Inchworm sign of endometrial cancer on diffusion-weighted MRI: radiology-pathology correlation.

AIM: To perform radiology-pathology correlation of the inchworm sign on diffusion-weighted imaging (DWI) in patients with endometrial cancer. MATERIALS AND METHODS: Consecutive patients (345) with histopathologically proven endometrial cancer who underwent preoperative magnetic resonance imaging (MRI), including DWI images, and hysterectomy were included in the present study. The inchworm sign was defined as a hypointense stalk between hyperintense endometrial cancer and hypointense myometrium on DWI images. A genitourinary pathologist reviewed the resected specimen at the site of the inchworm sign. RESULTS: The inchworm sign on DWI images was observed in 32 (9.3%) patients. On T2-weighted images, areas of hypointense stalk on DWI images showed hypointensity in 31 (97%) patients and hyperintensity in one (3%). Among them, the depth of myometrial invasion at histopathology was superficial (<50% myometrial invasion) in 28 (87.5%) patients and deep (≥50% myometrial invasion) in four (12.5%). As a result of histopathological investigation, the hypointense stalk of the inchworm sign was mainly composed of various degrees of stromal proliferation, including smooth muscle cells and metaplastic fibromuscular stroma, with or without intervening endometrial cancer. CONCLUSION: The inchworm sign of endometrial cancer on DWI images usually indicated superficial myometrial invasion and was caused by a stalk composed of stromal proliferation with or without intervening endometrial cancer.

Cancer stem-like cells of ovarian clear cell carcinoma are enriched in the ALDH-high population associated with an accelerated scavenging system in reactive oxygen species.

OBJECTIVE: In ovarian cancer cases, recurrence after chemotherapy is frequently observed, suggesting the involvement of ovarian cancer stem-like cells (CSCs). The chemoresistance of ovarian clear cell carcinomas is particularly strong in comparison to other epithelial ovarian cancer subtypes. We investigated the relationship between a CSC marker, aldehyde dehydrogenase 1 (ALDH1), and clinical prognosis using ovarian clear cell carcinoma tissue samples. Furthermore, we investigated the antioxidant mechanism by which CSCs maintain a lower reactive oxygen species (ROS) level, which provides protection from chemotherapeutic agents. METHODS: Immunohistochemical staining was performed to examine the CSC markers (CD133, CD44, ALDH1) using ovarian clear cell carcinoma tissue samples (n=81). Clear cell carcinoma cell lines (KOC-7C, OVTOKO) are separated into the ALDH-high and ALDH-low populations by ALDEFLUOR assay and fluorescence-activated cell sorting (FACS). We compared the intracellular ROS level, mRNA level of the antioxidant enzymes and Nrf2 expression of the two populations. RESULTS: High ALDH1 expression levels are related to advanced stage in clear cell carcinoma cases. ALDH1 expression significantly reduced progression free survival. Other markers are not related to clinical stage and prognosis. ALDH-high cells contained a lower ROS level than ALDH-low cells. Antioxidant enzymes were upregulated in ALDH-high cells. ALDH-high cells showed increased expression of Nrf2, a key transcriptional factor of the antioxidant system. CONCLUSIONS: ALDH-positive CSCs might have increased Nrf2-induced antioxidant scavengers, which lower ROS level relevant to chemoresistance in ovarian clear cell carcinoma.

Leiomyoma and rhabdomyoma of the vagina . Vaginal myoma.

Vaginal fibromyomas (leiomyomas and rhabdomyomas) are rare; approximately 300 cases have been reported in the literature. They usually present as a mass per vaginum or dyspareunia or pressure symptoms on the urinary tract. However, they sometimes have an unusual presentation that is largely responsible for the relative difficulty in preoperative diagnosis. Preoperative imaging and careful examination may help to rule out malignancy. Recurrence occurs infrequently but the practical approach entails immediate careful excision. Surgical excision through the vaginal route has been the traditional approach, but abdominoperineal route may be necessary for huge tumours.

Chemotherapy-induced female infertility and protective action of gonadotropin-releasing hormone analogues.

This review aimed to critically discuss the current protocols using gonadotropin-releasing hormone analogue (GnRHa) for the management of chemotherapy-induced premature ovarian failure. In in-vitro experiments, GnRHa retards doxorubicin-induced granulosa cell damage, suggesting an additional GnRH's activity to protect the gonads during chemotherapy through GnRH receptor-mediated mechanism(s). GnRHa acts to protect the gonads during radiation and/or chemotherapy by preferentially steering cells into cell cycle arrest with a decline in response to the chemotherapeutic agents. The ovarian protection by GnRHa co-treatment against chemotherapy can enable the preservation of future fertility in survivors and prevent the bone demineralisation and osteoporosis associated with hypooestrogenism and ovarian failure.

