Creating a Global Community of Practice for Oncofertility.

Fertility preservation in the cancer setting, known as oncofertility, is a field that requires cross-disciplinary interaction between physicians, basic scientists, clinical researchers, ethicists, lawyers, educators, and religious leaders. Funded by the National Institutes of Health, the Oncofertility Consortium (OC) was formed to be a scientifically grounded, transparent, and altruistic resource, both intellectual and monetary, for building this new field of practice capable of addressing the unique needs of young patients with cancer. The OC has expanded its attention to include other nonmalignant conditions that can threaten fertility, and the work of the OC now extends around the globe, involving partners who together have created a community of shared effort, resources, and practices. The OC creates materials that are translated, disseminated, and amended by all participants in the field, and local programs of excellence have developed worldwide to accelerate the pace and improve the quality of oncofertility research and practice. Here we review the global oncofertility programs and the capacity building activities that strengthen these research and clinical programs, ultimately improving patient care.

Fertility preservation in adolescent and young adult cancer patients: From a part of a national survey on oncofertility in Japan.

PURPOSE: This study evaluated the current status of reproductive disorders and provision of information on oncofertility to female adolescent and young adult (AYA) cancer patients in Japan. METHODS: A national survey of AYA cancer survivors was conducted. Children were <15 years old, and AYAs were 15-39 years old. Results from the survivors of other than gynecological disease who underwent chemotherapy were analyzed. RESULTS: Among the survivors, 41.4% were concerned about their reproductive function and infertility, and 36.2% were aware of menstrual cycle abnormalities. Among them, 15.5% (n = 20) of all and 21.2% (n = 17) of the AYA-onset survivors suffered infertility due to chemo- or radiotherapy and gave up childbearing. These rates were significantly higher than those of healthy AYAs. Although 80.8% of AYA-onset survivors answered that they had received information on reproductive function and infertility, only 55.8% had received information on fertility preservation methods. Furthermore, only 22.4% of all and 42.3% of AYA-onset survivors had received pretreatment information on fertility preservation methods. CONCLUSIONS: Not a few AYA cancer survivors reported reproductive dysfunction. These findings indicate that information provided on therapy-related problems before cancer treatment in Japan was insufficient and highlight the need to improve patient decision-making and support systems for fertility preservation.

Problems of reproductive function in survivors of childhood- and adolescent and young adult-onset cancer revealed in a part of a national survey of Japan.

PURPOSE: This study aimed to evaluate the current status of reproductive disorders as long-term complications in adolescent and young adult (AYA) cancer patients by comparing survivors of childhood-onset with those of AYA-onset cancer in Japan. METHODS: We conducted a national survey of AYA cancer survivors and healthy AYAs and analyzed the results from survivors who underwent chemotherapy and reported fertility problems as their current concern. RESULTS: Among all of the childhood-onset survivors, 27 (35.5%; nine males [28.1%] and 18 females [40.9%]) listed reproduction fertility problems as their current concern. Among all AYA-onset survivors, 25 (69.5%; 1/4 males [25.0%] and 24/32 females [75.0%]) listed these problems as a current concern. In contrast, 96.3% (26/27) of all childhood-onset cancer survivors and 68.0% (17/25) of all AYA-onset cancer survivors who received chemotherapy listed these problems as a current concern. CONCLUSIONS: A considerable number of both childhood-onset and AYA-onset cancer survivors, and especially those who had undergone chemotherapy, reported reproductive dysfunction as a delayed complication. It is vitally important to establish a supportive care system both for the patients whose fertility was abolished after the completion of cancer treatment and prophylactically for patients before they begin treatment.

Management of ovarian hyperstimulation syndrome with abdominal compartment syndrome, based on intravesical pressure measurement.

There are few reports on abdominal compartment syndrome that are caused by ovarian hyperstimulation syndrome (OHSS). Here, a case of a 29 year old woman is reported in which intravesical pressure measurement was useful in the management of severe OHSS that had been complicated by abdominal compartment syndrome. The patient's urinary output and general condition did not improve after the initial treatment. The woman's intra-abdominal pressure was evaluated indirectly, based on her intravesical pressure, and was found to be significantly elevated. The patient's urinary volume increased after a 14 mm Hg decrease in the intravesical pressure was achieved by the drainage of ascitic fluid. Intravesical pressure measurement was useful in the management of the general condition of this patient with OHSS.

