Kazutoshi Matsunami

Enhancement of Growth-Promoting Activity in Extract from Uterine Cancers by Protein Kinase C in Human Endometrial Fibroblasts

Uterine cervical and corpus cancers have been reported to synthesize and secrete a putative peptide mitogen, which elicits a potent proliferative response in fibroblasts by a mechanism independent of phosphoinositide turnover. The extract from human uterine cervical cancer stimulated [3H]thymidine incorporation into human endometrial fibroblasts in a dose-dependent manner. Concomitant exposure of the fibroblasts to thrombin or fibroblast growth factor (FGF) led to synergistic enhancement of the extract-stimulated [3H]thymidine incorporation into fibroblasts. An apparent maximal activity of the extract in the presence of thrombin or FGF was 2-fold higher than that in the absence of them, implying that thrombin or FGF acted at a stage after the interaction of the mitogen in the extract with its specific receptor. Insulin or epidermal growth factor failed to augment the growth-promoting activity in the extract. The stimulatory action of thrombin or FGF was mimicked by protein kinase C activators, phorbol-12-myristate-13-acetate (PMA) or 1-oleoyl-2-acetyl glycerol, but not by Ca2+ ionophore A23187. When the fibroblasts were first exposed to the extract for 4 h and then to PMA, PMA succeeded to augment the mitogenic activity in the same manner. The identical effects of protein kinase C activators with thrombin or FGF suggested that both types of ligand share a similar signaling cascade of action, activation of protein kinase C. These results demonstrated that the growth-promoting activity in uterine cancer extract could be enhanced by the agents which promote phosphoinositide metabolism through activation of protein kinase C. These findings could give a new insight into pathophysiology of the interaction between malignant cells and their stromal cells, fibroblasts.

New generation nonhormonal management for hot flashes

Hot flashes are very common in women in menopause and can have a detrimental effect on quality of life. Hormone therapy (estrogen with or without progestin) remains the gold standard treatment for hot flashes, but concerns for the risk of hormone therapy have resulted in its decline and a demand for nonhormonal treatments with demonstrated efficacy for hot flashes. Several nonhormonal therapies have been tested in randomized placebo-controlled trials including nonpharmacologic approaches and pharmacologic nonhormonal agents. Among them, two classes of nonhormonal medications have been demonstrated to effectively alleviate hot flashes: γ-aminobutyric acid (GABA) analogs and selective serotonin reuptake inhibitors (SSRIs). This article discusses the superior efficacy of the newer nonhormonal prescriptions for the treatment of hot flashes when compared with estrogen replacement therapy, and provides some recommendations regarding use of them in peri- and postmenopausal women.

Prolactin binds to human endometrial fibroblasts and inhibits mitogenicity of an endometrial carcinoma extract.

Abstract Uterine endometrial carcinoma has been reported to synthesize and secrete a putative peptide mitogen that elicits a potent proliferative response in endometrial fibroblasts. The extract from endometrial carcinoma stimulated [3H]thymidine incorporation into human endometrial fibroblasts in a dose-dependent manner. Concomitant exposure of the fibroblasts to prolactin (PRL) led to a remarkable inhibition of the extract-stimulated mitogenic activity of the fibroblasts. This inhibition was dependent on PRL dose, and maximal effect occurred at 1 μM of PRL. PRL (10 nM) suppressed an apparent maximal activity of the extract by 50%, and the half-maximal stimulated effect of the extract on thymidine incorporation was observed at the same concentration in the absence or presence of PRL. This noncompetitive manner may imply that PRL acts at a stage after the interaction of the mitogen in the extract with the specific receptor for mitogen. When the fibroblasts were first exposed to the extract for 12 hr and then to PRL, PRL suppressed the mitogenic activity with no lag. The rapid growth-inhibitory effect of PRL was mimicked by prostaglandin E1, but the combination of both types of ligand was not additive in the inhibitory action on growth. PRLand prostaglandin E1 may inhibit a similar mitogenic signaling cascade. Specific receptor sites for PRL were detected in the endometrial fibroblasts, showing high binding affinity (Kd =16.1 nM) and low binding capacity (Bmax = 1.59 pmol/mg protein). Treatment of the fibroblasts with the endometrial carcinoma extract induced no changes in the level of PRLreceptor, excluding the possibility that PRL competes for the binding sites with the mitogen. These findings would suggest that PRL may block the mitogenic activity of the fibroblasts stimulated by the endometrial carcinoma-derived mitogen via a PRL receptor-mediated mechanism, perhaps prostaglandin production.

Inhibitory action of estradiol on growth promoting activity in extract from uterine cancers

Extracts from uterine cervical and body cancers, but not from benign tumor or intact tissues tested, were found to contain a growth-promoting activity which induced the proliferation of human endometrial fibroblasts. Exposure of cultured fibroblasts to the cancer extracts increased the rate of [3H]thymidine incorporation in a dose-dependent manner. The activity was heat-labile, and not inactivated by removal of lipid-soluble material suggesting that the activity is associated with a protein. When the fibroblasts were preincubated with estradiol for 12 hours, but not for 1 hour, the extract-induced fibroblast proliferation was suppressed. The inhibitory effect of estradiol was dose related (EC50: 10 nM) and non-competitive, suggesting that the steroid may reduce the sensitivity of fibroblasts to the extracts. This is the first report to provide direct evidence that estradiol may play an inhibitory role in the action of growth factor-like peptide produced from malignant tumors.

