Nationwide survey of Japanese breast oncology and reproductive endocrinology departments about the impact of breast cancer treatment on fertility.

The purpose of this study is to assess the impact of breast cancer treatment on the reproductive potential. We conducted a nationwide survey of breast oncology and reproductive endocrinology and infertility (REI) departments using a questionnaire designed to assess the impact of breast cancer treatment on fertility. We received responses from 312 breast oncology departments (response rate, 31.9%) and 541 REI departments (response rate, 50.9%). The most common method of achieving pregnancy reported by breast oncology departments was natural insemination (69.6%), followed by assisted reproductive technology ( 15.6%) and intrauterine insemination (IUI; 14.8%). The most common method of achieving pregnancy reported by REI departments was conventional in vitro fertilization and/or intracytoplasmic sperm injection (51.0%), followed by natural insemination with or without ovulation induction (40.0%) and IUI (8.0%). The overall pregnancy rate for patients who underwent treatment for infertility at REI departments after breast cancer treatment was 39.0%. Vast patients who experienced breast cancer treatments conceived mainly by natural insemination based on the data from breast oncology departments. On the other hand, 61.0% of the patients who visited REI departments presumably due to infertility by natural insemination did not conceive even by infertility treatments with exclusive knowledge in REI departments.

Ovarian hyperstimulation closely associated with resumption of follicular growth after chemotherapy during tamoxifen treatment in premenopausal women with breast cancer: a multicenter retrospective cohort study.

BACKGROUND: We previously reported that tamoxifen (TAM)-induced ovarian hyperstimulation (OHS) is associated with high serum concentrations of estradiol in premenopausal women with breast cancer. To investigate risk factors for TAM-induced OHS, we performed a retrospective multicenter study. METHODS: Premenopausal patients who received surgical therapy for endocrine-dependent breast cancer (n = 235) were recruited in this study and classified into 4 groups: group A, treated with TAM alone; group B, TAM treatment after 2-year-combined therapy with a gonadotropin-releasing hormone (Gn-RH) agonist; group C, TAM treatment after chemotherapy; group D, 5-year-combined therapy with TAM and a Gn-RH agonist. A serum estradiol value of more than 300 pg/mL or mean follicular diameter of more than 30 mm was defined as OHS. RESULTS: The incidence of OHS in group A (n = 13/26, 50.0%) was significantly higher than those in group B (n = 17/63, 27.0%), group C (n = 20/110, 18.2%), and group D (n = 0/36, 0%). The incidence of OHS was significantly correlated with aging, and the median serum concentration of estradiol in the presence of OHS was 823.0 pg/mL. The incidence of OHS (less than 47 years old) was 62.5% in group A, 48.6% in group B, and 28.2% in group C, respectively. Notably, the incidence rate of OHS following amenorrhea in group C (n = 13/20, 65.0%) was significantly higher than that in group B (n = 1/17, 5.9%). CONCLUSIONS: These findings indicate that the onset of OHS following amenorrhea was common in the post-chemotherapeutic group, while its ratio was low in the group after Gn-RH analog treatment, suggesting that combined treatment-based management involving TAM therapy is necessary for premenopausal patients with breast cancer.

A successful case of neoadjuvant chemotherapy and radical hysterectomy during pregnancy for advanced uterine cervical cancer accompanied by neonatal erythroderma.

Recent reports showed that neoadjuvant chemotherapy (NAC) has been successfully applied to treat advanced uterine cervical cancers during pregnancy. However, its side effects on the fetus remain unclear. Here, we report a 33-year-old primipara who underwent four courses of NAC therapy, paclitaxel and cisplatin, from 17 to 27 weeks of gestation due to uterine cervical cancer stage IB2. At 31 weeks of gestation, cesarean section and radical hysterectomy were performed, and a female baby weighing 1446 g was born. Although pre- and postnatal courses were uneventful, neonatal erythroderma over the entire body was observed just after delivery. The pathological diagnosis was ichthyosiform erythroderma, which was later demonstrated to be keratitis-ichthyosis-deafness syndrome, by exome sequencing analysis. Although her skin disorder was consistent with keratitis-ichthyosis-deafness syndrome, the skin condition gradually improved after delivery. These findings suggest that NAC therapy during pregnancy might cause or exacerbate systemic skin lesions in the fetus/neonate.

Subserous invasion of VEGF-C-producing cancer cells is a possible risk factor for ileal ulceration in the non-metastatic mucosal layer during bevacizumab-combined chemotherapy for recurrent ovarian cancer: A case report.

