Relugolix for oral treatment of uterine leiomyomas: a dose-finding, randomized, controlled trial.

BACKGROUND: Uterine leiomyomas are the most common neoplasm affecting women and frequently cause heavy menstrual bleeding and pain. Gonadotropin-releasing hormone (GnRH) receptor antagonists provide fast symptom relief and show promise as a medical (non-surgical) treatment option and as a presurgical treatment to reduce leiomyoma size. The aim of this study was to evaluate the efficacy and safety of three dose levels of oral relugolix, a small molecule GnRH receptor antagonist, in Japanese women with uterine leiomyomas and heavy menstrual bleeding. METHODS: This phase 2, multicenter, double-blind, parallel-group study was conducted at 36 sites in Japan in women with uterine leiomyomas and heavy menstrual bleeding, defined as a pictorial blood loss assessment chart (PBAC) score of ≥ 120 in one menstrual cycle. Patients were randomized 1:1:1:1 to relugolix 10, 20, or 40 mg, or placebo, orally once daily for 12 weeks. The primary endpoint was the proportion of patients with a total PBAC score of < 10 from week 6 to 12. A sample size of 50 patients per group was estimated to provide ≥ 95% power, based on the comparison of relugolix 40 mg with placebo using a chi-square test with a significance level of 5% (two-sided). RESULTS: From November 2011 to September 2012, 216 patients were randomized and 214 patients (99.1%) were analyzed. The proportion (difference vs. placebo) of patients that achieved the primary endpoint in the placebo and 10-, 20-, and 40-mg relugolix groups were 0%, 20.8% (95% confidence interval [CI]: 9.3-32.3, P < .001), 42.6% (95% CI: 29.4-55.8, P < .001), and 83.3% (95% CI: 73.4-93.3, P < .001), respectively. Though treatment-emergent adverse events were similar between the 20- and 40-mg groups, the incidence rates were more frequent compared with the placebo group. Most of these adverse events were mild or moderate in intensity. CONCLUSIONS: Relugolix decreased menstrual blood loss in women with uterine leiomyomas in a dose-response manner, and was generally well tolerated. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT01452659 , NCT01452659 (registered 17/10/2011); JAPIC Clinical Trial Information, https://www.clinicaltrials.jp , JapicCTI-111590 (registered 31/08/2011).

Relugolix, a novel oral gonadotropin-releasing hormone antagonist, in the treatment of pain symptoms associated with uterine fibroids: a randomized, placebo-controlled, phase 3 study in Japanese women.

OBJECTIVE: To investigate the efficacy and safety of the oral gonadotropin-releasing hormone receptor antagonist, relugolix, in patients experiencing uterine fibroid-associated pain. DESIGN: Phase 3, multicenter, randomized, double-blind, placebo-controlled study. SETTING: Medical centers. PATIENT(S): Premenopausal Japanese women (N = 65) experiencing moderate-to-severe uterine fibroid-associated pain with a maximum Numerical Rating Scale (NRS) score of ≥4 were randomized and completed the study. INTERVENTION(S): Once-daily 40 mg relugolix (n = 33) or placebo (n = 32) for 12 weeks. MAIN OUTCOME MEASURE(S): Primary end point: proportion of patients with a maximum NRS score of ≤1 during the 28-day period before the final dose of study drug. Secondary end points: proportion of patients with no pain (NRS = 0) and percentage of days without pain during the 28-day period before the final dose of study drug; adverse events. RESULT(S): More patients receiving relugolix versus placebo achieved a maximum NRS score of ≤1 during the 28-day period before the final dose of study drug (57.6% vs. 3.1%). Similarly, more patients receiving relugolix versus placebo achieved a maximum NRS score of 0 (48.5% vs. 3.1%) and experienced more days without pain (96.4% vs. 71.4%). More patients receiving relugolix versus placebo experienced treatment-emergent adverse events (TEAEs; 87.9% vs. 56.3%); however, the rate of treatment discontinuation was low and not different between groups. Most TEAEs were mild to moderate in intensity. TEAEs (≥10%) included hot flush, metrorrhagia, hyperhidrosis, and menorrhagia, consistent with relugolix's mechanism of action, and viral upper respiratory tract infection. CONCLUSION(S): Relugolix improved uterine fibroid-associated pain and was well tolerated. CLINICAL TRIAL REGISTRATION NUMBERS: NCT02655224. JAPIC CLINICAL TRIAL INFORMATION: JapicCTI-163127.