Gi protein-mediated translocation of serine/threonine phosphatase to the plasma membrane and apoptosis of ovarian cancer cell in response to gonadotropin-releasing hormone antagonist cetrorelix.

Serine/threonine protein phosphatase 2A (PP2A), a crucial enzyme in apoptosis control, has been demonstrated within the plasma membrane as well as in the soluble fraction. This study aimed to examine hormonal translocation of PP2A to the plasma membrane in gonadotropin-releasing hormone (GnRH)-responsive ovarian cancer cells. Apoptosis of ovarian cancer cell lines Caov-3 and SK-Ov-3 was quantified by nuclear morphology after staining with Hoechst 33342 dye. PP2A protein and activity in plasma membrane were assessed by immunohistochemical staining with PP2A-specific antibodies and by the measurement of the dephosphorylation of phosphopeptide highly selective for the PP2A, respectively. Incubation for 48 h with a GnRH antagonist cetrorelix caused parallel increases in the percentage of cells undergoing apoptosis and the membrane-associated PP2A activity; half-maximal effects occurred with 5 nmol/l cetrorelix. PP2A protein was also localised to the plasma membrane when the cell lines were exposed to cetrorelix. Pretreatment of the cells with pertussis toxin, but not cholera toxin, completely inhibited cetrorelix-stimulated apoptotic cell death and PP2A redistribution. These findings demonstrate that translocation of PP2A to plasma membrane is closely coupled to the onset of apoptosis in ovarian cancer cells exposed to GnRH antagonist. These GnRH-induced cellular events may be mediated through pertussis toxin-sensitive Gi protein-linked GnRH receptor.

Gonadotrophin-releasing hormones agonist therapy increases peritoneal fibrinolytic activity and prevents adhesion formation after myomectomy.

The aim of this study was to evaluate uterine adhesions after myomectomy and peritoneal fibrinolytic capacity in women treated with gonadotrophin-releasing hormone agonist (GnRHa) before surgery. A prospective observational study comprised 15 infertile women who underwent myomectomy. Before surgery, 10 were treated with buserelin acetate (900 microg/day) for 10-12 weeks followed by additional postoperative treatment with GnRHa for 4 weeks (GnRHa group) and five received no treatment (control group). Peritoneal fluid specimens were taken at the beginning of myomectomy and the adhesions were estimated by second-look surgery (caesarean section or laparoscopy). Levels of plasminogen activator (PA) and PA inhibitor (PAI) were determined by enzyme-immunosorbent assays. Pre- and postoperative GnRHa therapy significantly reduced adhesion formation compared with control groups (adhesion scores; 0.2 +/- 0.4 vs. 2 +/- 1, P<0.0001). GnRHa group showed a significant decrease in PAI level (P<0.0001) but no significant change in PA level, suggesting increased fibrinolytic capacity in peritoneal fluid from GnRHa-treated patients. These data suggest that GnRHa therapy is successful in preventing adhesion formation after myomectomy. GnRHa-induced shift to more fibrinolytic activity, mainly because of a decreased level of PAI, may play a critical role in the mechanism of the GnRHa's action on postoperative adhesion development.

Treatment of perimenopausal women with uterine myoma: successful use of a depot GnRH agonist leading to a natural menopause.

Gonadotrophin-releasing hormone agonists (GnRHa) reduce the size of uterine fibroids and relieve patients of myoma-related symptoms. However, rapid regrowth frequently occurs after the therapy is stopped. We attempted to determine whether GnRHa therapy could lead perimenopausal women carrying symptomatic myomas to the natural onset of the menopause. A retrospective analysis of 145 patients who received GnRHa for 24 weeks demonstrated that after cessation of therapy no menstruation occurred over 25 weeks in women aged over 45 years, with elevated levels of follicle-stimulating hormone (FSH) and luteinising hormone (LH) > 25 mIU/ml. To extend this study, we studied prospectively 21 women, aged 45 years and older who had regular menstruation with symptoms attributed to myomas and elevated days 3 - 5 FSH and days 3 - 5 LH levels ( > 25 mIU/ml). After discontinuation of GnRHa (leuprorelin acetate, 1.88 mg) therapy for 6 months, menstruation occurred in only two of 21 individuals but the remaining 19 cases had no menstrual bleeding. It is suggested from this study that the rise in early follicular phase serum gonadotrophins, in particular FSH > 25 mIU/ml, may precede the natural menopause following (or during) GnRHa therapy in older women. Measuring days 3 - 5 serum FSH concentrations may make it easier to decide on the optimal duration of therapy for symptomatic uterine fibroids in perimenopausal women aged > 45 years.