A 65-year-old woman received chemotherapy using taxane and carboplatin prior and following optimal debulking surgery for ovarian cancer stage IV. Five months later, intra-abdominal recurrence was diagnosed, and second-line chemotherapy using nogitecan and bevacizumab was administered. After five courses, the patient presented with a symptom of subileus and subsequent intestinal perforation occurred. An emergent surgery revealed two perforation sites and longitudinally extended ulcerative lesions in the ileum. Pathologically, although metastatic sites were not observed in the submucus layer just beneath the ulcers, there were a number of vascular endothelial growth factor (VEGF)-C-positive cancer cell invasion sites along with marked edema and an increase of the lymphatic endothelial cell marker 'podoplanin'-positive cells in subserous regions. Since bevacizumab is able to inhibit VEGF-A, but not VEGF-C, and induce compensatory increase in VEGF-C production, these findings suggest that the local disturbance of lymphatic circulation in the subserous regions by VEGF-C-producing cancer cells is a possible risk factor for the development of intestinal ulceration and perforation during bevacizumab therapy.

Tamoxifen-induced ovarian hyperstimulation during premenopausal hormonal therapy for breast cancer in Japanese women.

PURPOSE: Tamoxifen is an anti-estrogenic drug that is widely used for endocrine-dependent breast cancer as adjuvant hormonal therapy, and its use has been reported to be frequently associated with high levels of serum estradiol. Since the population of premenopausal women receiving tamoxifen therapy is growing in Japan, we retrospectively analyzed the incidence of ovarian hyperstimulation by tamoxifen therapy in Japanese women. METHODS: Eleven patients who received surgical therapy for endocrine-dependent breast cancer and showed high values of serum estradiol during post-operative tamoxifen therapy were recruited in this study and evaluated by examining the serum concentration of follicular stimulating hormone (FSH) and follicular development. RESULTS: The mean age, serum concentrations of estradiol and FSH, and follicular diameter were 41.3 years old, 1015.8 pg/mL, 11.8 mIU/mL, and 3.47 cm, respectively. In 6 cases, multiple follicular development was observed, while the other cases showed single follicular development with a mean serum estradiol level of 848.6 pg/mL and follicular diameter of 4.46 cm. There was no significant difference in age or FSH concentration between the two groups. The mean periods from the start of the single administration of tamoxifen to the initial detection of a high estradiol concentration was 716.5 days. CONCLUSIONS: These findings indicate that tamoxifen could stimulate the ovarian function even after 2-year treatment. Since single and multiple follicular developments with large sizes were observed, dual mechanisms through the inhibition of both negative and positive feedback to the hypothalamic-pituitary-axis can be proposed to explain the adverse effects of tamoxifen on ovarian function.

Evaluation of transvaginal peritoneal surgery in young female patients.

BACKGROUND: The transvaginal approach is being used for natural orifice transluminal endoscopic surgery (NOTES), and reports of the clinical use of transvaginal NOTES have increased rapidly. However, hasty use of a transvaginal route may cause unexpected complications. Infertility or dyspareunia after transvaginal NOTES in young women is one of the most important issues to be resolved. The purpose of this study was to assess long-term complications, including infertility and dyspareunia, after transvaginal peritoneal surgery. METHODS: An anonymous questionnaire was sent to 73 young patients who had undergone ovarian cystectomy using a transvaginal approach from 2003 to 2011. The questionnaire contained 15 questions; 6 dealt with fertility, and 8 dealt with discomfort after surgery. A 5-point scale was used to evaluate patients' overall satisfaction with surgery. RESULTS: Forty-four (60 %) questionnaires were returned. The patients' mean age was 33.0 years, and the mean postoperative follow-up period was 16.5 months. Of responders younger than age 40 years, 24 did not use contraception, and 9 (38 %) conceived. The pregnancy rate among women younger than age 30 years was 60 %. Two (5 %) women reported temporary dyspareunia 1 month after surgery, but none developed permanent dyspareunia. The average patient satisfaction score was 4.12. CONCLUSIONS: There was no evidence to suggest that transvaginal peritoneal surgery causes infertility or dyspareunia. The majority of patients gave a high evaluation to vaginal ovarian cystectomy, suggesting the usability of a transvaginal approach for intraperitoneal surgery in young premenopausal women.

An alternative system for transvaginal removal of dermoid cyst and a comparative study with laparoscopy.

