Bone morphogenetic protein (BMP) signaling determines neuroblastoma cell fate and sensitivity to retinoic acid.

Retinoic acid (RA) is a standard-of-care neuroblastoma drug thought to be effective by inducing differentiation. Curiously, RA has little effect on primary human tumors during upfront treatment but can eliminate neuroblastoma cells from the bone marrow during post-chemo consolidation therapy-a discrepancy that has never been explained. To investigate this, we treated a large cohort of neuroblastoma cell lines with RA and observed that the most RA-sensitive cells predominantly undergo apoptosis or senescence, rather than differentiation. We conducted genome-wide CRISPR knockout screens under RA treatment, which identified BMP signaling as controlling the apoptosis/senescence vs differentiation cell fate decision and determining RA's overall potency. We then discovered that BMP signaling activity is markedly higher in neuroblastoma patient samples at bone marrow metastatic sites, providing a plausible explanation for RA's ability to clear neuroblastoma cells specifically from the bone marrow, seemingly mimicking interactions between BMP and RA during normal development.

Vasculature-on-a-chip technologies as platforms for advanced studies of bacterial infections.

Bacterial infections frequently occur within or near the vascular network as the vascular network connects organ systems and is essential in delivering and removing blood, essential nutrients, and waste products to and from organs. In turn, the vasculature plays a key role in the host immune response to bacterial infections. Technological advancements in microfluidic device design and development have yielded increasingly sophisticated and physiologically relevant models of the vasculature including vasculature-on-a-chip and organ-on-a-chip models. This review aims to highlight advancements in microfluidic device development that have enabled studies of the vascular response to bacteria and bacterial-derived molecules at or near the vascular interface. In the first section of this review, we discuss the use of parallel plate flow chambers and flow cells in studies of bacterial adhesion to the vasculature. We then highlight microfluidic models of the vasculature that have been utilized to study bacteria and bacterial-derived molecules at or near the vascular interface. Next, we review organ-on-a-chip models inclusive of the vasculature and pathogenic bacteria or bacterial-derived molecules that stimulate an inflammatory response within the model system. Finally, we provide recommendations for future research in advancing the understanding of host-bacteria interactions and responses during infections as well as in developing innovative antimicrobials for preventing and treating bacterial infections that capitalize on technological advancements in microfluidic device design and development.

"In our community, we normalize pain": discussions around menstruation and uterine fibroids with Black women and Latinas.

BACKGROUND: Uterine fibroids are non-cancerous neoplasms that arise from the uterus affecting over 75% of women. However, there is a disparity with Black women having an increased prevalence of nearly 80%. Black women also experience increased symptom burden, including younger age at the time of diagnosis and increased number and volume of fibroids. Less is known about other ethnoracially diverse women such as Latinas and the potential cultural impacts on fibroid burden and treatment. METHODS: Community engagement studios were conducted to facilitate discussions with stakeholders on their uterine fibroid and menstruation experience. We recruited Black women (n = 6) diagnosed with uterine fibroids and Latinas (n = 7) without uterine fibroids. We held two virtual community engagement studios split by uterine fibroid diagnosis. The studios were not audio recorded and notes were taken by four notetakers. The notes were thematically analyzed in Atlas.ti using content analysis. RESULTS: Participants felt there was a lack of discussion around menstruation overall, whether in the home or school settings. This lack of menstruation education was pronounced when participants had their first menstruation experience, with many unaware of what to expect. This silence around menstruation led to a normalization of painful menstruation symptoms. When it came to different treatment options for uterine fibroids, some women wanted to explore alternative treatments but were dismissed by their healthcare providers. Many participants advocated for having discussions with their healthcare provider about life goals to discuss different treatment options for their uterine fibroids. CONCLUSION: Despite uterine fibroid diagnosis, there is silence around menstruation. Menstruation is a normal biological occurrence and needs to be discussed to help prevent delayed diagnosis of uterine fibroids and possibly other gynecological disorders. Along with increased discussions around menstruation, further discussion is needed between healthcare providers and uterine fibroid patients to explore appropriate treatment options.