Iron regulatory protein 2 in ovarian endometrial cysts.

Ovarian endometrial cysts cause some kinds of ovarian cancer, and iron is considered as one factor of carcinogenesis. In contrast, hypoxia is associated with progression, angiogenesis, metastasis, and resistance to therapy in cancer. We investigated hypoxia-induced perturbation of iron homeostasis in terms of labile iron, iron deposition, and iron regulatory protein (IRP) in ovarian endometrial cysts. Iron deposition, expression of IRPs, and a protein marker of hypoxia in human ovarian endometrial cysts were analyzed histologically. The concentration of free iron and the pO2 level of the cyst fluid of human ovarian cysts (n = 9) were measured. The expression of IRP2 under hypoxia was investigated in vitro by using Ishikawa cells as a model of endometrial cells. Iron deposition and the expression of IRP2 and Carbonic anhydrase 9 (CA9) were strong in endometrial stromal cells in the human ovarian endometrial cysts. The average concentration of free iron in the cyst fluid was 8.1 ± 2.9 mg/L, and the pO2 was 22.4 ± 5.2 mmHg. A cell-based study using Ishikawa cells revealed that IRP2 expression was decreased by an overload of Fe(II) under normoxia but remained unchanged under hypoxia even in the presence of excess Fe(II). An increase in the expression of IRP2 caused upregulation of intracellular iron as a result of the response to iron deficiency, whereas the protein was degraded under iron-rich conditions. We found that iron-rich regions existed in ovarian endometrial cysts concomitantly with the high level of IRP2 expression, which should generally be decomposed upon an overload of iron. We revealed that an insufficient level of oxygen in the cysts is the main factor for the unusual stabilization of IRP2 against iron-mediated degradation, which provides aberrant uptake of iron in ovarian endometrial stromal cells and can potentially lead to carcinogenesis.

Creating a Global Community of Practice for Oncofertility.

Fertility preservation in the cancer setting, known as oncofertility, is a field that requires cross-disciplinary interaction between physicians, basic scientists, clinical researchers, ethicists, lawyers, educators, and religious leaders. Funded by the National Institutes of Health, the Oncofertility Consortium (OC) was formed to be a scientifically grounded, transparent, and altruistic resource, both intellectual and monetary, for building this new field of practice capable of addressing the unique needs of young patients with cancer. The OC has expanded its attention to include other nonmalignant conditions that can threaten fertility, and the work of the OC now extends around the globe, involving partners who together have created a community of shared effort, resources, and practices. The OC creates materials that are translated, disseminated, and amended by all participants in the field, and local programs of excellence have developed worldwide to accelerate the pace and improve the quality of oncofertility research and practice. Here we review the global oncofertility programs and the capacity building activities that strengthen these research and clinical programs, ultimately improving patient care.

Treatment and prognosis of bone metastasis from cervical cancer (KCOG-G1202s).

AIM: The early and precise diagnosis and proper palliative treatment of bone metastasis is important for improving the quality of life of cervical cancer patients. The aim of this study was to clarify the clinical features, treatment modalities and prognosis of bone metastasis in cervical cancer patients in Japan. METHODS: The medical records of 75 cervical cancer patients with bone metastasis who were treated between January 2000 and December 2010 were retrospectively analyzed in a multi-institutional study. RESULTS: Fifty-four patients (72.0%) had a single bone metastasis. Bone metastases were found in the spine (46.7%) and pelvis (42.7%). Forty-three patients (57.3%) also had extra-osseous metastases. Most of the patients received radiotherapy, chemotherapy or both, but 25 patients (33.3%) received palliative care only. Bisphosphonates were given as palliative therapy to 25 patients (33.3%). The median overall survival after the diagnosis of bone metastasis was significantly shorter in patients with extra-osseous metastases than in those without extra-osseous metastases (14 vs 5 months; P < 0.05). The survival of patients who received chemotherapy following radiotherapy or concurrent chemoradiotherapy was significantly longer than that of the patients who received palliative care. On multivariate analysis, the presence of extra-osseous metastasis was an independent predictor of survival in patients with bone metastasis from cervical cancer. CONCLUSIONS: Multidisciplinary treatment might improve the prognosis of patients with bone metastasis who do not have extra-osseous lesions.

