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Aim: This study aims to identify demographic factors, area-based social determinants of health (SDOH), and clinical features associated with medical decision-making after pediatric out-of-hospital cardiac arrest (OHCA)., Methods: This is a retrospective, exploratory, descriptive analysis of patients < 18 years old admitted to the pediatric intensive care unit (ICU) after OHCA from 2011 to 2022 (n = 217) at an urban tertiary care, free-standing children's hospital. Outcomes of interest included: (1) whether a new advance care plan (ACP) (defined as a written advance directive including do not resuscitate and/or do not intubate) was ordered during hospitalization, and (2) whether the patient was discharged with new medical technology (defined as tracheostomy and/or feeding tube). Logistic regression models identified features associated with these outcomes., Results: Of the 217 patients, 78 patients (36%) had a new ACP placed during their admission. Of the survivors, 26% (27/102) were discharged home with new medical technology. Factors associated with ACP were greater change in Pediatric Cerebral Performance Category (PCPC) score (aOR = 1.49, 95% CI [1.28-1.73], p-value < 0.001) and palliative care consultation (aOR = 2.39, 95% CI [1.16-4.89], p-value 0.018). Factors associated with new medical technology were lower change in PCPC score (aOR = 0.76, 95% C.I. [0.61-0.95], p-value = 0.015) and palliative care consultation (aOR = 7.07, 95% CI [3.01-16.60], p-value < 0.001). There were no associations between area-based SDOH and outcomes., Conclusions: Understanding factors associated with decision-making related to ACP after OHCA is critical to optimize counseling for families. Multi-institutional studies are warranted to identify whether these findings are generalizable., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: To evaluate for associations between a child's neighborhood, as categorized by Child Opportunity Index (COI 2.0), and 1) PICU mortality, 2) severity of illness at PICU admission, and 3) PICU length of stay (LOS)., Design: Retrospective cohort study., Setting: Fifteen PICUs in the United States., Patients: Children younger than 18 years admitted from 2019 to 2020, excluding those after cardiac procedures. Nationally-normed COI category (very low, low, moderate, high, very high) was determined for each admission by census tract, and clinical features were obtained from the Virtual Pediatric Systems LLC (Los Angeles, CA) data from each site., Interventions: None., Measurements and Main Results: Among 33,901 index PICU admissions during the time period, median patient age was 4.9 years and PICU mortality was 2.1%. There was a higher percentage of admissions from the very low COI category (27.3%) than other COI categories (17.2-19.5%, p < 0.0001). Patient admissions from the high and very high COI categories had a lower median Pediatric Index of Mortality 3 risk of mortality (0.70) than those from the very low, low, and moderate COI groups (0.71) ( p < 0.001). PICU mortality was lowest in the very high (1.7%) and high (1.9%) COI groups and highest in the moderate group (2.5%), followed by very low (2.3%) and low (2.2%) ( p = 0.001 across categories). Median PICU LOS was between 1.37 and 1.50 days in all COI categories. Multivariable regression revealed adjusted odds of PICU mortality of 1.30 (95% CI, 0.94-1.79; p = 0.11) for children from a very low versus very high COI neighborhood, with an odds ratio [OR] of 0.996 (95% CI, 0.993-1.00; p = 0.05) for mortality for COI as an ordinal value from 0 to 100. Children without insurance coverage had an OR for mortality of 3.58 (95% CI, 2.46-5.20; p < 0.0001) as compared with those with commercial insurance., Conclusions: Children admitted to a cohort of U.S. PICUs were often from very low COI neighborhoods. Children from very high COI neighborhoods had the lowest risk of mortality and observed mortality; however, odds of mortality were not statistically different by COI category in a multivariable model. Children without insurance coverage had significantly higher odds of PICU mortality regardless of neighborhood., Competing Interests: Dr. McCrory received funding from the Wake Forest Department of Anesthesiology. Dr. Maddux’s institution received funding from the National Institute of Child Health and Human Development (K23HD096018) and the Francis Family Foundation. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Objective: Perform a scoping review of supervised machine learning in pediatric critical care to identify published applications, methodologies, and implementation frequency to inform best practices for the development, validation, and reporting of predictive models in pediatric critical care., Design: Scoping review and expert opinion., Setting: We queried CINAHL Plus with Full Text (EBSCO), Cochrane Library (Wiley), Embase (Elsevier), Ovid Medline, and PubMed for articles published between 2000 and 2022 related to machine learning concepts and pediatric critical illness. Articles were excluded if the majority of patients were adults or neonates, if unsupervised machine learning was the primary methodology, or if information related to the development, validation, and/or implementation of the model was not reported. Article selection and data extraction were performed using dual review in the Covidence tool, with discrepancies resolved by consensus., Subjects: Articles reporting on the development, validation, or implementation of supervised machine learning models in the field of pediatric critical care medicine., Interventions: None., Measurements and Main Results: Of 5075 identified studies, 141 articles were included. Studies were primarily (57%) performed at a single site. The majority took place in the United States (70%). Most were retrospective observational cohort studies. More than three-quarters of the articles were published between 2018 and 2022. The most common algorithms included logistic regression and random forest. Predicted events were most commonly death, transfer to ICU, and sepsis. Only 14% of articles reported external validation, and only a single model was implemented at publication. Reporting of validation methods, performance assessments, and implementation varied widely. Follow-up with authors suggests that implementation remains uncommon after model publication., Conclusions: Publication of supervised machine learning models to address clinical challenges in pediatric critical care medicine has increased dramatically in the last 5 years. While these approaches have the potential to benefit children with critical illness, the literature demonstrates incomplete reporting, absence of external validation, and infrequent clinical implementation., Competing Interests: Drs. Bennett’s and Mayampurath’s institution received funding from the National Heart, Lung, and Blood Institute. Drs. Bennett, Dziorny, Kamaleswaran and Mayampurath received support for article research from the National Institutes of Health (NIH). Dr. Bennett’s institution received funding from the National Institute of Child Health and Human Development and the National Center for Advancing Translational Sciences. Dr. Sanchez-Pinto received funding from Celldom, Allyx, and Saccharo. Dr. Martin’s institution received funding from the Children’s Hospital Colorado Research Institute and the Thrasher Research Fund. Dr. Kamaleswaran’s institution received funding from the NIH. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Objective: Terminal extubation (TE) and terminal weaning (TW) during withdrawal of life-sustaining therapies (WLSTs) have been described and defined in adults. The recent Death One Hour After Terminal Extubation study aimed to validate a model developed to predict whether a child would die within 1 hour after discontinuation of mechanical ventilation for WLST. Although TW has not been described in children, pre-extubation weaning has been known to occur before WLST, though to what extent is unknown. In this preplanned secondary analysis, we aim to describe/define TE and pre-extubation weaning (PW) in children and compare characteristics of patients who had ventilatory support decreased before WLST with those who did not., Design: Secondary analysis of multicenter retrospective cohort study., Setting: Ten PICUs in the United States between 2009 and 2021., Patients: Nine hundred thirteen patients 0-21 years old who died after WLST., Interventions: None., Measurements and Main Results: 71.4% ( n = 652) had TE without decrease in ventilatory support in the 6 hours prior. TE without decrease in ventilatory support in the 6 hours prior = 71.4% ( n = 652) of our sample. Clinically relevant decrease in ventilatory support before WLST = 11% ( n = 100), and 17.6% ( n = 161) had likely incidental decrease in ventilatory support before WLST. Relevant ventilator parameters decreased were F io2 and/or ventilator set rates. There were no significant differences in any of the other evaluated patient characteristics between groups (weight, body mass index, unit type, primary diagnostic category, presence of coma, time to death after WLST, analgosedative requirements, postextubation respiratory support modality)., Conclusions: Decreasing ventilatory support before WLST with extubation in children does occur. This practice was not associated with significant differences in palliative analgosedation doses or time to death after extubation., Competing Interests: Dr. Pringle’s institution received funding from the National Institutes of Health (NIH) (Ul1TR001427); she received support for article research from the NIH. Dr. Winter received support for article research from the LK Whittier Foundation. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Purpose: We aimed to explore patient's experience of chemotherapy-induced menopausal symptoms; to ascertain how patients tried to alleviate their symptoms and how health professionals supported them in order to identify current unmet needs., Methods: We designed a retrospective cross-sectional exploratory study of a sample of 11 women who received multi-agent combination chemotherapy for Gestational Trophoblastic Neoplasia. Postal surveys using the Greene Climacteric Scale (GCS) questionnaire followed up by semi-structured telephone interviews were used. Framework analysis technique was used to generate descriptions of patient's experiences., Results: Symptoms of feeling tired or lacking in energy, loss of interest in sex, muscle and joint pains and difficulty in concentrating affected participants the most. The menopausal symptoms appear to be temporary; symptoms such as hot flushes and night sweats seem to subside with resumption of menses. Others are more gradual with some evidence that mental health takes longer to recover. Regarding potential symptoms, some women do not retain the information given to them at discharge following end of treatment, which GTD services need to take into consideration when supporting patients., Conclusion: Patients need to be more optimally prepared for post-chemotherapy recovery with each patient's needs and support being individually tailored. How information is discussed and disseminated needs improving to ensure patients retain the information they receive at discharge. Recommendations include the creation of menopause information booklet, alongside further developing virtual nurse-led follow up clinics post chemotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2023. Published by Elsevier Ltd. All rights reserved.)

