Can systematic lymphadenectomy be omitted for low-risk endometrial cancer?

The objective of this study was to identify pathological indicators that could be used to identify a subgroup of patients with apparent stage I endometrial cancer who do require retroperitoneal lymphadenectomy. 188 T1 endometrial cancer patients underwent primary surgery at Tokushima University Hospital. We retrospectively evaluated their clinical records and histopathological factors. Systematic lymphadenectomy was performed for 149 patients, and 39 patients (grade 1 with < 5 mm of myometrial invasion) were treated without lymphadenectomy. Lymph node metastases were found in 19 (12.8%) of the lymphadenectomy cases. Twenty-four patients with a T1a endometrium-limited lesion did not exhibit lymph node metastasis. Three (3.1%) of the 95 patients with a T1a lesion exhibited lymph node metastasis, and these 3 cases exhibited approximately 50% myometrial invasion. The 39 low-risk patients who did not undergo systematic lymphadenectomy remain alive without recurrence. Systematic lymphadenectomy could be omitted for patients with a grade 1 tumor and minor myometrial invasion of less than 5mm. J. Med. Invest. 65:221-224, August, 2018.

Clinical Significance of Vascular Endothelial Growth Factor Expression and Microvessel Density in Invasive Cervical Cancer.

To determine whether vascular endothelial growth factor (VEGF) expression and microvessel density are predictive of prognosis in cases of invasive cervical cancer, correlations among VEGF expression, microvessel density, and clinicopathological parameters were identified. VEGF expression was evaluated in 50 cervical cancer samples by immunohistochemical staining. Microvessel density was assessed by immunostaining for CD31-positive endothelial cells in the most vascularized areas of tumors. VEGF expression and microvessel density were significantly higher in adenocarcinomas than in squamous cell carcinomas. However, in cases of adenocarcinoma, no significant correlations were found among VEGF expression, microvessel density, and clinicopathological parameters. In contrast, for squamous cell carcinomas, microvessel density was significantly higher in cases at an advanced stage and in those with several other poor prognostic factors. The finding that cervical adenocarcinomas exhibited greater VEGF expression and microvessel density than squamous cell carcinomas may explain the poorer prognosis of adenocarcinoma compared with squamous cell carcinoma. Moreover, microvessel density in squamous cell carcinomas was significantly correlated with poor prognostic factors. Therefore, there is possibility that bevacizumab, a humanized monoclonal antibody against VEGF-A, may be useful in the initial treatment targeting angiogenesis for early-stage cervical cancer.

Magnetic resonance manifestations of villoglandular papillary adenocarcinoma of the uterine cervix with a fern-leaf-like appearance.

Villoglandular papillary adenocarcinoma (VGPA) is a rare subtype of cervical adenocarcinoma that generally affects young women and has a favorable prognosis. Its preoperative diagnosis is important to avoid excessive surgery. We report the magnetic resonance (MR) findings of a case in which the cervical tumor showed a fern-leaf-like appearance on high resolution T2-weighted images obtained at 3 tesla. MR imaging clearly showed this pathological feature that may suggest this disease.

Clear cell adenocarcinoma arising from clear cell adenofibroma of the ovary: value of DWI and DCE-MRI.

Clear cell adenofibroma (CCAF) is a rare surface epithelial-stromal tumor of the ovary and recently considered another precursor of clear cell adenocarcinoma (CCA) other than endometrioma. We report magnetic resonance (MR) findings of a borderline CCAF that contained a small CCA focus. The tumor manifested a characteristic "black sponge" appearance. The CCA focus showed high signal intensity on diffusion-weighted imaging (DWI) and early enhancement on dynamic contrast-enhanced (DCE) MR imaging (DCE-MRI), and the CCAF components showed low signal intensity on DWI and gradually increasing contrast enhancement on DCE-MRI.

Adjuvant chemotherapy following concurrent chemoradiotherapy for uterine cervical cancer with lymphadenopathy.