Targeting DCAF5 suppresses SMARCB1-mutant cancer by stabilizing SWI/SNF.

Whereas oncogenes can potentially be inhibited with small molecules, the loss of tumour suppressors is more common and is problematic because the tumour-suppressor proteins are no longer present to be targeted. Notable examples include SMARCB1-mutant cancers, which are highly lethal malignancies driven by the inactivation of a subunit of SWI/SNF (also known as BAF) chromatin-remodelling complexes. Here, to generate mechanistic insights into the consequences of SMARCB1 mutation and to identify vulnerabilities, we contributed 14 SMARCB1-mutant cell lines to a near genome-wide CRISPR screen as part of the Cancer Dependency Map Project1-3. We report that the little-studied gene DDB1-CUL4-associated factor 5 (DCAF5) is required for the survival of SMARCB1-mutant cancers. We show that DCAF5 has a quality-control function for SWI/SNF complexes and promotes the degradation of incompletely assembled SWI/SNF complexes in the absence of SMARCB1. After depletion of DCAF5, SMARCB1-deficient SWI/SNF complexes reaccumulate, bind to target loci and restore SWI/SNF-mediated gene expression to levels that are sufficient to reverse the cancer state, including in vivo. Consequently, cancer results not from the loss of SMARCB1 function per se, but rather from DCAF5-mediated degradation of SWI/SNF complexes. These data indicate that therapeutic targeting of ubiquitin-mediated quality-control factors may effectively reverse the malignant state of some cancers driven by disruption of tumour suppressor complexes.

DNAJB1-PRKACA fusion neoantigens elicit rare endogenous T cell responses that potentiate cell therapy for fibrolamellar carcinoma.

Fibrolamellar carcinoma (FLC) is a liver tumor with a high mortality burden and few treatment options. A promising therapeutic vulnerability in FLC is its driver mutation, a conserved DNAJB1-PRKACA gene fusion that could be an ideal target neoantigen for immunotherapy. In this study, we aim to define endogenous CD8 T cell responses to this fusion in FLC patients and evaluate fusion-specific T cell receptors (TCRs) for use in cellular immunotherapies. We observe that fusion-specific CD8 T cells are rare and that FLC patient TCR repertoires lack large clusters of related TCR sequences characteristic of potent antigen-specific responses, potentially explaining why endogenous immune responses are insufficient to clear FLC tumors. Nevertheless, we define two functional fusion-specific TCRs, one of which has strong anti-tumor activity in vivo. Together, our results provide insights into the fragmented nature of neoantigen-specific repertoires in humans and indicate routes for clinical development of successful immunotherapies for FLC.

Prevalence and impact of fertility concerns in young women with breast cancer.

Survey data from the Mayo Clinic Breast Disease Registry were used to assess fertility counseling and fertility preservation strategies in a modern cohort of young women with breast cancer. One hundred respondents were identified who were under age 50 at the time of breast cancer diagnosis and who expressed interest in future childbearing near the time of diagnosis and/or 1 year later. Ninety-three percent of the 81 respondents to the year one survey recalled fertility counseling prior to cancer treatment. Most who reported a high level of fertility concern declared that this concern had impacted their treatment decisions, often shortening their planned duration of endocrine therapy. Approximately half had taken steps to preserve future fertility, and a third had used a gonadotropin-releasing hormone agonist either alone or combined with another method (e.g., embryo or oocyte cryopreservation).

A spatial cell atlas of neuroblastoma reveals developmental, epigenetic and spatial axis of tumor heterogeneity.

