Emerging therapies for postmenopausal vaginal atrophy

Symptoms related to vaginal atrophy are a significant problem for postmenopausal women and estrogen has been the gold standard for its treatment. A number of recent reviews of vaginal estrogen products are available. This review will, therefore, focus on other products and potential products for this indication, including the tissue selective estrogen complex and selective estrogen receptor modulators. Additionally, lesser-studied approaches will be discussed.     

Vaginal brachytherapy alone for patients with Stage II endometrial cancer with inner half cervical stromal invasion

PurposeThe purpose of this study was to review outcomes of women with Stage II endometrial carcinoma with inner half cervical stromal invasion treated with adjuvant vaginal brachytherapy (VB) alone.Methods and MaterialsA single-institution retrospective chart review identified consecutive patients with Stage II endometrial cancer and inner half cervical stromal invasion treated with VB alone from 2011 to 2015. Patients who received chemotherapy or external beam radiotherapy were excluded. Patient and disease characteristics were collected. Association between variables and outcomes were assessed using Fisher's exact or Wilcoxon rank sum test.ResultsFifty-seven patients were identified over 5 years with a median followup of 46.8 months. Carcinoma was endometrioid Grade 1 (43.9%), 2 (36.8%), 3 (5.3%), or serous (14.0%). Depth of myometrial invasion was inner half in 75.4%. Lymphovascular invasion was seen in 28.1%, and lymph node assessment was performed in 43.9% of patients. The median depth of cervical stromal invasion was 1.25 mm (n = 48 patients). The median percentage of the cervical stromal wall invaded by tumor (obtained in 40 patients) was 16.7%. Seven (12.3%) patients recurred at a median of 16.9 months. Five-year estimates of progression-free survival and overall survival were 81.5% and 78.5%, respectively. The only factor associated with recurrence, progression-free survival or overall survival on bivariate analysis was high-grade (Grade 3 or serous) disease (p = 0.031).ConclusionsVB alone can be considered for Stage II patients with inner half cervical stromal invasion and Grade 1–2 disease. Systemic therapy may be required for patients with Grade 3 and serous histology as 75% (3/4) of these recurrences were outside the pelvis.     

DNA transfer during laundering may yield complete genetic profiles

In a number of child sexual abuse cases, the alleged perpetrator is a member of the nuclear family. In those cases, there is a possibility that the suspect’s DNA was innocently deposited onto the child’s clothing without acts of sexual assault ever occurring, for example via secondary transfer within the washing machine. To assess the quantity and quality of DNA that may be transferred among clothing during laundering, we conducted three series of experiments. First, we evaluated the level of spermatozoa that may be transferred by washing pristine pairs of underwear with bed sheets containing a varying number of ejaculates. Secondly, we explored whether current genetic methods may also detect the transfer of DNA from vaginal secretions during a machine wash. Finally, we analyzed the background levels of DNA on children’s underwear collected from control families where sexual abuse never occurred. For both spermatozoa and vaginal secretions, we revealed that sufficient amounts of DNA may transfer onto laundered clothing to yield complete genetic profiles. Furthermore, DNA from relatives living within the same household was found in most cuttings taken from control children’s underwear. Based on these findings, we present a framework for the handling and interpretation of intrafamilial sexual abuse cases. These suggestions should help determine whether DNA was deposited directly onto a fabric or merely transferred during a wash.     

Routes of delivery for progesterone and progestins

The trends in postmenopausal hormonal therapy (HT) seem to favor the non-oral delivery routes for both the estrogen and the progestin for women with an intact uterus. Targeting the lowest possible dose of the progestin or of the natural hormone progesterone to be delivered directly to the uterus, the target organ for which it is designed, would avoid the possible drawbacks of systemic effects of progestins on other targets. Several delivery systems are either available or in development including vaginal gels and vaginal rings delivering the physiological hormone progesterone or intrauterine systems delivering very low doses of levonorgestrel. In addition, transdermal gels and spray are under development and can deliver very low doses of Nestorone a 19-norprogesterone derivative, not active orally but with high progestational activity when given via non-oral routes. The assumption that these new delivery systems should lead to an improved risk/benefit ratio in HT will need to be demonstrated in larger randomized controlled studies.     

