Should children ever donate kidneys? Views of U.S. transplant centers

The retinoblastoma (RB) gene was the first defined tumor suppressor gene. While originally described in retinoblastoma, more recently alterations in RB have been described in a number of other human neoplasms and there has been a suggestion that alteration of RB may play a significant role in the development of endometrial carcinoma. We examined RB protein expression by immunohistochemistry in a series of cases including normal endometrium, endometrial hyperplasia, and endometrial carcinoma. A relatively homogeneous pattern of staining was observed in proliferative endometrium, while weak or absent reactivity was noted in secretory endometrium. A heterogeneous pattern of reactivity was observed in 10/10 cases of hyperplasia, 66/70 cases of endometrial adenocarcinoma, and 7/7 cases of uterine carcinosarcoma. An altered pattern of reactivity was observed in the remaining 4/70 cases of adenocarcinoma. All of the cases with altered reactivity were high grade neoplasms. We conclude that alteration of RB protein expression is uncommon in endometrial adenocarcinoma and when it does occur, it may represent a late event in carcinogenesis.     

Effect of fire on understory birds of a gallery forest in central Brazil

We developed a new quantitative method for detecting abnormal glycolipid expression in endometrial cells using a monoclonal antibody (MSN-1) and analyzed the glycolipid antigen recognized by MSN-1 in 173 clinical endometrial cell samples (66 normal endometria, 39 endometrial hyperplasias, and 68 endometrial adenocarcinomas). The mean glycolipid antigen levels in normal endometrium, endometrial hyperplasia, and endometrial carcinoma were 0.42 +/- 1.37, 2.13 +/- 3.84, and 19.4 +/- 25.8 (mean +/- SD) units, respectively. If the cutoff rate of this assay was fixed at 1.8 units, the positivity rates for patients with normal endometrium, endometrial hyperplasia, and endometrial carcinoma were 6.1% (4/66), 28.2% (11/39), and 76.5% (52/68), respectively. In 35 endometrial carcinoma patients, endometrial smears were simultaneously performed, and there were 22 positive smears (62.9%). When the cytological diagnosis was combined with our assay, 94.3% (33/35) of the carcinomas were detected. Thus, this assay seems to be a supplementary diagnostic method for endometrial carcinoma.     

Fatty acid synthase expression in endometrial carcinoma: correlation with cell proliferation and hormone receptors

BACKGROUND: Fatty acid synthase (FAS), a biosynthetic enzyme, normally functions in the liver to convert dietary carbohydrate to fat, but it is minimally expressed in most other normal adult tissues. FAS is expressed at markedly elevated levels in subsets of human breast, ovarian, and prostate carcinomas that are associated with poor prognoses. During the menstrual cycle, the expression of FAS in the human endometrium is closely linked to the expression of the proliferation antigen Ki-67, estrogen receptor (ER), and progesterone receptor (PR). METHODS: This study reports the expression patterns of these antigens in 35 endometrial carcinomas as determined by immunohistochemical analysis. RESULTS: All cases demonstrated a close direct correlation between FAS and Ki-67 expression. Average FAS expression levels were correlated with tumor grade. Twenty-five carcinomas that were positive for ER and PR showed close correlation in expression of FAS, Ki-67, and hormone receptors. Individual tumors displayed varying degrees of heterogeneity of expression. A few well-differentiated carcinomas showed very low expression of all four antigens, similar to the antigenic profile of secretory endometrium. Nine high grade carcinomas that were negative for ER and PR also showed close correlation in expression of FAS and Ki-67 with uniformly high expression. CONCLUSIONS: These data suggest the following hypothesis: In hormone-dependent endometrial cells, FAS expression is part of the estrogen-driven cellular response that leads to proliferation; however, its linkage to proliferation is such that FAS expression is maintained in proliferating cells in endometrial carcinomas that acquire hormone independence. The use of these four antibodies as a panel may increase the diagnostic utility of ER and PR immunohistochemistry for tumor classification and prediction of the responsiveness of tumors to hormonal therapy.     