Objective: To assess the HIV prevalence in patients diagnosed with gestational trophoblastic neoplasia (GTN)., Design: A retrospective single centre cohort study., Methods: A database from the Sheffield Trophoblastic Disease Centre (STDC), Sheffield, UK was searched between 1st January 2015 and 31st December 2021. A total of 3,591 patients were referred to STDC with a diagnosis of gestational trophoblastic disease (GTD), of which 221 (6.2%) were treated for GTN. The prevalence of HIV-positive tests in GTN patients was assessed., Results: HIV testing was performed in 93% GTN patients ( n  = 205/221). Overall, 1.3% of GTN patients ( n  = 3/221) were HIV-positive, involving two known HIV-positive patients and one new diagnosis. This equates to a HIV prevalence of 14 : 1000, which is ∼7 to 9× higher than the HIV prevalence in Sheffield (1.9 per 1000) and Yorkshire and Humber (1.5 per 1000)., Conclusion: Given the extremely high HIV prevalence in our population, 'opt out' HIV testing is recommended within our specialist trophoblastic centre for all referred GTD and GTN patients. There is little reason to suspect that the prevalence of HIV-positive patients is any lower in the cohort of GTD patients referred to specialist trophoblastic centres for hCG screening alone, without requiring chemotherapy, particularly considering that most GTN arises from GTD., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: The International Federation of Gynecology and Obstetrics (FIGO) scoring system uses the sum of eight risk-factors to predict single-agent chemotherapy resistance in Gestational Trophoblastic Neoplasia (GTN). To improve ease of use, this study aimed to generate: (i) streamlined models that match FIGO performance and; (ii) visual-decision aids (nomograms) for guiding management., Methods: Using training (n = 4191) and validation datasets (n = 144) of GTN patients from two UK specialist centres, logistic regression analysis generated two-factor models for cross-validation and exploration. Performance was assessed using true and false positive rate, positive and negative predictive values, Bland-Altman calibration plots, receiver operating characteristic (ROC) curves, decision-curve analysis (DCA) and contingency tables. Nomograms were developed from estimated model parameters and performance cross-checked upon the training and validation dataset., Results: Three streamlined, two-factor models were selected for analysis: (i) M1, pre-treatment hCG + history of failed chemotherapy; (ii) M2, pre-treatment hCG + site of metastases and; (iii) M3, pre-treatment hCG + number of metastases. Using both training and validation datasets, these models showed no evidence of significant discordance from FIGO (McNemar's test p > 0.78) or across a range of performance parameters. This behaviour was maintained when applying algorithms simulating the logic of the nomograms., Conclusions: Our streamlined models could be used to assess GTN patients and replace FIGO, statistically matching performance. Given the importance of imaging parameters in guiding treatment, M2 and M3 are favoured for ongoing validation. In resource-poor countries, where access to specialist centres is problematic, M1 could be pragmatically implemented. Further prospective validation on a larger cohort is recommended., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Approximately 10% to 15% of triple-negative breast cancers (TNBC) have deleterious mutations in BRCA1 and BRCA2 and may benefit from PARP inhibitor treatment. PARP inhibitors may also increase exogenous replication stress and thereby increase sensitivity to inhibitors of ataxia telangiectasia and Rad3-related (ATR) protein. This phase II study examined the activity of the combination of PARP inhibitor, olaparib, and ATR inhibitor, ceralasertib (AZD6738), in patients with advanced TNBC., Patients and Methods: Patients with TNBC on most recent biopsy who had received 1 or 2 lines of chemotherapy for advanced disease or had relapsed within 12 months of (neo)adjuvant chemotherapy were eligible. Treatment was olaparib 300 mg twice a day continuously and celarasertib 160 mg on days 1-7 on a 28-day cycle until disease progression. The primary endpoint was confirmed objective response rate (ORR). Tissue and plasma biomarker analyses were preplanned to identify predictors of response., Results: 70 evaluable patients were enrolled. Germline BRCA1/2 mutations were present in 10 (14%) patients and 3 (4%) patients had somatic BRCA mutations. The confirmed ORR was 12/70; 17.1% (95% confidence interval, 10.4-25.5). Responses were observed in patients without germline or somatic BRCA1/2 mutations, including patients with mutations in other homologous recombination repair genes and tumors with functional homologous recombination deficiency by RAD51 foci., Conclusions: The response rate to olaparib and ceralasertib did not meet prespecified criteria for activity in the overall evaluable population, but responses were observed in patients who would not be expected to respond to olaparib monotherapy., (©2023 The Authors; Published by the American Association for Cancer Research.)

Background: Approximately one-third of patients with low-risk Gestational Trophoblastic Neoplasia (WHO 0-6) develop methotrexate-resistance (MTX-R). In the UK, subsequent treatment with either actinomycin-D (ActD) or multi-agent combination chemotherapy has depended on whether the hCG was above or below an hCG threshold. To reduce exposure to combination chemotherapy (CC), over the years the UK service has raised this threshold as well as using single-agent carboplatin AUC6 3-weekly at MTX-R instead of CC. Updated results for carboplatin demonstrate an 86% complete hCG response (hCG CR) but associated with haematological dose-limiting toxicity., Methods: In 2017, single-agent carboplatin became the national standard second-line treatment following MTX-R at hCG of >3000 IU/L. Carboplatin was changed to two-weekly AUC4 scheduling and continued until normal hCG plus 3 consolidation cycles. For patients failing to respond, CC (Etoposide-Actinomycin-D or EMA-CO) was introduced., Results: 22 evaluable patients with a median hCG at MTX-R of 10,147 IU/L (IQR 5527-19,639) received carboplatin AUC4 2-weekly (median no. of cycles = 6, IQR 2-8). Of these, 36% achieved a hCG CR. All 14 non-CR patients were cured with subsequent CC; 11 and 2 patients with 3rd line and 4th line CC respectively and 1 patient following 5th line CC and hysterectomy. Overall survival remains 100%., Conclusion: Carboplatin is not sufficiently active in the second-line treatment of low-risk MTX-resistant GTN. New strategies are required to increase hCG CR and spare more toxic CC regimens., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

Objectives: To describe the doses of opioids and benzodiazepines administered around the time of terminal extubation (TE) to children who died within 1 hour of TE and to identify their association with the time to death (TTD)., Design: Secondary analysis of data collected for the Death One Hour After Terminal Extubation study., Setting: Nine U.S. hospitals., Patients: Six hundred eighty patients between 0 and 21 years who died within 1 hour after TE (2010-2021)., Measurements and Main Results: Medications included total doses of opioids and benzodiazepines 24 hours before and 1 hour after TE. Correlations between drug doses and TTD in minutes were calculated, and multivariable linear regression performed to determine their association with TTD after adjusting for age, sex, last recorded oxygen saturation/F io2 ratio and Glasgow Coma Scale score, inotrope requirement in the last 24 hours, and use of muscle relaxants within 1 hour of TE. Median age of the study population was 2.1 years (interquartile range [IQR], 0.4-11.0 yr). The median TTD was 15 minutes (IQR, 8-23 min). Forty percent patients (278/680) received either opioids or benzodiazepines within 1 hour after TE, with the largest proportion receiving opioids only (23%, 159/680). Among patients who received medications, the median IV morphine equivalent within 1 hour after TE was 0.75 mg/kg/hr (IQR, 0.3-1.8 mg/kg/hr) ( n = 263), and median lorazepam equivalent was 0.22 mg/kg/hr (IQR, 0.11-0.44 mg/kg/hr) ( n = 118). The median morphine equivalent and lorazepam equivalent rates after TE were 7.5-fold and 22-fold greater than the median pre-extubation rates, respectively. No significant direct correlation was observed between either opioid or benzodiazepine doses before or after TE and TTD. After adjusting for confounding variables, regression analysis also failed to show any association between drug dose and TTD., Conclusions: Children after TE are often prescribed opioids and benzodiazepines. For patients dying within 1 hour of TE, TTD is not associated with the dose of medication administered as part of comfort care., Competing Interests: Dr. Winter’s institution received funding from the L.K. Whittier Foundation. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Objectives: Gestational Trophoblastic Neoplasia (GTN) is a rare group of malignant placental-related tumours requiring systemic anti-cancer treatment. Leptomeningeal disease (LMD) related to GTN is not well reported with no consensus in optimal treatment. We offer recommendations for management of these patients., Methods: We discuss five patients with GTN who presented with features of LMD and were diagnosed with gadolinium-enhanced MRI brain, all of whom received low dose induction etoposide-cisplatin (EP) followed by either EP-etoposide, methotrexate (CNS) and actinomycin-D (EMA) or EMA(CNS)-cyclophosphamide and vincristine (CO)., Results: Four out of the five patients additionally received intrathecal methotrexate. Four patients had complete hCG response to first line multi-agent chemotherapy, one patient required second line paclitaxel, cisplatin alternating with paclitaxel, etoposide (TP/TE), where paclitaxel was substituted with nab-paclitaxel due to anaphylaxis, followed by hysterectomy. One of the four initial complete hCG responders relapsed in the lung requiring further systemic treatment with subsequent lobectomy. Patient reported outcomes indicate persistent neurological symptoms are mild and do not affect functionality and quality of life., Conclusion: With a follow-up range of 2-6 years, all five patients remain cured demonstrating excellent survival outcomes with the avoidance of whole-brain radiotherapy in all cases., Competing Interests: Declaration of Competing Interest The authors have no conflict of interests to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aim: Out-of-hospital cardiac arrest (OHCA) in pediatric patients is associated with high rates of mortality and neurologic injury, with no definitive evidence-based method to predict outcomes available. A prognostic scoring tool for adults, The Brain Death After Cardiac Arrest (BDCA) score, was recently developed and validated. We aimed to validate this score in pediatric patients., Methods: Retrospective cohort study of pediatric patients admitted to 5 PICUs after OHCA between 2011 and 2021. We extracted BDCA score elements for those who survived at least 24 hours but died as a result of their OHCA. We assessed score discrimination for the definitive outcome of brain death. Subgroup analysis was performed for infants < 12mo versus children ≥ 12mo, those who likely had brain death but had withdrawal of life sustaining therapy (WLST) prior to declaration, and by etiology and duration of arrest., Results: 389 subjects were identified across 5 institutions, with 282 meeting inclusion criteria. 169 (59.9%) were formally declared brain dead; 58 (20.6%) had findings consistent with brain death but had withdrawal of life sustaining therapies prior to completion of formal declaration. Area under the receiver operating characteristic curve for the age ≥ 12mo cohort was 0.82 [95% CI 0.75, 0.90], which mirrored the adult subject AUCs of 0.82 [0.77, 0.86] and 0.81 [0.76, 0.86] in the development and validation cohorts. Scores demonstrated worse discrimination in the infant cohort (AUC = 0.61)., Conclusions: The BDCA score shows promise in children ≥ 12mo following OHCA and may be considered in conjunction with existing multimodal prognostication approaches., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Gestational trophoblastic neoplasia (GTN) patients are treated according to the eight-variable International Federation of Gynaecology and Obstetrics (FIGO) scoring system, that aims to predict first-line single-agent chemotherapy resistance. FIGO is imperfect with one-third of low-risk patients developing disease resistance to first-line single-agent chemotherapy. We aimed to generate simplified models that improve upon FIGO. Logistic regression (LR) and multilayer perceptron (MLP) modelling (n = 4191) generated six models (M1-6). M1, all eight FIGO variables (scored data); M2, all eight FIGO variables (scored and raw data); M3, nonimaging variables (scored data); M4, nonimaging variables (scored and raw data); M5, imaging variables (scored data); and M6, pretreatment hCG (raw data) + imaging variables (scored data). Performance was compared to FIGO using true and false positive rates, positive and negative predictive values, diagnostic odds ratio, receiver operating characteristic (ROC) curves, Bland-Altman calibration plots, decision curve analysis and contingency tables. M1-6 were calibrated and outperformed FIGO on true positive rate and positive predictive value. Using LR and MLP, M1, M2 and M4 generated small improvements to the ROC curve and decision curve analysis. M3, M5 and M6 matched FIGO or performed less well. Compared to FIGO, most (excluding LR M4 and MLP M5) had significant discordance in patient classification (McNemar's test P < .05); 55-112 undertreated, 46-206 overtreated. Statistical modelling yielded only small gains over FIGO performance, arising through recategorisation of treatment-resistant patients, with a significant proportion of under/overtreatment as the available data have been used a priori to allocate primary chemotherapy. Streamlining FIGO should now be the focus., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Post-treatment detection of circulating tumour DNA (ctDNA) in early-stage triple-negative breast cancer (TNBC) patients predicts high risk of relapse. c-TRAK TN assessed the utility of prospective ctDNA surveillance in TNBC and the activity of pembrolizumab in patients with ctDNA detected [ctDNA positive (ctDNA+)]., Patients and Methods: c-TRAK TN, a multicentre phase II trial, with integrated prospective ctDNA surveillance by digital PCR, enrolled patients with early-stage TNBC and residual disease following neoadjuvant chemotherapy, or stage II/III with adjuvant chemotherapy. ctDNA surveillance comprised three-monthly blood sampling to 12 months (18 months if samples were missed due to coronavirus disease), and ctDNA+ patients were randomised 2 : 1 to intervention : observation. ctDNA results were blinded unless patients were allocated to intervention, when staging scans were done and those free of recurrence were offered pembrolizumab. A protocol amendment (16 September 2020) closed the observation group; all subsequent ctDNA+ patients were allocated to intervention. Co-primary endpoints were (i) ctDNA detection rate and (ii) sustained ctDNA clearance rate on pembrolizumab (NCT03145961)., Results: Two hundred and eight patients registered between 30 January 2018 and 06 December 2019, 185 had tumour sequenced, 171 (92.4%) had trackable mutations, and 161 entered ctDNA surveillance. Rate of ctDNA detection by 12 months was 27.3% (44/161, 95% confidence interval 20.6% to 34.9%). Seven patients relapsed without prior ctDNA detection. Forty-five patients entered the therapeutic component (intervention n = 31; observation n = 14; one observation patient was re-allocated to intervention following protocol amendment). Of patients allocated to intervention, 72% (23/32) had metastases on staging at the time of ctDNA+, and 4 patients declined pembrolizumab. Of the five patients who commenced pembrolizumab, none achieved sustained ctDNA clearance., Conclusions: c-TRAK TN is the first prospective study to assess whether ctDNA assays have clinical utility in guiding therapy in TNBC. Patients had a high rate of metastatic disease on ctDNA detection. Findings have implications for future trial design, emphasising the importance of commencing ctDNA testing early, with more sensitive and/or frequent ctDNA testing regimes., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Single-agent methotrexate (MTX) is commonly used as first-line treatment for low-risk gestational trophoblastic neoplasia (LR-GTN), although no international consensus exists on the optimal treatment regimen to maximise complete hCG response (CR) and minimise relapse rates. Current regimens differ in the route of administration, dose scheduling, and use of flat-dose, body surface area (BSA)- or weight-based dosing. In the UK a methotrexate-folinic acid (MTX-FA) 8-day 50 mg intramuscular flat-dose regimen is used, with 15 mg oral folinic acid rescue. In LR-GTN patients, we aim to determine the effect of MTX dose adjustment by BSA and weight upon chemotherapy response and disease relapse., Methods: Between January 1973 and August 2020, 935 LR-GTN patients treated with first-line MTX-FA were identified from a single UK specialist trophoblastic centre. Of these, 364 were included, of which 178 (49%) had a CR to first-line MTX-FA. Subgroup analyses were performed upon: (i) patients who changed chemotherapy due to MTX toxicity (n = 33); and (ii) patients with a FIGO score of 5-6 (n = 85). Logistic regression analysis explored the relationship between BSA or weight adjusted MTX dosing and: (i) CR to first-line chemotherapy; (ii) incidence of disease relapse. Linear regression analyses assessed the correlation of BSA and weight with the number of MTX-FA cycles required to achieve CR., Results: In LR-GTN patients, BSA and weight adjusted MTX-FA dosing did not influence CR to first-line chemotherapy or the incidence of disease relapse. The number of MTX cycles required to achieve CR was not associated with BSA or weight. These findings were maintained in a subgroup analysis of FIGO 5-6 patients. The incidence of MTX toxicity was not influenced by BSA or weight., Conclusions: In the treatment of LR-GTN, dose individualisation using BSA or weight is not required, and fixed dosing continues to be preferred as the UK standard., Competing Interests: Declaration of Competing Interest MCW reports consulting fees from Easai, Pfizer, Gilead, Novartis, Genomic Health and Roche, personal fees and non-financial support from Lilly outside the submitted work. The remaining authors have no conflicts of interest to declare., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Accurately predicting time to death after withdrawal of life-sustaining treatment is valuable for family counseling and for identifying candidates for organ donation after cardiac death. This topic has been well studied in adults, but literature is scant in pediatrics. The purpose of this report is to assess the performance and clinical utility of the available tools for predicting time to death after treatment