Investigating the feasibility of temperature-controlled accelerated drug release testing for an intravaginal ring

The objective of the present study was to investigate if temperature can be utilized to accelerate drug release from Nuvaring®, a reservoir type intravaginal ring based on polyethylene vinyl acetate copolymer that releases a constant dose of contraceptive steroids over a duration of 3 weeks. The reciprocating holder apparatus (USP 7) was utilized to determine real-time and accelerated etonogestrel release from ring segments. It was demonstrated that drug release increased with increasing temperature which can be attributed to enhanced drug diffusion. An Arrhenius relationship of the zero-order release constants was established, indicating that temperature is a valid parameter to accelerate drug release from this dosage form and that the release mechanism is maintained under these accelerated test conditions. Accelerated release tests are particularly useful for routine quality control to assist during batch release of extended release formulations that typically release the active over several weeks, months or even years, since they can increase the product shelf life. The accelerated method should therefore be able to discriminate between formulations with different release characteristics that can result from normal manufacturing variance. In the case of Nuvaring®, it is well known that the process parameters during the extrusion process strongly influence the polymeric structure. These changes in the polymeric structure can affect the permeability which, in turn, is reflected in the release properties. Results from this study indicate that changes in the polymeric structure can lead to a different temperature dependence of the release rate, and as a consequence, the accelerated method can become less sensitive to detect changes in the release properties. When the accelerated method is utilized during batch release, it is therefore important to take this possible restriction into account and to evaluate the accelerated method with samples from non-conforming batches that are explicitly “out of specification” under real-time test conditions.     

The impact of rectal/bladder filling and applicator positioning on in vivo rectal dosimetry in vaginal cuff brachytherapy using an enhanced therapy setting

PurposeThe impact of rectal filling and bladder volume on in vivo rectal dosimetry (IVD) in vaginal cuff brachytherapy (VCBT) is unknown. The purpose of this study was to compare rectal doses from IVD with those calculated from treatment planning and to identify influencing factors.Materials and MethodsWe collected data of 80 VCBT sessions, four for each of 20 patients. Each was retrospectively compared with doses determined by the treatment planning system. Factors potentially predicting the IVD rectum dose were analyzed.ResultsFor a series of 80 brachytherapy applications, the calculated mean dose to the rectum was 2.52 Gy. The mean difference between all calculated and measured doses for the 80 applications with five probe positions each was 0.09 Gy (p = 0.952) proving high overall accordance between IVD and calculated doses at the rectum. The mean volume of the rectum was 119 ± 57 cm³. The rectal volume was not statistically significantly associated with the IVD or the calculated rectum doses. At the third and fourth rectal probe position in craniocaudal ordering, increased filling of the urinary bladder resulted in decreased measured and calculated doses (p < 0.05 for both). A rectum pointing position of the applicator significantly increased the maximum rectum dose compared with a bladder-oriented position (p < 0.05).ConclusionsIVD provided valuable data for rectal exposure in VCBT. Increased bladder filling and vaginal applicator positioning off the rectum elicited related with less rectal radiation exposure, whereas rectal filling did not. Further confirmation including assessment of IVD in bladder is pending to define optimal dosimetric conditions in VCBT.     

Occult vaginal cancer recurrence after hysterectomy: a case report and literature review

Vaginal cancer is a rare disease of the lower genital tract. We present the case of a 54-year-old woman with occult vaginal cancer after hysterectomy for cervical intraepithelial neoplasia (CIN) III. Despite persistently negative cytology and colposcopy results, a lesion was finally detected by vagino-recto-abdominal examination and she underwent radical parametrectomy and lymph node dissection. We consider the possibility that transabdominal suturing of the vaginal cuff after hysterectomy may reduce the ability to detect subsequent vaginal lesions, and discuss the benefits of a vaginal suture approach. We recommend that suturing the vagina apex transvaginally instead of transabdominally would benefit patients during follow-up.