The present study aimed to retrospectively evaluate the efficacy and toxicities of adjuvant chemotherapy with paclitaxel and carboplatin (TC) following concurrent cisplatin-based chemoradiation (CCRT) in patients with cervical cancer with lymphadenopathy (N1). A total of 37 patients with FIGO stage IB2-IVA cervical carcinoma with N1 (median age 57 years, range 31-74 years) were enrolled. External beam radiation therapy was followed by high-dose-rate brachytherapy. In cases of suspected para-aortic lymphadenopathy or common iliac lymph node involvement, extended radiotherapy fields were applied. Positive lymph nodes were externally radiated. Cisplatin was administered weekly at a dose of 30 mg/m(2) during external beam radiation therapy. Adjuvant therapy was administered to 17 patients and comprised carboplatin (6 mg/ml/min) and paclitaxel (175 mg/m(2)) administered monthly after CCRT, and repeated every 4 weeks for 3-6 cycles. Over a median 21.5-month follow-up, no significant differences were found in the recurrence rate, progression-free survival, overall survival, or median interval to recurrence with N1 cervical cancer patients between the two groups. Patients with para-aortic lymphadenopathy who received CCRT and adjuvant chemotherapy had a more favorable overall and disease-free survival than those treated with CCRT alone. However, 16/17 patients developed grade 3-4 leukopenia and 14/17 patients developed severe hematologic toxicity during adjuvant chemotherapy. In conclusion, adjuvant chemotherapy consisting of full dose TC therapy after CCRT was not well tolerated in general and exhibited no benefit to N1 cervical cancer patients. However, it may be of therapeutic advantage over CCRT alone in cervical cancer patients with para-aortic lymphadenopathy.

Gene gun-mediated skin transfection with FL gene suppresses the growth of murine fibrosarcoma.

AIM: Particle-mediated transfection is known as an efficient method of non-viral gene transfer. Flt3 ligand (FL) is a growth factor for hematopoietic progenitors; it promotes the growth of dendritic cells (DC). DCs are powerful antigen-presenting cells (APCs) and show a remarkable capacity to stimulate antigen-specific T-cell responses. In this study, we intended to investigate the suppressive effect on tumor growth by gene gun-mediated transfer of FL in a murine model. METHODS: C57BL/6J mice were injected intradermally with MCA205 cells. DNA (pNGVL-hFLex)-coated gold particles were delivered to the mouse skin surrounding the target tumor. The expression of FL was determined by RT-PCR. Analyses by immunohistochemistry and fluorescence-activated cell sorter (FACS) revealed an increase in the number of DC after treatment with FL. RESULTS: Gene gun-mediated pNGVL-hFLex transfer significantly inhibited the growth of the MCA205 tumor. FL transfer markedly increased the number of CD11c(+) DCs in the tumor tissue. Further, the FL-transfected mice exhibited a significantly higher number of CD80(+) MHC-II cells. CONCLUSION: We successfully performed FL therapy using an in vivo gene gun in order to effectively mobilize DCs in situ and induce suppressive immunity.

Effects of raloxifene on the production of cytokines in stimulated whole blood in ex vivo and in vitro studies.

PURPOSE: The aims of this study were to determine the effects of raloxifene therapy on production of cytokines and in vitro effects of raloxifene on production of cytokines by whole blood cultures. METHODS: We obtained samples of peripheral blood from 6 postmenopausal women with osteopenia at baseline and after 3 and 6 months of raloxifene therapy and 10 postmenopausal women who did not receive raloxifene therapy. Whole blood from raloxifene-treated women was stimulated with lipopolysaccharide (LPS) or phytohemeagglutinin (PHA). Whole blood from postmenopausal women who were not treated with raloxifene was preincubated with raloxifene at concentrations of 10(-10)-10(-7) M and then stimulated with LPS or PHA. Concentrations of IL-1ß, IL-4, IL-6, IL-12p40, IL-12p70, TNF-α and IFN-γ in the supernatant were measured by respective ELISAs. RESULTS: In ex vivo cultures, raloxifene therapy inhibited LPS-stimulated production of IL-1ß, IL-6, IL-12p40, IL-12p70 and TNF-α, but not PHA-stimulated production of IL-4 and IFN-γ. In in vitro cultures, raloxifene at a concentration (10(-9) M) inhibited LPS-stimulated production of IL-1ß, IL-6 and IL-12p40 and PHA-stimulated production of IFN-γ. CONCLUSIONS: Raloxifene therapy decreases the production of IL-1ß, IL-6, IL-12 and TNF-α but not that of IL-4 and IFN-γ, suggesting that modulation of cytokines could play a role in the mechanisms of the osteoprotective effect of raloxifene.