Oral Gonadotropin-Releasing Hormone Antagonist Relugolix Compared With Leuprorelin Injections for Uterine Leiomyomas: A Randomized Controlled Trial.

OBJECTIVE: To investigate the noninferiority of relugolix compared with leuprorelin acetate in reducing heavy menstrual bleeding associated with uterine leiomyomas. METHODS: In a double-blind, double-dummy trial, premenopausal women with uterine leiomyomas and heavy menstrual bleeding defined as a pictorial blood loss assessment chart score of at least 120 were randomized in a 1:1 ratio to relugolix (40 mg, oral, once daily) or leuprorelin acetate (1.88 mg or 3.75 mg, monthly injection) for 24 weeks. The primary endpoint was the proportion of patients with a total pictorial blood loss assessment chart score of less than 10 for weeks 6-12. Secondary endpoints included myoma and uterine volumes, and hemoglobin levels. A sample size of 144 patients per group (n=288) was estimated to provide at least 90% power to demonstrate noninferiority (prespecified noninferiority margin -15%; one-sided 0.025 level of significance). RESULTS: From March 2016 to September 2017, 281 patients were randomized (relugolix, n=139, leuprorelin n=142). Demographic and baseline characteristics were well balanced; mean pictorial blood loss assessment chart score was 254.3 in the relugolix group and 263.7 in the leuprorelin group. The proportion of patients with total pictorial blood loss assessment chart score of less than 10 for weeks 6-12 was 82.2% in the relugolix group and 83.1% in the leuprorelin group, demonstrating noninferiority of relugolix compared with leuprorelin (relugolix-leuprorelin difference -0.9%; 95% CI: -10.10 to 8.35; prespecified noninferiority margin -15%; P=.001). Reductions in myoma and uterine volumes and increases in hemoglobin levels were comparable in the two groups. Relugolix was associated with an earlier effect on menstrual bleeding than leuprorelin (pictorial blood loss assessment chart score of less than 10, 64.2% vs 31.7% [relugolix-leuprorelin difference 32.5%; 95% CI: 20.95-44.13%] for weeks 2-6 and pictorial blood loss assessment chart score of 0, 52.6% vs 21.8% [30.7%; 95% CI: 19.45-42.00%] for weeks 2-6) and faster recovery of menses after treatment discontinuation (relugolix median [Q1, Q3], 37 days [32.0, 46.0]; leuprorelin median, 65 days [54.0, 77.0]). Adverse events and bone mineral density loss were similar between relugolix and leuprorelin treatment groups. CONCLUSION: In women with uterine leiomyomas, once-daily treatment with relugolix, an oral gonadotropin-releasing hormone antagonist, demonstrated noninferiority to monthly leuprorelin for improvement of heavy menstrual bleeding at 6-12 weeks of treatment, had a more rapid effect on menstrual bleeding, and was generally well tolerated. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02655237; JAPIC Clinical Trial Information, JapicCTI-163128. FUNDING SOURCE: Takeda Pharmaceutical Company Limited and an affiliate of NovaQuest Capital Management LLC.

Erythropoietin Receptor Antagonist Suppressed Ectopic Hemoglobin Synthesis in Xenografts of HeLa Cells to Promote Their Destruction.