Impedance of a goat eye lens

Cyclins are essential proteins in cell cycle control, and their deranged expression has been reported to be associated with malignant transformation. Involvement of cyclins in the development of endometrioid carcinomas of the endometrium was studied immunohistochemically using antibodies against both cyclin A and tumor suppressor gene product p53, and their expression was compared with that of Ki-67 antigen. Sixty-two cases of endometrial endometrioid carcinoma and 20 cases of normal endometrium (10 proliferative and 10 secretory phase) were examined. Of the 62 endometrioid carcinomas, atrophic endometrium and hyperplasia were found adjacent to the cancers in 30 and 19 cases respectively. Cyclin A was expressed in < 1% of the glandular cells of normal endometrium in the proliferative phase and in hyperplasia, but was negligible in normal secretory phase and atrophic endometrium. p53 was almost always negative in normal endometrium and hyperplasia. Of the 62 endometrioid carcinomas, 12 tumors (19.4%) overexpressed cyclin A and 21 tumors (33.8%) overexpressed p53 (positive cells > 1%). Cyclin A and p53 were more frequently expressed in poorly differentiated tumors than in well differentiated tumors (cyclin A, p = 0.002; p53, p = 0.016). In addition, cyclin A-positive cells were topographically related to those cells positive for p53 as well as Ki-67. In conclusion, the abnormal expression of cyclin A and p53 is associated with high-grade endometrial endometrioid carcinomas.     

Tumor necrosis factor-alpha mRNA and protein in endometrial tumors: analysis by in situ hybridization and immunocytochemistry

Abnormal expression of polypeptide growth factors and their receptors is closely associated with tumorigenic transformation. In this study tumor necrosis factor-alpha (TNF-alpha) mRNA and protein were analyzed in polyps and proliferative lesions of endometrium as well as in low and high grade endometrial tumors by using in situ hybridization and immunocytochemistry. All samples contained products of the TNF-alpha gene. Histochemical scores (HS), which reflect the proportion of cells positive for TNF-alpha message or protein and the intensities of the signals, were higher for epithelial than for stromal cells. Benign lesions (endometrial polyps) contained little TNF-alpha mRNA or protein, whereas specific message was abundant in proliferative lesions (hyperplasia, adenofibroma). Although neoplastic cells in both low and high grade endometrial tumors contained TNF-alpha mRNA, two major differences were observed: HS for TNF-alpha mRNA were significantly less in low grade than in high grade neoplasms, and TNF-alpha message was restricted to the nucleus in low grade adenocarcinoma cells but was abundant in the cytoplasm of high grade tumor cells. In contrast to cells in benign and proliferative lesions, TNF-alpha protein scores in endometrial tumor cells were inversely rather than positively correlated with TNF-alpha mRNA scores. Collectively, the findings in this study are consistent with the postulate that TNF-alpha is useful to endometrial tumor cells and suggest that production may increase as cells diverge from normal.     

Altered gamma-catenin expression correlates with poor survival in patients with bladder cancer

PURPOSE: We studied the expression of alpha-, beta-, gamma- catenin and E-cadherin in transitional cell carcinoma (TCC) and normal bladder epithelium and correlated these results with pathological and clinical parameters. MATERIALS AND METHODS: We used an avidin-biotin immunoperoxidase technique to examine the cellular localization of alpha-catenin, beta-catenin, gamma-catenin and E-cadherin in 68 TCC and 14 normal bladder biopsies. RESULTS: E-cadherin, alpha-catenin, beta-catenin and gamma-catenin were expressed in a normal membranous pattern in all normal bladder epithelium specimens. Loss of normal surface E-cadherin, alpha-catenin, beta-catenin and gamma-catenin expression was found in 52/68 (76.4%) tumors, 57/68 (83.8%) tumors, 54/68 (79.4%) tumors and 54/68 (79.4%) tumors (p <0.001). There was a significant correlation between the loss of normal membranous expression of catenins and E-cadherin and increased grade (p <0.05). A highly significant correlation was observed between the loss of expression of E-cadherin, alpha-catenin and gamma-catenin, but not beta-catenin, with increased TNM stage (p <0.05). The abnormal expression of gamma-catenin as well as E-cadherin was correlated with poor survival (p <0.05). CONCLUSIONS: E-cadherin-gamma-catenin complex may be a useful prognostic marker in bladder cancer. Work is in progress to establish whether normal membranous catenin expression can be enhanced by gene transfer or biological therapy to induce a less invasive and metastatic phenotype.     