The role of blood in early endometrial-peritoneal interactions in a syngeneic mouse model of endometriosis.

PURPOSE: The aim of this study was to clarify the role of blood in the early stage of development of endometriotic lesions by developing a syngeneic transplantation model using immunocompetent mice. METHODS: Endometriotic lesions were induced in C57BL/6 mice by an intraperitoneal injection of endometrial fragments plus saline or endometrial fragments plus blood. Some endometrial fragments plus blood were injected with heparin, hirudin or tissue plasminogen activator (tPA). Endometriotic lesions on days 1, 3 and 5 were evaluated by gross and microscopic findings. RESULTS: The areas of endometriotic lesions in the blood group (6.4 ± 1.7 mm2) were significantly larger than those in the saline group (0.5 ± 0.3 mm2). The areas of endometriotic lesions were significantly reduced by the addition of heparin, hirudin or tPA. On day 1, endometriotic lesions in the blood group were observed on the peritoneum in five of the six mice. Endometriotic lesions on days 3 and 5 were significantly larger than those on day 1. On day 5, endometriotic lesions appeared cystic in all the mice. CONCLUSIONS: Blood accelerates the early stage of development of endometriotic lesions when endometrial fragments plus blood are injected. Blood property might be involved in early endometrial-peritoneal interactions.

The impact of systematic para-aortic and pelvic lymphadenectomy on survival in patients with optimally debulked ovarian cancer.

AIM: The objective of this study was to verify the impact of systematic retroperitoneal lymphadenectomy on survival in patients with ovarian cancer. MATERIAL & METHODS: During 2001­2005, clinical records of 118 patients with epithelial ovarian cancer were collected in Tokushima prefecture. From a number of hospitals, patients in one group were treated without systematic lymphadenectomy, and in another group, patients were treated with routine systematic lymphadenectomy. Clinical records were reviewed retrospectively and progression-free survival (PFS) and overall survival (OS) were compared. RESULTS: Sixty-two patients were staged as I­II according to the macroscopic findings at surgery. Forty of these patients received systematic lymphadenectomy and 22 patients did not. The 5-year OS was 100 and 80%, respectively (P = 0.07). The 5-year PFS was 94 and 71%, respectively (P = 0.04). In patients with clear cell adenocarcinoma, 3-year OS and PFS were significantly better in the lymphadenectomy group (P = 0.01, P = 0.046, respectively). The 56 patients staged as III­IV according to the macroscopic findings at surgery were optimally debulked. Twenty-eight of these patients received systematic lymphadenectomy and 28 patients did not. There is no difference in the 5-year OS (65 and 66%, respectively; P = 0.71) or the 5-year PFS (30 and 52%, respectively; P = 0.48). CONCLUSION: This study has demonstrated that the systematic lymphadenectomy had benefit only in patients with ovarian cancer macroscopically confined to the pelvis. In patients with clear cell adenocarcinoma, systematic lymphadenectomy was beneficial. To the contrary, systematic lymphadenectomy had no benefit on OS or PFS in patients with advanced ovarian cancer if optimally debulked.

Long-term recurrence-free survivor after laparoscopic removal of solitary adrenal metastasis from endometrial adenocarcinoma.

Solitary adrenal metastasis from endometrial adenocarcinoma is extremely rare. We report herein the case of a laparoscopically resected solitary adrenal metastasis originating from endometrial adenocarcinoma. The patient was a 55-year-old woman who had undergone total abdominal hysterectomy for stage IIIc endometrial carcinoma, followed by 7 courses of adjuvant chemotherapy comprising carboplatin and paclitaxel. However, the patient developed an isolated right adrenal metastasis 15 months postoperatively. The solitary adrenal metastasis (diameter, 5.7 cm) was removed laparoscopically. The patient has now been in good health without recurrence for 5 years and 7 months after laparoscopic surgery. To the best of our knowledge, this is the first case of solitary adrenal metastasis originating from endometrial adenocarcinoma that is controlled for the long term by successful laparoscopic resection.