The aim of this study is to explore a cause-oriented therapy for patients with uterine cervical cancer that expresses erythropoietin (Epo) and its receptor (EpoR). Epo, by binding to EpoR, stimulates the proliferation and differentiation of erythroid progenitor cells into hemoglobin-containing red blood cells. In this study, we report that the HeLa cells in the xenografts expressed ε, γ, and α globins as well as myoglobin (Mb) to produce tetrameric α2ε2 and α2γ2 and monomeric Mb, most of which were significantly suppressed with an EpoR antagonist EMP9. Western blotting revealed that the EMP9 treatment inhibited the AKT-pAKT, MAPKs-pMAPKs, and STAT5-pSTAT5 signaling pathways. Moreover, the treatment induced apoptosis and suppression of the growth and inhibited the survival through disruption of the harmonized hemoprotein syntheses in the tumor cells concomitant with destruction of vascular nets in the xenografts. Furthermore, macrophages and natural killer (NK) cells with intense HIF-1α expression recruited significantly more in the degenerating foci of the xenografts. These findings were associated with the enhanced expressions of nNOS in the tumor cells and iNOS in macrophages and NK cells in the tumor sites. The treated tumor cells exhibited a substantial number of perforations on the cell surface, which indicates that the tumors were damaged by both the nNOS-induced nitric oxide (NO) production in the tumor cells as well as the iNOS-induced NO production in the innate immune cells. Taken together, these data suggest that HeLa cells constitutively acquire ε, γ and Mb synthetic capacity for their survival. Therefore, EMP9 treatment might be a cause-oriented and effective therapy for patients with squamous cell carcinoma of the uterine cervix.

Exposure to ethinyl estradiol prenatally and/or after sexual maturity induces endometriotic and precancerous lesions in uteri and ovaries of mice.

Unrecognizable exposure to estrogenic substance may cause estrogen-dependent diseases, endometriosis and cancer. Pregnant mice (ICR/Jcl, CLEA) were exposed to 0.01 mg ethinyl estradiol (EE2 )/kg per day or vehicle (olive oil) through oral intubation from day 11 to 17 of gestation. They delivered their offspring and raised them. When the experimental female F1 mice were at 8 weeks of age, they were not exposed to EE2 or to the same dose of EE2 or to vehicle twice a week until 20 weeks of age. The control female F1 mice were exposed to the same dose of EE2 or vehicle alone, similarly. All mice were killed at 28 weeks of age. The resected uteri and ovaries were processed for microscopic examinations and for determination of the aromatase mRNA levels and aromatase protein through quantitative RT-PCR and Western blotting, respectively. Adenomyosis and adenocarcinomatous changes were significantly discernible in the EE2 -exposed uteri, and incidence of ectopic glands and serous cysts were significantly increased in the prenatally EE2 -exposed ovaries as compared with respective controls. Significant upregulation of the aromatase mRNA was seen in the prenatally EE2 -exposed uteri and in the EE2 -exposed ovaries. The aromatase protein was identified in all ovaries examined, and in EE2 -exposed uteri but not in controls and confirmed its localization in eutopic and ectopic glands, abnormally proliferated lesions and the lining of the cysts. Taken together, continuous EE2 exposure may cause endometriotic and precancerous lesions due to excessive estrogen synthesis in both target organs.

Erythropoietin is involved in hemoprotein syntheses in developing human decidua.

Before establishment of feto-placental circulation, decidua can synthesize hemoproteins to maintain oxygen homeostasis in situ. Using the human decidua of induced abortions ranging from 5 to 8 weeks of gestation, we determined the expression levels of erythropoietin, erythropoietin receptor, cytoglobin, myoglobin, embryonic-, fetal- and adult hemoglobin mRNA by quantitative RT-PCR analysis and identified their proteins by Western blot and immunohistochemical analyses. Erythropoietin signaling was demonstrated in phosphatidylinositol-3-kinase/protein kinase B pathway by Western blot, and the transcriptional factors for erythroid and non-erythroid heme synthesis were examined by RT-PCR analysis. In decidua, erythropoietin and its receptor mRNAs, erythropoietin receptor protein and phosphatidylinositol-3-kinase, were expressed with a peak at 6 weeks of gestation. Moreover, the decidua during 5 to 8 weeks of gestation expressed embryonic, fetal and adult hemoglobins additionally cytoglobin and myoglobin at transcriptional and protein levels. The heme portion of these hemoproteins is considered to be synthesized by non-erythroid δ-aminolevulinate synthase. These hemoproteins were discernible especially in decidual cells concomitant with cytotrophoblast cells and macrophage in these developing decidua. Considering the different capacity for oxygen binding and dissociation among hemoglobins with the oxygen storage capacity for cytoglobin and myoglobin, these hemoproteins appear to play a role in oxygen demand in decidua in situ before development of feto-placental circulation under the control of erythropoietin signaling.