withdrawal in children., Data Sources: Terms related to predicting time to death after treatment withdrawal were searched in PubMed and Embase from 1993 to November 2021., Study Selection: Studies endeavoring to predict time to death or describe factors related to time to death were included. Articles focusing on perceptions or practices of treatment withdrawal were excluded., Data Extraction: Titles, abstracts, and full text of articles were screened to determine eligibility. Data extraction was performed manually. Two-by-two tables were reconstructed with available data from each article to compare performance metrics head to head., Data Synthesis: Three hundred eighteen citations were identified from the initial search, resulting in 22 studies that were retained for full-text review. Among the pediatric studies, predictive models were developed using multiple logistic regression, Cox proportional hazards, and an advanced machine learning algorithm. In each of the original model derivation studies, the models demonstrated a classification accuracy ranging from 75% to 91% and positive predictive value ranging from 0.76 to 0.93., Conclusions: There are few tools to predict time to death after withdrawal of life-sustaining treatment in children. They are limited by small numbers and incomplete validation. Future work includes utilization of advanced machine learning models., Competing Interests: Supported, in part, by the LK Whittier Foundation. The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Inhaled L-epinephrine is a known treatment of severe croup and postextubation upper airway obstruction. L-epinephrine can be delivered continuously in the vapor phase, but the indications, safety, and efficacy of this novel practice have yet to be evaluated. Theoretical risks are tachycardia, hypertension, and dysrhythmias. The study objective was to describe patient characteristics and vital sign changes related to continuous vaporized L-epinephrine use in critically ill children with the hypothesis that it can be practically and safely administered to children with subglottic edema and lower airway obstruction., Design: Retrospective cohort study., Setting: PICU and cardiothoracic ICU in a tertiary academic children's hospital., Patients: Patients age 0-21 years treated with continuous vaporized L-epinephrine from 2013 to 2019., Interventions: None., Measurements and Main Results: Continuous vaporized L-epinephrine was administered 140 times to 129 subjects via a high-flow nasal oxygen device. The median age was 10.6 months (1.3; interquartile range, 4.8-17.1 mo). The most common indications were lower respiratory tract obstruction (45%), postextubation subglottic edema (31%), and croup (16%). Eighty-eight percent had no escalation of respiratory support within 24 hours of initiation of continuous vaporized L-epinephrine, 5% progressed to require endotracheal intubation, and 3% were reintubated within 24 hours of initiation of continuous vaporized L-epinephrine following an extubation attempt. After starting continuous vaporized L-epinephrine, 85% of subjects had a decrease in heart rate and 80% had a decrease in respiratory rate. Six subjects had an increase in heart rate, and eight had an increase in blood pressure of more than 20% from baseline. These subjects did not receive interventions specific to these vital sign changes, including discontinuation of continuous vaporized L-epinephrine., Conclusions: Continuous vaporized L-epinephrine was safely administered to critically ill children with most subjects demonstrating a decrease in heart rate, blood pressure, and respiratory rate., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background: Radiotherapy reduces in-breast recurrence risk in early breast cancer (EBC) in older women. This benefit may be small and should be balanced against treatment effect and holistic patient assessment. This study described treatment patterns according to fitness and impact on health-related quality-of-life (HRQoL)., Methods: A multicentre, observational study of EBC patients aged ≥ 70 years, undergoing breast-conserving surgery (BCS) or mastectomy, was undertaken. Associations between radiotherapy use, surgery, clinico-pathological parameters, fitness based on geriatric parameters and treatment centre were determined. HRQoL was measured using the European Organisation for the Research and Treatment of Cancer (EORTC) questionnaires., Results: In 2013-2018 2811 women in 56 UK study centres underwent surgery with a median follow-up of 52 months. On multivariable analysis, age and tumour risk predicted radiotherapy use. Among healthier patients (based on geriatric assessments) with high-risk tumours, 534/613 (87.1%) having BCS and 185/341 (54.2%) having mastectomy received radiotherapy. In less fit individuals with low-risk tumours undergoing BCS, 149/207 (72.0%) received radiotherapy. Radiotherapy effects on HRQoL domains, including breast symptoms and fatigue were seen, resolving by 18 months., Conclusion: Radiotherapy use in EBC patients ≥ 70 years is affected by age and recurrence risk, whereas geriatric parameters have limited impact regardless of type of surgery. There was geographical variation in treatment, with some fit older women with high-risk tumours not receiving radiotherapy, and some older, low-risk, EBC patients receiving radiotherapy after BCS despite evidence of limited benefit. The impact on HRQoL is transient., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Low-risk gestational trophoblastic neoplasia (GTN), defined as FIGO/WHO score 0-6, is highly curable with an overall survival rate, which is approximately 100%. For most low-risk GTN patients, first-line single-agent chemotherapy with either methotrexate or actinomycin-D is recommended with overall complete human chorionic gonadotrophin (hCG) response rates of 60%-90% in mostly retrospective, non-randomised studies. The few randomised trials that exist are not appropriately powered or designed to define the optimal first-line treatment. Approximately 25%-30% of low-risk patients will develop resistance to initial single-agent chemotherapy with an increase in the FIGO score, a diagnosis of choriocarcinoma, higher pre-treatment hCG and the presence of metastatic disease being associated with an increase in the risk of resistance. The optimal treatment of patients scoring WHO 5 and 6 remains poorly defined given that approximately 70%-80% of these patients develop resistance to first-line single-agent chemotherapy, and there is an urgent need to refine the FIGO/WHO scoring system so that these patients can be identified for more intensive therapy from the outset. Despite this, almost all low-risk patients who experience treatment failure with first-line monotherapy will be cured with either sequential single-agent chemotherapy or multiagent chemotherapy with or without surgery. Given the associated increased short and longer-term toxicities associated with multi-agent chemotherapy, promising strategies to reduce the exposure of women to combination chemotherapy in low-risk disease have been investigated, including the use of carboplatin and immune check-point inhibitors. Further evaluation is required to define optimal patient selection, particularly with the use of immunotherapeutic agents given their significant increased costs and lack of longer-term safety data. Although there is a clear need to revise the FIGO/WHO (2000) scoring system, consistent international use of this is recommended to facilitate the comparison of data along with future focus in the development of international collaborative translational and clinical research, including randomised controlled trials., Competing Interests: Declaration of competing interest Dr Winter reports consulting fees from Easai, Pfizer, Novartis, Genomic Health and Roche, personal fees and non-financial support from Lilly outside the submitted work., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Chemotherapy improves outcomes for high risk early breast cancer (EBC) patients but is infrequently offered to older individuals. This study determined if there are fit older patients with high-risk disease who may benefit from chemotherapy., Methods: A multicentre, prospective, observational study was performed to determine chemotherapy (±trastuzumab) usage and survival and quality-of-life outcomes in EBC patients aged ≥70 years. Propensity score-matching adjusted for variation in baseline age, fitness and tumour stage., Results: Three thousands four hundred sixteen women were recruited from 56 UK centres between 2013 and 2018. Two thousands eight hundred eleven (82%) had surgery. 1520/2811 (54%) had high-risk EBC and 2059/2811 (73%) were fit. Chemotherapy was given to 306/1100 (27.8%) fit patients with high-risk EBC. Unmatched comparison of chemotherapy versus no chemotherapy demonstrated reduced metastatic recurrence risk in high-risk patients(hazard ratio [HR] 0.36 [95% CI 0.19-0.68]) and in 541 age, stage and fitness-matched patients(adjusted HR 0.43 [95% CI 0.20-0.92]) but no benefit to overall survival (OS) or breast cancer-specific survival (BCSS) in either group. Chemotherapy improved survival in women with oestrogen receptor (ER)-negative cancer (OS: HR 0.20 [95% CI 0.08-0.49];BCSS: HR 0.12 [95% CI 0.03-0.44]).Transient negative quality-of-life impacts were observed., Conclusions: Chemotherapy was associated with reduced risk of metastatic recurrence, but survival benefits were only seen in patients with ER-negative cancer. Quality-of-life impacts were significant but transient., Trial Registration: ISRCTN 46099296., (© 2021. The Author(s).)

