The selenoenzyme type I iodothyronine deiodinase: a new tumor suppressor in ovarian cancer.

The selenoenzyme type I iodothyronine deiodinase (DIO1) catalyzes removal of iodine atoms from thyroid hormones. Although DIO1 action is reported to be disturbed in several malignancies, no work has been conducted in high-grade serous ovarian carcinoma (HGSOC), the most lethal gynecologic cancer. We studied DIO1 expression in HGSOC patients [The Cancer Genome Atlas (TCGA) data and tumor tissues], human cell lines (ES-2 and Kuramochi), normal Chinese hamster ovarian cells (CHO-K1), and normal human fallopian tube cells (FT282 and FT109). To study its functional role, DIO1 was overexpressed, inhibited [by propylthiouracil (PTU)], or knocked down (KD), and cell count, proliferation, apoptosis, cell viability, and proteomics analysis were performed. Lower DIO1 levels were observed in HGSOC compared to normal cells and tissues. TCGA analyses confirmed that low DIO1 mRNA expression correlated with worse survival and therapy resistance in patients. Silencing or inhibiting the enzyme led to enhanced ovarian cancer proliferation, while an opposite effect was shown following DIO1 ectopic expression. Proteomics analysis in DIO1-KD cells revealed global changes in proteins that facilitate tumor metabolism and progression. In conclusion, DIO1 expression and ovarian cancer progression are inversely correlated, highlighting a tumor suppressive role for this enzyme and its potential use as a biomarker in this disease.

Impact of surgeon annual volume on short-term maternal outcome in cesarean delivery.

BACKGROUND: The annual procedure volume is an accepted marker for quality of care and has been documented in various medical fields. Surgeon volume has been shown to correlate with morbidity and mortality rates in surgical and high-risk medical procedures. Although cesarean delivery is 1 of the most common surgical procedures in the United States, the link between a surgeon's annual cesarean delivery volume and maternal outcome has never been tested. OBJECTIVE: The purpose of this study was to evaluate the impact of a surgeon's annual volume on short-term maternal outcome in cesarean deliveries. STUDY DESIGN: We performed a retrospective cohort study in a single tertiary center between 2006 and 2013. Cesarean deliveries were categorized into 2 groups based on the annual volume of cesarean delivery of the attending obstetrician. The "low" group included obstetricians with a low annual volume, whose annual volume of cesarean delivery was lower than median. The "high" group comprised obstetricians with a high annual volume whose annual volume was at median and above. Further analyses were done for quartiles and for 4 clinical relevant groups according to the annual number of cesarean deliveries that were performed/supervised by the attending obstetrician (≤20, 21-60, 61-120, and >120). The primary outcome was a composite adverse maternal outcome that included ≥1 of the following outcomes: urinary or gastrointestinal tract injuries, hemoglobin drop >3 g/dL, blood transfusion, relaparotomy, puerperal fever, prolonged maternal hospitalization, and readmission. Secondary outcomes were operative times (skin incision to delivery and overall). RESULTS: A total of 11,954 cesarean deliveries were included; the median annual number of cesarean deliveries that were performed/supervised by 1 obstetrician was 48. Unadjusted analysis suggested that the patients in the high group had fewer urinary and gastrointestinal injuries (18/9278 [0.2%] vs 16/2676 [0.6%] injuries; P < .001), less blood loss as measured by hemoglobin drop >3 g/dL (1053/9278 [11.5%] vs 366/2676 [13.8%]; P < .001), and fewer cases of prolonged maternal hospitalization (80/9278 [0.9%] vs 39/2676 [1.5%]; P = .006). The rate of blood transfusion, relaparotomy, puerperal febrile morbidity, and readmission to hospital did not differ between groups. Multivariable regression analysis showed that cesarean delivery performed/supervised by the high group resulted in a significantly lower composite adverse maternal outcome (15.8% vs 18.9%; odds ratio, 0.86; 95% confidence interval, 0.78-0.95; P = .004). This was related primarily to a decreased frequency of urinary and gastrointestinal injuries, lower likelihood of hemoglobin drop >3 g/dL, and lower incidence of prolonged maternal hospitalization. Operative times were significantly shorter for the high group. Composite adverse maternal outcome ranged from 21.8% in the lowest quartile to 17.9% in quartile 2, to 17.4% in quartile 3, and 15.6% in quartile 4. quartile 4 served as the reference; quartile 3 had an odds ratio of 1.14 (95% confidence interval, 1.01-1.29; P = .029); quartile 2 had an odds ratio of 1.18 (95% confidence interval, 1.02-1.36; P = .021, and quartile 1 had an odds ratio of 1.51 (95% confidence interval, 1.14-1.99; P = .004) for composite adverse maternal outcome. Composite adverse maternal outcome ranged from 21.5% in clinical group 1 to 17.5% in clinical group 2, to 17.9% in clinical group 3, and 15.2% in clinical group 4 (P = .001). Cesarean delivery performed/supervised by clinical groups 2, 3, and 4 in comparison with clinical group 1 were associated with a statistically significant risk reduction, (23%, 25%, and 34% respectively). CONCLUSION: Maternal composite morbidity is decreased as the volume of cesarean deliveries that are performed or supervised by obstetricians increases.