The objective was to introduce a new system for transvaginal removal of ovarian cyst and to evaluate its feasibility. With a new transvaginal system, ultrasound-assisted culdotomy, and laparoscopy supported cystectomy if vaginal procedure failed. The authors conducted a retrospective review in which 35 cases using new vaginal ovarian cystectomy were compared with 40 cases of laparoscopic cystectomy for the treatment of dermoid cyst. All cystectomies were completed without conversion to laparotomy and complications. In a case from vaginal group, laparoscopy was required. No differences existed in operating time, hemoglobin decrease, and C-reactive protein value between groups. Laparoscopically supported vaginal ovarian cystectomy with ultrasound-guided culdotomy was equivalent to laparoscopic cystectomy as to invasiveness and preserved the option of a completely vaginal approach. When a presumed benign dermoid cyst is located in cul-de-sac, this operation may represent a preferable alternative to an exclusively laparoscopic or exclusively vaginal ovarian cystectomy.

Frequency of myeloid dendritic cells can predict the efficacy of Wilms' tumor 1 peptide vaccination.

BACKGROUND: The object of this study was to investigate the clinical predictive capability of peripheral myeloid dendritic cells (DCs) in Wilms' tumor 1 (WT1) vaccine therapy for patients with gynaecological cancer. PATIENTS AND METHODS: Six patients with WT1/human leukocyte antigen (HLA)-A*2402-positive gynaecological cancer were included in this study. The patients received intradermal injections of a modified 9-mer WT1 peptide every week for 12 weeks. Peripheral blood samples were obtained at 0, 4, 8 and 12 weeks after the initial vaccination. Circulating DCs were detected by flow cytometry. RESULTS: The frequencies of CD14(+)CD16(+)CD33(+)CD85(+) myeloid DCs were significantly higher in the therapeutically effective group than in therapeutically inert group (p<0.05). CONCLUSION: These results suggested that myeloid DCs, which should be associated with inducing cytotoxic T-cells, provided additional prognostic information in the use of cancer peptide vaccine.

The culdotomy two U procedure for vaginal ovarian cystectomy.

When transvaginal removal of ovarian cysts is performed successfully, the procedure compares favorably with laparoscopy in terms of invasiveness. However, the approach into peritoneal cavity has been laborious. The objective was to evaluate feasibility of an ultrasound-guided culdotomy using a newly developed umbrella needle. New culdotomy was performed on 36 patients with ovarian cysts. Each cyst was directly punctured by the needle from vagina under ultrasound guidance. The vaginal walls on both sides of the needle were incised with an electric scalpel. Through the wound, cyst was exteriorized and enucleated. Preoperative characteristics of patients, outcome, operating time, blood loss, complications, and cyst histology were analyzed. Culdotomy was performed successfully in all cases. Operating time was less than 10 minutes and blood loss was less than 10 mL. There were no culdotomy-associated complications. Culdotomy assisted by ultrasound imaging and an umbrella needle is a simple, safe, and reliable method for vaginal ovarian cystectomy.

Wilms' tumor 1 (WT1) peptide immunotherapy for gynecological malignancy.

BACKGROUND: The object of this study was to investigate the safety and clinical response of immunotherapy targeting the WT1 (Wilms' tumor 1) gene product in patients with gynecological cancer. PATIENTS AND METHODS: Twelve patients with WT1/human leukocyte antigen (HLA)-A*2402-positive gynecological cancer were included in a Phase II clinical trial of WT1 vaccine therapy. In all the patients, the tumors were resistant to standard therapy. The patients received intradermal injections of a HLA-A*2402-restricted, modified 9-mer WT1 peptide every week for 12 weeks. Tumor size, which was measured by computed tomography (CT), was determined every 4 weeks. The responses were analyzed according to Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS: The protocol was well tolerated; only local erythema occurred at the WT1 vaccine injection site. The clinical responses were as follows: stable disease (SD) in 3 patients and progressive disease (PD) in 9 patients. No patients had a complete (CR) or partial response (PR). The disease control rate was 25.0%. CONCLUSION: Although a small, uncontrolled, nonrandomized trial, this study showed that WT1 vaccine therapy for patients with gynecological cancer was safe and produced a clinical response.

Granulysin produced by uterine natural killer cells induces apoptosis of extravillous trophoblasts in spontaneous abortion.

