NSF after Gadovist exposure: a case report and hypothesis of NSF development.

So far no cases of nephrogenic systemic fibrosis (NSF) have been published on macrocyclical gadolinium-based contrast media (Gd-CM), assumed as low NSF risk CM due to their complex stability. In our haemodialysis-dependent patient, the first symptoms indicating NSF appeared about 16 months after the exposure to Gadovist, a macrocyclical Gd-CM, and 1 month after x-ray angiography with iodinated CM (Ultravist). This indicates that in addition to excretory renal failure and Gd-CM exposure, the loss of biosynthetic renal function could be essential for NSF development. A hypothesis of possible pathways involved in the development of NSF is presented.

Immunohistochemical evidence of ubiquitous distribution of the metalloendoprotease insulin-degrading enzyme (IDE; insulysin) in human non-malignant tissues and tumor cell lines.

Immunohistochemical evidence of ubiquitous distribution of the metalloprotease insulin-degrading enzyme (IDE; insulysin) in human non-malignant tissues and tumor cells is presented. Immunohistochemical staining was performed on a multi-organ tissue microarray (pancreas, lung, kidney, central/peripheral nervous system, liver, breast, placenta, myocardium, striated muscle, bone marrow, thymus, and spleen) and on a cell microarray of 31 tumor cell lines of different origin, as well as trophoblast cells and normal blood lymphocytes and granulocytes. IDE protein was expressed in all the tissues assessed and all the tumor cell lines except for Raji and HL-60. Trophoblast cells and granulocytes, but not normal lymphocytes, were also IDE-positive.

Expression of metalloprotease insulin-degrading enzyme insulysin in normal and malignant human tissues.

Insulin-degrading enzyme (IDE, insulysin, insulinase; EC 3.4.22.11), a thiol metalloendopeptidase, is involved in intracellular degradation of insulin, thereby inhibiting its translocation and accumulation to the nucleus. Recently, protein expression of IDE has been demonstrated in the epithelial ducts of normal breast and breast cancer tissue. Utilizing four different antibodies generated against different epitopes of the IDE molecule, we performed Western blot analysis and immunohistochemical staining on several normal human tissues, on a plethora of tumor cell lines of different tissue origin, and on malignant breast and ovarian tissue. Applying the four IDE-directed antibodies, we demonstrated IDE expression at the protein level, by means of immunoblotting and immunocytochemistry, in each of the tumor cell lines analyzed. Insulin-degrading enzyme protein expression was found in normal tissues of the kidney, liver, lung, brain, breast and skeletal muscle, as well as in breast and ovarian cancer tissues. Immunohistochemical visualization of IDE indicated cytoplasmic localization of IDE in each of the cell lines and tissues assessed. In conclusion, we performed for the first time a wide-ranging survey on IDE protein expression in normal and malignant tissues and cells thus extending our knowledge on the cellular and tissue distribution of IDE, an enzyme which to date has mainly been studied in connection with Alzheimer's disease and diabetes but not in cancer.

Progestin and breast cancer. The missing pieces of a puzzle.

The previous assumption that progestin does not promote breast cancer development needs to be re-examined since a growing body of evidence indicates the opposite. Data from recent experimental trials and results from clinical and epidemiological studies on hormonal contraceptives and hormone replacement therapy (HRT) have been confronted with breast cancer cases known from the German database of adverse drug reactions (ADR), reported in association with the use of progestin only contraceptives (POC) and combined oral contraceptives (COC). Also cases reported in association with HRT have been analysed. The available data complement one another showing a tumour promoting potential of progestin, possibly higher than that of a combination of estrogen and progestin. These assumptions are based on the following facts: 1) in estrogen-supplemented animals, progesterone has been shown to reactivate the growth of regressed tumour xenograft obtained from breast cancer cell lines, expressing both estrogen and progesterone receptor; 2) antiprogestin has been revealed to suppress the reactivation of the growth of tumour xenograft and to fully suppress the development of breast cancer in an animal model for BRCA1 gene mutation; 3) metabolites of progesterone have been recognised as potent regulators of cell proliferation, cell detachment and apoptosis; 4) progesterone has been shown to inhibit, in a dose-dependent manner, apoptosis in breast cancer cell lines and apoptosis induced by doxorubicin and 5-fluorouracyl (drugs used in breast cancer treatment); 5) an association between breast cancer and HRT was suspected upon the addition of progestin on a regular basis for the prevention of endometrial cancer; 6) in a randomised placebo-controlled trial on HRT an increased risk of breast cancer was shown for the combination of estrogen and progestin, but not for estrogen alone; 7) in epidemiological studies on POC the recognition of an increased breast cancer risk was most probably impeded due to previously unrecognised systematic selection bias; 8) in a large epidemiological study on the risk of early-onset breast cancer in association with COC an increased risk was detected for COC use up to 1975, but no increased, even a slightly decreased, risk was shown for users of low-dose COC, applied since 1976; 9) a considerably higher number of breast cancer cases have been reported from Germany on POC than on the widespread used COC [corrected] (111 versus 12); 10) the big resemblance among the breast cancers reported for POC and their similarity with breast malignancies diagnosed in pregnancy suggest the existence of a pattern rather than pure coincidence [corrected]

Immunohistochemical demonstration of the zinc metalloprotease insulin-degrading enzyme in normal and malignant human breast: correlation with tissue insulin levels.

Insulin is a hormone crucial to metabolism and an essential growth factor for normal and neoplastic tissues. We have now determined insulin in extracts of 23 primary breast cancer specimens and of non-neoplastic breast tissues by a chemiluminescent immunoassay. Remarkably, insulin was measured only in grade 3 tumors, whereas grade 2 carcinomas and the normal mammary gland were each insulin-negative. We also performed immunohistochemistry for insulin-degrading enzyme (IDE), a cytoplasmic zinc metalloprotease belonging to the inverzincin family and participating in insulin cleavage. IDE was detected in most insulin-positive grade 3 carcinomas, indicating that it might be dysfunctional in these anaplastic tumors. IDE was equally present in the insulin-negative grade 2 carcinomas. Moreover, five grade 3 carcinomas and one grade 2 carcinoma displayed a loss of heterozygosity in the 10q chromosomal region harboring the IDE gene, but, despite these alterations, IDE was detected immunohistochemically, indicating a retention of the second allele. Compared to the expression of IDE in 92% of the tumors examined, only 57% of 21 normal breast specimens stained positively for IDE. In contrast to this increase in IDE-positive epithelial cells in breast cancer vs. normal breast, additional immunohistochemical analysis of 17 node-positive breast carcinomas and corresponding tumor-bearing lymph nodes showed that IDE expression decreases from primary tumor to lymph node metastasis. Altogether, this study represents the first demonstration of IDE in normal and neoplastic human mammary tissues. Our present report should also provide an experimental starting point towards exploring a potential role of IDE in the control of tumor progression.