Neuroblastoma is a pediatric cancer arising from the developing sympathoadrenal lineage with complex inter- and intra-tumoral heterogeneity. To chart this complexity, we generated a comprehensive cell atlas of 55 neuroblastoma patient tumors, collected from two pediatric cancer institutions, spanning a range of clinical, genetic, and histologic features. Our atlas combines single-cell/nucleus RNA-seq (sc/scRNA-seq), bulk RNA-seq, whole exome sequencing, DNA methylation profiling, spatial transcriptomics, and two spatial proteomic methods. Sc/snRNA-seq revealed three malignant cell states with features of sympathoadrenal lineage development. All of the neuroblastomas had malignant cells that resembled sympathoblasts and the more differentiated adrenergic cells. A subset of tumors had malignant cells in a mesenchymal cell state with molecular features of Schwann cell precursors. DNA methylation profiles defined four groupings of patients, which differ in the degree of malignant cell heterogeneity and clinical outcomes. Using spatial proteomics, we found that neuroblastomas are spatially compartmentalized, with malignant tumor cells sequestered away from immune cells. Finally, we identify spatially restricted signaling patterns in immune cells from spatial transcriptomics. To facilitate the visualization and analysis of our atlas as a resource for further research in neuroblastoma, single cell, and spatial-omics, all data are shared through the Human Tumor Atlas Network Data Commons at www.humantumoratlas.org.

A pilot study of mitochondrial response to an in vivo prosthetic joint Staphylococcus aureus infection model.

Prosthetic joint infections (PJI) are associated with orthopaedic morbidity and mortality. Mitochondria, the "cell's powerhouses," are thought to play crucial roles in infection response and in increased risk of sepsis mortality. No current research discusses PJI's effect on mitochondrial function and a lack of understanding of immune-infection interactions potentially hinders patient care. The purpose of this pilot study was to evaluate the impact of simulated PJI on local tissue mitochondrial function. Using an established prosthetic implant-associated in vivo model, tissues were harvested from the surgical limb of a methicillin-sensitive Staphylococcus aureus implant-associated infection group (n = 6) and compared to a noninfected group (n = 6) at postoperative day (POD) 21. Using mitochondrial coupling assays, oxygen consumption rate and extracellular acidification rate were assessed in each group. Electron flow through mitochondrial complexes reflected group activity. Electron Paramagnetic Resonance (EPR) spectrometry measured the oxidizing potential of serum samples from infected versus noninfected groups. On POD21, colony-forming units per gram of tissue showed 5 × 109 in the infected group and 101 in the noninfected group (p < 0.0001). Maximal respiration and oxygen consumption due to adenosine triphosphate synthesis were significantly lower in isolated mitochondria from infected limbs (p = 0.04). Both groups had similar complex I, III, IV, and V activity (p > 0.1). Infected group EPR signal intensity reflecting reactive oxygen species levels was 1.31 ± 0.30 compared to 1.16 ± 0.28 (p = 0.73) in the noninfected group. This study highlights PJI's role in mammalian cell mitochondrial dysfunction and oxidative tissue damage, which can help develop interventions to combat PJI.

Relugolix combination therapy in Black/African American women with symptomatic uterine fibroids: LIBERTY Long-Term Extension study.