The indication for induction of labor impacts the risk of cesarean delivery.

OBJECTIVE: The risk of cesarean delivery following labor induction has been clearly established. While numerous factors are known to impact this risk, the indication for induction has rarely been examined as a risk factor. This study aimed to examine the relationship between indication for induction and ultimate mode of delivery after labor induction. METHODS: A retrospective cohort study was conducted examining all cases of labor induction in a tertiary center university teaching hospital over a one-year period. The primary outcome measure was mode of delivery (vaginal delivery versus cesarean delivery) and its relationship to the indication for induction. Secondary outcome measures were: parity, maternal age, birth week, cervical maturity, use of epidural anesthesia, fetal birth weight and fetal sex. RESULTS: Seven hundred and ninety-six women met inclusion criteria, of which 17.1% ultimately underwent cesarean delivery. Using multivariate analysis, fetal indications for induction (including intra-uterine growth restriction, oligohydramnios, placental abruption, macrosomia and post-term pregnancy) were found to significantly increase the risk of cesarean delivery in nulliparous women. The other significant factor was birth after week 40 + 0. CONCLUSIONS: The indication for labor induction impacts the risk of cesarean delivery. Specifically, induction of labor for fetal indications significantly increases the risk of cesarean delivery in nulliparous women.

Iron deficiency anemia at admission for labor and delivery is associated with an increased risk for Cesarean section and adverse maternal and neonatal outcomes.

BACKGROUND: Maternal iron deficiency anemia (IDA) impacts placenta and fetus. We evaluated effects of IDA at admission for delivery on cesarean rates, and adverse maternal and neonatal outcomes. STUDY DESIGN AND METHODS: Medical records from Jerusalem (2005-2012) identified women with a live-birth singleton fetus in cephalic presentation of any gestational age and excluded planned cesarean, chronic/gestational diseases identified with anemia. Study population was divided into anemic and non-anemic women using WHO criteria. MAIN OUTCOME MEASURES: cesarean rate, and adverse outcomes (maternal: packed cells transfusion, early post-partum hemorrhage, preterm delivery; and neonatal: 5' Apgar < 7, Neonatal Intensive Care Unit [NICU] admission, extreme birthweights). Continuous variable analysis and multivariate backward step-wise logistic regression models were prepared with Odds Ratios (OR) and 95% confidence intervals (CI). RESULTS: In all, 96,066 deliveries were registered, of which 75,660 (78.8%) were included. IDA was present in 7,977 women (10.5%). Anemia at birth was significantly associated with cesarean section (OR 1.30; 95%CI, 1.13-1.49, p < 0.001), packed cells transfusion (OR 5.48; 95%CI, 4.57-6.58, p < 0.001), preterm delivery (OR 1.54; 95%CI, 1.36-1.76, p < 0.001), macrosomia (OR 1.23; 95%CI, 1.12-1.35, p < 0.001), Large for Gestational Age (OR 1.29; 95%CI, 1.20-1.39, p < 0.001), Apgar 5' < 7 (OR 2.21; 95%CI, 1.84-2.64, p < 0.001), and NICU admission (OR 1.28; 95%CI, 1.04-1.57, p = 0.018). CONCLUSION: Iron deficiency anemia at delivery is associated with an increased risk for cesarean section and adverse maternal and neonatal outcomes in otherwise healthy women. Monitoring/correction of hemoglobin concentrations even in late pregnancy may prevent these adverse events.