An evaluation of the Gifu Model in a trial for a new regional oncofertility network in Japan, focusing on its necessity and effects.

Purpose: We evaluated our 2-year experience of the regional oncofertility network in Gifu Prefecture (GPOFS) in order to establish a more sophisticated regional oncofertility networking model in Japan. Methods: Questionnaires were distributed twice in January 2013 to 57 departments in 35 hospitals that provide cancer treatment in Gifu Prefecture, before the establishment of the regional oncofertility network. The number and type of disease of the referred adolescent and young adult (AYA) cancer patients who visited the oncofertility clinic in Gifu University Hospital via the GPOFS were analyzed. Results: The majority of regional oncologists are aware of the need to provide information about oncofertility to their patients, but they cannot provide sufficient information due to their lack of knowledge about reproductive medicine. Eighty-one AYA patients were referred to our clinic for oncofertility counseling in the first 2 years after the establishment of the GPOFS. Conclusions: The GPOFS as the first regional oncofertility network in Japan has just started and may be working to help both AYA cancer patients and their oncologists. The nationwide establishment of the regional oncofertility network model could help both AYA cancer patients and oncologists.

Exploratory study of pre-surgical medications with dienogest or leuprorelin in laparoscopic cystectomy of endometrial cysts.

AIM: The aim of this study was to compare the effects of pre-surgical medication with dienogest or leuprorelin on post-surgical ovarian function. MATERIAL AND METHODS: We conducted an exploratory study in two centers in Japan that comprised 30 patients with ovarian endometrial cysts for whom surgical excision was planned. Patients were enrolled and divided into pre-surgical medication groups with dienogest or leuprorelin for 12 weeks. Thereafter, patients were treated by laparoscopic cystectomy. The primary outcome was ovarian function post-surgery, as assessed by serum anti-Müllerian hormone (AMH) level, antral follicle count (AFC) and resumption of menses. Secondary outcome was the effect of pre-surgical medication, as assessed by the size of endometrial cysts and visual analog scale (VAS) score. Serum AMH, AFC, size of endometrial cysts, and VAS scores were measured at baseline (before medication), after medication (1 day before surgery), and at 4 and 12 weeks post-surgery. RESULTS: Serum AMH levels did not change after pre-surgical medication with either dienogest or leuprorelin. Although AMH decreased after surgery, it recovered by 12 weeks post-surgery in both groups with no statistically significant difference. Mean AFC did not change after surgery in either group. Menses returned by 12 weeks post-surgery in all patients except for those who were pregnant. The rate of reduction of endometrial cyst volume did not differ between the groups. Both dienogest and leuprorelin were associated with substantial reductions in VAS scores. CONCLUSION: There were no statistically significant differences between pre-surgical medication with dienogest and leuprorelin in post-surgical ovarian function. Both medications were effective in reducing endometrial cyst volume and VAS score.

Ovarian mucinous cystadenoma coexisting with benign Brenner tumor: MR imaging findings.

PURPOSE: The purpose of this study was to describe the MR imaging findings of ovarian mucinous cystadenomas coexisting with benign Brenner tumors. MATERIALS AND METHODS: MR images with a 1.5-T unit obtained in five consecutive patients (age range, 51-72 years; mean age, 61 years) with surgically confirmed ovarian mucinous cystadenomas coexisting with benign Brenner tumors were retrospectively reviewed for the presence, configuration, and signal intensity of cystic and solid components of the lesions. RESULTS: Tumors ranged in size from 7.5 to 22.1 cm (mean, 13.5 cm). In four patients (80%), the size of mucinous cystadenoma (range 6.4-22.1 cm; mean, 12.5 cm) was larger than that of Brenner tumor (range 0.2-9.1 cm; mean, 2.8 cm). All patients (100%) had cystic, and three (60%) had solid components. Four patients (80%) showed multilocular cystic, and one (20%) showed unilocular cystic appearance. MR imaging findings were classified into three patterns: (1) a bulky solid mass adjacent to the cystic component, (2) a mural nodule at the periphery of the cystic component, and (3) a cystic component without a detectable solid component. All four multilocular cystic areas exhibited "stained glass" appearances on both T1- and T2-weighted images, and all three solid areas showed homogeneous hypointensity on T2-weighted images. CONCLUSION: Mucinous cystadenomas were often larger than the coexisting benign Brenner tumors. Mucinous cystadenomas coexisting with benign Brenner tumors should be considered when multilocular or unilocular cystic components are accompanied by homogeneously hypointense solid components on T2-weighted images.