High-risk gestational trophoblastic neoplasia (GTN) is highly chemosensitive with an excellent prognosis with treatment. Historically in the United Kingdom, the high-risk regimens used have been M-EA (methotrexate, etoposide, dactinomycin) (Sheffield) and EMA-CO (methotrexate, etoposide, dactinomycin / cyclophosphamide, vincristine) (Charing Cross, London) with prior published data suggesting no difference in survival between these. Our Sheffield treatment policy changed in 2014, switching from M-EA to EMA-CO, aiming to reduce time in hospital, and harmonise UK practice. We aimed to report the toxicities, response rates and survival outcomes for 79 patients with high-risk GTN treated in the first-line setting with either M-EA (n = 59) or EMA-CO (n = 20) from 1998 to 2018. Median duration of treatment was similar (M-EA, 17.3 weeks (IQR 13.9-22.6) and 17.6 weeks (IQR 13.4-20.7) with EMA-CO. For M-EA, overall human chorionic gonadotrophin (hCG) complete response (CR) rate was 84.7% (n = 50/59). Two patients died of drug-resistant disease after several lines of multiagent chemotherapy; overall survival is 96.6% (median follow-up 10.4 years). For EMA-CO, overall hCG CR rate was 70%, overall survival is 100% (median follow-up 4 years). In our experience, patients treated with EMA-CO experienced an apparent increased incidence of neutropenia, non-neutropenic Grade 3-4 infection, peripheral neuropathy and more treatment delays and nights in hospital. Granulocyte-colony stimulating factor, after both EMA and CO arms, titrated to baseline neutrophil count improved the toxicity profile. Both treatment regimens are associated with excellent prognosis; selection of regimen may be further guided by individual patients' personal, social and family circumstances. There is further rationale to explore whether these regimens can be refined, such as 2-weekly EMA, to optimise patient experience and reduce toxicity while maintaining efficacy., (© 2020 UICC.)

Background: Primary endocrine therapy may be an alternative treatment for less fit women with oestrogen receptor (ER)-positive breast cancer. This study compared quality-of-life (QoL) outcomes in older women treated with surgery or primary endocrine therapy., Methods: This was a multicentre, prospective, observational cohort study of surgery or primary endocrine therapy in women aged over 70 years with operable breast cancer. QoL was assessed using European Organisation for Research and Treatment of cancer QoL questionnaires QLQ-C30, -BR23, and -ELD14, and the EuroQol Five Dimensions 5L score at baseline, 6 weeks, and 6, 12, 18, and 24 months. Propensity score matching was used to adjust for baseline variation in health, fitness, and tumour stage., Results: The study recruited 3416 women (median age 77 (range 69-102) years) from 56 breast units. Of these, 2979 (87.2 per cent) had ER-positive breast cancer; 2354 women had surgery and 500 received primary endocrine therapy (125 were excluded from analysis due to inadequate data or non-standard therapy). Median follow-up was 52 months. The primary endocrine therapy group was older and less fit. Baseline QoL differed between the groups; the mean(s.d.) QLQ-C30 global health status score was 66.2(21.1) in patients who received primary endocrine therapy versus 77.1(17.8) among those who had surgery plus endocrine therapy. In the unmatched analysis, changes in QoL between 6 weeks and baseline were noted in several domains, but by 24 months most scores had returned to baseline levels. In the matched analysis, major surgery (mastectomy or axillary clearance) had a more pronounced adverse impact than primary endocrine therapy in several domains., Conclusion: Adverse effects on QoL are seen in the first few months after surgery, but by 24 months these have largely resolved. Women considering surgery should be informed of these effects., (© The Author(s) 2021. Published by Oxford University Press on behalf of BJS Society Ltd.)

Background: The International Federation of Gynaecology and Obstetrics (FIGO) score identifies gestational trophoblastic neoplasia (GTN) patients as low- or high-risk of single-agent chemotherapy resistance (SACR). Computed tomography (CT) has greater sensitivity than chest X-ray (CXR) in detecting pulmonary metastases, but effects upon outcomes remain unclear., Methods: Five hundred and eighty-nine patients underwent both CXR and CT during GTN assessment. Treatment decisions were CXR based. The number of metastases, risk scores, and risk category using CXR versus CT were compared. CT-derived chest assessment was evaluated as impact upon treatment decision compared to patient outcome, incidence of SACR, time-to-normal human chorionic gonadotrophin hormone (TNhCG), and primary chemotherapy resistance (PCR)., Results: Metastasis detection (p < 0.0001) and FIGO score (p = 0.001) were higher using CT versus CXR. CT would have increased FIGO score in 188 (31.9%), with 43 re-classified from low- to high-risk, of whom 23 (53.5%) received curative single-agent chemotherapy. SACR was higher when score (p = 0.044) or risk group (p < 0.0001) changed. Metastases on CXR (p = 0.019) but not CT (p = 0.088) lengthened TNhCG. Logistic regression analysis found no difference between CXR (area under the curve (AUC) = 0.63) versus CT (AUC = 0.64) in predicting PCR., Conclusions: CT chest would improve the prediction of SACR, but does not influence overall treatment outcome, TNhCG, or prediction of PCR. Lower radiation doses and cost mean ongoing CXR-based assessment is recommended.

Introduction: Older patients with early breast cancer (EBC) derive modest survival benefit from chemotherapy but have increased toxicity risk. Data on the impact of chemotherapy for EBC on quality of life in older patients are limited, but this is a key determinant of treatment acceptance. We aimed to investigate its effect on quality of life in older patients enrolled in the Bridging the Age Gap study., Materials and Methods: A prospective, multicentre, observational study of EBC patients ≥70 years old was conducted in 2013-2018 at 56 UK hospitals. Demographics, patient, tumour characteristics, treatments and adverse events were recorded. Quality of life was assessed using the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaires (EORTC-QLQ) C30, BR23 and ELD 15 plus the Euroqol-5D (eq-5d) over 24 months and analysed at each time point using baseline adjusted linear regression analysis and propensity score-matching., Results: Three thousand and four hundred sixteen patients were enrolled in the study; 1520 patients undergoing surgery and who had high-risk EBC were included in this analysis. 376/1520 (24.7%) received chemotherapy. At 6 months, chemotherapy had a significant negative impact in several EORTC-QLQ-C30 domains, including global health score, physical, role, social functioning, cognition, fatigue, nausea/vomiting, dyspnoea, appetite loss, diarrhoea and constipation. Similar trends were documented on other scales (EORTC-QLQ-BR23, EORTC-QLQ-ELD15 and EQ-5D-5L). Its impact was no longer significant at 18-24 months in unmatched and matched cohorts., Conclusions: The negative impact of chemotherapy on quality-of-life is clinically and statistically significant at 6 months but resolves by 18 months, which is crucial to inform decision-making for older patients contemplating chemotherapy., Trial Registration Number Isrctn: 46099296., Competing Interests: Conflict of interest statement The authors declare no conflict of interest. Professors Stephen Walters and Thompson Robinson are National Institute for Health Research (NIHR) Senior Investigators; Jenna Morgan is a NIHR Clinical Lecturer; and Kate Lifford is funded by the NIHR as part of this project. The views expressed in this article are those of the author(s) and not necessarily those of the NIHR, or the Department of Health and Social Care., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Accurate prediction of time to death after withdrawal of life-sustaining therapies may improve counseling for families and help identify candidates for organ donation after cardiac death. The study objectives were to: 1) train a long short-term memory model to predict cardiac death within 1 hour after terminal extubation, 2) calculate the positive predictive value of the model and the number needed to alert among potential organ donors, and 3) examine associations between time to cardiac death and the patient's characteristics and physiologic variables using Cox regression., Design: Retrospective cohort study., Setting: PICU and cardiothoracic ICU in a tertiary-care academic children's hospital., Patients: Patients 0-21 years old who died after terminal extubation from 2011 to 2018 (n = 237)., Interventions: None., Measurements and Main Results: The median time to death for the cohort was 0.3 hours after terminal extubation (interquartile range, 0.16-1.6 hr); 70% of patients died within 1 hour. The long short-term memory model had an area under the receiver operating characteristic curve of 0.85 and a positive predictive value of 0.81 at a sensitivity of 94% when predicting death within 1 hour of terminal extubation. About 39% of patients who died within 1 hour met organ procurement and transplantation network criteria for liver and kidney donors. The long short-term memory identified 93% of potential organ donors with a number needed to alert of 1.08, meaning that 13 of 14 prepared operating rooms would have yielded a viable organ. A Cox proportional hazard model identified independent predictors of shorter time to death including low Glasgow Coma Score, high Pao2-to-Fio2 ratio, low-pulse oximetry, and low serum bicarbonate., Conclusions: Our long short-term memory model accurately predicted whether a child will die within 1 hour of terminal extubation and may improve counseling for families. Our model can identify potential candidates for donation after cardiac death while minimizing unnecessarily prepared operating rooms., Competing Interests: Drs. Winter's, Day's, and Wetzel’s institutions received funding from The L. K. Whittier Foundation. Dr. Aczon received support for article research from L.K. Whittier Foundation. Dr. Newth received funding from Philips Research North America and Hamilton Medical AG. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2020 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Lentiviral-mediated integration of a CFTR transgene cassette into airway basal cells is a strategy being considered for cystic fibrosis (CF) cell-based therapies. However, CFTR expression is highly regulated in differentiated airway cell types and a subset of intermediate basal cells destined to differentiate. Since basal stem cells typically do not express CFTR, suppressing the CFTR expression from the lentiviral vector in airway basal cells may be beneficial for maintaining their proliferative capacity and multipotency. We identified miR-106b as highly expressed in proliferating airway basal cells and extinguished in differentiated columnar cells. Herein, we developed lentiviral vectors with the miR-106b-target sequence (miRT) to both study miR-106b regulation during basal cell differentiation and detarget CFTR expression in basal cells. Given that miR-106b is expressed in the 293T cells used for viral production, obstacles of viral genome integrity and titers were overcome by creating a 293T-B2 cell line that inducibly expresses the RNAi suppressor B2 protein from flock house virus. While miR-106b vectors effectively detargeted reporter gene expression in proliferating basal cells and following differentiation in the air-liquid interface and organoid cultures, the CFTR-miRT vector produced significantly less CFTR-mediated current than the non-miR-targeted CFTR vector following transduction and differentiation of CF basal cells. These findings suggest that miR-106b is expressed in certain airway cell types that contribute to the majority of CFTR anion transport in airway epithelium.