Magnetic resonance imaging in the evaluating of double uterus and associated urinary tract anomalies: a report of five cases.

Uterine anomalies are associated with unilateral renal aplasia. We present the MR features of five cases with 'double' uteri. The anomalies consisted of four cases of uterus didelphys and one of a complete septate uterus. All the cases with uterus didelphys also had a longitudinal vaginal septum. The MR diagnoses were confirmed with hysterosalpingography and with laparoscopy. In one case of didelphic uterus, MR images predicted the (three-dimensional helical) computer tomography (CT)-pyelographic diagnosis of renal aplasia in which the single kidney was normal. The study shows that MR is a valuable tool for the diagnosis of not only uterine anomalies but also associated anomalies in other systems.

Gynecologic tumors and symptoms in childhood and adolescence.

Although tumors are rarely seen in girls, they should be considered in differential diagnosis because of the high incidence of potential malignancy in genital tumors compared with adults. Ultrasonography can quickly evaluate the underlying cause of genital symptoms or signs and allow timely intervention, while magnetic resonance imaging accurately measures the extent and location of the vaginal lesion. As a result of modern progress in the chemotherapy regimens, the prompt and precise detection of either benign or malignant tumors can lead to both cure and preservation of fertility with conservative surgery whenever possible. With the widespread use of obstetrical ultrasonography, fetal abdominal tumors are being diagnosed with increasing frequency. Most of these tumors will undergo spontaneous resolution within the first few months of life.

Comparative genomic hybridization analysis of genetic aberrations associated with development and progression of biliary tract carcinomas.

BACKGROUND: Little is known about genetic aberrations associated with development and progression of biliary tract carcinomas. METHODS: To study chromosomal aberrations associated with development and progression of biliary tract carcinomas, the authors used comparative genomic hybridization to examine 50 such carcinomas. RESULTS: Gains in part or in whole of chromosomes 1q, 8q, and 20q and losses of 5q, 8p, 9p, and 18q were detected frequently in early stage (T1/T2 classification) biliary tract carcinomas (> or = 40% of 19 early stage tumors), and they also were found in advanced stage (T3/T4 classification) tumors. In particular, loss of 9p was the most frequently observed aberration in both early stage (15 of 19; 78%) and advanced stage tumors (21 of 31; 68%). The frequencies of gains of 7p12-p14 (P < 0.003), 7p21-pter (P < 0.007), and 7q31 (P < 0.01) differed significantly between biliary tract carcinoma with and without distant metastasis. Also, gains of 5p and 19q13 and loss of 6q14-q16 were more frequent in tumors with lymph node metastasis than in those without it (P < 0.02). CONCLUSIONS: It is likely that loss of 9p is one of the genetic aberrations critical for the development of biliary tract carcinoma, whereas gains of 5p, 7p, 7q, and 19q and loss of 6q are considered later events associated with tumor progression and are thought to confer metastatic potential to biliary tract carcinomas.

Lysophosphatidic acid prevents apoptosis in fibroblasts via G(i)-protein-mediated activation of mitogen-activated protein kinase.

Lysophosphatidic acid (LPA) is a naturally occurring phospholipid with multiple biological functions. In the present study, we demonstrate that, besides its mitogenic activity, LPA is a potent survival factor, preventing serum-deprivation-induced apoptosis in fibroblasts and other cell types. Both the proliferative effect and survival activity of LPA are sensitive to the action of pertussis toxin (PTX), indicating that both processes are mediated by G(i) protein(s). We therefore focused on the role of G(i)-protein-mediated signalling events in the promotion of cell survival by LPA. In addition to activation of mitogen-activated protein kinase (MAPK), LPA stimulates a modest PTX-sensitive phosphorylation/activation of the serine/threonine kinase Akt, a survival mediator downstream of phosphoinositide 3-kinase (PI3K). Inhibition of PI3K with LY 294002 or wortmannin resulted in a marked inhibition of LPA-induced DNA synthesis, and yet the survival activity of LPA decreased by only 20-30%, suggesting a limited input of the PI3K-Akt cascade in LPA-induced cell survival. In contrast, inhibition of MAPK activation by the MEK-1 inhibitor, PD 98059, blocked both the proliferative and survival effects of LPA. These results indicate that LPA promotes cell survival largely via G(i)-protein-mediated activation of ERK1/ERK2, or other PD 98059-sensitive member(s) of the MAPK family.