Sex-role reversal and the absence of extra-pair fertilization in Wilson''s phalaropes

Human endometrial leukocytes undergo regular cyclical changes during the menstrual cycle, with a striking increase in the phenotypically unusual population of CD56+ CD16- endometrial granulated lymphocytes (eGLs) in the late secretory phase and early pregnancy. The factors that regulate this increase in eGL numbers are unclear; their unusual morphology, however, has led to the suggestion that they undergo apoptosis at the end of the menstrual cycle. Apoptosis, bcl-2 expression, and proliferative activity were examined in the stroma of normal cycling, progesterone-treated, and early-pregnancy endometrium. The expression of bcl-2 and the Ki67 proliferation marker by highly purified (> 98% CD56+) eGLs from endometrium during the menstrual cycle and from first-trimester decidua was also studied. Apoptotic cells were rarely observed in the endometrial stroma of any of the samples examined. Stromal bcl-2 expression, however, increased from the proliferative to the premenstrual phase, and double immunohistochemical labeling demonstrated large numbers of bcl-2+ CD56+ eGLs. In contrast, Ki67 expression was high in the endometrial stroma during the proliferative phase, fell during the secretory phase, and rose again premenstrually, because of expression by eGLs. Isolated CD56+ eGLs also showed high bcl-2 and Ki67 expression at the end of the menstrual cycle. Unlike premenstrual endometrium, progesterone-treated endometrium and first-trimester decidua contained few proliferating cells, expressed high levels of bcl-2, and showed no evidence of apoptosis. Thus, eGLs do not undergo apoptosis in premenstrual endometrium, and their regulatory mechanisms remain to be clarified.     

Expression of the 67-kD laminin receptor, galectin-1, and galectin-3 in advanced human uterine adenocarcinoma

Alterations of tumor cell interactions with laminin, a basement membrane glycoprotein, are consistent features of the invasive and metastatic phenotype. Qualitative and quantitative changes in the expression of cell surface laminin-binding proteins have been correlated with the ability of cancer cells to cross basement membranes during the metastatic cascade. Such phenotypic modifications are usually associated with poor prognosis. In this study, the authors examined the possibility that expression of three laminin-binding proteins, the 67-kD laminin receptor (67LR), galectin-1, and galectin-3, is altered in human endometrial cancer in a fashion similar to that reported in other carcinomas, such as breast, colon, and ovarian cancer. Twenty advanced uterine adenocarcinomas were analyzed for expression of these three molecules using immunoperoxidase staining and specific antibodies. The authors found a significant increase in the expression of the 67LR and galectin-1 in cancer cells compared with normal adjacent endometrium (P = .0004 and .0022, respectively). As observed in other carcinomas, a significant down-regulation of galectin-3 expression was found in endometrial cancer cells compared with normal mucosa (P = .02). In the galectin-3 positive tumors, galectin-3 was detected in the cytoplasm and/or nucleus of cancer cells. Interestingly, tumors in which galectin-3 was detected only in the cytoplasm were characterized by deeper invasion of the myometrium than lesions where galectin-3 was found both in nucleus and cytoplasm (P = .02). This study shows an alteration of nonintegrin laminin-binding protein expression in advanced human endometrial cancer. Further studies on larger populations should determine the prognostic value of the detection of these laminin-binding proteins in endometrial carcinoma. Inverse modulation of the 67LR and galectin-3 appears to be a phenotypical feature of invasive carcinoma.     