A case of metastatic malignant melanoma of the ovary with a multilocular cystic appearance on MR imaging.

Ovarian metastasis from malignant melanoma is rare and usually appears as a solid ovarian mass. We report a case of ovarian metastasis from cutaneous malignant melanoma that proved to be a diagnostic dilemma. The ovarian metastasis exhibited a multilocular cystic appearance on magnetic resonance imaging, mimicking a mucinous ovarian tumor with massive ascites.

Ovarian fibromatosis: magnetic resonance imaging findings with pathologic correlation.

Ovarian fibromatosis is a rare benign nonneoplastic condition with ovarian enlargement in young women and characterized by a proliferation of collagen-producing spindle cells surrounding normal ovarian structures. We reported magnetic resonance findings of a case that the affected ovarian parenchyma with follicles was surrounded by very low intense thick fibrous tissue on T2-weighted images such as "black garland" around the ovary. The magnetic resonance findings well reflected the pathological feature of the disease and may be diagnostic.

[Neoadjuvant chemotherapy followed by radical surgery compared to concurrent chemotherapy in stage I b2- III b cervical cancer].

For the treatment of bulky cervical cancer, the most promising modality is surgery followed neoadjuvant chemotherapy( NAC-S)or concurrent chemoradiation therapy (CCRT). The purpose of this study is to compare the efficacy and complications associated with each treatment. The CCRT group included significantly more elderly and advanced patients than the NAC-S group. From 2001 to 2005, 76 consecutive previously untreated patients with bulky cervical cancer staged as I b2- III b were treated with NAC-S or CCRT. The response rate of NAC was 63% and 84% of patients received radical surgery. There was no significant difference in the intra-pelvic or extra-pelvic recurrence rate between NAC-S and CCRT group. In addition, there was no significant difference in 3-year relapse-free survival or overall survival. When we consider the bias, these results suggest that CCRT is superior to NAC-S.

Malignant Brenner tumor with transition from benign to malignant components: computed tomographic and magnetic resonance imaging findings with pathological correlation.

We report computed tomographic and magnetic resonance findings of an ovarian malignant Brenner tumor with transition from benign to malignant components. The tumor was demonstrated as a cystic mass with solid mural components. The benign component contained dense calcifications on computed tomography and showed very low intensity on T2-weighted images, whereas the malignant component showed high intensity. The admixture of 2 components may well reflect the pathological feature and may be a diagnostic clue to malignant Brenner tumor.

Transition of leptin receptor expression during pubertal development in female rat pituitary.

Leptin is thought to play important roles in pubertal development and reproductive function in the female. Leptin receptor is expressed in various tissues including the pituitary and hypothalamus. We investigated the transition of leptin receptor (Ob-R) expression in female rat pituitary during pubertal development. Real-time RT-PCR was performed for long-form leptin receptor (Ob-Rb) and short-form leptin receptor (Ob-Ra) in the pituitary and cerebrum of the rats aged 4 (juvenile), 6 (pubertal), and 8 weeks (adult). Double immunohistochemical colocalization of Ob-R and luteinizing hormone (LH) was performed in pituitaries from 4-week-old female rats. Serum leptin concentrations of 4-, 6-, and 8-week-old rats were measured by radioimmunoassay. In the pituitary, expression of Ob-Rb mRNA in 4-week-old rats (1.00 +/- 0.16) was significantly higher than in 8-week-old rats (0.61 +/- 0.07, p<0.05), although expression of Ob-Ra mRNA did not differ among 4-, 6-, and 8-week-old rats. In cerebrum, Ob-Ra and Ob-Rb mRNA expressions did not differ significantly among 4-, 6-, and 8-week-old rats. Intense staining of Ob-R and colocalization of Ob-R and LH were seen in 4-week-old rat pituitary. On the other hand, serum concentrations of leptin in 6- and 8-week-old rats were significantly higher than those in 4-week-old rats (p<0.05, p<0.01, respectively). In conclusion, since the pituitary gonadotroph is a potential target of leptin, the juvenile rat pituitary might prepare for a subsequent increase of serum leptin concentration by expressing Ob-Rb.

