New treatment strategies for uterine sarcoma using secreted frizzled­related proteins.

Secreted frizzled-related proteins (SFRPs) are involved in the development of various types of cancer and function by suppressing the Wnt signaling pathway. To elucidate the clinical implications of SFRPs in uterine sarcoma, SFRP expression levels and their effects on uterine leiomyosarcoma cells were examined. Immunostaining for SFRP4 was performed on uterine smooth muscle, uterine fibroid and uterine leiomyosarcoma tissues. Additionally, the effects of SFRP4 administration on cell viability, migration and adhesion were evaluated in uterine leiomyosarcoma SKN cells using the WST-1 assay (Roche Diagnostics) and the CytoSelect™ 24-well Cell Migration Assay Kit and the CytoSelect™ 48-well Cell Adhesion Assay Kit. The expression levels of SFRP4 in uterine leiomyosarcoma tissues were lower than those in normal smooth muscle and uterine fibroid tissues. In addition, SFRP4 suppressed the viability and migration, and increased the adhesion ability of uterine leiomyosarcoma cells compared with in the control group. In conclusion, SFRP4 may suppress the viability and migration, and enhance the adhesion of sarcoma cells. These results suggested that SFRP4 could be considered as a novel therapeutic target for uterine sarcoma.

Age-Dependent Changes in the Effects of Androgens on Female Metabolic and Body Weight Regulation Systems in Humans and Laboratory Animals.

In recent years, the effects of androgens on metabolic and body weight regulation systems and their underlying mechanisms have been gradually revealed in females. In women and experimental animals of reproductive age, androgen excess can adversely affect metabolic functioning, appetite, and body weight regulation. In addition, excess androgens can increase the risk of metabolic disorders, such as obesity, insulin resistance, and diabetes. These unfavorable effects of androgens are induced by alterations in the actions of hypothalamic appetite-regulatory factors, reductions in energy expenditure, insulin resistance in skeletal muscle, and ß-cell dysfunction. Interestingly, these unfavorable effects of androgens on metabolic and body-weight regulation systems are neither observed nor evident in ovariectomized animals and post-menopausal women, indicating that the adverse effects of androgens might be dependent on the estrogen milieu. Recent findings may provide novel sex- and age-specific strategies for treating metabolic diseases.

Changes in Serum Oxytocin Levels under Physiological and Supraphysiological Gonadal Steroid Hormone Conditions in Women of Reproductive Age: A Preliminary Study.

Oxytocin (OT) affects many behavioral, psychological, and physiological functions, including appetite and body weight regulation. Central and peripheral OT levels are markedly affected by gonadal steroids, especially estrogen, and the anorectic effects of estrogen are partially mediated by OT in rodents. In this study, the relationship between the estrogen milieu and serum OT levels was evaluated in women of reproductive age under physiological (n = 9) and supraphysiological estrogenic conditions (n = 7). Consequently, it was found that serum OT levels were increased in physiological (the ovulatory phase) and supraphysiological (on the day of the human chorionic gonadotropin trigger in an ovarian stimulation cycle) estrogenic conditions, and that serum OT levels were positively correlated with serum estradiol levels. On the other hand, serum OT levels were negatively correlated with serum progesterone levels, and there was no correlation between serum and follicular OT levels. These results suggest that OT levels may be positively and negatively regulated by estrogen and progesterone, respectively, in humans. However, the physiological roles of these actions of gonadal steroids on OT remain unclear.

Effect of intraperitoneal docetaxel on ovarian function in mice.

Taxanes are important chemotherapeutic agents used to manage breast cancer and gynaecological malignancies. However, ovarian toxicity induced by the taxane docetaxel (DOC) is of great concern. We investigated DOC-induced toxicity in the ovaries of female CD1 strain mice. The mice were divided into control (saline), DOC-5 (5 mg/kg DOC), and DOC-10 (10 mg/kg DOC) groups and administered saline or DOC on the first day of the study and two weeks later. Two weeks after the second dose, the ovaries were removed for analysis after inducing superovulation. Ovary weight, the number of secondary follicles, and the total number of follicles were reduced after DOC administration. Additionally, the expression levels of caspase-3 and the pro-apoptotic protein Bcl-2 interacting mediator of cell death (BIM) increased. Our findings suggest that high-dose DOC induces damage to growing follicles; however, it may not affect primordial follicles.Impact statementWhat is already known on this subject? Docetaxel (DOC) is one of the most effective chemotherapeutic agents used to manage various cancers. Some in-vitro studies have examined paclitaxel-induced ovarian toxicity; however, limited research on DOC is available.What do the results of this study add? We investigated DOC-induced ovarian toxicity in female CD1 strain mice at 5 mg/kg and 10 mg/kg. We found that DOC reduced ovary weight, the number of secondary follicles, and the total number of follicles, with the higher dose having a higher effect.What are the implications of these findings for clinical practice and/or further research? We believe that our study makes a significant contribution to the knowledge about the effect of DOC on ovarian function.