Induction of labor at term following external cephalic version in nulliparous women is associated with an increased risk of cesarean delivery.

PURPOSE: To determine whether induction of labor (IOL) after successful external cephalic version (ECV) is associated with an increased risk of cesarean delivery (CD) compared with IOL with spontaneous cephalic presentation. METHODS: Retrospective case-control study. All women having IOL after successful ECV were eligible. Each woman in the study group was matched for parity, age and indication for induction with two consecutive controls having IOL and spontaneous cephalic presentation. The primary outcome measure was CD. Secondary outcomes measures were operative vaginal delivery, perineal tear/episiotomy and post-partum hemorrhage. RESULTS: 79 women enrolled in the study group were matched with 158 controls. The overall incidence of CD was significantly higher in the study group compared with the control group (20.3 vs. 10.1 %; OR 2.25, 95 % CI 1.06-4.79, P = 0.03). After dividing the groups according to parity, the difference in the CD rate remained statistically significant for nulliparous women (36.7 vs. 15 %; OR 3.28, 95 % CI 1.17-9.16, P = 0.02), but not for multiparous women (10.2 vs. 7.1 %; OR 1.48, 95 % CI 0.44-4.92, P = 0.53). There was no significant difference in adjusted odds ratios for secondary outcomes. CONCLUSION: Induction of labor after successful ECV in nulliparous women increased the risk of CD compared with IOL with spontaneous cephalic presentation.

Antepartum Membrane Stripping in GBS Carriers, Is It Safe? (The STRIP-G Study).

OBJECTIVE: Stripping of the membranes is an established and widely utilized obstetric procedure associated with higher spontaneous vaginal delivery rates, reduced need for formal induction of labor and a lower likelihood of post-term pregnancy. Due to the theoretical concern of bacterial seeding during the procedure many practitioners choose not to sweep the membranes in Group B Streptococcus (GBS) colonized patients. We conducted 'the STRIP-G study' in order to determine whether maternal and neonatal outcomes are affected by GBS carrier status in women undergoing membrane stripping. STUDY DESIGN: We conducted a prospective study in a tertiary referral center, comparing maternal and neonatal outcomes following membrane stripping among GBS-positive, GBS-negative, and GBS-unknown patients. We compared the incidence of composite adverse neonatal outcomes (primary outcome) among the three study groups, while secondary outcome measure was composite adverse maternal outcomes. RESULTS: A total of 542 women were included in the study, of which 135 were GBS-positive, 361 GBS-negative, and 46 GBS-unknown status. Demographic, obstetric, and intra-partum characteristics were similar for all groups. Adverse neonatal outcomes were observed in 8 (5.9%), 31 (8.6%), and 2 (4.3%) in the GBS-positive, GBS-negative, and unknown groups, respectively (P = 0.530), (Odds Ratio between GBS-Positive vs. GBS-Negative groups 0.67 (95%, CI = 0.30-1.50)); while composite adverse maternal outcomes occurred in 9 (6.66%), 31 (8.59%), and 5 (10.87%) in the GBS-positive, GBS-negative, and unknown groups, respectively (P = 0.617). CONCLUSIONS: Antepartum membrane stripping in GBS carriers appears to be a safe obstetrical procedure that does not adversely affect maternal or neonatal outcomes.

Perimortem cesarean section for maternal and fetal salvage: concise review and protocol.

Cardiopulmonary arrest is a rare event during pregnancy and labor. Perimortem cesarean section has been resorted to as a rare event since ancient times; however, greater awareness regarding this procedure within the medical community has only emerged in the past few decades. Current recommendations for maternal resuscitation include performance of the procedure after five minutes of unsuccessful cardiopulmonary resuscitation. If accomplished in a timely manner, perimortem cesarean section can result in fetal salvage and is also critical for maternal resuscitation. Nevertheless, deficits in knowledge about this procedure are common. We have reviewed publications on perimortem cesarean section and present the most recent evidence on this topic, as well as recommending our "easy-to-access protocol" adapted for resuscitation following maternal collapse.