Explant test with skin and peritoneum of the neonatal rat as a predictive test of tolerance of local anti-infective agents in wounds and body cavities

Müllerian inhibiting substance (MIS), alpha-inhibin, and CD99 are expressed by normal and neoplastic sex cord and stromal gonadal derivatives. The expression of MIS, inhibin, and CD99 was evaluated by immunohistochemistry in a series of 19 sex cord-stromal tumors and seven ovarian endometrioid carcinomas resembling sex cord-stromal tumors. Normal ovaries and testes from patients with the androgen insensitivity syndrome were used as control. All three markers were detected in primordial ovarian follicles and immature seminiferous tubules. Both inhibin and MIS were expressed by all sex cord-stromal tumors, but inhibin immunostaining appeared stronger and more diffusely distributed. CD99 was expressed by all adult and juvenile granulosa cell tumors, but only focally by Sertoli-Leydig cell tumors. In Sertoli-Leydig cell tumors, the three markers were predominantly expressed by the Sertoli cells. None of the seven endometrioid carcinomas with a sex cord-stromal pattern was positive for MIS or inhibin; two of them reacted for CD99, but their staining patterns were not membranous. Inhibin immunoreactivity was also detected in foci of stromal luteinization, occasionally present in these tumors. MIS, inhibin, and CD99 are potentially useful markers in the differential diagnosis between sex cord-stromal tumors and endometrioid carcinomas resembling sex cord-stromal tumors.     

Managing hypertensive urgencies in primary care

The c-kit gene product (CD117) is known to be expressed by a variety of normal human tissue cell types, including breast epithelium, germ cells, melanocytes, immature myeloid cells, and mast cells. To further characterize the expression of this antigen, 117 normal human tissues and 576 human tumors were studied by paraffin section immunohistochemistry. Varying degrees of CD117 expression were identified in various normal cells and in 53% of all tumors studied. In most cases (42% of total), CD117 expression was weak. Expression was most common in mast cell disease (100%), testicular germ cell tumors (100%), endometrial carcinomas (100%), papillary and follicular thyroid carcinomas (100%), small cell carcinomas (91%), malignant melanomas (90%), and ovarian epithelial carcinomas (87%). Strong immunoreactivity was only identified in cases of mast cell disease (11 of 11 cases), serous ovarian carcinoma (3 of 16), malignant melanoma (2 of 40), small cell lung carcinoma (one of seven), and adenoid cystic carcinoma (one of one). Although the pattern of reactivity was primarily cytoplasmic, a membrane staining pattern was seen in a subset of cases, and strong membrane staining was identified in normal mast cells and all cases of mast cell disease. The lack of tumor specificity of weak expression of this antigen limits its diagnostic utility in most cases. However, the strong membrane reactivity for CD117 identified in mast cells may be useful in the diagnosis of mast cell disorders.     

Correlation of very late activation integrin and CD44 expression with extrarenal invasion and metastasis of renal cell carcinomas

Cell adhesion molecules mediate cell-cell and cell-matrix interactions, and they are thought to play an important role in tumor invasion and metastasis. Altered expression of integrins and CD44 in renal cell carcinoma has been recently demonstrated, but an association with invasive or metastatic behavior has not been reported. We examined very late activation (VLA) integrin and CD44 expression in 37 renal cell carcinomas and correlated adhesion molecule expression with multiple histological and clinical parameters. Most tumors exhibited positive staining for VLA3 (81%). Approximately one third of the tumors stained positively for VLA6 and CD44, and fewer (27%) were positive for VLA2. Only a few tumors were positive for VLA4 (8%) and VLA5 (14%). Most of the tumors exhibiting positive staining showed a combination of membranous and cytoplasmic staining patterns. Low-grade tumors positive for VLA6 showed a tendency for basilar staining of the tumor cells, whereas high-grade tumors exhibited diffuse cytoplasmic staining. All tumors exhibiting weak or strong positive staining for VLA4 or VLA5 showed extrarenal invasion or were known to have developed metastases at the time of nephrectomy. All tumors strongly positive for VLA2 or CD44 showed invasion beyond the renal capsule or metastases. In contrast to a previous study, no association was observed between positive staining and tumor grade. Nor were tumor size, architectural pattern, cell type, or DNA ploidy found to be associated with particular staining patterns. Although many of the invasive tumors showed no difference in VLA integrin or CD44 expression compared with tumors confined to the kidney, increased expression in some of them suggests that these cell adhesion molecules may contribute to the invasive or metastatic phenotype.     

