Fully percutaneous fetoscopic repair of myelomeningocele: 30-month follow-up data.

OBJECTIVE: This observational study reports on the postnatal mortality and 30-month outcome of children who underwent fully percutaneous fetoscopic repair of myelomeningocele (MMC) at a single center in Giessen, Germany. METHODS: Between October 2010 and August 2014, a total of 72 patients underwent fully percutaneous fetoscopic MMC closure at 21 + 0 to 29 + 1 (mean, 23 + 5) weeks' gestation. Of these, 52 (72%) participated in this study; however, 30-month mortality data are available for all 72 children. Children were examined at four timepoints: shortly after birth and at 3 months, 12 months and 30 months of corrected age. The patients underwent age-specific standardized neurological examinations and assessment of leg movements and ambulation at all timepoints. Cognitive and motor development were assessed using the Bayley Scales of Infant Development, second edition (BSID-II), at 30 months. RESULTS: All 72 children survived the intrauterine procedure, however, four (5.6%) infants died postnatally (including two of the 52 comprising the study cohort). Of the 52 patients included in the study, 11.5% were delivered before the 30th week of gestation (mean, 33 + 1 weeks) and, of the survivors, 48.1% had ventriculoperitoneal shunt placement. Of the 50 infants that were alive at 30 months, independent ambulation, without orthosis, was feasible for 46%. At 30 months of follow-up, 46% of children presented with a functional level that was at least two segments better than the anatomical level of the lesion. At 30 months, 70% of the children presented with BSID-II psychomotor development index score of ≥ 70 and 80% with BSID-II mental development index score of ≥ 70. CONCLUSION: Intrauterine repair of MMC by percutaneous fetoscopy shows largely similar outcomes to those reported for open repair, with respect to mortality, prematurity, shunt-placement rates, motor and mental development and free ambulation. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Percutaneous minimal-access fetoscopic surgery for spina bifida aperta. Part II: maternal management and outcome.

OBJECTIVE: To assess maternal morbidity and outcome in women undergoing minimal-access fetoscopic surgery for spina bifida aperta. METHODS: This was a retrospective study of 51 women undergoing minimal-access fetoscopic surgery to improve postnatal neurological outcome of spina bifida aperta, at a mean gestational age of 24 weeks, at our center between July 2010 and June 2013. We analyzed various perioperative complications of surgery, namely: maternal and fetal death, need for maternal blood transfusion, placental abruption, pulmonary edema, spontaneous labor, oligohydramnios, chorioamnionitis, chorioamniotic membrane separation, duration of hospitalization, amniotic fluid leakage, gestational age at delivery and status of hysterotomy site. RESULTS: In none of the 51 women was there maternal demise, spontaneous labor, placental abruption or a need for maternal blood transfusion in the perioperative period. Chorioamniotic membrane separation occurred in one patient, mild pulmonary edema occurred in one and oligohydramnios occurred in seven. All fetuses survived surgery, but there was one very early preterm delivery 1 week after the procedure and this neonate died immediately, from early postoperative chorioamnionitis. Amniotic fluid leakage occurred in 43 patients, at a mean gestational age of 29.7 (range, 22.6-37.3) weeks; two of these patients developed chorioamnionitis. Duration of maternal hospitalization after surgery was 7.2 (range, 4-12) days. Mean gestational age at delivery was 33 (range, 24.6-38.1) weeks. All abdominal and uterine trocar insertion sites healed well. CONCLUSION: Minimal-access fetoscopic surgery for spina bifida aperta is apparently safe for most maternal patients. Despite the common occurrence of amniotic leakage, the majority of women deliver beyond 32 weeks of gestation.

[Development of an interprofessional train-the-trainer programme to implement shared decision-making in medical rehabilitation clinics]. / Entwicklung eines interprofessionellen Train-the-Trainer-Programms zur Implementierung der partizipativen Entscheidungsfindung in Rehabilitationskliniken.

BACKGROUND AND AIMS: Until now, training programmes on shared decision-making (SDM) have been designed exclusively for medical decision-making and predominantly for physicians. How-ever, interprofessional treatment, such as in medical rehabilitation, is very important in the treatment of chronic diseases. This requires an extended understanding of shared decision-making. Therefore the aim of the study is to develop an interprofessional training (IPT) for implementation of shared decision-making (SDM) in rehabilitation clinics. METHODS: The needs and preferences of the persons undergoing rehabilitation were collected in 4 focus groups, with frequency of answers analyzed by means of inductive category formation. The providers' preferences and requirements concerning a training programme on shared decision-making were assessed through an expert survey and underwent a mainly descriptive-explorative evaluation as well as a partial content analysis. RESULTS: 36 patients took part in the focus groups. Besides the wish for more participation in treatment decisions, they expressed further needs, such as more time and respect. The -experts of the 4 clinics (n=34, rate of response: 71%) also assessed these aspects of the patient-provider interaction as relevant. However, they saw the highest training need in the area of interdisciplinary team interactions. CONCLUSION: The interprofessional training programme "Fit for SDM" was developed on the basis of these results, and consists of 2 modules for the implementation of shared decision-making in medical rehabilitation. Module 1 focuses on external participation (provider-patient interaction), Module 2 on internal participation (team interaction). Module 2 was additionally used for preparing executives in their role as multipliers in the team. The training is currently being evaluated in a cluster-randomized multicentre study.

Betulinic acid-induced apoptosis in leukemia cells.