Preoperative differentiation between tumor-related ovarian torsion and rupture of ovarian cyst preoperatively diagnosed as benign: a retrospective study.

INTRODUCTION: Patients with ovarian cyst sometimes present with acute abdomen caused by ovarian torsion or rupture, which are difficult to differentiate preoperatively. The purpose of this study was to determine preoperative features of patients with ovarian cyst that could be used in differentiation. MATERIAL AND METHODS: Among 1723 patients with a preoperative diagnosis of benign ovarian cyst who underwent surgery between 1995 and 2010, 77 patients with ovarian torsion and 21 patients with ruptured ovarian cyst were retrospectively evaluated. The mean preoperative age, serum C-reactive protein (CRP) level, white blood cell count, body temperature, cyst size, and rate of acute abdomen were compared between the two groups, and postoperative pathological data were also collected. RESULTS: There were significant differences between the torsion and rupture groups in the mean preoperative CRP levels (0.9 mg/dL vs 6.6 mg/dL, respectively; P<0.01) and in the mean ovarian cyst sizes (9.7 cm vs 6.7 cm, respectively; P=0.04). CONCLUSION: In this study, the patients with ruptured ovarian cyst had elevated CRP levels. Another study has demonstrated that there was risk for necrosis in torsion patients with elevated CRP levels who presented more than 10h after the onset of acute abdomen. Therefore, preoperative differential diagnosis between ovarian torsion and rupture may be possible by combining the findings from preoperative imaging, data on the time from onset of acute abdomen, and CRP values.

The significance of laparoscopy in determining the optimal management plan for infertile patients with suspected tubal pathology revealed by hysterosalpingography.

The fallopian tube has numerous functions, including ovum pick-up, the place of fertilization of the ovum and cleavage of the embryo, and transfer of the embryo to the uterus. Tubal pathology impairs functions of the fallopian tube and reduces fertility. The degree of tubal pathology determines the possibility for fertility. The evaluation of the fallopian tube is necessary to determine the management plan of infertility. Hysterosalpingography (HSG) is often performed as a first line approach to assess tubal patency and the presence of adhesions; however, HSG has limitations in detecting tubal pathology. In the current study, we evaluated the significance of laparoscopy in determining the optimal management plan for infertile patients with suspected tubal pathology revealed by HSG. Between 1997 and 2009, 127 patients with suspected tubal pathology as demonstrated by HSG underwent laparoscopy at Kinki University Hospital, and a retrospective analysis was performed. Of 87 patients with unilateral tubal pathology revealed by HSG, 20 patients (23.0%) were given an indication for assisted reproductive technology (ART), based on the laparoscopic findings. Of 40 patients with bilateral tubal pathology revealed by HSG, 33 patients (82.5%) with bilateral tubal pathology detected by laparoscopy were given a high indication for ART. Laparoscopy enables exact evaluation of the fallopian tube and selection of the optimal management plan in infertile patients with suspected tubal pathology revealed by HSG. Therefore, laparoscopy should be performed in infertile patients with suspected tubal pathology revealed by HSG, as it is of diagnostic importance.

Cutaneous metastasis from primary adenocarcinoma of the vagina: a case report.

Cutaneous metastasis in vaginal cancer is an extremely rare event and no cases of cutaneous metastasis from primary vaginal adenocarcinoma have been found. We report the clinicopathologic features, including cytopathologic findings, of the first case of cutaneous metastasis to the anterior chest wall from a sporadic-type advanced primary vaginal adenocarcinoma. Our present case suggested that cytopathologic examination should be performed as soon as possible when a patient exhibits multiple subcutaneous nodules or a painful cutaneous ulcer during treatment of advanced gynecologic cancer.