Background: Circulating tumour DNA (ctDNA) testing might provide a current assessment of the genomic profile of advanced cancer, without the need to repeat tumour biopsy. We aimed to assess the accuracy of ctDNA testing in advanced breast cancer and the ability of ctDNA testing to select patients for mutation-directed therapy., Methods: We did an open-label, multicohort, phase 2a, platform trial of ctDNA testing in 18 UK hospitals. Participants were women (aged ≥18 years) with histologically confirmed advanced breast cancer and an Eastern Cooperative Oncology Group performance status 0-2. Patients had completed at least one previous line of treatment for advanced breast cancer or relapsed within 12 months of neoadjuvant or adjuvant chemotherapy. Patients were recruited into four parallel treatment cohorts matched to mutations identified in ctDNA: cohort A comprised patients with ESR1 mutations (treated with intramuscular extended-dose fulvestrant 500 mg); cohort B comprised patients with HER2 mutations (treated with oral neratinib 240 mg, and if oestrogen receptor-positive with intramuscular standard-dose fulvestrant); cohort C comprised patients with AKT1 mutations and oestrogen receptor-positive cancer (treated with oral capivasertib 400 mg plus intramuscular standard-dose fulvestrant); and cohort D comprised patients with AKT1 mutations and oestrogen receptor-negative cancer or PTEN mutation (treated with oral capivasertib 480 mg). Each cohort had a primary endpoint of confirmed objective response rate. For cohort A, 13 or more responses among 78 evaluable patients were required to infer activity and three or more among 16 were required for cohorts B, C, and D. Recruitment to all cohorts is complete and long-term follow-up is ongoing. This trial is registered with ClinicalTrials.gov, NCT03182634; the European Clinical Trials database, EudraCT2015-003735-36; and the ISRCTN registry, ISRCTN16945804., Findings: Between Dec 21, 2016, and April 26, 2019, 1051 patients registered for the study, with ctDNA results available for 1034 patients. Agreement between ctDNA digital PCR and targeted sequencing was 96-99% (n=800, kappa 0·89-0·93). Sensitivity of digital PCR ctDNA testing for mutations identified in tissue sequencing was 93% (95% CI 83-98) overall and 98% (87-100) with contemporaneous biopsies. In all cohorts, combined median follow-up was 14·4 months (IQR 7·0-23·7). Cohorts B and C met or exceeded the target number of responses, with five (25% [95% CI 9-49]) of 20 patients in cohort B and four (22% [6-48]) of 18 patients in cohort C having a response. Cohorts A and D did not reach the target number of responses, with six (8% [95% CI 3-17]) of 74 in cohort A and two (11% [1-33]) of 19 patients in cohort D having a response. The most common grade 3-4 adverse events were raised gamma-glutamyltransferase (13 [16%] of 80 patients; cohort A); diarrhoea (four [25%] of 20; cohort B); fatigue (four [22%] of 18; cohort C); and rash (five [26%] of 19; cohort D). 17 serious adverse reactions occurred in 11 patients, and there was one treatment-related death caused by grade 4 dyspnoea (in cohort C)., Interpretation: ctDNA testing offers accurate, rapid genotyping that enables the selection of mutation-directed therapies for patients with breast cancer, with sufficient clinical validity for adoption into routine clinical practice. Our results demonstrate clinically relevant activity of targeted therapies against rare HER2 and AKT1 mutations, confirming these mutations could be targetable for breast cancer treatment., Funding: Cancer Research UK, AstraZeneca, and Puma Biotechnology., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objective: To determine the optimal duration of human chorionic gonadotrophin (hCG) surveillance following treatment for low and high risk gestational trophoblastic neoplasia (GTN) and establish whether the current surveillance protocol that recommends life-long hCG monitoring requires revision., Methods: A population-based cohort study was undertaken using a national registry, comprising patients from both tertiary trophoblastic disease treatment units in the UK (London and Sheffield). All patients who received chemotherapy for low or high risk GTN in the UK between 1958 and 2014 in London and 1973 and 2015 in Sheffield (n = 4201) were included in the study. Patients with placental site trophoblastic tumours and epithelioid trophoblastic tumours were excluded due to their distinct clinical behavior, treatment and follow-up requirements. The risk of recurrence with time following completion of chemotherapy for low or high risk GTN was measured., Results: The overall risk of relapse in this national cohort of 4201 patients was 4.7% (198/4201) with a median time to recurrence of 117.5 days (range 9 days to 6.54 years). The greatest risk of recurrence occurred in the first year after completing treatment for either low or high risk GTN measuring 72.7% (n = 112) or 86.4% (n = 38), respectively. The subsequent recurrence risk reduced over time with none observed beyond 7 years., Conclusions: The absence of any recurrences beyond seven years following completion of chemotherapy for GTN indicates that the UK policy of life-long hCG surveillance is unnecessary. Our revised conservative protocol recommends stopping after 10 years., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background/objectives: Ethical challenges in pediatric oncology arise at every stage of illness. However, there are sparse data on the content of and reason for ethics consultations in the field. We sought to evaluate the content and characteristics of ethics consultations in pediatric patients at a cancer center., Design/methods: We retrospectively identified ethics consultations performed for patients diagnosed with cancer at ≤21 years of age who were treated in the Department of Pediatrics from 2007 to 2017. Using an established coding schema, two independent reviewers analyzed the content of ethics consultation notes and identified core ethical issues and relevant contextual issues. Demographic, clinical, and consultation-specific data were also collected., Results: Thirty-five consultations were performed for 32 unique patients. The most commonly identified ethical issues were obligation to provide nonbeneficial treatment (29%) and resuscitation preferences (26%). Communication conflicts were the most commonly identified contextual issue (40%). There were two themes that emerged repeatedly but were not a part of the original coding schema-four consultations (11%) that involved physicians questioning their obligation to provide potentially toxic treatment in the setting of poor patient/parent compliance, and two consultations (6%) related to complex risk-benefit analysis in the setting of an invasive procedure with uncertain benefit., Conclusions: Pediatric ethics consultations are infrequent at this specialty cancer hospital. Ethical issues focused on treatment and end-of-life care and included a diversity of communication conflicts., (© 2019 Wiley Periodicals, Inc.)

