A first-in-human study of the novel metabolism-based anti-cancer agent SM-88 in subjects with advanced metastatic cancer.

Purpose SM-88 (D,L-alpha-metyrosine; racemetyrosine) is a novel anti-cancer agent, used with melanin, phenytoin, and sirolimus (SMK Therapy). This pilot first-in-human study characterized the safety, tolerability, and efficacy of SMK Therapy in subjects with advanced metastatic cancer. Methods All subjects (n = 30) received SMK Therapy for an initial 6 week Cycle (5 days on, 2 off per week) and continued if well tolerated. Safety signals, clinical response, overall survival, progression free survival (PFS), and quality of life changes were assessed. Results The most common drug related adverse events were hyperpigmentation and rash. All drug related adverse events were mild to moderate in intensity. Following treatment with SMK Therapy, 4 subjects achieved complete response, 6 partial response, and 17 stable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (total clinical benefit 90%). Responses were observed within 6 weeks, and continued to improve, with 3 complete and 3 partial responders achieving best response after at least 3.2 months. Durable stable disease was observed, lasting a median duration of 11 months (range 1-31 months). Median overall survival for all subjects was 29.8 months, and median PFS was 13 months. Following 6 weeks of treatment, most (83.3%) subjects showed an improvement in Eastern Cooperative Oncology Group (ECOG) score and an improvement in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ 30) global health status (baseline 61.2 ± 25.0; end of Cycle 1 80.7 ± 14.7; n = 29; p < 0.001). Conclusions The results of this study support continued development of SM-88.

Uterus transplantation: on the edge.

Uterus transplantation for absolute uterus factor infertility is moving closer to human trials. The indication for uterus transplantation is evident as is its potential to ameliorate the social and personal burdens of these patients. The extensive collaborative research efforts between animal works, advancements in transplantation medicine, and immune suppression have culminated in demonstrating its apparent feasibility. As for the concerns regarding its risk, in perspective it is similar to other high-risk pregnancies. Moving uterus transplantation toward clinical applications obviously will require a continued commitment of research and support.

Oral diindolylmethane (DIM): pilot evaluation of a nonsurgical treatment for cervical dysplasia.

OBJECTIVE: Standard surgical treatment for CIN may impair fertility generating a need for alternative treatment options. We tested the efficacy and toxicity of oral DIM in the treatment of CIN 2 or 3 lesions. METHODS: Patients with biopsy-proven cervical intraepithelial neoplasia (CIN) 2 or 3 scheduled for loop electrosurgical excision procedure (LEEP) were randomized 2:1 to receive diindolylmethane (DIM) (BioResponse-DIM, BioResponse, Boulder, CO) orally at approximately 2 mg/kg/day for 12 weeks or placebo (defatted rice bran, BioResponse). Subjects were evaluated every 3-4 months for 1 year. Analysis of data up to 1 year was assessed including Pap smear, HPV, colposcopy, biopsy and physical examination were performed at follow-up. Central pathology review confirmed all histology diagnoses. RESULTS: To date, 64 subjects (mean age 28 years, range 18-61) have been enrolled (45 in the DIM arm, 19 in the placebo arm), with 60 available for analysis. Average follow-up was 6 months. At enrollment, 58% were diagnosed with CIN 2 and 42% with CIN 3, 57% of subjects were Caucasian, 15% African American, 12% Hispanic and 17% Asian. During treatment 2 subjects (3%) complained of nausea (grade 2) at the 3- to 4-month visit. No systemic toxicities were observed (normal CBC, LFTs, comprehensive metabolic). Forty-six subjects had biopsies at first follow-up (77%). Twenty-one subjects (47%) in the DIM group had improved CIN with a decrease by 1-2 grades or a normal result. Median time to improvement was 5 months. Improved Pap smear was seen in 49% (22/45) with either a less severe abnormality or normal result. Colposcopy improved in twenty-five subjects in the DIM group (56%). Of these 25 subjects, 21 (84%) had improved colposcopic impression, 13 (52%) had a decrease in involved quadrants and 18 (72%) had a decrease in lesion number. Complete colposcopic response was observed in 4 subjects (9%). Stratifying by level of dysplasia, age, race, HPV status, tobacco use, contraceptive used did not alter the results. At median follow-up of 6 months, 85% of subjects have not required LEEP based on routine clinical triage of improving global assessment. There was no statistically significant difference in any outcome between the DIM and placebo group. CONCLUSION: Oral DIM at 2 mg/kg/day is well tolerated with no significant toxicity. We observed a high rate of clinically significant improvement in confirmed CIN 2 or 3 lesions among both treatment groups in this randomized clinical trial.