Retrospective evaluation of tumor markers in ovarian mature cystic teratoma and ovarian endometrioma.

AIM: The aim of this study was to evaluate the correlation between clinicopathological characteristics and serum levels of tumor markers in patients with ovarian endometrioma (OE) and ovarian mature cystic teratoma (MCT). MATERIAL AND METHODS: Values of CA125, CA19-9, and sialyl Tn antigen (STN) were retrospectively investigated in 321 patients with OE. CA125, CA19-9, STN, and squamous cell carcinoma antigen (SCC) were examined in 435 patients with MCT. RESULTS: Mean values of CA125, CA19-9, and STN were 105.3 U/mL, 58.0 U/mL, and 31.1 U/mL in OE, while the values were 26.8 U/mL, 246.8 U/mL, and 24.7 U/mL in MCT. Abnormal elevation of CA125, CA19-9, and STN was observed in 53.3%, 38.9, and 13.5 of OE, and in 12.9, 50.6, and 4.6% of MCT, respectively. CA125 level was significantly higher in bilaterally occurring OE and premenopausal patients with MCT, while the value of CA19-9 was significantly higher in cases of bilaterally occurring MCT. Furthermore, the levels of CA125 and CA19-9 showed significant correlations with tumor diameter, while the levels of STN and SCC showed no significant correlations with tumor diameter. The highest CA125 level (9513 U/mL) was observed in OE and the highest CA19-9 level (25 590 U/mL) was observed in MCT. CONCLUSION: Although abnormal increases in the levels of CA125 and CA19-9 were often observed, the levels of STN were not influenced by clinicopathologic factors in OE and MCT. Further studies of the clinical usefulness of STN for detecting malignant tumors in OE and MCT are needed.

Primary adenomyoma of the fallopian tube mimicking tubal malignant tumor.

We report a rare case of adenomyoma localized only in the left fallopian tube mimicking tubal malignant tumor. A 45-year-old woman presented with mild pelvic pain, dysmenorrhea and left adnexal mass. Magnetic resonance imaging showed a solid tumor, suspected primary cancer of the fallopian tube, and serum carbohydrate antigen 125 was elevated to 72 U/mL (normal; 0-35). At surgery, the tumor was revealed as a left fallopian tube tumor without torsion. Postoperative histopathology showed that the tumor included bundle-like growing non-atypical leiomyoma cells and ectopic normal endometrium accompanied with endometrial stroma and we diagnosed primary adenomyoma of the left fallopian tube. Adenomyoma localized only in the fallopian tube is a rare entity and it can occur only in the fallopian tube.

Study of the correlation between tumor size and cyst rupture in laparotomy and laparoscopy for benign ovarian tumor: is 10 cm the limit for laparoscopy?

AIM: Laparoscopy is the gold standard for treatment of benign ovarian cysts, although there is a risk of intraoperative cyst rupture if the lesion is cancerous. This study is aimed at comparing the incidence of cyst rupture to tumor size in both laparotomy and laparoscopy in order to select the optimum surgical procedure for ovarian cysts. METHODS: A total of 1483 cases of benign ovarian cysts were surgically treated at our center between 1995 and 2010. These cases were divided into three groups according to the maximum diameter of the ovarian tumors: <5 cm, ≥5 cm but <10 cm, and ≥10 cm. The incidence of cyst rupture was compared between laparotomy and laparoscopy according to the size of the tumor in ovarian tumorectomy and adnexectomy. RESULTS: The incidence of cyst rupture was significantly higher in ovarian tumorectomy by laparoscopy than by laparotomy. Cyst rupture occurred independent of the tumor size in both laparoscopy and laparotomy. For adnexectomy for tumors smaller than 10 cm, there was no significant difference by tumor size in the incidence of cyst rupture between laparoscopy and laparotomy; however, the incidence of cyst rupture was significantly higher in laparoscopy of tumors sized 10 cm or larger than in the laparotomy of tumors of similar size; the incidence was also greater than laparoscopy of tumors smaller than 10 cm. CONCLUSION: Laparotomy, rather than laparoscopy, is recommended in cases of ovarian cysts with any finding suggestive of malignancy.