BACKGROUND: In the LIBERTY Long-Term Extension study, once-daily relugolix combination therapy (40 mg relugolix, estradiol 1 mg, norethindrone acetate 0.5 mg) substantially improved uterine fibroid-associated heavy menstrual bleeding throughout the 52-week treatment period in the overall study population. OBJECTIVE: Black or African American women typically experience a greater extent of disease and symptom burden of uterine fibroids vs other racial groups and have traditionally been underrepresented in clinical trials. This secondary analysis aimed to assess the efficacy and safety of relugolix combination therapy in the subgroup population of Black or African American women with uterine fibroids in the LIBERTY Long-Term Extension study. STUDY DESIGN: Black or African American premenopausal women (aged 18-50 years) with uterine fibroids and heavy menstrual bleeding who completed the 24-week randomized, placebo-controlled, double-blind LIBERTY 1 (identifier: NCT03049735) or LIBERTY 2 (identifier: NCT03103087) trials were eligible to enroll in the 28-week LIBERTY Long-Term Extension study (identifier: NCT03412890), in which all women received once-daily, open-label relugolix combination therapy. The primary endpoint of this subanalysis was the proportion of Black or African American treatment responders: women who achieved a menstrual blood loss volume of <80 mL and at least a 50% reduction in menstrual blood loss volume from the pivotal study baseline to the last 35 days of treatment by pivotal study randomized treatment group. The secondary outcomes included rates of amenorrhea and changes in symptom burden and quality of life. RESULTS: Overall, 241 of 477 women (50.5%) enrolled in the LIBERTY Long-Term Extension study self-identified as Black or African American. In Black or African American women receiving continuous relugolix combination therapy for up to 52 weeks, 58 of 70 women (82.9%; 95% confidence interval, 72.0%-90.8%) met the treatment responder criteria for reduction in heavy menstrual bleeding (primary endpoint). A substantial reduction in menstrual blood loss volume from the pivotal study baseline to week 52 was demonstrated (least squares mean percentage change: 85.0%); 64.3% of women achieved amenorrhea; 59.1% of women with anemia at the pivotal study baseline achieved a substantial improvement (>2 g/dL) in hemoglobin levels; and decreased symptom severity and distress because of uterine fibroid-associated symptoms and improvements in health-related quality of life through 52 weeks were demonstrated. The most frequently reported adverse events during the cumulative 52-week treatment period were hot flush (12.9%), headache (5.7%), and hypertension (5.7%). Bone mineral density was preserved through 52 weeks. CONCLUSION: Once-daily relugolix combination therapy improved uterine fibroid-associated heavy menstrual bleeding in most Black or African American women who participated in the LIBERTY Long-Term Extension study. The safety and efficacy profile of relugolix combination therapy in Black or African American women was consistent with previously published results from the overall study population through 52 weeks. Findings from this subanalysis will assist shared decision-making by helping providers and Black or African American women understand the efficacy and safety of relugolix combination therapy as a pharmacologic option for the management of uterine fibroid-associated symptoms.

COVID-19 risk communication gaps, needs, and strategies related to pandemic preparedness plans among vulnerable, Black American subgroups: A qualitative study.

OBJECTIVE: Improving current and future risk communication plans is critical to mitigate the COVID-19 pandemic and begin to prepare for future pandemics. Minority groups, particularly African Americans, have been limited in engagement to prepare these plans which has been demonstrated to be disadvantageous. We report findings from a qualitative study that describes gaps, needs, and strategies to improve communication among vulnerable, Black American subgroups during the COVID-19 pandemic. METHODS: Sixty-two Black Americans in uniquely, vulnerable subgroups participated in qualitative, semi-structured interviews from May to September 2020. Thematic analyses were used to identify themes. RESULTS: Participants were 16 essential workers, 16 parents, 15 young adults, and 15 individuals with underlying medical conditions. Emerging themes were: (1) Poor communication and miscommunication fueled fear and confusion; (2) Information sources and channels: How do I choose one?; (3) Communication needs were simple yet complex; (4) All information sources are not trusted information sources; (5) Preferred yet trusted channels and types of information; and (6) Dissemination of COVID Research: Why and How. Subgroups varied in information sources and processes for choosing the source, communication needs, and channels and types of information needed. They shared why they did and did not trust certain sources along with the importance of COVID research dissemination to promote informed decision-making throughout the pandemic. DISCUSSION: This study found that Black American subgroups had diverse, yet trusted and non-trusted messages, messengers, and strategies for communication and wanted research results disseminated. We describe multi-level stakeholders and strategies to help improve risk communication for pandemics, and potentially preparedness and health outcomes.

Follicle Stimulating Hormone (FSH) as a Predictor of Decreased Oocyte Yield in Patients with Normal Anti-Müllerian Hormone (AMH) and Antral Follicle Count (AFC).

