Direct intra-tumoral injection of zinc-acetate halts tumor growth in a xenograft model of prostate cancer

Intracellular levels of zinc have shown a strong inverse correlation to growth and malignancy of prostate cancer. To date, studies of zinc supplementation in prostate cancer have been equivocal and have not accounted for bioavailability of zinc. Therefore, we hypothesized that direct intra-tumoral injection of zinc could impact prostate cancer growth. In this study, we evaluated the cytotoxic properties of the pH neutral salt zinc acetate on the prostate cancer cell lines PC3, DU145 and LNCaP. Zinc acetate killed prostate cancer cell lines in vitro, independent of androgen sensitivity, in a dose-dependent manner in a range between 200 and 600 μM. Cell death occurred rapidly with 50% cell death by six hours and maximal cell death by 18 hours. We next established a xenograft model of prostate cancer and tested an experimental treatment protocol of direct intra-tumoral injection of zinc acetate. We found that zinc treatments halted the growth of the prostate cancer tumors and substantially extended the survival of the animals, whilst causing no detectable cytoxicity to other tissues. Thus, our studies form a solid proof-of-concept that direct intra-tumoral injection of zinc acetate could be a safe and effective treatment strategy for prostate cancer

A Randomized Trial of Progesterone in Women with Bleeding in Early Pregnancy

BACKGROUND Bleeding in early pregnancy is strongly associated with pregnancy loss. Progesterone is essential for the maintenance of pregnancy. Several small trials have suggested that progesterone therapy may improve pregnancy outcomes in women who have bleeding in early pregnancy. METHODS We conducted a multicenter, randomized, double-blind, placebo-controlled trial to evaluate progesterone, as compared with placebo, in women with vaginal bleeding in early pregnancy. Women were randomly assigned to receive vaginal suppositories containing either 400 mg of progesterone or matching placebo twice daily, from the time at which they presented with bleeding through 16 weeks of gestation. The primary outcome was the birth of a live-born baby after at least 34 weeks of gestation. The primary analysis was performed in all participants for whom data on the primary outcome were available. A sensitivity analysis of the primary outcome that included all the participants was performed with the use of multiple imputation to account for missing data. RESULTS A total of 4153 women, recruited at 48 hospitals in the United Kingdom, were randomly assigned to receive progesterone (2079 women) or placebo (2074 women). The percentage of women with available data for the primary outcome was 97% (4038 of 4153 women). The incidence of live births after at least 34 weeks of gestation was 75% (1513 of 2025 women) in the progesterone group and 72% (1459 of 2013 women) in the placebo group (relative rate, 1.03; 95% confidence interval [CI], 1.00 to 1.07; P=0.08). The sensitivity analysis, in which missing primary outcome data were imputed, resulted in a similar finding (relative rate, 1.03; 95% CI, 1.00 to 1.07; P=0.08). The incidence of adverse events did not differ significantly between the groups. CONCLUSIONS Among women with bleeding in early pregnancy, progesterone therapy administered during the first trimester did not result in a significantly higher incidence of live births than placebo. (Funded by the United Kingdom National Institute for Health Research Health Technology Assessment program; PRISM Current Controlled Trials number, ISRCTN14163439. opens in new tab.

Who is at risk of endometrial cavity breach at laparoscopic myomectomy?

Background: Submucous and large intramural fibroids cause heavy menstrual bleeding and can negatively impact reproductive outcomes. Large submucous and non-cavity distorting fibroids need to be removed laparoscopically. One of the risks of a laparoscopic myomectomy is breaching the endometrial cavity and there have been suggestions that this increases the risk of intrauterine adhesions. The aim of this study was to examine the role of various demographic and pre-operative ultrasound variables at predicting the risk of endometrial cavity breach during laparoscopic myomectomy. Methods: This was a retrospective study of women who underwent a laparoscopic myomectomy. Women who had more than one fibroid removed and women who did not have pre-operative ultrasound images available were excluded. The size of the fibroid, minimum distance from the endometrial cavity, surface area, intra-cavity surface area, protrusion ratio and extra-cavity size as well as the women's age, parity and pre-operative GnRH analogue use were recorded. The outcome measure was the breach of the endometrial cavity at myomectomy. Univariate analysis was performed to identify variables that are associated with a cavity breach. A logistic regression analysis was used to identify the most significant predictor of a breach. Results: A total of 66 women were included in the study. From these, 10 women sustained a cavity breach. All pre-operative ultrasound variables, i.e. minimum distance of the fibroid from the cavity (p=0.001), protrusion ratio (p=0.001), total surface area (p=0.020), intra-cavity surface area (p=0.001), size (p=0.030) and extra-cavity size (p=0.001) were statistically different between the group that had a cavity breach and the group that did not. In a logistic regression model, protrusion ratio was selected as the best predictor of a breach (OR 1.22; 95% CI 1.10 - 1.37). All breaches occurred in women who were not given GnRH analogue. Conclusion: Identifying patients at increased risk of a cavity breach facilitates better individualized pre-operative counselling regarding the risk of a breach and the possibility of intrauterine adhesions. It will also trigger more intra-operative vigilance to minimize the risk of breaching the cavity and, subsequently, the risk of intrauterine adhesions if a breach does occur

The cost-effectiveness of progesterone in preventing miscarriages in women with early pregnancy bleeding: an economic evaluation based on the PRISM Trial

Objectives: To assess the cost‐effectiveness of progesterone compared with placebo in preventing pregnancy loss in women with early pregnancy vaginal bleeding. Design: Economic evaluation alongside a large multi‐centre randomised placebo‐controlled trial. Setting: Forty‐eight UK NHS early pregnancy units. Population: Four thousand one hundred and fifty‐three women aged 16–39 years with bleeding in early pregnancy and ultrasound evidence of an intrauterine sac. Methods: An incremental cost‐effectiveness analysis was performed from National Health Service (NHS) and NHS and Personal Social Services perspectives. Subgroup analyses were carried out on women with one or more and three or more previous miscarriages. Main outcome measures: Cost per additional live birth at ≥34 weeks of gestation. Results: Progesterone intervention led to an effect difference of 0.022 (95% CI −0.004 to 0.050) in the trial. The mean cost per woman in the progesterone group was £76 (95% CI −£559 to £711) more than the mean cost in the placebo group. The incremental cost‐effectiveness ratio for progesterone compared with placebo was £3305 per additional live birth. For women with at least one previous miscarriage, progesterone was more effective than placebo with an effect difference of 0.055 (95% CI 0.014–0.096) and this was associated with a cost saving of £322 (95% CI −£1318 to £673). Conclusions: The results suggest that progesterone is associated with a small positive impact and a small additional cost. Both subgroup analyses were more favourable, especially for women who had one or more previous miscarriages. Given available evidence, progesterone is likely to be a cost‐effective intervention, particularly for women with previous miscarriage(s)