Immune changes are known to occur in recurrent spontaneous abortion, but it is unclear whether either maternal natural killer (NK) cells or T cells attack fetus-derived trophoblasts. To clarify the immunological causes of spontaneous abortion, we examined the relationship between cytotoxic granule proteins in decidual lymphocytes, such as granulysin, granzyme B, and perforin, and the induction of apoptosis in extravillous trophoblasts (EVTs). The number of granulysin-positive CD56(bright) NK cells increased significantly in the decidua basalis during spontaneous abortion compared with normal pregnancy; however, granzyme B- and perforin-positive cells did not change. Interestingly, the expression of granulysin was also detected in the nuclei of EVTs in spontaneous abortion samples. When IL-2-stimulated CD56(bright) NK cells were cocultured with EVT cells (HTR-8/SV40neo), granulysin was found initially in the cytoplasm and then accumulated in the nuclei of the HTR-8/SV40neo cells. Furthermore, transfected cells expressing a GFP-granulysin fusion protein induced apoptosis in HTR-8/SV40neo cells independently of caspases. Our results suggest that granulysin-positive uterine NK cells attack EVTs; subsequently, the uNK-derived granulysin actively accumulates in the nuclei of EVTs, causing the death of EVTs due to apoptosis. These data support a new apoptosis pathway for trophoblasts via uNK-derived granulysin, suggesting that granulysin is involved in spontaneous abortion.

Cytokine profile of natural killer cells in early human pregnancy.

PROBLEM: To examine whether the NK1/NK2/NK3/NKr1 paradigm can be adapted in natural killer (NK) cells. METHOD OF STUDY: Mononuclear cells were isolated from peripheral blood and/or decidua in healthy non-pregnant women (n = 17), early pregnant women (6-12 weeks of gestation, n = 17) and miscarriage cases (6-11 weeks of gestation, n = 10). We investigated the production of transforming growth factor (TGF)-beta, interleukin (IL)-4, IL-5, IL-10, IL-13, interferon (IFN)-gamma and tumor necrosis factor-alpha from peripheral blood- and decidual-CD56bright NK cells and -CD56dim NK cells by flow cytometry. RESULTS: In the peripheral blood of the non-pregnant subjects, the main populations of CD56bright NK cells and CD56dim NK cells were IFN-gamma-producing NK1 type cells. Populations of IL-10-producing NKr1 type cells in peripheral blood CD56bright NK cells and CD56dim NK cells in early pregnant women were significantly greater compared with those in non-pregnant women, and these cells population decreased in miscarriage cases. In the early pregnancy decidua, the main populations of CD56bright NK cells and CD56dim NK cells were TGF-beta-producing NK3 type cells, and NK1 type cells were rare. NK3 type cells in decidua were significantly decreased in miscarriage cases compared with those in normal pregnant subjects. IL-4-, IL-5- or IL-13-producing NK2 type cells were rare in peripheral blood and decidua. CONCLUSION: These data support the NK1/NK2/NK3/NKr1 hypothesis. NKr1 type cells in peripheral blood and NK3 type cells in decidua might play some important roles in the maintenance of pregnancy by regulation of maternal immune function.

IDO expression on decidual and peripheral blood dendritic cells and monocytes/macrophages after treatment with CTLA-4 or interferon-gamma increase in normal pregnancy but decrease in spontaneous abortion.

Recent data demonstrated that CD4+CD25+ regulatory T (Treg) cells and an enzyme called indoleamine 2,3-dioxygenase (IDO) mediate maternal tolerance to the fetus. Interestingly, Treg cells express the CTLA-4 molecule on their surface, and B7 (CD80/86) ligation by CTLA-4 enhanced IDO activity of dendritic cells (DCs) and monocytes by the induction of interferon gamma (IFN-gamma) production. In this study, we studied the IDO expression on peripheral blood monocytes and decidual monocytes or DCs after treatment with CTLA-4/Fc fusion protein or IFN-gamma using flow cytometry. IDO expressions on both peripheral blood DC and decidual DC and monocytes were up-regulated during normal pregnancy. On the other hand, both IDO expression on DC and monocytes after IFN-gamma treatment or CTLA-4 treatment were decreased in spontaneous abortion cases. The expression of CD86 on peripheral blood and decidual monocytes and DC in spontaneous abortion cases was lower compared with those in normal pregnancy subjects. Also, IFN-gamma production by decidual and peripheral blood mononuclear cells after CTLA-4/Fc treatment in spontaneous abortion cases was significantly lower than those in normal pregnancy subjects. These data suggest that CTLA-4 on Treg cells up-regulates IDO expression on decidual and peripheral blood DC and monocytes by the induction of IFN-gamma production.