Effects of undernutrition and low energy availability on reproductive functions and their underlying neuroendocrine mechanisms.

It has been well established that undernutrition and low energy availability disturb female reproductive functions in humans and many animal species. These reproductive dysfunctions are mainly caused by alterations of some hypothalamic factors, and consequent reduction of gonadotrophin-releasing hormone (GnRH) secretion. Evidence from literature suggests that increased activity of orexigenic factors and decreased activity of anorexigenic/satiety-related factors in undernourished conditions attenuate GnRH secretion in an integrated manner. Likewise, the activity of kisspeptin neurons, which is a potent stimulator of GnRH, is also reduced in undernourished conditions. In addition, it has been suggested that gonadotrophin-inhibitory hormone, which has anti-GnRH and gonadotrophic effects, may be involved in reproductive dysfunctions under several kinds of stress conditions. It should be remembered that these alterations, i.e., promotion of feeding behavior and temporary suppression of reproductive functions, are induced to prioritize the survival of individual over that of species, and that improvements in metabolic and nutritional conditions should be considered with the highest priority.

Changes in Endogenous Oxytocin Levels and the Effects of Exogenous Oxytocin Administration on Body Weight Changes and Food Intake in Polycystic Ovary Syndrome Model Rats.

Polycystic ovary syndrome (PCOS) is frequently seen in females of reproductive age and is associated with metabolic disorders that are exacerbated by obesity. Although body weight reduction programs via diet and lifestyle changes are recommended for modifying reproductive and metabolic phenotypes, the drop-out rate is high. Thus, an efficacious, safe, and continuable treatment method is needed. Recent studies have shown that oxytocin (OT) reduces body weight gain and food intake, and promotes lipolysis in some mammals, including humans (especially obese individuals), without any adverse effects. In the present study, we evaluated the changes in endogenous OT levels, and the effects of acute and chronic OT administration on body weight changes, food intake, and fat mass using novel dihydrotestosterone-induced PCOS model rats. We found that the serum OT level was lower in PCOS model rats than in control rats, whereas the hypothalamic OT mRNA expression level did not differ between them. Acute intraperitoneal administration of OT during the dark phase reduced the body weight gain and food intake in PCOS model rats, but these effects were not observed in control rats. In contrast, chronic administration of OT decreased the food intake in both the PCOS model rats and control rats. These findings indicate that OT may be a candidate medicine that is efficacious, safe, and continuable for treating obese PCOS patients.

Neuroendocrine mechanisms of reproductive dysfunctions in undernourished condition.

It is well known that undernourished conditions disturb female reproductive functions in many species, including humans. These alterations are mainly caused by a reduction in gonadotrophin-releasing hormone (GnRH) secretion from the hypothalamus. Evidence from the literature suggests that some hypothalamic factors play pivotal roles in the coordination of reproductive functions and energy homeostasis in response to environmental cues and internal nutritional status. Generally, anorexigenic/satiety-related factors, such as leptin, alpha-melanocyte-stimulating hormone, and proopiomelanocortin, promote GnRH secretion, whereas orexigenic factors, such as neuropeptide Y, agouti-related protein, orexin, and ghrelin, attenuate GnRH secretion. Conversely, gonadotrophin-inhibitory hormone, which exerts anti-GnRH and gonadotrophic effects, promotes feeding behavior in many species. In addition, the activity of kisspeptin, which is a potent stimulator of GnRH, is reduced by undernourished conditions. Under normal nutritional conditions, these factors are coordinated to maintain both feeding behavior and reproductive functions. However, in undernourished conditions their activity levels are markedly altered to promote feeding behavior and temporarily suppress reproductive functions, in order to prioritize the survival of the individual over that of the species.

A novel PCOS rat model and an evaluation of its reproductive, metabolic, and behavioral phenotypes.

BACKGROUND: Although animal models of PCOS have been used in many studies, none of them can reproduce both the reproductive and metabolic phenotypes of PCOS. In addition, behavioral parameters have not been evaluated in PCOS animal models. PURPOSE: We tried to produce an improved rat model of PCOS, and the reproductive, metabolic, and behavioral phenotypes of the model rats were evaluated. METHODS: Female rats were implanted with silicon tubes containing oil-dissolved dihydrotestosterone (Oil-DHT) as a new PCOS model. Their phenotypes were compared with those of conventional PCOS model rats (DHT), into which tubes containing crystalline DHT were implanted, and non-DHT-treated rats (control). RESULTS: Both the Oil-DHT and DHT rats showed greater body weight gain, food intake, and fat depot weight than the control rats. Furthermore, these groups showed fewer estrous stages and increased numbers of cystic follicles. The DHT rats exhibited lower ovarian and uterine weights than the control rats, whereas no such changes were observed in the Oil-DHT rats. The Oil-DHT and DHT rats showed less locomotor activity in the light phase than the control rats. CONCLUSIONS: Our proposed PCOS model reproduced both the reproductive and metabolic phenotypes of PCOS and may have potential for PCOS research.

Pilot study of a combination of S-1 and paclitaxel for patients with peritoneal metastasis from gastric cancer.

BACKGROUND: This pilot study was carried out to evaluate the efficacy of chemotherapy for patients with peritoneal dissemination from gastric cancer or positive lavage cytology diagnosed by staging laparoscopy. METHODS: Sixteen patients were enrolled. Paclitaxel was administered at 120 mg/m(2) on day 1 and S-1 was administered orally at 80 mg/m(2) for 14 consecutive days, followed by a 1-week rest, as one course. After five courses of this therapy, the primary gastric tumors were evaluated and second-look laparoscopy was performed for patients showing partial response or stable disease with clinical benefit. RESULTS: Partial response or stable disease with clinical benefit was confirmed in seven and five patients, respectively, and these patients underwent second-look laparoscopy. No viable cancer cells were detected on cytopathological investigation during second-look laparoscopy in 9 patients who underwent surgical treatment. The intent-to-treat response rate for gastric tumor was 44% and the rate of disappearance of peritoneal metastasis was 38% (6 cases) at surgery. The median survival time was 555 days. Leucopenia of grade 3 and neutropenia of grade 3 were recognized in two and three patients, respectively. CONCLUSION: This chemotherapy regimen may be an acceptable option for patients with peritoneal dissemination. We plan to study this regimen further in gastric cancer patients with peritoneal dissemination.

[Case report--a long-term surviving patient who received lymph node dissection of skip metastasis from rectosigmoid cancer to bilateral lateral lymph nodes].

Skip metastasis in colorectal cancer consists of about 10% of lymph node metastases. We report a rare long-term surviving patient of skip metastasis to lateral nodes after lymph node dissection. A forty-two years old female received anterior resection for advanced rectosigmoid cancer. Because pathological stage of the patient was stage IIIa (T3N1M0), standard adjuvant chemotherapy was provided. Serum CEA increased just two years after the first operation. PET scan showed abnormal FDG uptake in lymph nodes along the aorta. Lymph nodes along the inferior mesenteric artery (IMA), bilateral common iliac artery and aorta were dissected. There were metastases to nodes along the common iliac artery but no metastasis along the IMA was observed. So we diagnosed it as skip metastasis. The patient is still alive without any metastasis after 6 years from the second operation.

[Outcome of therapy for type 4 gastric cancer with peritoneal metastasis--diagnosis by laparoscopy and effect of chemotherapy].