Insulin-like growth factor-I expression in normal and diseased endometrium

While the role of steroid hormones in the regulation of endometrial proliferation and differentiation is well established, the effects of growth factors and their receptors in normal and neoplastic endometrium remain a matter of debate. Previous studies have documented the positive effects of insulin-like growth factor-I (IGF-I) on epithelial cell proliferation and the active production of this growth factor in endometrial tissues. In view of decreased expression of transforming growth factor-beta1 (TGF-beta1), an antagonist of IGF-I, in endometrial carcinoma, we investigated the expression of IGF-I, at both the mRNA and protein levels, and the immunoreactivity for type I IGF-I receptor in 30 formalin-fixed, paraffin-embedded tissue samples of normal and neoplastic endometrium, in order to possibly clarify the role of IGF-I in endometrial proliferation and differentiation. Our results demonstrate a reduced expression of IGF-I mRNA in endometrial carcinomas compared with non-neoplastic tissues, despite equivalent immunohistochemical expression of IGF-I and IGF-I receptor. Our data suggest that IGF-I and its corresponding receptor may not be directly involved in endometrial cancer cell proliferation and differentiation in vivo, though other components of the IGF-I system (e.g., IGF binding proteins) may affect endometrial malignant transformation and tumor progression.     

Amplification and expression of c-erbB2 oncogene in normal, hyperplastic, and malignant endometria

OBJECTIVE: To study the correlation of development and survival with amplification of c-erbB2 oncogene in endometrial carcinoma. METHODS: The amplification and expression of c-erbB2 oncogene were determined from formalin-fixed, paraffin-embedded tissues of 25 normal, 31 hyperplastic, and 72 malignant samples of the endometrium in 128 patients, using differential polymerase chain reaction (DPCR) and an immunohistochemical technique. RESULTS: Amplified c-erbB2 (2 to 12 copies) were found in two of 25 (8.0%) normal, 15 of 31 (48.4%) hyperplastic, and 45 of 72 (62.5%) malignant samples. When the results of DPCR were compared with those of the immunohistochemical method, the negative findings concide well with one another, i.e., nonamplification was associated with the absence of immunoreactivity. It was noted that the amplified c-erbB2 was found more significantly in complex and a typical hyperplasias than in simple hyperplasias. The high-level c-erbB2 amplification (at least five copies) was significantly correlated with the histological grade of endometrial carcinoma and vascular or lymphatic invasion. No correlation was seen between c-erbB2 amplification and overall survival in the present group of patients. CONCLUSIONS: The amplified c-erbB2 may play a potential role in the early development of some endometrial carcinomas. The high-level c-erbB2 amplification may identify a subset of aggressive endometrial carcinoma that involves vascular or lymphatic invasiveness and poor cell differentiation playing the role of a marker for clinical prognosis.     

Overexpression of the 67-kD laminin receptor correlates with tumour progression in human colorectal carcinoma

The high affinity 67-kD laminin receptor (67LR) is a cell surface protein whose expression is increased in a number of human carcinoma models. To date, 67LR expression in colorectal carcinomas has been examined in a small number of cases. 67LR expression has been immunohistochemically analysed in a large series of human colorectal neoplasms, using the MLuC5 monoclonal antibody. The study included 59 samples of non-neoplastic mucosa, 45 polyps (11 hyperplastic, 34 adenomas), 196 carcinomas, and lymph node metastases of 87 carcinomas. Epithelial cells of normal mucosa and hyperplastic polyps were negative or showed weak positivity in the paranuclear and apical areas of the cytoplasm. In adenomas and carcinomas, the staining was stronger, with a membranous or cytoplasmic pattern. The expression of 67LR correlated significantly with the progression from normal mucosa (22 per cent) to adenoma (44 per cent), carcinoma (61 per cent), and lymph node metastasis (75 per cent) (P < 0.0001). Expression of the laminin receptor showed a tendency to be more frequently positive in advanced stage (III+IV; 67 (III+IV; 67 per cent) when compared with early stage (I+II) carcinomas (54 per cent). The difference, however, was not statistically significant (P = 0.058). In addition, 14 out of 28 (50 per cent) primary carcinomas without 67LR expression became positive in lymph node metastases, while most (86 per cent) of the MLuC5-positive primary carcinomas were also immunoreactive in metastases. In conclusion, these results indicate that 67LR is up-regulated in the progression of human colorectal carcinomas and may play a role in the local and metastatic progression of these tumours.     