Cystic fibrosis (CF) is a multiorgan disease caused by mutations in the cystic fibrosis transmembrane conductance regulator ( CFTR ). In patients with CF, abnormalities initiate in several organs before birth. However, the long-term impact of these in utero pathologies on disease pathophysiology is unclear. To address this issue, we generated ferrets harboring a VX-770 (ivacaftor)-responsive CFTR G551D mutation. In utero VX-770 administration provided partial protection from developmental pathologies in the pancreas, intestine, and male reproductive tract. Homozygous CFTR G551D/G551D animals showed the greatest VX-770-mediated protection from these pathologies. Sustained postnatal VX-770 administration led to improved pancreatic exocrine function, glucose tolerance, growth and survival, and to reduced mucus accumulation and bacterial infections in the lung. VX-770 withdrawal at any age reestablished disease, with the most rapid onset of morbidity occurring when withdrawal was initiated during the first 2 weeks after birth. The results suggest that CFTR is important for establishing organ function early in life. Moreover, this ferret model provides proof of concept for in utero pharmacologic correction of genetic disease and offers opportunities for understanding CF pathogenesis and improving treatment., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: Placental-site trophoblastic (PSTT) and epithelioid trophoblastic tumours (ETT) are the rarest malignant forms of gestational trophoblastic disease (GTD). Our prior work demonstrated that an interval of ≥48 months from the antecedent pregnancy was associated with 100% death rate, independent of the stage. Here, we assess whether modified treatments for these patients have increased survival and identify new prognostic factors., Methods: The United Kingdom GTD database was screened to identify all PSTT/ETT cases diagnosed between 1973 and 2014. Data and survival outcomes from our prior patient cohort (1976-2006) were compared to our new modern cohort (2007-2014), when intensified treatments were introduced., Results: Of 54,743 GTD patients, 125 (0.23%) were diagnosed with PSTT and/or ETT. Probability of survival at 5 and 10 years following treatment was 80% (95% CI 72.8-87.6%) and 75% (95% CI 66.3-84.3%), respectively. Univariate analysis identified five prognostic factors for reduced overall survival (age, FIGO stage, time since antecedent pregnancy, hCG level, mitotic index) of which stage IV disease (HR 6.18, 95% CI 1.61-23.81, p = 0.008) and interval ≥48 months since antecedent pregnancy (HR 14.57, 95% CI 4.17-50.96, p < 0.001) were most significant on multivariable analysis. No significant differences in prognostic factors were seen between the old and new patient cohort. However, the new cohort received significantly more cisplatin-based and high-dose chemotherapy, and patients with an interval ≥48 months demonstrated an improved median overall survival (8.3 years, 95% CI 1.53-15.1, versus 2.6 years, 95% CI 0.73-4.44, p = 0.·005)., Conclusion: PSTT/ETT with advanced FIGO stage or an interval ≥48 months from their last known pregnancy have poorer outcomes. Platinum-based and high-dose chemotherapy may help to improve survival in poor-prognosis patients.

Background: Clinical deterioration is difficult to detect in hospitalized children. The pediatric Rothman Index (pRI) is an early warning score that incorporates vital signs, laboratory studies, and nursing assessments to generate deterioration alerts., Objectives: (1) Evaluate the timing of pRI alerts and clinicians recognizing deterioration or escalating care prior to critical deterioration events (CDEs) and (2) determine whether the parameters triggering alerts were clinically related to deterioration., Design: CDEs are unplanned transfers to the intensive care unit with noninvasive ventilation, tracheal intubation, and/or vasopressor infusion in the 12 hours after transfer. Using one year of data from a large freestanding children's hospital without the pRI, we analyzed CDEs that would have been preceded by pRI alerts. We (1) compared the timing of pRI alerts to time-stamped notes describing changes in patient status and orders reflecting escalations of care and (2) identified score component(s) that caused alerts to trigger and determined whether these were clinically related to CDE etiology., Results: Fifty CDEs would have triggered pRI alertsif the pRI had been in use (sensitivity 68%). In 90% of CDEs, the first clinician note reflecting change in patient status and/or the first order reflecting escalation of care preceded the first pRI alert. All of the vital sign and laboratory components of the pRI and 51% of the nursing components were clinically related to the etiology of the CDE., Conclusions: Evidence that clinicians were awareof deterioration preceded pRI alerts in most CDEs that generated alerts in the preceding 24 hours.

Objective: The objective of the study was to evaluate the effect of high-dose chemotherapy (HDC) with peripheral blood stem cell support (PBSCS) on survival of patients with gestational trophoblastic neoplasia (GTN) with either refractory choriocarcinomas or a poor-prognosis placental site/epithelioid trophoblastic tumours (PSTT/ETTs)., Methods: Databases of two referral centres for gestational trophoblastic disease were searched, and 32 patients treated with HDC between 1994 and 2015 were identified. Tissue samples were retrieved for genetic evaluation. Cox regression analyses were performed to identify possible predictors of overall survival (OS)., Results: HDC induced a sustained complete response in 7 patients. Overall, 41% (13/32) of the patients remained disease free after HDC with or without additional treatment. Patients who survived had much lower human chorionic gonadotropin (hCG) values (all ≤12 IU/L) before and after HDC than those who died of disease. Univariable Cox regression analysis demonstrated that hCG >12 IU/L before or after HDC, International Federation of Gynaecology and Obstetrics (FIGO) stage II-IV and presence of metastases at the time of diagnosis were significantly associated with adverse OS. However, only hCG values before HDC remained significant in a multivariable model (p < 0.001). Five of 11 (45%) patients with PSTT/ETT presenting ≥48 months after antecedent pregnancy and 6 of 14 (43%) patients with refractory choriocarcinoma were in remission. Three treatment-related deaths occurred., Conclusions: Despite 3 treatment-induced deaths, HDC with PBSCS appears to be active in salvaging selected patients with poor-prognosis PSTT/ETTs and refractory choriocarcinomas. Low hCG values before HDC seems a beneficial predictor of OS and may suggest that HDC acts more like a consolidation therapy., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: To determine whether post-pregnancy human chorionic gonadotrophin screening after previous hydatidiform mole identifies patients with recurrent gestational trophoblastic disease., Study Design: A retrospective evaluation of 9315 patients who underwent post-pregnancy screening from 2000 to 2009, as part of the National Gestational Trophoblastic Disease Service in the UK., Results: Patients with previous hydatidiform mole, who had human chorionic gonadotrophin screening after one or more subsequent pregnancies, were identified (n = 9315). Of these, 8630 patients had an initial hydatidiform mole that did not require chemotherapy. In 12,329 subsequent pregnancy events, screening with human chorionic gonadotrophin identified 3 cases of gestational trophoblastic neoplasm. The remaining 685 patients developed gestational trophoblastic neoplasm, following their initial hydatidiform mole and required chemotherapy. In this group there were 1012 further pregnancy events, human chorionic gonadotrophin screening identified 3 patients with gestational trophoblastic neoplasm. The overall recurrence rate was 6 in 13,341 events (risk 1: 2227). The rate was 3 in 12,329 (risk 1:4110) for HM that did not require chemotherapy and 3 in 1012 (1:337) for previously treated gestational trophoblastic neoplasm. All 6 patients with recurrent disease were successfully treated with chemotherapy., Conclusion: Routine post-pregnancy human chorionic gonadotrophin screening may be safely discontinued in patients with one previous uncomplicated hydatidiform mole., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Adjuvant bisphosphonates (BPs) are recommended as part of routine early breast cancer treatment for many postmenopausal (PM) women within the past year. There is a paucity of 'real world' data on compliance and patient satisfaction with oral BPs in this population. The aim of our study was to investigate patient reported compliance and toxicity of these drugs in a retrospective cohort study., Patients and Methods: 413 patient were identified as receiving adjuvant oral BPs as part of their breast cancer treatment in the past 12 months from five NHS hospitals. The validated Osteoporosis Patient Treatment Satisfaction Questionnaire (OPSAT-Q) was sent to all suitable patients ( n  = 389)., Results: 295 (76%) of patients responded. Average age was median (range) 67 (35-89). The majority of patients had T1 (52%), N0 (61%) grade 2 (58%) ER positive (87%), HER2 negative (84%) breast cancer and were PM at diagnosis of breast cancer (93%). All patients had been prescribed at least 1 month of oral ibandronate 50 mg daily. Review of items rated on the 7-point scale (1 = very dissatisfied to 7 = very satisfied), the mean item scores ranged from 5.0 (lowest) for time required to take oral BPs, to 6.1 (highest) for how easy it is to remember to take the medication. <10% of patients were extremely bothered by heartburn or stomach upset. 16% of responders stopped oral BPs with 10% of those converting onto IV BPs., Conclusions: Prevalence of severe side effects in a 'real world' population of PM women receiving adjuvant BPs is low and these drugs are generally well accepted and tolerated by patients.