Calcium concentration and artificial precipitates in human pancreatic juice.

We studied the role of the increase in the calcium concentration in pure pancreatic juice of alcoholic noncalcified chronic pancreatitis. Pure pancreatic juice was obtained endoscopically. The pancreatic juice from patients with chronic pancreatitis was adjusted to pH 7.5; then the calcium concentration was adjusted to 0.4, 2.9, 5.4, or 10.4 mmol/L. Artificial precipitates were produced by incubation of the samples at 37 degrees C for 6 hours. Proteins in the artificial precipitates were separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), and the protein patterns were compared with the patterns of natural protein plugs from patients with chronic pancreatitis. The amount of the precipitate increased as the added calcium increased. The protein patterns of SDS-PAGE of the artificial precipitates were similar to those of protein plugs. Albumin, a-amylase, lipase, trypsinogen, and chymotrypsinogen were identified by immunoblotting both in the precipitate and in the protein plug. The increased calcium concentrations in pancreatic juice induced the formation of precipitates whose protein composition was similar to that of protein plugs. An increased calcium concentration in human pancreatic juice may play an important role in the pathogenesis of protein plugs.

Sarcomatous transformation of a prolactinoma associated with development of a fatal internal carotid artery pseudoaneurysm--case report.

A 21-year-old female with a 5-year history of prolactinoma was referred to our hospital because of cerebrospinal fluid leakage and meningitis immediately following a third transsphenoidal operation for a rapidly growing tumor. Histological examination of the tumor removed at the second transsphenoidal operation found atypical epithelial and sarcomatous components. Administration of bromocriptine, radiotherapy, and chemotherapy were initiated. Emergent craniotomy was required for rapid regrowth of the tumor. Histological examination found predominant sarcomatous components. Tumor growth was difficult to control. The patient died of subarachnoid hemorrhage due to rupture of a pseudoaneurysm involving the C1 portion of the right internal carotid artery. Pituitary adenoma rarely shows malignant transformation. In this case, prolactinoma underwent malignant change to sarcoma. Development of the pseudoaneurysm may have resulted from surgical manipulation, radiotherapy, or tumor invasion.

A gonadotropin-releasing hormone-responsive phosphatase hydrolyses lysophosphatidic acid within the plasma membrane of ovarian cancer cells.

Lysophosphatidic acid (LPA) mediates pleomorphic effects on multiple cell lineages, including an increased proliferative response of ovarian cancer cells both in vitro and in vivo, at least in part through the novel expression of LPA receptors. Thus, LPA hydrolysis is necessary to limit the duration of LPA's action on multiple cell types, including ovarian cancer cells. We determined the principal mechanism of LPA hydrolysis by ovarian cancer cells and its regulation by GnRH, which is known to have antiproliferative actions on ovarian carcinomas. LPA-hydrolyzing activity in cell membranes of ovarian cancer specimens was assessed by measuring the conversion of exogenous [3H-oleoyl]LPA to [3H]oleic acid or mono[3H-oleoyl]glycerol. Approximately 98% of LPA hydrolysis could be accounted for by the dephosphorylation of LPA to yield monoglyceride, with the deacylation reaction accounting for less than 1% of LPA hydrolysis. The phosphatase activity in the plasma membrane ovarian cancer cells was approximately 2.5- and 8-fold higher than those in microsome and homogenate fractions, respectively. The membrane phosphatase was Mg2+ independent and insensitive to inhibition by N-ethylmaleimide, characteristics suggestive of phosphatidic acid phosphatase activity. Incubation of membranes from GnRH receptor-positive ovarian cancer specimens with the GnRH agonist, buserelin, induced a dose-dependent increase in LPA phosphatase activity, with a half-maximal effect occurring with 30 nmol/L buserelin. The stimulatory action of buserelin could be neutralized by displacement of GnRH from its receptor by the GnRH antagonist, antide. The plasma membranes from GnRH receptor-negative ovarian cancer specimens did not respond to GnRH stimulation. LPA phosphatase activity was also increased when the ovarian cancer cell line Caov-3 was exposed to GnRH agonist in intact cells before assay of cell membranes. These data demonstrate that LPA is hydrolyzed in the plasma membrane of ovarian cancer cells by the action of LPA phosphatase and provide initial evidence for functional coupling of LPA phosphatase to GnRH receptor occupancy.