Metal transcription factor-1 is involved in hypoxia-dependent regulation of placenta growth factor in trophoblast-derived cells.

Placenta growth factor (PlGF) is a placental angiogenic factor. Metal-responsive transcription factor (MTF)-1 was reported to take part in the hypoxic induction of PlGF in RAS-transformed mouse fibroblasts. We contrarily showed that PlGF mRNA and protein levels decreased under hypoxia in a choriocarcinoma BeWo cell line derived from trophoblast. In this report, we examined whether hypoxia-dependent regulation of the PlGF gene in these cells also depends on MTF-1. We analyzed the effect of hypoxia on MTF-1 expression, and it was revealed to be decreased. Moreover, MTF-1 small interfering RNA treatment decreased PlGF mRNA level. To investigate the transcription of PlGF under hypoxia, we cloned promoter region of the human PlGF. Promoter deletion analysis suggested that triple repeats of metal-responsive element located between -511 and -468 bp in the promoter are important for the hypoxic regulation of PlGF. Treatment with MTF-1 small interfering RNA resulted in the significant decreased luciferase activity in PlGF reporter constructs. Chromatin immunoprecipitation showed the binding of the MTF-1 protein to the promoter region. We examined MTF-1 immunoreactivity in trophoblasts of term placental tissue from patients with normal pregnancies and preeclampsia, which represents a condition of placental hypoxia. Immunoreactivity of the MTF-1 protein was decreased in placentas from pregnant women with preeclampsia when compared with those from normal pregnant women. Taken together, these findings suggest that MTF-1 is involved in hypoxia-dependent regulation of PlGF in trophoblast-derived cells.

Parathyroid hormone-related protein-secreting uterine endometrioid adenocarcinoma.

The diagnosis of parathyroid hormone-related protein (PTHrP)-secreting metastatic uterine endometrioid cancer was made in a 32-year-old Japanese woman with humoral hypercalcemia of malignancy. The primary endometrial cancer had been removed, and the tumor was diagnosed as Grade 1 endometrioid adenocarcinoma with shallow myometrial invasion. Salvage chemotherapy (paclitaxel and calboplatin) was started from 5 months after surgery when recurrent tumors were detected in the peritoneum and liver. Despite the salvage chemotherapy, the tumor progressed and hypercalcemia became evident with elevated PTHrP whereas no bone metastasis was identified. To the best of our knowledge, this is the first reported case of hypercalcemia due to PTHrP secretion in uterine endometrioid adenocarcinoma.

Rapid changes of flow-mediated dilatation after surgical menopause.

OBJECTIVES: Estrogen acts directly on endothelial nitric oxide synthase through a non-genomic mechanism, resulting in rapid dilatation of blood vessels. In this study, we examined the change of endothelial function after surgical menopause. METHODS: In 20 subjects who underwent gynecological operations (ovariectomy (OVX) 12, sham (SHAM) operation 8), postoperative changes of flow-mediated dilatation (FMD) of the brachial artery were examined using ultrasonography. Postoperative changes of the response to nitroglycerin (NTG) were also studied in these patients. RESULTS: In the OVX group, significant decreases of FMD were observed 1 week after the operation, although no changes were observed in the response to NTG. In the SHAM group, no remarkable changes of FMD or the response to NTG were observed after the operation. CONCLUSIONS: OVX influences endothelium-dependent vasodilatation within as little as 1 week. Therefore, it may be important to address the rapid changes of circulation after surgical menopause in order to prevent cardiovascular disease.