Toolsets available for in-depth analysis of scRNA-seq datasets by biologists with little informatics experience is limited. Here, we describe an informatics tool (PyMINEr) that fully automates cell type identification, cell type-specific pathway analyses, graph theory-based analysis of gene regulation, and detection of autocrine-paracrine signaling networks in silico. We applied PyMINEr to interrogate human pancreatic islet scRNA-seq datasets and discovered several features of co-expression graphs, including concordance of scRNA-seq-graph structure with both protein-protein interactions and 3D genomic architecture, association of high-connectivity and low-expression genes with cell type enrichment, and potential for the graph structure to clarify potential etiologies of enigmatic disease-associated variants. We further created a consensus co-expression network and autocrine-paracrine signaling networks within and across islet cell types from seven datasets. PyMINEr correctly identified changes in BMP-WNT signaling associated with cystic fibrosis pancreatic acinar cell loss. This proof-of-principle study demonstrates that the PyMINEr framework will be a valuable resource for scRNA-seq analyses., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Epithelioid Trophoblastic Tumor (ETT) is an extremely rare form of Gestational Trophoblastic Neoplasia (GTN). Knowledge on prognostic factors and optimal management is limited. We identified prognostic factors, optimal treatment, and outcome from the world's largest case series of patients with ETT., Methods: Patients were selected from the international Placental Site Trophoblastic Tumor (PSTT) and ETT database. Fifty-four patients diagnosed with ETT or mixed PSTT/ETT between 2001 and 2016 were included. Cox regression analysis was used to identify prognostic factors for overall survival (OS)., Results: Forty-five patients with ETT and 9 patients with PSTT/ETT were included. Thirty-six patients had FIGO stage I and 18 had stages II-IV disease. Patients were treated with surgery (n = 23), chemotherapy (n = 6), or a combination of surgery and chemotherapy (n = 25). In total, 39 patients survived, including 22 patients with complete sustained hCG remission for at least 1 year. Patients treated with surgery as first line treatment had early-stage disease and all survived. Most patients treated with chemotherapy with or without surgery had FIGO stages II-IV disease (55%). They underwent multiple lines of chemotherapy. Eleven of them did not survive. Interval since antecedent pregnancy and FIGO stage were prognostic factors of OS (p = 0.012; p = 0.023 respectively)., Conclusions: Advanced-stage disease and an interval of ≥48 months since the antecedent pregnancy are poor prognostic factors of ETT. Surgery seems adequate for early-stage disease with a shorter interval. Advanced-stage disease requires a combination of treatment modalities. Because of its rarity, ETT should be treated in a centre with experience in GTN., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Gestational trophoblastic disease is a rare complication of pregnancy that can develop into cancer. Medical outcomes of gestational trophoblastic disease are well researched, but the effect of the disease on health-related quality of life (HRQOL) requires attention if care is to be improved. This systematic review was designed to establish the effect of gestational trophoblastic disease and its treatment on HRQOL and to identify the appropriateness of HRQOL measures. Quantitative studies found HRQOL in long-term survivors of gestational trophoblastic disease to be at or above population norms. The disease had a negative effect on HRQOL for patients who experienced physical, psychological, and social sequelae related to the condition. Clinically significant levels of anxiety, depression, sexual dysfunction, and fertility-related distress were found in these patients. The results should be treated with caution because the evidence base was limited to small heterogeneous samples, data were retrospective, and a range of measures was used. Within qualitative studies on HRQOL for survivors of gestational trophoblastic disease, new conditions emerged, including nerve damage, fatigue, amenorrhoea, and grief. These areas are not captured in existing patient-reported outcome measures, and the content might not be valid for this population. Further qualitative research might lead to the development of a specific patient-reported outcome measure for gestational trophoblastic disease, providing reliable, meaningful, and valid assessments, and allowing longitudinal data to be obtained., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Although β-cell dysfunction in cystic fibrosis (CF) leads to diabetes, the mechanism by which the cystic fibrosis transmembrane conductance regulator (CFTR) channel influences islet insulin secretion remains debated. We investigated the CFTR-dependent islet-autonomous mechanisms affecting insulin secretion by using islets isolated from CFTR knockout ferrets. Total insulin content was lower in CF as compared with wild-type (WT) islets. Furthermore, glucose-stimulated insulin secretion (GSIS) was impaired in perifused neonatal CF islets, with reduced first, second, and amplifying phase secretion. Interestingly, CF islets compensated for reduced insulin content under static low-glucose conditions by secreting a larger fraction of islet insulin than WT islets, probably because of elevated SLC2A1 transcripts, increased basal inhibition of adenosine triphosphate-sensitive potassium channels (K-ATP), and elevated basal intracellular Ca2+. Interleukin (IL)-6 secretion by CF islets was higher relative to WT, and IL-6 treatment of WT ferret islets produced a CF-like phenotype with reduced islet insulin content and elevated percentage insulin secretion in low glucose. CF islets exhibited altered expression of INS, CELA3B, and several β-cell maturation and proliferation genes. Pharmacologic inhibition of CFTR reduced GSIS by WT ferret and human islets but similarly reduced insulin secretion and intracellular Ca2+ in CFTR knockout ferret islets, indicating that the mechanism of action is not through CFTR. Single-molecule fluorescent in situ hybridization, on isolated ferret and human islets and ferret pancreas, demonstrated that CFTR RNA colocalized within KRT7+ ductal cells but not endocrine cells. These results suggest that CFTR affects β-cell function via a paracrine mechanism involving proinflammatory factors secreted from islet-associated exocrine-derived cell types., (Copyright © 2017 Endocrine Society.)

The classification system for Gestational trophoblastic neoplasia (GTN) has proved a controversial topic for over 100years. Numerous systems simultaneously existed in different countries, with three main rival classifications gaining popularity, namely histological, anatomical and clinical prognostic systems. Until 2000, prior to the combination of the FIGO and WHO classifications, there was no worldwide consensus on the optimal classification system, largely due to a lack of high quality data proving the merit of one system over another. Remarkably, a validated, prospectively tested classification system is yet to be conducted. Over time, increasing criticisms have emerged regarding the currently adopted combined FIGO/WHO classification system, and its ability to identify patients most likely to develop primary chemotherapy resistance or disease relapse. This is particularly pertinent for patients with low-risk disease, whereby one in three patients are resistant to first line therapy, rising to four out of five women who score 5 or 6. This review aims to examine the historical basis of the GTN classification systems and critically appraise the evidence on which they were based. This culminates in a critique of the current FIGO/WHO prognostic system and discussion surrounding clinical preference versus evidence based practice., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: To evaluate the outcome of patients treated with second-line chemotherapy for methotrexate-resistant low-risk GTN at the Sheffield Centre, UK between 2001 and 2015, including the novel use of single-agent carboplatin as a strategy to reduce exposure to combination chemotherapy., Methods: 392 low-risk GTN patients were treated with first-line methotrexate. The selection of chemotherapy regimen following methotrexate-resistance depended on the volume of residual disease as indicated by the serum hCG value at the time, with patients switching to either single-agent dactinomycin at an hCG level<150IU/L from 2001-2010 and <300IU/L since 2010, or to combination treatment with etoposide/dactinomycin (EA) above these thresholds. In order to reduce exposure to more toxic combination chemotherapy regimens, our treatment policy was revised in 2011, with the recommendation of single-agent carboplatin as an alternative to EA at hCG levels >300IU/L., Results: 136 (35%) of 392 received second-line chemotherapy following methotrexate-resistance. 59 patients received single-agent dactinomycin with 53 (90%) patients achieving complete hCG response, 3 patients requiring combination chemotherapy or surgery, and 3 patients subsequently spontaneously resolving. 56 patients received EA chemotherapy with hCG complete response in 50 (89%) patients, and the remaining 6 patients were cured with further multi-agent chemotherapy or surgery. With carboplatin, 17/21 (81%) achieved an overall complete hCG response rate, with 4 patients requiring third-line EA. Carboplatin was well tolerated with no significant alopecia; myelosuppression was the most significant toxicity. Overall survival for all patients was 100%., Conclusion: These data show the continued excellent outcomes for methotrexate-resistant low-risk patients treated with single-agent dactinomycin or EA. