BACKGROUND Because low grade serous carcinoma of the ovary is relatively chemo resistant disease, this study evaluated Selumetinib (AZD6244), an inhibitor of mitogen-activated protein kinase kinase (MEK-1/2), and explored associations between RAS, and RAF family mutations with clinical outcome. METHODS Women with recurrent low-grade serous ovarian or peritoneal carcinoma were eligible and received Selumetinib at 100 mg. orally b.i.d. until progression or toxicity were enrolled in Gynecologic Oncology protocol 239(NCT00551070). This trial has been completed and we are reporting the results. The primary endpoint of this trial was to examine tumor response rate to Selumetinib. The study used all-treated patients to determine response rate and overall survival. FINDINGS Fifty-two patients were enrolled over two years. Eight patients (15.4%) had complete (1) or partial (7) responses, and 34 (65%) had stable disease. There were no treatment-related deaths. There were three observed grade 4 toxicities and 46 grade 3 toxicities that occurred in more than one patient. Observed grade 4 toxicities were cardiac (1), pain (1), and pulmonary (1). Grade 3 toxicities that occurred included gastrointestinal (13), dermatologic (9), and metabolic (7). CONCLUSIONS Selumetinib is well tolerated, and is active in the treatment of recurrent low-grade serous carcinoma. In exploratory analyses, response to Selumetinib did not appear to be related to RAS/RAF mutational status. The 63% disease control is encouraging and worthy of further evaluation of MEK inhibitors in this population. This study was supported by National Cancer Institute grants to the Gynecologic Oncology Group.
Matrix metalloproteinases are a highly regulated family of enzymes, that together can degrade most components of the extracellular matrix. These proteins are active in normal and pathological processes involving tissue remodeling; however, their sites of synthesis and specific roles are poorly understood. Using in situ hybridization, we determined cellular distributions of matrix metalloproteinases and tissue inhibitor of metalloproteinase-1, an inhibitor of matrix metalloproteinases, in endometrium during the reproductive cycle. The mRNAs for all the metalloproteinases were detected in menstrual endometrium, but with different tissue distributions. The mRNA for matrilysin was localized to epithelium, while the others were detected in stromal cells. Only the transcripts for the 72-kD gelatinase and tissue inhibitor of metalloproteinases-1 were detected throughout the cycle. Transcripts for stromelysin-2 and the 92-kD gelatinase were only detected in late secretory and menstrual endometrium, while those for matrilysin, the 72-kD gelatinase, and stromelysin-3 were also consistently detected in proliferative endometrium. These data indicate that matrix metalloproteinases are expressed in cell-type, tissue, and reproductive cycle-specific patterns, consistent with regulation by steroid hormones, and with specific roles in the complex tissue growth and remodeling processes occurring in the endometrium during the reproductive cycle. (J. Clin. Invest. 1994.94:946-953.) Key words: in situ hybridization * reproductive cycle * matrilysin -stromelysin -RNA
The metalloproteinase matrilysin is widely expressed in the epithelial tumor cells of malignant colorectal adenocarcinomas. Approximately 50% of benign adenomas also express low levels of matrilysin that is focally localized. The expression of stromelysin-1, stromelysin-3, and gelatinase A was observed in the stromal component of several carcinomas and was not present in adenomatous tissue. The expression of interstitial collagenase and gelatinase B was observed in occasional adenomas and carcinomas. Stromelysin-2 transcripts were not detectable in any of the samples examined. Tissue inhibitor of metalloproteinase-1 gene expression was widespread and was observed in both epithelial and stromal cells of adenomas and carcinomas. These results indicate that matrilysin gene expression is an early event in colorectal tumorigenesis and that the expression of stromelysin-1, stromelysin-3, and gelatinase A is primarily a late event. The observed gene expression patterns suggest that matrilysin may participate in early events in tumor progression and that multiple members of the metalloproteinase family may work in concert to facilitate late-stage tumor invasion and metastasis.