UNLABELLED: Laparoscopy (st-lap) was performed for type 4 advanced gastric cancer cases, and chemotherapy was performed for P1 or CY1[ P(+)] cases. We present the results here. SUBJECTS: The subjects were type 4 advanced gastric cancer cases from October 2002 to December 2007 who underwent st-lap, as well as 7 P0 and CY0 [P(-)] cases (the operative group), and 18 P(+) cases which underwent chemotherapy (the chemotherapy group). The administration of S-1 (80 mg/m2: days 1-14)+PTX (120 mg/m2: day 1) every 3 weeks was the basic regimen of chemotherapy. RESULTS: After 5- course of chemotherapy, st-lap was performed in 11-PR case(61%) and 4-SD case, in which clinical symptoms had improved. An operation was performed for 11-P(-) case. Overall, there was 8-P(-) case(44%). The 1-and 3-year survival rates in the chemotherapy group in the 11 cases for which an operation was performed were 82 and 36%, respectively, and the 7 non-operative cases were 57 and 14%, respectively. Although there were no significant differences, the outcome was more favorable in the operative group. The 1-and 2-year survival rates in the operative and chemotherapy groups were 72, 39, 51 and 34%, respectively, and there was no significant difference. DISCUSSION: It was suggested that in cases of type 4 advanced gastric cancer, chemotherapy was necessary not only in P(+) but also in P(-) cases. Further investigation regarding the necessity of resection and choice of therapeutic regimen is required.

[A case of epidermoid cyst in the intrapancreatic accessory spleen mimicking pancreatic malignant tumor].

We report a rare case of an epidermoid cyst in the intrapancreatic accessory spleen with producing CA19-9. A 42-year-old woman was referred to department of internal medicine of our hospital due to growing cystic lesion at the pancreatic tail. Laboratory tests on admission revealed a high serum CA19-9 (102.0 U/mL). Ultrasound sonography detected a 25-mm monolocular cystic tumor with thick capsule and septum. The capsule and septum was enhanced on computed tomography. Endoscopic examination of upper gastrointestinal tract and colon revealed normal. CA19-9 was elevated up to 147.3 U/mL after 2-month follow-up, and she was referred to department of digestive surgery. We suspected a mucinous cystic neoplasm or endocrine tumor, and distal pancreatectomy was performed. The surgical specimen showed a septate cyst surrounded by brown solid tissue resembling normal spleen. The patient was discharged on postoperative day 11. Histological diagnosis was an epidermoid cyst originated from an intrapancreatic accessory spleen. Immunohistochemical analysis of CA19-9 in the epidermoid cyst showed clear staining of the inner epithelium of the cyst. The serum CA19-9 value was confirmed to decline to normal 1 month after resection.

[A case of metastatic pancreatic cancer after combination chemotherapy with uracil-tegafur and gemcitabine].

We report a case of pancreas head cancer with liver metastasis treated with uracil-tegafur (UFT) and gemcitabine combined chemotherapy. A 66-year-old man was referred to our hospital for obstructive jaundice. We planned to perform a pancreatoduodenectomy, but a small nodule was found at laparotomy on the liver surface. The histopathological diagnosis was adenocarcinoma, so we inserted a self-expandable metallic stent (EMS) in this inoperable pancreas head cancer. We performed 9 courses of UFT and gemcitabine (GEM) combination chemotherapy. Renewed liver metastases did not appear, and the pancreas head tumor partially responded. Pancreatoduodenectomy was performed, and EMS could not be separated from the common bile duct. After treatment with an additional 11 courses of chemotherapy, he took S-1 orally because of a tumor recurrence. He survived for 24 months from the first laparotomy. Combination chemotherapy and surgery enhanced the survival benefit in this case.

[Pilot study of neo-adjuvant chemotherapy involving intraperitoneal administration of paclitaxel and oral S-1 for patients with T3 gastric cancer].

The prognosis of patients with T3 gastric cancer is poor, even if a curative resection is performed. Novel combination neo-adjuvant chemotherapy has been introduced for T3 gastric cancer patients. This pilot study involving 5 patients was performed between December 2002 and March 2003. They were diagnosed with gastric cancer with serosal invasion (T3) without P1 and CY1 by staging laparoscopy. We selected a combined chemotherapy with both paclitaxel and S-1. Paclitaxel at 60 mg/m2 was administered intraperitoneally on days 1 and 8, and S-1 at 80 mg/m2 was administered orally for 14 days followed by a 7-day-rest, as one course. After one course of this therapy, surgery was performed. The plasma concentration of paclitaxel was measured in two patients. Toxicites were generally mild, and no serious adverse reactions were observed. The plasma concentration of paclitaxel was about 100 ng/mL in the period of 1-6 hours after the administration. After one course, four patients underwent a total gastrectomy and one distal gastrectomy. The final histological stagings were included one stage IB, one stage II, one stage IIIA, one stage IIIB, and one stage IV. Three patients died at 10, 11, and 16 months after the initial treatment, and two have survived for 64 and 62 months. As the intraperitoneal administration of paclitaxel and oral S-1 was well-tolerated, further studies should be conducted involving T3 gastric cancer patients.