Ovarian function following targeted anti-angiogenic therapy with bevacizumab (Review)

Improvements in cancer therapy have enabled further insight into the long-term effects of treatment, including the highly prevalent gonadal failure. The focus of treatment has been shifted to the preservation of fertility, which may be achieved by preventing ovarian toxicity. To this end, new molecular-targeted agents, including monoclonal antibodies, have been developed and used in a standard procedure for managing different cancers. However, the prolonged antitumor activity of these drugs may cause the emergence of new toxic effects. The aim of the present review was to discuss the leading toxic effect of the anti-angiogenic agent bevacizumab on ovarian function in female patients of reproductive age, which may be observed and expected during in clinical practice. The majority of bevacizumab-induced side effects are expected to be transient and eliminated within the anticipated drug clearance time frame; however, fundamental investigations on these effects are required for generating more evidence-based practice guidelines.

Spontaneous Perforation of Pyometra Presenting as Acute Abdomen and Pneumoperitoneum Mimicking Those of Gastrointestinal Origin

Gastrointestinal (GI) perforation accounts for over 90% of acute abdomen and pneumoperitoneum. The presence of pneumoperitoneum secondary to spontaneously perforated pyometra is an interesting yet confusing finding given the absence of gastrointestinal (GI) perforation, because pyometra is more common in postmenopausal women. We report an instructive case of diffuse peritonitis caused by spontaneous perforation of pyometra. A 70-year-old postmenopausal female was admitted to surgical emergency with signs of diffuse peritonitis. After resuscitation, an emergency laparotomy was performed because of suspicion of GI perforation. At laparotomy, about 2,000 mL of purulent fluid was found to be present in peritoneal cavity, while GI tract was intact. A rent with a diameter of 5 mm was found on anterior fundus of uterus. A total abdominal hysterectomy with a bilateral salpingo-oophorectomy was performed. Despite intensive care and a course of antibiotics, the patient died of multiple organ failure resulting from sepsis on postoperative day 16. Our case illustrates the importance of clinical knowledge of acute gynecological diseases, which are not uncommonly encountered by the general surgeon. Moreover, good appreciation of pelvic anatomy and close collaboration with gynecology and GI surgery colleagues is essential as operative intervention is often required.

Malignant neoplasia arising from ovarian remnants following bilateral salpingo‑oophorectomy (Review)

Ovarian remnant syndrome (ORS) is a rare, but well-known gynecological complication, most often induced by difficult bilateral salpingo-oophorectomy (BSO) procedures that leave residual ovarian tissue on the pelvic wall. The most common preexisting conditions for this complication include endometriosis, pelvic inflammatory disease and prior abdominal surgery. The residual ovarian tissue may eventually cause malignant development. A total of 12 cases of malignant and benign tumors (clear cell adenocarcinoma in 1 case, mucinous-type tumors in 2, endometrioid-type tumors in 5, adenocarcinoma in 3 and border serous neoplasia in 1) and 21 benign cysts developing from an ovarian remnant have been described in the literature to date. Endometriosis, known to increase the risk of ovarian cancer, predisposes patients to ORS, with an incidence rate of 30 to 50% in ORS patients with ovarian carcinoma. Although the true incidence of ORS remains unknown, when endometriotic adhesions are diagnosed during BSO, the possibility of ORS and subsequent ovarian malignant transformation may mandate complete surgical resection.

Sequential Management with Gonadotropin-Releasing Hormone Agonist and Dienogest of Endometriosis-Associated Uterine Myoma and Adenomyosis

Uterine leiomyoma and adenomyosis represent the most common benign tumors of the female reproductive system (Levy, 2008; Parker, 2007; Sankaran & Manyonda, 2008). These tumors are estrogen dependent, develop during the reproductive period, and are suppressed with menopause. Traditional treatments for myomas and adenomyosis have been various types of surgical techniques. Medical management of these tumors is an approach that has been used recently and is attractive for many gynecologists because of its relative ease and lack of complications (pelvic organ adhesion) compared with surgery. Indications for therapy are similar to those for surgical removal of these tumors and focus on preserving fertility and/or the patient’s desire to maintain her uterus. Medications used include androgens, antiprogestogens (mifepristone), raloxifen, and gonadotropin-releasing hormone agonist (GnRHa) (Levy, 2008; Parker, 2007; Sankaran & Manyonda, 2008; Schweppe, 1999). At present, considering efficiency and safety issues, none of the above agents obtained adequate popularity except for GnRHa. However, GnRHa also have disadvantages including bone loss and menopausal symptoms. The effect of GnRHa is transient and reversal of estrogen deprivation occurs soon after discontinuation of the GnRHa and most myoma and adenomyosis returns to their initial size within several months after discontinuation.

Preoperative value of CT angiography in the laparoscopic removal of rudimentary uterine horn

Computed tomography (CT) angiography, a minimally invasive technique for vascular imaging, has been shown to be an excellent tool for imaging the pelvic arteries and their branches. This report describes the accuracy of CT angiography in the preoperative evaluation of the blood supply for laparoscopic dissection of rudimentary horn. The rudimentary horn was successfully removed laparoscopically with minimal blood loss.

Abdominal Dermolipectomy at Laparotomy with HugeOvarian Benign Tumor

Obesity is a common health problem and defined as a body mass index (BMI) of 30 kg/m2 or greater; morbid obesity is defined as a BMI 40 kg/m2 or greater. Apart from the limited securing an operative view, obesity has a significantly higher risk of postoperative deep vein thrombosis, surgical site infections, nerve injury, and urinary infection [1,2]. Abdominoplasty and dermolipectomy are originally a form of cosmetic surgery used to make the abdomen tighter and defined as a surgical procedure in which excess skin and fat in the abdominal area is removed [3,4]. We present one patient of severe obesity with large amounts of redundant skin and fat extending to lower abdomen, in whom an abdominal dermolipectomy was performed at the time of laparotomy against giant ovarian tumor. (Figure 1).