Pseudoaldosteronism induced by administration of a massive dose of glycyrrhizin]

Formalin-fixed tissues from 100 endometria and 50 brains were grouped and studied by the technic of mixed-cell agglutination reaction (MCAR) for studying isoantigens A, B, and H (O). MCAR's were negative in all 45 of the endometria from subjects with endometrial carcinomas, where as MCAR's were positive in the epithelium of endometrial glands of the remaining 55 subjects (cyclic phases of endometrium and benign lesions). MCAR's were negative in all benign and malignant brain tumors and normal brain tissues used in this study. In view of the present findings and in the light of previous observations, the isonatigen loss in adenocarcinomas is greater than such losses in other types of malignancies so far studied. The cause of the negative MCAR's in normal brain tissue and brain tumours is not known, but they may be attributable to lack of isoantigens in normal brain tissue.     

Expression of the plasminogen activation system in kidney cancer correlates with its aggressive phenotype

Malignant tumors contrast with benign ones in their ability to invade adjacent tissue and to metastasize. The urokinase plasminogen activator is a proteolytic enzyme that can facilitate these processes. In many carcinomas, the concentration of the urokinase plasminogen activator system is high. The high expression of these enzymes is related to tumor grade. In this study, we have investigated whether secretion of the urokinase plasminogen activator, urokinase plasminogen activator receptor, and plasminogen activator inhibitor 1 in normal kidney tissue and kidney cancer tissue follows this pattern. We have found that urokinase plasminogen activator, urokinase plasminogen activator receptor, and plasminogen activator inhibitor 1 were expressed in higher levels in kidney cancers (squamous cell carcinoma and renal cell carcinoma) than in normal kidney tissue and that these differences were statistically significant (P < or = 0.05). In renal cell carcinomas, we have observed differences between normal kidney tissue and renal cell carcinomas in males and Caucasians but not in females and African Americans (P < or = 0.05). Expression of the urokinase plasminogen activator system was also higher in grade III tumors when compared with lower-grade tumors or normal tissue.     

Effects of troglitazone and metformin on glucose and lipid metabolism: alterations of two distinct molecular pathways

Using an experimental model of rat colon adenocarcinoma, we have recently shown that the presence of H blood-group antigen on variants of the CD44 adhesion molecule carrying amino acids encoded by exon v6 (CD44v6), increased the cells' tumorigenicity. In the present study, colon adenocarcinomas were induced by 1,2-dimethylhydrazine treatment in rats. Using immunohistochemistry, biopsies of normal, precancerous and carcinomatous colon mucosa were evaluated for expression A and H blood group antigens and CD44s and CD44v6 antigens. Normal rat colon showed strong and homogeneous expression of blood-group antigen A, but weak expression of H antigen. Several weeks before the appearance of tumours, dysplastic glands were strongly stained with anti-H reagents, while their A antigen was lost. Expression of CD44v6 was weak and restricted to some cells at the bottom of normal crypts. No obvious change was observed before appearance of severe dysplasia. In carcinomas, a strong but irregular expression of A, H and CD44v6 antigens was observed. In moderately differentiated carcinomas, A and H antigens were present at the apical surface of cells, whereas CD44v6 was found at the basolateral side. Only carcinomatous cells with loss of polarity, found in poorly differentiated cancers or infiltrated in the muscularis mucosae, were found to coexpress blood-group H or A and CD44v6 antigens at their surface.