Carcinomatous meningitis during systematic chemotherapy in a patient with advanced small-cell neuroendocrine carcinoma of the uterine cervix.

Carcinoma meningitis with uterine cervical cancer is an extremely rare event. We present the clinicopathologic characteristics and diagnostic imaging findings of a patient with advanced small-cell neuroendocrine carcinoma of the cervix who had developed carcinoma meningitis during systematic chemotherapy.

Reversible posterior leukoencephalopathy syndrome accompanying eclampsia: correct diagnosis using preoperative MRI.

Reversible posterior leukoencephalopathy syndrome (RPLS) is characterized by clinical symptoms such as seizures, visual disturbance, and altered mental status. It also presents abnormal findings on computed tomography (CT) and magnetic resonance imaging (MRI) indicating cerebral edema in the white matter of the occipital, temporal, and parietal lobes. Both the clinical symptoms and abnormal imaging findings can be reversed by controlling blood pressure or treating the underlying condition including infection. This report describes a patient with RPLS that occurred secondary to eclampsia. A 26-year-old female, gravida 0 para 0, developed weakness and pain in her upper and lower extremities and gait disturbance during the 34th week of pregnancy, and severe pregnancy-induced hypertension near the end of the 37th week. On the first day of the 38th week, she developed constricted visual fields and complained of visual illusions. MRI revealed a high-signal-intensity area in the right occipital lobe. Immediately after MRI, the patient had a 10-sec tonic convulsion. Diagnosed with eclampsia, she underwent emergency cesarean section. MRI on the 2nd postoperative day showed that the high-signal-intensity area was slightly improved. Her visual illusions were diminished by the 4th postoperative day, and almost all subjective symptoms disappeared by the 7th postoperative day. The patient was discharged at 12th postoperative day. We recommend MRI not only for symptomatic patients with suspected RPLS, but also for asymptomatic patients with severe pregnancy-induced hypertension. If findings such as cerebral edema are observed on MRI, immediate delivery should be considered before eclamptic seizures or exacerbation of neurological symptoms.

Predictive factors for ovarian necrosis in torsion of ovarian tumor.

Most cases of ovarian torsion require emergency surgery; the ovary has become necrotic and cannot be conserved. Preoperative determination of the ovarian necrosis extent is difficult but it may increase the likelihood of the ovary conservation. In this study, we retrospectively evaluated the findings in ovarian torsion among patients with ovarian tumors who underwent emergency surgery at a single hospital for possible preoperative indicators of ovarian viability. We thus evaluated 77 patients who were intraoperatively diagnosed with torsion of ovarian tumor between 1995 and 2010. These patients were classified into three groups depending on the postoperative histopathological findings: necrotic, congestive, and normal. Preoperative C-reactive protein (CRP) level, leukocyte count, and body temperature, along with tumor size, degree of torsion, time from the onset of abdominal pain to surgery, and incidence of acute abdomen were compared among the three groups. The sensitivity, specificity, and positive and negative predictive values of the preoperative serum CRP levels for ovarian necrosis were calculated. The CRP level, degree of torsion, and time from the onset of abdominal pain to surgery were significantly higher in the necrotic group than in the normal group. The sensitivity and specificity of the CRP level for necrosis were 35% and 83%, respectively, and positive and negative predictive values were 38% and 82% respectively. The potential for ovary conservation in suspected ovarian torsion should be greater if the tumor is non-malignant, the time from the onset of abdominal pain to operation is short, and the CRP level is < 0.3 mg/dl.

Incidental detection of breast apocrine carcinoma via endometrial cytology.

