Osteosarcoma occurring in osteogenesis imperfecta

We describe a case history of a 24-year-old male with osteogenesis imperfecta (OI) who developed osteosarcoma of the left thigh. High-dose ifosfamide therapy caused marked tumor regression of multiple lung metastases. Immunohistochemically, the tumor cells were diffusely positive for the p53 protein. Mutation of the p53 gene was not detected by direct genomic sequencing of exons 4–8. The radiographic characteristics, including irregularly distributed osteolytic lesions and cortical discontinuity, should not be confused with hyperplastic callus formation, a benign process. A biopsy is critical to establish the differential diagnosis between osteosarcoma and common hyperplastic callus formation in OI; however, it must be applied with great care.     

Identification of α1-adrenoceptor subtypes in the dog prostate

Summary The ₁-adrenoceptor subtypes of dog prostate were characterized in binding and functional experiments. In saturation experiments, [³H]prazosin bound to ₁-adrenoceptors with high affinity. In the displacement experiments, unlabelled prazosin and WB4101 biphasically inhibited the binding of 400 pM [³H]prazosin, suggesting the presence of at least two distinct affinity sites for prazosin or WB4101. The proportion of high-affinity sites was approximately 10%. HV723 also recognized two distinct affinity sites but the proportion of high-affinity sites was approximately 20%. From these results the presence of three distinct ₁-adrenoceptor subtypes was suggested: presumably subtypes _1A (high affinity for prazosin and WB4101), _1N (high affinity for only HV723) and _1L (low affinity for the three antagonists) according to the recently proposed ₁-adrenoceptor subclassification. The density of subtype _1L was much higher than that of subtypes _1A and _1N subtypes. In the functional experiments, prazosin, WB4101 and HV723 competitively antagonized the contractile response to noradrenaline with low affinities close to those estimated for the _1L subtypes. These results suggest that the contractile response to noradrenaline in the dog prostate is mediated predominantly through _1L subtype -adrenoceptors.     

A clinicopathologic evaluation of "depth" in cases of endometrial adenocarcinoma

A total of 573 cases of endometrial adenocarcinomas, composed of patients that had been hysterectomized from 1949 to 1985 at the Cancer Institute Hospital in Tokyo, have been clinicopathologically investigated to evaluate the degree of the myometrial invasion, meaning the "Depth" as a postoperative prognostic factor of this type of cancer. These patients were classified into groups, depending on the depth of the invasion. The Depth d group, showing a myometrial invasional depth of over two-thirds of the uterine wall, revealed a rate of 61.3% of the lymph node metastasis positive cases, and accounted for 50.0% of the postoperative survivals. These values were statistically worse, when compared to those of the Depth a to c groups, which showed less invasional depth. Thus it was concluded that "Depth" is an important prognostic factor in cases of an endometrial adenocarcinoma.     

Immunohistochemical detection of P-glycoprotein in breast cancer and its significance as a prognostic factor

Overexpression of P-glycoprotein (Pgp) in tumors is one of the major mechanisms which mediates the multidrug resistance (MDR) phenotype. To evaluate the prognostic significance of Pgp in breast cancer, Pgp expression was examined in paraffin-embedded tissue sections of 94 breast cancer specimens by immunohistochemistry. Tissue specimens were obtained by mastectomy without preoperative chemotherapy. UIC2 monoclonal antibody which recognizes an extracellular epitope of human Pgp was employed. Of the 94 breast cancer specimens, 35 (37.2%) were positive for Pgp expression. Pgp expression had no correlation with menopausal or hormone receptor status, axillary lymph node involvement or tumor size. However, a significant correlation was observed between Pgp expression and disease relapse (p = 0.0322). Pgp-positive patients showed a significantly shorter disease-free survival period than Pgp-negative patients by the Kaplan-Meier method (p = 0.0433). These results suggest that immunohistochemical detection of Pgp in breast cancer tissue may have prognostic value after radical operation.     

The development of a small bowel volvulus in the early postoperative period following a distal gastrectomy: Report of a case

A 51-year-old Japanese man who underwent a standard distal gastrectomy for cancer of the stomach developed abdominal pain when oral intake was commenced on the 6th postoperative day after an uneventful postoperative course. Complete obstruction of the jejunum led to a sudden deterioration in his general condition and a laparotomy was performed, revealing counterclockwise rotation of the mesenterium. The necrotic portion of the small intestine was removed, while 10 cm of the upper jejunum and 100 cm of the terminal ileum were preserved. His second postoperative course was uneventful apart from the development of intestinal hurry, which is now under medical control 9 months after his second laparotomy.     

Intracellular activation and cytotoxic action of RS-1541 against cultured human tumor cells

RS-1541, an acyl-derivative of rhizoxin (Fig. 1), is a potent antitumor compound. This agent showed cytotoxicity in vitro on some cultured human tumor cells, although it was less potent than rhizoxin. Rhizoxin exhibited antitumor effects by inhibiting the polymerization of tubulin, whereas RS-1541 did not inhibit tubulin polymerization in vitro. However, cell cycle analysis in vivo showed that the two agents had the same mode of action. The cytotoxicity of RS-1541 was enhanced when the initial cell density of the cells was increased. The cytotoxicity was also enhanced when the membrane fraction of St-4 cells, which were the most sensitive to RS-1541 among the cell lines tested, was added to the target cells. When St-4 cells were incubated with [¹⁴C]-RS-1541, significant amounts of [¹⁴C]-rhizoxin were produced within the cells. Further fractionation of the crude membrane showed that the activity that enhanced the cytotoxicity of RS-1541 (RS-1541-enhancing activity) belonged to the mitochondrial-lysosomal fraction, not to the microsomal fraction. Both the enhancing activity and the activity that converting [¹⁴C]-RS-1541 to [¹⁴C]-rhizoxin (RS-1541-converting activity) were inhibited by treatment with chloroquine, an inhibitor of lysosomal function. Cholesterol esterase derived fromCandida cylindracea had RS-1541-enhancingand-converting activities. These data suggest that RS-1541 exerts its cytotoxic action after being converted to rhizoxin within the cells by a lysosomal enzyme such as cholesterol esterase.Abbreviations DMSO Dimethylsulfoxide - PBS(-) Ca²⁺ Mg²⁺-free phosphate-buffered saline - HCO60 hydrogenated castor oil polyethylene glycor ether - DMA dimethylacetamide - RSB reticulocyte standard buffer, consisting of 10mM NaCl, 1.5 mM MgCl₂, and 10 mM TRIS-HCl, (pH 7.4) - TLC thin-layer chromatography - ara-C 1--D-arabinofuranosylcytosine - LDL low-density lipoprotein     

Tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) stimulate osteoclastic bone resorption

As both tissue inhibitor of metalloproteinases-1 (TIMP-1) and TIMP-2 have been reported to inhibit bone resorption, we examined whether TIMP-1 or TIMP-2 in fetal calf serum (FCS), with which culture media were supplemented, affected osteoclastic bone resorption in vitro. Contrary to our expectation, almost complete suppression of osteoclastic bone resorption was observed when both TIMP-1 and TIMP-2 were removed from the FCS. Bone resorption was, however, almost fully restored by the addition of recombinant TIMPs. TIMPs stimulate bone resorption at significantly lower concentrations (∼ng/ml) than those (∼μg/ml) required to inhibit bone resorption. To understand the mechanism of TIMP-dependent bone resorption, we counted and compared the number of tartrate-resistant acid phosphatase-(TRAP-) positive and multinuclear cells in cultures containing either 10% FCS or TIMP-1-free and/or TIMP-2-free FCS. There was essentially no difference in number among these, suggesting that the TIMP role seems to be related to the functional expression of osteoclasts. Metallo-proteinase inhibitors, either BE16627B[l-N-(N-hydroxy-2-isobutylsuccinynamoyl)-seryl-l-valine] or R94138 {N-methyl-(3S)-2-[(2R)-2-hydroxycarbamoylmethylundecanoyl] hexahydropyridazine-3-carboxamide}, could not replace TIMPs, suggesting that the osteoclast-stimulating activity of TIMPs cannot be ascribed to merely their inhibitory effect on matrix metalloproteinases. Received: Oct. 15, 1998 / Accepted: April 5, 1999     

L-cis diltiazem attenuates intracellular Ca(2+) overload by metabolic inhibition in guinea pig myocytes

We have previously demonstrated that treatment with L-cis diltiazem reduced cardiac infarct size in vivo. To examine the effect of L-cis diltiazem on Ca(2+) overload induced by ischemia/reperfusion, we used a model for Ca(2+) overload produced by metabolic inhibition in isolated guinea pig myocytes. Intracellular Ca(2+) concentration ([Ca(2+)](i)) was quantified by fura-2 fluorescence microscopy and Ca(2+) overload was induced by inclusion of 1 microM of carbonyl cyanide m-chrolophenylhydrazone (CCCP) for 40 min treatment followed by washout for 30 min. This treatment caused a large [Ca(2+)](i) elevation as well as a sustained contracture of the cardiomyocytes. The increase was suppressed by 10 microM of 2-[2-[4-(4-nitrobenzyloxy) phenyl] ethyl] isothiourea methanesulphonate (KB-R7943), a specific inhibitor of the Na(+)/Ca(2+) exchanger, but not by nitrendipine (10 microM). L-cis Diltiazem (10 microM) attenuated the [Ca(2+)](i) increase, suggesting that L-cis diltiazem elicits a cardioprotective effect via attenuation of the [Ca(2+)](i) increase induced by metabolic inhibition and energy repletion.