Background: The purpose of the current study was to determine the utility of early follicular phase follicle-stimulating hormone (FSH) testing in patients undergoing in vitro fertilization (IVF). Methods: This was a retrospective review of patients from 2012 to 2015 at Mayo Clinic in Rochester, Minnesota, USA. Included subjects had a normal anti-Müllerian hormone (AMH) of 1 to 9 ng/ml and antral follicle count (AFC) of 10 to 29. Patients were stratified by FSH level when associated estradiol was less than 50 ng/ml. In total, 225 patients were categorized into three groups: high FSH (FSH ≥10 IU/L; n= 36), normal FSH (>5 IU/L and <10 IU/L; n=170), and low FSH (FSH ≤5 IU/L; n= 19). ANOVA and multiple logistic regression were used for statistical comparisons and for evaluation of the relationships between variables; significance level was set at <0.05. Results: There were no significant differences in demographics, IVF cycle type, or peak estradiol level between the groups. Patients with a high basal FSH level had a similar clinical pregnancy rate and live birth rate compared to controls and patients with low FSH. High FSH level was associated with decreased follicular development (17 versus 22; p<0.01), oocyte yield (15 versus 18; p=0.02), and embryo yield (8 versus 10; p=0.04) despite higher total doses of gonadotropins. Conclusion: Patients with normal AMH and AFC levels could be further stratified into lower responders and starting doses of medications can be adjusted based on high basal FSH levels. Therefore, it is suggested to counsel patients on pregnancy outcomes which seem to be quite similar regardless of the FSH level.

New Non-Steroidal Topical Therapies for Inflammatory Dermatoses-Part 3: Roflumilast.

Topical corticosteroids have remained the initial and long-term topical treatment option for inflammatory dermatitis conditions since the 1950s. A number of non-steroidal topicals for treatment of inflammatory dermatoses have been developed in the recent decades, such as topical calcineurin inhibitors (tacrolimus ointment and pimecrolimus cream), vitamin D analogues, and phophodiesterase-4 inhibitors (crisaborole), but none had the combination of broad therapeutic range, relatively rapid onset of action, tolerability, and wide-spread clinical success that allowed topical glucocorticosteroids to remain the mainstay of therapy. This situation has shifted dramatically with three non-steroidal new molecular entities, each with completely different mechanisms of action, receiving approval of the Food and Drug Administration (FDA) in the past year. Topical ruxolitinib, a Janus kinase (JAK) inhibitor, was the first to receive FDA approval, specifically for treating atopic dermatitis, and was the subject of the first report in this series. Subsequently, topical tapinarof, an aryl hydrocarbon receptor modulating agent, was approved by the FDA for treating plaque psoriasis in May 2022 and was the focus of the second report in this series. Finally, and most recently in July 2022, topical roflumilast, a highly potent phosphodiesterase-4 inhibitor, has received FDA approval for treating plaque psoriasis, and is the subject of the third and final report in this series. In addition to their unique mechanisms of action and spectra of activity, each of these agents has unique clinical characteristics, including degree of efficacy, rapidity of onset of efficacy, potential remittive effects, and safety and tolerability profiles. In this three-part series, we reviewed and summarized the data surrounding each agent, providing a comprehensive overview that would allow dermatologists to integrate them confidently and appropriately into treatment paradigms. Part three focuses on topical roflumilast, a highly potent phosphodiesterase-4 inhibitor.

Communication Interactions, Needs, and Preferences During Clinical Encounters of African American Parent-Child Dyads.

Human papillomavirus (HPV) vaccination rates remain suboptimal among African American adolescents. Although provider recommendations during clinical encounters are believed to be highly effective in increasing uptake and series completion, little has been reported about parent-child perspectives on the counseling received during these encounters. Among African American parent-child dyads, we sought to explore and compare interactions, needs, and preferences during clinical encounters by child's HPV vaccination status. We applied a qualitative, phenomenological study design to conduct semi-structured interviews with African American parent-child dyads representing children who were unvaccinated (n = 10), had initiated but not completed (n = 11), or had completed the HPV vaccine series (n = 9). Using iterative, inductive-deductive thematic analysis, five themes were generated: (1) parents' attitudes varied about the HPV vaccine but were mostly positive for vaccines in general; (2) patient-parent-provider clinical encounters from the parent perspective; (3) patient-parent-provider clinical encounters from the child perspective; (4) methods of distribution of supplemental HPV information; and (5) communication desired on HPV vaccination by parents and children. Parents stating they received a provider's recommendation increased by vaccination status (unvaccinated: 6 out of 10; initiated: 7 out of 11; completed: 9 out of 9). Most parents and children were not satisfied with provider communication on the HPV vaccine and used supplemental materials to inform decision-making. Ongoing communication on the HPV vaccine was requested even post-vaccination of the child. During clinical encounters, children and parental messaging needs are similar yet dissimilar. We offer communication strategies and messaging that can be used for African American parent-child dyads by child HPV vaccination status during a clinical encounter.