Outcomes of subsequent pregnancies after conservative treatment for placenta accreta.

OBJECTIVE: To estimate the association between conservative treatment for placenta accreta and subsequent pregnancy outcomes. METHODS: In a retrospective study, data were analyzed on women who received conservative treatment for placenta accreta (removal of the placenta with uterine preservation) at a tertiary hospital in Jerusalem, Israel, between 1990 and 2000. Data were collected on subsequent pregnancies and neonatal outcomes until 2010, and compared with those from a matched control group of women who did not have placenta accreta. RESULTS: A total of 134 women were included in both groups. Placenta accreta occurred in 62 (22.8%) of 272 subsequent deliveries in the study group for which data were available and 5 (1.9%) of 266 in the control group (relative risk [RR] 12.13; 95% confidence interval [CI] 4.95-29.69; P<0.001). Early postpartum hemorrhage occurred in 23 (8.6%) of 268 deliveries in the study group and 7 (2.6%) of 268 in the control group (RR 3.29; 95% CI 1.43-7.53; P<0.001). The odds ratio for recurrent placenta accreta in subsequent deliveries in the study group was 15.41 (95% CI 6.09-39.03; P<0.001). CONCLUSION: Although subsequent pregnancies after conservative treatment for placenta accreta were mostly successful, the risk of recurrent placenta accreta and postpartum hemorrhage is high in future deliveries.

Preliminary evaluation of novel skin closure of Pfannenstiel incisions using cold helium plasma and chitosan films.

OBJECTIVE: To assess the safety and performance of a new energy-based skin closure system (BioWeld1(TM)) for the surgical Pfannenstiel incision in patients scheduled for elective cesarean section. METHODS: This prospective, single center, non-randomized study included 20 patients who were scheduled for elective cesarean section. The BioWeld1 system was performed after suturing the internal layers of the cesarean section incision. A clinical evaluation of safety and efficacy was performed for 1, 2, 4-7, 21, and 45 d after the procedure. The Vancouver Scar Scale (VSS) was used to evaluate scarring. RESULTS: Up to 21 d after the procedure, no safety device-related adverse events were reported. All patients had full closure of the epidermis, a very low total VSS score, and no evidence of discharge, redness, edema, or thermal damage. None of the patients exhibited more than a mild degree of encrustation. CONCLUSION: The BioWeld1 System has been shown to be safe and effective for skin closure in cesarean section.

Mutant KRAS is a druggable target for pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDA) represents an unmet therapeutic challenge. PDA is addicted to the activity of the mutated KRAS oncogene which is considered so far an undruggable therapeutic target. We propose an approach to target KRAS effectively in patients using RNA interference. To meet this challenge, we have developed a local prolonged siRNA delivery system (Local Drug EluteR, LODER) shedding siRNA against the mutated KRAS (siG12D LODER). The siG12D LODER was assessed for its structural, release, and delivery properties in vitro and in vivo. The effect of the siG12D LODER on tumor growth was assessed in s.c. and orthotopic mouse models. KRAS silencing effect was further assessed on the KRAS downstream signaling pathway. The LODER-encapsulated siRNA was stable and active in vivo for 155 d. Treatment of PDA cells with siG12D LODER resulted in a significant decrease in KRAS levels, leading to inhibition of proliferation and epithelial-mesenchymal transition. In vivo, siG12D LODER impeded the growth of human pancreatic tumor cells and prolonged mouse survival. We report a reproducible and safe delivery platform based on a miniature biodegradable polymeric matrix, for the controlled and prolonged delivery of siRNA. This technology provides the following advantages: (i) siRNA is protected from degradation; (ii) the siRNA is slowly released locally within the tumor for prolonged periods; and (iii) the siG12D LODER elicits a therapeutic effect, thereby demonstrating that mutated KRAS is indeed a druggable target.