Yael Hants

Mutant KRAS is a druggable target for pancreatic cancer

Significance Pancreatic cancer is still one of the major challenges in clinical oncology. Mutant KRAS is a driving oncogene in the majority of human pancreatic cancer cases. We have made an effort to meet this challenge by developing a therapeutic platform for local and prolonged delivery of siRNA. Our results show that the siRNA targeted against KRAS mutations with a local prolonged release system knocks down KRAS expression in vitro and in vivo, leading to an antitumor effect. Our report describes an applicable and efficient delivery method of siRNA that overcomes the major obstacles of toxicity and organ accessibility. Notably our approach enabled the conversion of KRAS from a nondruggable to a potentially druggable cancer target. 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.

Outcomes of subsequent pregnancies after conservative treatment for placenta accreta

To estimate the association between conservative treatment for placenta accreta and subsequent pregnancy outcomes.

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

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.

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

Abstract 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.

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.

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.

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

Abstract Objective: To assess the safety and performance of a new energy-based skin closure system (BioWeld1TM) 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.

Perimortem cesarean section: three possible procedures to overcome atonic bleeding after successful resuscitation - Authors' reply.

Sir, While we appreciate the comments of Prof. Matsubara (1), the thrust of our study (2) was to increase awareness of perimortem cesarean section and its immediate pitfalls: because maternal resuscitation is invariably an emergency procedure, we report on a protocol that we believe can be amenable to most obstetricians/ surgeons. We mention coagulation events and the need for uterotonics as a preliminary step that has been proven to be effective in prevention of uterine atony. All other interventions mentioned by Prof. Matsubara (1) (such as uterine compression sutures techniques, hysterectomy and intrauterine balloon) are not immediately available at all medical facilities, but more importantly, as Prof. Matsubara concedes, these have not been proven to be effective prophylactically (we did not discuss the management of over-invasive placenta disorders) and may prove ultimately to be damaging. The merits of management of catastrophic obstetric interventions is a tangential but separate issue and in our opinion should be reviewed by each institution and adapted to existing medical and transport capacities.