Betulinic acid (BA), a natural component isolated from Birch trees, effectively induces apoptosis in neuroectodermal and epithelial tumor cells and exerts little toxicity in animal trials. Here, we show that BA-induced marked apoptosis in 65% of primary pediatric acute leukemia cells and all leukemia cell lines tested. When compared for in vitro efficiency with conventionally used cytotoxic drugs, BA was more potent than nine out of 10 standard therapeutics and especially efficient in tumor relapse. No crossresistances were found between BA and any cytotoxic drug. Intracellular apoptosis signaling in leukemia tumor cells paralleled the pathway found in neuroectodermal cells involving caspases, but not death receptors. In isolated mitochondria, BA induced release of both cytochrome c and Smac. Taken together, BA potently induces apoptosis in leukemia cells and should be further evaluated as a future drug to treat leukemia.

Cell cycle-arrested tumor cells exhibit increased sensitivity towards TRAIL-induced apoptosis.

Resting tumor cells represent a huge challenge during anticancer therapy due to their increased treatment resistance. TNF-related apoptosis-inducing ligand (TRAIL) is a putative future anticancer drug, currently in phases I and II clinical studies. We recently showed that TRAIL is able to target leukemia stem cell surrogates. Here, we tested the ability of TRAIL to target cell cycle-arrested tumor cells. Cell cycle arrest was induced in tumor cell lines and xenografted tumor cells in G0, G1 or G2 using cytotoxic drugs, phase-specific inhibitors or RNA interference against cyclinB and E. Biochemical or molecular arrest at any point of the cell cycle increased TRAIL-induced apoptosis. Accordingly, when cell cycle arrest was disabled by addition of caffeine, the antitumor activity of TRAIL was reduced. Most important for clinical translation, tumor cells from three children with B precursor or T cell acute lymphoblastic leukemia showed increased TRAIL-induced apoptosis upon knockdown of either cyclinB or cyclinE, arresting the cell cycle in G2 or G1, respectively. Taken together and in contrast to most conventional cytotoxic drugs, TRAIL exerts enhanced antitumor activity against cell cycle-arrested tumor cells. Therefore, TRAIL might represent an interesting drug to treat static-tumor disease, for example, during minimal residual disease.

Enhanced anti-tumour effects of Vinca alkaloids given separately from cytostatic therapies.

BACKGROUND AND PURPOSE: In polychemotherapy protocols, that is for treatment of neuroblastoma and Ewing sarcoma, Vinca alkaloids and cell cycle-arresting drugs are usually administered on the same day. Here we studied whether this combination enables the optimal antitumour effects of Vinca alkaloids to be manifested. EXPERIMENTAL APPROACH: Vinca alkaloids were tested in a preclinical mouse model in vivo and in vitro in combination with cell cycle-arresting drugs. Signalling pathways were characterized using RNA interference. KEY RESULTS: In vitro, knockdown of cyclins significantly inhibited vincristine-induced cell death indicating, in accordance with previous findings, Vinca alkaloids require active cell cycling and M-phase transition for induction of cell death. In contrast, anthracyclines, irradiation and dexamethasone arrested the cell cycle and acted like cytostatic drugs. The combination of Vinca alkaloids with cytostatic therapeutics resulted in diminished cell death in 31 of 36 (86%) tumour cell lines. In a preclinical tumour model, anthracyclines significantly inhibited the antitumour effect of Vinca alkaloids in vivo. Antitumour effects of Vinca alkaloids in the presence of cytostatic drugs were restored by caffeine, which maintained active cell cycling, or by knockdown of p53, which prevented drug-induced cell cycle arrest. Therapeutically most important, optimal antitumour effects were obtained in vivo upon separating the application of Vinca alkaloids from cytostatic therapeutics. CONCLUSION AND IMPLICATIONS: Clinical trials are required to prove whether Vinca alkaloids act more efficiently in cancer patients if they are applied uncoupled from cytostatic therapies. On a conceptual level, our data suggest the implementation of polychemotherapy protocols based on molecular mechanisms of drug-drug interactions. LINKED ARTICLE: This article is commented on by Solary, pp 1555-1557 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.12101.

NOXA as critical mediator for drug combinations in polychemotherapy.

During polychemotherapy, cytotoxic drugs are given in combinations to enhance their anti-tumor effectiveness. For most drug combinations, underlying signaling mechanisms responsible for positive drug-drug interactions remain elusive. Here, we prove a decisive role for the Bcl-2 family member NOXA to mediate cell death by certain drug combinations, even if drugs were combined which acted independently from NOXA, when given alone. In proof-of-principle studies, betulinic acid, doxorubicin and vincristine induced cell death in a p53- and NOXA-independent pathway involving mitochondrial pore formation, release of cytochrome c and caspase activation. In contrast, when betulinic acid was combined with either doxorubicine or vincristine, cell death signaling changed considerably; the drug combinations clearly depended on both p53 and NOXA. Similarly and of high clinical relevance, in patient-derived childhood acute leukemia samples the drug combinations, but not the single drugs depended on p53 and NOXA, as shown by RNA interference studies in patient-derived cells. Our data emphasize that NOXA represents an important target molecule for combinations of drugs that alone do not target NOXA. NOXA might have a special role in regulating apoptosis sensitivity in the complex interplay of polychemotherapy. Deciphering the differences in signaling of single drugs and drug combinations might enable designing highly effective novel polychemotherapy regimens.