A pilot safety and tolerability study of a nonhormonal vaginal contraceptive ring.

OBJECTIVE: To conduct a pilot safety and tolerability study of the Ovaprene ring (Poly-Med Inc., Clemson University, Clemson, South Carolina) as a barrier contraceptive. STUDY DESIGN: Open-label, single-arm, observational study in a convenient sample of volunteers. Women meeting inclusion criteria and using another contraceptive method were instructed in proper insertion of the ring at the completion of their menses, with removal at their subsequent menses or 29 days. Baseline Pap smears, vaginal cultures and colposcopy were performed, with follow-up postcoital testing and acceptability questionnaires. RESULTS: Twenty women enrolled; all completed one cycle of use. Rings were inserted properly and retained in place (range, 5-29 days). Patient questionnaires revealed no pain or bleeding, and no colposcopic abnormalities were seen. Semiquantitative cultures yielded no significant changes in vaginal flora. Postcoital testing revealed nonviable sperm (motile/total, mean count/10 high power fields) 2/ > 20 in the vaginal pool and 0/0 in cervical mucus. There were no serious adverse effects. CONCLUSION: The Ovaprene device is well tolerated and acceptable to sexually active women and their partners.

Uterus transplant: evidence and ethics.

Absolute uterine infertility affects millions of women in the United States and more throughout the world. For instance, each year in the United States about 5,000 hysterectomies are performed in women under the age of 24. In total, nearly 9 million women of reproductive age have had a hysterectomy. Based on fecundity rates, thousands of these women may be candidates for uterus transplantation. An ongoing study enrolling some of these potential recipients onto a uterus transplant "waiting list" has revealed that most of these women have Rokitansky syndrome, hysterectomy secondary to endometriosis, cervical cancer, or compelling personal accounts justifying their candidacy. Fertility restoration by uterus transplantation was derived from fertility preservation research, including the development of the radical trachelectomy, oxygenation and perfusion of the in situ uterus, and work with organ donor networks. A decade of modern animal research set the foundation for this human work. Ongoing experiments include stable, long-term large animal allografts for investigating immunosuppression regimens and other transplantation details. Each of the animal models has contributed to the current knowledge base. Recently, nonhuman primates have been used to further investigate the possibility of human uterus transplantation. Nonhuman primate anatomy is analogous to that of humans with notable exceptions. The first human uterus transplant surgery took place in 2000, but it did not result in a pregnancy. However, taken in total, the magnitude of the intervening work from multiple groups throughout the world has made uterus transplantation a topic for discussion. It may also soon be a reality.

Uterus transplant techniques in primates: 10 years' experience.

Preserving and restoring fertility are important quality-of-life outcomes for cancer survivors and others who cannot bear children. Transplantation has advanced sufficiently to allow nonvital organ transplant to become a reality. Together, research on reproductive organs and transplantation has resulted in live human births from ovary transplants used to treat absolute ovary factor infertility. Each year, approximately 5,000 women under the age of 25 years undergo a hysterectomy. From various other causes, approximately 9 million women of childbearing age in the United States currently have absolute uterine factor infertility due to the absence of the uterus. Research on uterus transplantation has been reported for decades from multiple institutions around the world. Our group has been involved in the area for more than 10 years. To encourage other investigations in this area, we summarize our results in primates as a proof of concept that uterus transplants can be theoretically done.

Human uterus retrieval from a multi-organ donor.

OBJECTIVE: To determine if a uterus can be retrieved for reproductive organ transplantation and to describe the surgical technique. METHODS: We participated in a local organ donor network retrieval team for over 6 months. Heart-beating, brain-dead multi-organ donors were identified through an existing donor network following routine protocols. RESULTS: After institutional review board and organ donor network approval of the uterus transplantation project, approximately 1,800 eligible organ donors were identified as required by legislation. Multi-organ procurement surgery took place in approximate 150 of these, with nine specifically consented for the uterus retrieval. Regularly performed multi-organ transplantation retrievals included the uterus without complications in eight donors. Pedicles used included the ovarian, uterine, or internal iliac vessels. After retrieval, serial histology sections throughout the period of cold ischemia, taken every 15-30 minutes, showed no signs of change over 12 hours of cold ischemia. CONCLUSION: The human uterus can be obtained from local organ donor networks using existing protocols. LEVEL OF EVIDENCE: III.