generated if rf>rc+eL. In this case, the waveform is peaked with leading and trailing edges that converge to 0 if eKrh so that there is substantial displacement of the indigenous hunter-gatherers by the initial farmers.

[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.

[A case of Evans's syndrome in which thrombocytopenia and hemolysis was improved by Sairei-to].

A 51-year-old male diagnosed as having Evans's syndrome in 1991 was treated with 25 mg of prednisolone, but his anemia and thrombocytopenia progressed. Thus, in November 1993, treatment was begun with Sairei-to, a Chinese herbal medicine consisting of several water-soluble plant extracts. Following administration of 9.0 g/day of Sairei-to granules along with prednisolone, the platelet count increased from 6.1 x 10(4)/microliters to 12.3 x 10(4)/microliters after one week, while hemoglobin levels rose from 9.5 g/dl to 12.0 g/dl after three weeks. The patient maintained a good physical condition after the prednisolone dose was reduced, although Coomb's test and PAIgG levels remained positive. Sairei-to-seems to be a promising therapeutic agent for steroid-resistant ITP and AIHA, and seems to have no side effects.

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.