Patricia Noël

Spironolactone-related inhibitors of type II 17β-hydroxysteroid dehydrogenase: chemical synthesis, receptor binding affinities, and proliferative/antiproliferative activities

The family of 17beta-hydroxysteroid dehydrogenases (17beta-HSDs) catalyzes the formation and inactivation of testosterone (T), dihydrotestosterone (DHT), and estradiol (E2), thus playing a crucial role in the regulation of active steroid hormones in target tissues. Among the five known 17beta-HSD enzymes, type II catalyzes the oxidation of E2 into estrone (E1), T into androstenedione, DHT into androstanedione, and 20alpha-dihydroprogesterone into progesterone. Specific inhibitors are thus an interesting means to study the regulation and to probe the structure of type II 17beta-HSD. In this context, we have efficiently synthesized a series of 7alpha-thioalkyl and 7alpha-thioaryl derivatives of spironolactone that inhibit type II 17beta-HSD. These new C19-steroidal inhibitors possess two important pharmacophores, namely 17-spiro-gamma-lactone and a bulky side-chain at the 7alpha-position. It was found that a para-substituted benzylthio group at the 7alpha-position enhances the inhibitory potency of spironolactone derivatives on type II 17beta-HSD. In fact, the compound with a para-hydroxy-benzylthio group showed an IC50 value of 0.5 microM against type II 17beta-HSD, whereas the compound with a para-[2-(1-piperidinyl)-ethoxy]-benzylthio group inhibited this enzyme with an IC50 value of 0.7 microM. The latter inhibitor is more selective than the former because it did not show any inhibitory potency against P450 aromatase as well as any affinity towards four steroid receptors (AR, PR, GR, ER). As a result, this inhibitor did not show any proliferative effect on androgen-sensitive Shionogi cells and estrogen-sensitive ZR-75-1 cells. These findings contribute to a better knowledge of the structure of type II 17beta-HSD and offer an interesting tool to study the regulation of this enzyme in several biological systems.

Simple vaginal trachelectomy in early-stage low-risk cervical cancer: a pilot study of 16 cases and review of the literature.

Objective This study aimed to evaluate the feasibility of simple vaginal trachelectomy and node assessment in patients with low-risk early-stage cervical cancer (<2 cm). Methods From May 2007 to November 2012, 16 women with low-risk small-volume cervical cancer underwent a simple vaginal trachelectomy preceded by laparoscopic sentinel node mapping plus or minus pelvic node dissection. Data were collected prospectively in a computerized database. Descriptive statistics and Kaplan-Meyer estimate were used for analysis. Results Patients’ median age was 30 years and 12 (75%) were nulliparous. Six had a diagnostic cone, 6 had a loop electrocautery excision procedure, 3 had cervical biopsies, and 1 had polyp excision. All patients underwent a preoperative pelvic magnetic resonance imaging. Four patients had stage IA1 with lymph vascular space invasion (LSVI), 6 IA2, and 6 IB1. Ten (62.5%) had squamous lesions, 7 had adenocarcinoma. LVSI was present in 4 cases, suspicious in 2, and absent in 10. There were 2 surgical complications: a trocar site hematoma and a vaginal laceration. The median OR time was 150 minutes (range, 120–180 minutes) and median blood loss was 50 mL (range, 50–150 mL). On final pathology, lymph nodes were negative in all patients. Thirteen (81%) patients had either no residual disease (6) or residual dysplasia only (7) in the trachelectomy specimen. Margins were negative in all cases. With a median follow-up of 27 months (range, 1–65 months), there have been no recurrences. The recurrence-free survival at 24 months is 100%. Eight patients have conceived: 3 were term deliveries and 4 are ongoing. Conclusions Simple trachelectomy and nodes seems to be a safe alternative in well-selected patients with early-stage low-risk cervical cancer. Our data will need to be confirmed in larger series.

MULTISTEP PRODUCTION OF BIOENGINEERED SKIN SUBSTITUTES: SEQUENTIAL MODULATION OF CULTURE CONDITIONS

SummaryMany studies are being conducted to define the role of growth factors in cutaneous physiology in order to add cytokines in a timely fashion for optimal tissue engineering of skin. This study is aimed at developing a multistep approach for the production of bioengineered skin substitutes, taking into account the effects of various growth factors according to the culture time. The use of a serum-supplemented medium throughout the whole culture period of skin substitutes was compared to the sequential use of specific additives at defined culture steps. Histological analysis revealed that serum was necessary for keratinocyte proliferation and migration on dermal substitutes during the first 2 d after their seeding. However, the serum-free medium presented some advantages when supplemented with different additives at specific culture steps. Interestingly, ascorbic acid added to the dermal substitutes before and after keratinocyte seeding maintained their cuboïdal morphology in the basal epidermal layer. In the absence of serum, collagen matrix degradation slowed down, and a better multilayered epidermal organization was obtained, notably with retinoic acid. Stratum corneum formation was also enhanced by fatty acids. Thus, sequential addition of exogenous factors to the medium used to produce skin substitutes can improve their structural features and functional properties in vitro.

Early Cervical Carcinoma and Fertility-sparing Treatment Options: MR Imaging as a Tool in Patient Selection and a Follow-up Modality

Because of the widespread use of cytologic screening programs in industrialized nations, cervical carcinoma is being diagnosed in younger patients and at an earlier stage. The traditional therapy for early-stage disease is radical hysterectomy with pelvic lymphadenectomy, which leads to infertility. In the past 20 years, fertility-sparing therapies, such as cervical conization and radical trachelectomy, have emerged and show good oncologic and obstetric outcomes. The selection criteria for vaginal radical trachelectomy include stages IA2 and IB1, a tumor that is smaller than 2 cm, distance from the internal os of at least 1 cm, limited stromal invasion, and no nodal or extracervical extension. Magnetic resonance (MR) imaging accurately depicts these criteria and is a necessary tool in the preoperative evaluation of patients with cervical carcinoma who are eligible for fertility-sparing surgery. The MR imaging report must provide the following pieces of information for adequate surgical planning: tridimensional diameters of the lesion, uterine and cervical lengths, the degree of stromal invasion, distance from the internal os, and the presence of extracervical or nodal involvement. Because patients also undergo follow-up MR imaging, radiologists must be familiar with the postoperative imaging appearance of the cervix. After trachelectomy, the uterovaginal anastomosis may appear end-to-end or with a neoposterior vaginal fornix. Vaginal wall thickening, hematomas, lymphoceles, and hematometra secondary to isthmic stenosis may be seen. The normal postoperative appearance must be differentiated from recurrent disease, which is seen as a mass with intermediate to high signal intensity in the vaginal vault or parametrium on T2-weighted images. Functional imaging, including diffusion-weighted and dynamic contrast-enhanced imaging, may help characterize recurrence.

Uterine arteriovenous malformations following gestational trophoblastic neoplasia: a systematic review

Uterine arteriovenous malformation (AVM) following gestational trophoblastic neoplasia (GTN) is a rare condition. It can be associated with chronic vaginal bleeding or life-threatening heavy bleeding, even after complete resolution of the tumor following chemotherapy. This analysis aimed to perform an extensive systematic review highlighting clinical symptoms, imaging, management and prognosis of this rare complication of GTN. We also describe an additional case of uterine AVM following GTN. We conducted a literature search using Medline, Embase and Cochrane library to analyze the clinical data of 49 published cases of uterine AVM following GTN. Median age of the women diagnosed with AVM was 29 years (range 15-49). Median gravidity was 2 (range 1-8) and 50% of women were nulligravida. Complete molar pregnancy was the most common initial gestational trophoblastic diagnosis (48%). Overall, 44 patients (88%) were symptomatic and presented with chronic or acute abnormal vaginal bleeding. Only 3 patients had an undetectable HCG level at the time of uterine AVM diagnosis. Hypo-echoic space in the myometrium is the most relevant finding on ultrasonography but the gold standard for the definitive diagnosis of AVMs is angiographic examination. Uterine artery embolization was the most common treatment option performed in 82% of the patients and was successful in controlling the bleeding in 85% of cases. We identified 20 pregnancies after successful embolization of uterine AVM following a GTN and 90% of them were successful. Because of the risk of life-threatening heavy bleeding, the diagnosis of uterine AVM should always be considered in patients with a history of recurrent unexplained vaginal bleeding after gestational trophoblastic neoplasia. Angiographic embolization is successful in the majority of cases and does not appear to compromise future pregnancy.

Parallel Imaging Artifacts in Body Magnetic Resonance Imaging

Objective To familiarize the reader with the fundamental concepts of partial parallel imaging (PPI); to review the technical aspects of PPI including calibration scan, coil geometry, and field of view (FOV); and to illustrate artifacts related to parallel imaging and describe solutions to minimize their negative impact. Results PPI has led to a significant advance in body magnetic resonance imaging by reducing the time required to generate an image without loss of spatial resolution. Although PPI can improve image quality, it is not free of artifacts, which can result in significant image degradation. Knowledge of these artifacts and how to minimize their effect is important to optimize the use of parallel imaging for specific body magnetic resonance imaging applications. Conclusions The reader will be introduced to the fundamental principles of PPI. Common imaging characteristics of PPI artifacts will be displayed with an emphasis on those seen with image-based methods, the principles behind their generation presented, and measures to minimize their negative impact will be proposed.

Optimizing cine MRI for uterine peristalsis: A comparison of three different single shot fast spin echo techniques

To determine the optimal single shot fast spin echo (SSFSE) technique by varying interval between image acquisitions for cine MRI of uterine peristalsis.