Breast apocrine carcinoma is a rare malignancy characterized histologically by a predominance of acidophilic tumor cells exhibiting apocrine metaplasia. Apocrine tumors represent only about 0.4% of all breast cancers. Many cases are diagnosed at stage I or II; thus, the prognosis is better than that for other types of breast cancer. Here we present a 57-year-old female patient with primary apocrine breast carcinoma that was incidentally discovered by endometrial cytology. The patient had undergone routine uterine cancer screening at the age of 56 with resulting positive endometrial cytology. Subsequent histological examination of an endometrial biopsy revealed suspected metastatic uterine adenocarcinoma. Further evaluation revealed a 3-cm mass in the left breast, which was histopathologically diagnosed as breast cancer. Dual procedures were performed at the departments of gynecology and breast surgery. The patient underwent a modified radical mastectomy of the left breast and left axillary lymph node dissection. Laparotomy revealed multiple adhesions throughout the peritoneal cavity that suggested invasive metastatic cancer, and a right adnexectomy was performed. Histopathological examination of the resected left breast and right ovary tissues revealed apocrine carcinoma. Thus, stage IV breast cancer was diagnosed. The patient finished 6 cycles of paclitaxel and is now under observation on an outpatient basis. In this patient, breast cancer was discovered incidentally through a detailed work-up after a positive result of endometrial cytology. Uterine cancer screening has the potential, although rare, to detect metastatic cancer originating elsewhere. This should be taken into consideration during the work-up due to positive endometrial cytology.

Indication for laparoscopically assisted vaginal hysterectomy.

OBJECTIVES: Total hysterectomy procedures include total abdominal hysterectomy (TAH), total vaginal hysterectomy (TVH), and laparoscopically assisted vaginal hysterectomy (LAVH). Our institution has introduced LAVH as a preferred option to the more invasive TAH. To date, no reports have proposed surgical indications for LAVH based on statistical analysis of surgical results. The purpose of this study was to establish criteria for performing LAVH through statistical analysis of a retrospective review of surgical outcomes in LAVH cases at our institution over a period of 15 years. METHODS: The medical records of 629 patients scheduled for LAVH for uterine fibroids and/or adenomyosis at our hospital were examined. Surgical results (blood loss, operative time, rates of conversion to laparotomy, and intraand postoperative complications) were compared among 9 groups classified by uterine weight. RESULTS: Statistically significant differences in surgical outcomes were found between the group with a uterine weight ≥ 800g and the other groups. CONCLUSION: We found that when the uterine weight was ≥ 800g, TAH was more appropriate because significant blood loss and/or complications would be expected during LAVH. A removed uterus weighing 800g is reportedly equivalent to a preoperative uterine size of approximately 12 cm. Therefore, LAVH may be safely indicated for patients with a uterine size ≤ 12 cm (approximately equivalent to the uterine size at 16-weeks gestation).

Evaluation of oral etoposide in combination with cisplatin for patients with recurrent cervical cancer: long-term follow-up results of a Japanese multicenter study.

AIM: To evaluate the efficacy and toxicities of cisplatin and daily oral etoposide in patients with recurrent cervical cancer. PATIENTS AND METHODS: Treatment was initiated with oral etoposide 25 mg/day for 21 consecutive days, with intravenous cisplatin at 50 mg/m², on day 1, every 4 weeks, then the etoposide dose was increased to 50 mg/day. RESULTS: Thirty patients were enrolled in this study. Twenty-seven (90.0%) patients had a history of prior treatment (cisplatin with concurrent chemoradiotherapy in 15, radiation therapy in 3, chemotherapy in 1, and both radiation therapy and chemotherapy in 9), and 22 (73.3%) patients had a treatment-free interval of less than 6 months. NCI-CTC grade 3/4 hematologic toxicities were leukopenia in 19 (63.3%), neutropenia in 17 (58.6%), anemia in 15 (50.0%) and thrombocytopenia in 6 (20.0%). Four patients developed febrile neutropenia. NCI-CTC grade 3 nonhematologic toxicities consisted of nausea/vomiting in 2 (6.7%), anorexia in 4 (13.3%) and fatigue in 2 (6.7%). The overall response rate was 16.7% including one complete response. The median progression-free survival period and overall survival period were 4.5 and 9.7 months, respectively. CONCLUSION: Combination chemotherapy consisting of oral etoposide and intravenous cisplatin is safe and effective for recurrent cervical cancer.