New Non-Steroidal Topical Therapies for Inflammatory Dermatoses-Part 2: Tapinarof.

Since its introduction in 1952, topical glucocorticosteroids remain the initial and long-term treatment option for various forms of inflammatory dermatitis. A number of non-steroidal topicals for treating inflammatory dermatoses have been developed in the recent decades (such as topical calcineurin inhibitors, vitamin D analogues, and phophodiesterase-4 inhibitors), but none had the combination of broad therapeutic range, relatively rapid onset of action, high tolerability, and wide-spread clinical success; this allowed topical glucocorticosteroids to remain the mainstay of therapy. This situation has shifted dramatically, with three non-steroidal new molecular entities, each with completely different mechanisms of action, receiving approval of the Food and Drug Administration (FDA) in the past year. Topical ruxolitinib, a Janus kinase (JAK) inhibitor, was approved by the FDA in September 2021 for atopic dermatitis, and was the subject of the first report in this review series. Subsequently, topical tapinarof, an aryl hydrocarbon receptor modulating agent, was approved by the FDA in May 2022 for treating plaque psoriasis, and is the focus of this present report. Finally and the most recently, topical roflumilast, a highly potent phosphodiesterase-4 inhibitor, received FDA approval in July 2022 for treating plaque psoriasis, and is reviewed in the third and final report in this series. In addition to their unique mechanisms of action and spectra of activity, each of these agents has unique clinical characteristics, including degree of efficacy, rapidity of onset of efficacy, potential remittive effects, and safety and tolerability profiles. In short, in this three-part series, we reviewed and summarized the data surrounding each agent, providing a comprehensive overview which would allow dermatologists to confidently and appropriately integrate them into treatment paradigms.

A plain language summary of the long-term relugolix combination therapy study for uterine fibroids.

What is this summary about? This is a summary of a research study (known as a clinical trial) called the LIBERTY extension study. The LIBERTY extension study is a long-term study looking at how well a medicine called relugolix combination therapy worked in reducing blood loss during menstrual periods in women with uterine fibroids with heavy menstrual periods. Women were included in the extension study if they finished the 24-week LIBERTY 1 or LIBERTY 2 studies. Heavy menstrual periods were considered to be menstrual blood loss of about one-third of a cup of blood (80 ml) per cycle for two cycles or about two-thirds of a cup of blood (160 ml) during one cycle. The LIBERTY extension study also looked at whether relugolix combination therapy was safe to take for up to 1 year. What were the results? Out of 770 total women with uterine fibroids with heavy menstrual bleeding who took part in the LIBERTY 1 and LIBERTY 2 studies, 476 took part in the LIBERTY extension study. From the start of the LIBERTY 1 and LIBERTY 2 studies through the end of the LIBERTY extension: 163 women took relugolix combination therapy for 52 weeks 149 women took relugolix alone for 12 weeks followed by relugolix combination therapy for 40 weeks 164 women took placebo for 24 weeks followed by relugolix combination therapy for 28 weeks The LIBERTY extension study showed that most women in all three treatment groups responded to relugolix combination therapy by having less bleeding during their menstrual periods, having improved anemia symptoms, and having stable bone mineral loss. Side effects were similar across treatment groups, and the most common side effects were headaches and hot flushes. What do the results mean? Women with uterine fibroids with heavy menstrual bleeding taking relugolix combination therapy may have fewer uterine fibroid bleeding symptoms for up to 1 year of treatment. Clinical Trial Registration: NCT03049735 (ClinicalTrials.gov) (LIBERTY 1) Clinical Trial Registration: NCT03103087 (ClinicalTrials.gov) (LIBERTY 2) Clinical Trial Registration: NCT03412890 (ClinicalTrials.gov) (LIBERTY extension study).

Paediatric Strategy Forum for medicinal product development of DNA damage response pathway inhibitors in children and adolescents with cancer: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration.

DNA damage response inhibitors have a potentially important therapeutic role in paediatric cancers; however, their optimal use, including patient selection and combination strategy, remains unknown. Moreover, there is an imbalance between the number of drugs with diverse mechanisms of action and the limited number of paediatric patients available to be enrolled in early-phase trials, so prioritisation and a strategy are essential. While PARP inhibitors targeting homologous recombination-deficient tumours have been used primarily in the treatment of adult cancers with BRCA1/2 mutations, BRCA1/2 mutations occur infrequently in childhood tumours, and therefore, a specific response hypothesis is required. Combinations with targeted radiotherapy, ATR inhibitors, or antibody drug conjugates with DNA topoisomerase I inhibitor-related warheads warrant evaluation. Additional monotherapy trials of PARP inhibitors with the same mechanism of action are not recommended. PARP1-specific inhibitors and PARP inhibitors with very good central nervous system penetration also deserve evaluation. ATR, ATM, DNA-PK, CHK1, WEE1, DNA polymerase theta and PKMYT1 inhibitors are early in paediatric development. There should be an overall coordinated strategy for their development. Therefore, an academia/industry consensus of the relevant biomarkers will be established and a focused meeting on ATR inhibitors (as proof of principle) held. CHK1 inhibitors have demonstrated activity in desmoplastic small round cell tumours and have a potential role in the treatment of other paediatric malignancies, such as neuroblastoma and Ewing sarcoma. Access to CHK1 inhibitors for paediatric clinical trials is a high priority. The three key elements in evaluating these inhibitors in children are (1) innovative trial design (design driven by a clear hypothesis with the intent to further investigate responders and non-responders with detailed retrospective molecular analyses to generate a revised or new hypothesis); (2) biomarker selection and (3) rational combination therapy, which is limited by overlapping toxicity. To maximally benefit children with cancer, investigators should work collaboratively to learn the lessons from the past and apply them to future studies. Plans should be based on the relevant biology, with a focus on simultaneous and parallel research in preclinical and clinical settings, and an overall integrated and collaborative strategy.

Cost-effectiveness of Myomectomy versus Hysterectomy in Women with Uterine Fibroids.

STUDY OBJECTIVE: Increasing evidence suggests that hysterectomy to treat uterine fibroids (UFs), even with ovarian conservation (OC), is associated with a 33% increased risk of coronary artery disease (CAD). We sought to compare the cost-effectiveness of various treatment approaches for UFs to understand the trade-offs among development of CAD vs new fibroids. DESIGN: We developed a Markov model to include women with UFs who no longer desired pregnancy. The outcomes of interest were quality-adjusted life-years (QALYs) and total treatment costs. We conducted sensitivity analyses to test the effect of uncertain model inputs. SETTING: Health system perspective. PATIENTS: A hypothetical cohort of 10 000 40-year-old women. INTERVENTIONS: Myomectomy, hysterectomy with OC, and hysterectomy without OC. MEASUREMENTS AND MAIN RESULTS: Myomectomy was the best-value strategy, costing US$528 217 and providing 19.38 QALYs. Neither hysterectomy with OC nor hysterectomy without OC was found to be cost-effective, assuming a willingness-to-pay threshold of $100 000 per QALY gain as hysterectomy with OC provided more benefit than myomectomy at an average cost of $613 144 to gain one additional QALY. The sensitivity analyses showed that if the risk of new symptomatic UFs that required treatment after myomectomy was more than 13%, annually (base case, 3.6%), or the quality of life after myomectomy was less than 0.815 (base case, 0.834), then myomectomy would no longer be cost-effective, under a willingness-to-pay amount of US$100 000. CONCLUSION: Myomectomy is an optimal treatment of UFs compared with hysterectomy among women aged 40 years. The increased risk of CAD after hysterectomy and its associated costs and the effects on morbidity and quality of life made hysterectomy a costlier and less effective long-term strategy.