[A case of advanced sigmoid colon cancer performed resection of liver metastases after long-term control by S-1 and CPT-11 combination chemotherapy].

A 60-year-old man diagnosed as advanced sigmoid colon cancer was performed sigmoidectomy and D3 lymph node dissection. Intra-operative findings were SE, P0H1N4M (-), and Stage IV. One month after the operation, we started a combination chemotherapy using S-1 plus CPT-11 as one course for five weeks. S-1 (120 mg/body/day) was orally administered continuously for 3 weeks, and CPT-11 (80 mg/m2) was done intravenously on days 1 and 15. A Follow-up abdominal CT scan revealed a drastic reduction of liver metastasis and disappearance of para-aortic lymph node swelling (PR in). The combination chemotherapy was once finished after eight courses due to the patient's request. However, we started to administer the same regimen to him again six months later because of re-growth of liver metastasis. An additional six-course administration resulted in a reduction of liver metastasis by CT scan, and no other abnormal concentration besides two liver metastases by PET-CT examination was observed, and we performed a partial resection (two parts) of the liver and cholecystectomy 24 months after the first operation. The patient has been alive with disease free for five months since the second operation.

[A long-term survival case of unresectable hepatohilar bile duct cancer treated with radiotherapy and hepatic arterial infusion chemotherapy ].

The patient, a 79-year-old woman, underwent distal gastrectomy for gastric cancer in November 2002. The lesion was judged to be T1 N0H0POM0 and fStage IA. A hepatohilar tumor was found 1 year after gastrectomy by CT scan. Radiological examinations revealed a presence of right portal vein stenosis and left portal vein obstruction due to hepatohilar bile duct cancer. Surgical treatment was considered to be difficult because of the consequence of the tumor involved in the right hepatic artery. We performed hepatic arterial infusion chemotherapy of 5-fluorouracil 1000 mg/body/week for 8 courses through the reservoir catheter. Radiation therapy was delivered concurrently with hepatic arterial infusion. The condition of the patient was good after receiving 40 Gy, Three months after the additional 20 Gy radiation, the tumor was markedly reduced in size, and was not detected 7 months thereafter. MRI showed no recurrence for three and a half years since chemo-radiation.

[Three cases of unresectable advanced gastric cancer treated with S-1 based chemotherapy after surgical bypass].

Case 1: The patient underwent gastrojejunostomy [T4 (pancreas), N2, P0, CY0] in April 2004, and then 23 courses of chemotherapy with S-1 + DOC (40 mg/m2/day 1:3 w). Then, the regimen was switched to CPT-11 because of a decreased efficacy of the treatment, and CPT-11 was continued for 10 courses. (The patient was alive for 36 months). Case 2: The patient was treated with S-1 [T4 (pancreas), N3, P0, CY0] after surgical bypass in November 2004. After two courses of chemotherapy with S-1, 9 courses of the second-line chemotherapy with PTX (120 mg/m2/day 1:3 w) were provided. As the disease progressed, 15 courses of CPT-11 (125 mg/m2/day 1: 2 w) were administered (The patient was alive for 29 months). Case 3: The patient was diagnosed as CY1 by staging laparoscopy in August 2005. The second-look laparoscopy revealed CY0 after 5 courses of S-1 + PTX (120 mg/m2/day1: 3 w). Although the second-look laparoscopy revealed CYO, gastrojejunostomy was performed because of P1 and T4 (pancreas). Chemotherapy with S-1 + PTX was continued for 18 courses, followed by OPT-11 (The patient was alive for 20 months). This report describes three cases of gastric cancer treated with S-1 based chemotherapy after surgical bypass, which resulted in the long-term survival and an improvement of the patients' quality of life.