The hallmark of the menstrual cycle is extensive steroid-dependent tissue turnover. Estrogen mediates endometrial cell growth and structural remodeling, whereas progeserone suppresses estrogen-dependent proliferation and promotes cellular differentiation. In nonfertile cycles, tissue degradation and menstruation occur as a consequence of steroidal deprivation as the ovarian corpus luteum fails. Stromalepithelial interactions are recognized as a necesary component in mediating steroid-induced endometrial turnover. Specific mRNAs for metalloproteinases of the stromelysin family are expressed during endometrial growth and menstrual breakdown but are absent in the progestin-dominated secretory phase. This expression pattern suggss involvement of stromelysins in remodeling the extracellular matrix of the endometrium during tissue growth and breakdown and implicates progesteronE in the suppression of these enzymes. We examined the regulation of endometrial stromelysins in explant cultures and found no acute effect ofestradiol on their expression, whereas progesterone was a potent inhibitor of stromelysin expression. Progesterone also suppressed stromelysin expression in cultures ofisolated stromal cells, but epithelial cells were progesterone insensitive. Coculture ofrecombined stromal and epithelial cells restored steroidal suppression of the epithelial-specific metalloproteinase. Our data confirm that progesterone inhibits endometrial stromelysins and further demonstrate the necessity for a stromalderived factor(s) as a mediator of steroid suppression of an epithelial metalloproteinase.The human endometrium undergoes extensive estradiolinduced growth and remodeling during the proliferative phase of the menstrual cycle, followed by secretory maturation in response to postovulatory progesterone (1). This rapid and extensive degree of steroid-mediated tissue development, which rivals that of many neoplasias, appears to be a necessary component of providing an environment suitable for sustaining hemochorial placentation (2). In the absence of implantation and the continued progestational environment of pregnancy, the superficial functionalis region of the endometrium undergoes degradation and is expelled with menstrual blood flow. Several laboratories have recently described the expression of matrix metalloproteinases (MMPs) in the normal, cycling human endometrium (3-6). These enzymes degrade many components of the extracellular matrix, including proteoglycans, glycoproteins, and basement membrane collagens (7). Our studies (5, 6) identified a cell type-specific expression pattern of mRNAs coding for members of the stromelysin family only during the proliferative and premenstrual/menstrual stage of the cycle; none of the enzymes were identified during the progesterone-dominated secretory menstrual interval. This pattern of expression suggests an active role for stromelysins during growth-associated structural remodeling as well as during the extensive tissue breakdown associated with menstruation.MMPs of the st...
Context. -: Myeloid sarcoma (MS) is a neoplasm of immature granulocytes, monocytes, or both involving any extramedullary site. The correct diagnosis of MS is important for adequate therapy, which is often delayed because of a high misdiagnosis rate.Objective. -: To evaluate the lineage differentiation of neoplastic cells in MS by immunohistochemistry, and to correlate the results with clinicopathologic findings and cytogenetic studies.Design. -: Histologic and immunohistochemical examinations were performed on formalin-fixed paraffin-embedded tissue samples from 13 cases of MS. They were classified according to the World Health Organization criteria. Chromosomal analysis data were available in 11 cases. Clinical, pathological, and cytogenetic findings were analyzed.Results. -: The study included six male and seven female patients with an age range of 25 to 72 years (mean, 49.3 years) and a male to female ratio of 1:1.2. MS de novo occurred in 4/13 (31%) of cases examined. The most sensitive immunohistochemical markers were CD43 and lysozyme present in all cases with MS (13/13, 100%). All de novo MS showed a normal karyotype, monoblastic differentiation, and lack of CD34. The most common chromosomal abnormalities in MS associated with a hematopoietic disorder were trisomy 8 and inv(16) (2/11, 18%). Conclusion. -:An immunohistochemical panel including CD43, lysozyme, myeloperoxidase (MPO), CD68 (or CD163), CD117, CD3 and CD20 can successfully identify the vast majority of MS variants in formalin-fixed paraffin-embedded tissue sections. The present report expands the spectrum of our knowledge showing that de novo MS has frequent monoblastic differentiation and frequently carries a normal karyotype.
Unlike most normal adult tissues, cyclic growth and tissue remodeling occur within the uterine endometrium throughout the reproductive years. The matrix metalloproteinases (MMPs), a family of structurally related enzymes that degrade specific components ofthe extracellular matrix are thought to be the physiologically relevant mediators of extracellular matrix composition and turnover. Our laboratory has identified MMPs of the stromelysin family in the cycling human endometrium, implicating these enzymes in mediating the extensive remodeling that occurs in this tissue. While the stromelysins are expressed in vivo during proliferation-associated remodeling and menstruation-associated endometrial breakdown, none of the stromelysins are expressed during the progesterone-dominated secretory phase of the cycle. Our in vitro studies of isolated cell types have confirmed progesterone suppression of stromal MMPs, but a stromalderived paracrine factor was found necessary for suppression of the epithelial-specific MMP matrilysin. In this report, we demonstrate that transforming growth factor (3 (TGF-13) is produced by endometrial stroma in response to progesterone and can suppress expression of epithelial matrilysin independent of progesterone. Additionally, we find that an antibody directed against the mammalian isoforms of TGF-P abolishes progesterone suppression of matrilysin in stromal-epithelial cocultures, implicating TGF-j8 as the principal mediator of matrilysin suppression in the human endometrium.
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