Myeloid-related protein-8/14 is associated with proinflammatory cytokines in cervical mucus.

Myeloid-related protein-8 (MRP-8), MRP-14, and MRP-8/14 are found in a variety of inflammatory conditions and are involved in the host defense system. The objective of this study was to determine the concentrations of MRP-8, MRP-14, and MRP-8/14 in human cervical mucus and the associations between MRP-8/14 and proinflammatory cytokines. Samples of cervical mucus were obtained using a syringe from sexually active women (n=97) during the preovulatory phase. Samples from seven women were obtained using a swab placed in the cervical canal during the proliferative, preovulatory, and luteal phases. Concentrations of MRP-8, MRP-14, MRP-8/14, IL-1alpha, IL-6, IL-8, and granulocyte elastase were measured using an ELISA. The mean levels of MRP-8, MRP-14, and MRP-8/14 in cervical mucus were 1.87, 0.46, and 23.90microg/ml, respectively. The concentration of MRP-8/14 showed positive correlations with concentrations of IL-1alpha (p<0.0001), IL-8 (p<0.0001), and granulocyte elastase (p<0.0001). However, there were no significant differences in MRP-8/14 levels in the cervical mucus of each patient during the menstrual cycle. MRP-8/14 was mainly detected in human cervical mucus and showed a positive correlation with proinflammatory cytokines. The MRP-8/14 level in cervical mucus may be useful as a marker of inflammation of the uterine cervix.

Undercarboxylated osteocalcin concentration in postmenopausal women receiving hormone therapy daily and on alternate days.

OBJECTIVE: Undercarboxylated osteocalcin (ucOC) is a sensitive marker of vitamin K status. The authors examined the difference in serum ucOC concentrations in postmenopausal women receiving hormone therapy (HT) daily and on alternate days, and assessed the association between ucOC and triglyceride concentrations, which are related to the transport of vitamin K. DESIGN: Seventy-three postmenopausal women were recruited for this study. Thirty-seven women received 0.625 mg of conjugated equine estrogens (CEE) and 2.5 mg of medroxyprogesterone acetate (MPA) daily, and 36 women received 0.625 mg of CEE and 2.5 mg of MPA on alternate days. The concentrations of serum ucOC, bone turnover markers, lipid profiles, and hormones were measured before and after 12 months of HT. RESULTS: The ucOC concentration in women taking HT daily was significantly (P < 0.01) lower than that in women taking HT on alternate days. Serum ucOC concentrations during HT showed a significant (P < 0.01) inverse correlation with estradiol concentrations during HT. Serum estradiol concentrations during HT showed a significant (P < 0.01) positive correlation with triglyceride concentrations during HT. Furthermore, ucOC concentrations during HT showed a significant (P < 0.05) inverse correlation with triglyceride concentrations in women receiving HT. CONCLUSIONS: The effect of HT on alternate days on ucOC concentration was weaker than the effect of HT daily. In addition, ucOC concentration after 12 months of HT daily might be decreased due to the conversion of ucOC to carboxylated OC by the effect of vitamin K through increased triglyceride levels induced by oral CEE.

Effects of postmenopausal hormone therapy every day and every other day on lipid levels according to difference in body mass index.

OBJECTIVE: The objective of this study was to determine the effects of postmenopausal estrogen and progestogen therapy (EPT) every day and every other day on lipid levels, particularly triglyceride (TG) levels, according to difference in body mass index (BMI). DESIGN: Ninety-nine postmenopausal women (mean age, 53.9 +/- 5.6 years; mean BMI, 22.8 +/- 2.8 kg/m) were randomly treated with EPT every other day or every day for 1 year. Fifty women received oral administration of 0.625 mg of conjugated equine estrogen (CEE) and 2.5 mg of medroxyprogesterone acetate (MPA) every other day, and 49 women received oral administration of 0.625 mg of CEE and 2.5 mg of MPA every day. Blood samples were collected at baseline and after 1 year of therapy for measurement of fasting TG, total cholesterol, high-density lipoprotein-cholesterol (HDL-C), and apolipoproteins. Data from 88 of the 99 postmenopausal women were used for analysis. RESULTS: In women whose BMI was 25 kg/m or higher, TG levels during EPT every day increased by 26.8%, while TG levels during EPT every other day decreased by 12.3%. There was a significant (P < 0.05) difference between percentage changes in TG during EPT every day and every other day. In women whose BMI was less than 25 kg/m, TG levels during EPT every day increased by 21.7%, while during EPT every other day TG levels did not change. The mean levels of estradiol during EPT every day in women whose BMI was less than 25 kg/m and in women whose BMI was 25 kg/m or higher were 28.5 and 38.7 pg/mL, respectively, the difference between these levels was significant (P < 0.01). On the other hand, there was no significant difference between levels of estradiol during EPT every other day in these two BMI groups. CONCLUSIONS: Triglyceride levels during EPT every day with conventional doses of CEE and MPA increased more in overweight and obese postmenopausal women in association with increased estrogen levels.

Serum estrogen level after hormone replacement therapy and body mass index in postmenopausal and bilaterally ovariectomized women.

OBJECTIVE: The objective of this study was to determine the relationships of serum estrogen levels after hormone replacement therapy (HRT) every other day and every day with body mass index (BMI) in postmenopausal and bilaterally ovariectomized women. METHODS: Eighty-six postmenopausal and 51 bilaterally ovariectomized women who had been suffering from vasomotor symptoms such as hot flush or atrophy of the vagina were randomly treated with HRT every other day or every day. Seventy-four patients received oral administration of 0.625 mg conjugated equine estrogen (CEE) and 2.5 mg medroxyprogesterone acetate (MPA) every other day, and 63 patients received oral administration of 0.625 mg CEE and 2.5 mg MPA every day as conventional HRT. RESULTS: Eighty-four postmenopausal and 50 bilaterally ovariectomized women completed this study. Serum estradiol levels after HRT every day in postmenopausal and bilaterally ovariectomized women were significantly (P <0.05 and <0.01, respectively) correlated with BMI, while those after HRT every other day were not correlated with BMI. The differences between estradiol levels after 12 months of treatment and initial estradiol levels were also significantly (P <0.01) correlated with BMI in both postmenopausal and bilaterally ovariectomized women who received HRT every day but not in women who received HRT every other day. Serum estrone level after HRT every day and the difference between estrone level after 12 months of treatment and initial estrone level were significantly (P <0.05 and <0.01, respectively) correlated with BMI only in bilaterally ovariectomized women. CONCLUSION: Serum estradiol levels after HRT every day increase more in overweight women than in non-overweight postmenopausal and bilaterally ovariectomized women. The results of the present study regarding the relationship between serum estradiol levels after HRT and BMI should be useful for selecting dosages of drugs to be used in HRT.

Serum estradiol concentration as measured by HPLC-RIA and bone mineral density in postmenopausal women during hormone replacement therapy.

OBJECTIVE: To determine the relationship between the serum estradiol concentration and bone mineral density (BMD) of the lumbar spine in postmenopausal women treated with conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA) every other day and every day. METHODS: Eighty-four postmenopausal women were randomly treated with hormone replacement therapy (HRT) every other day and every day. Forty-seven women received oral administration of 0.625 mg CEE and 2.5 mg MPA every other day, and 37 women received oral administration of 0.625 mg CEE and 2.5 mg MPA every day. BMD of the lumbar spine at 12 months and serum concentrations of estradiol and estrone at 6 and 12 months after treatment were examined. RESULTS: The estradiol concentration in subjects treated every other day showed a significant (p < 0.001) positive correlation with the percentage change in lumbar BMD, while that in subjects treated every day was not correlated with the percentage change in BMD. The differences between serum estradiol concentrations after 12 months of treatment and initial serum estradiol values in women treated every other day and every day also showed a significant (p < 0.01 and 0.05, respectively) positive correlation with percentage changes in BMD. In women treated every other day, body mass index (BMI) in the subjects in whom BMD did not increase was significantly (p < 0.01) lower than that in the subjects in whom BMD did increase. CONCLUSIONS: The serum estradiol concentration in women treated every other day has a strong positive correlation with the percentage change in lumbar BMD, but a higher estradiol concentration may be needed for women in whom BMD did not increase with HRT every other day after due consideration of individual characteristics such as BMI.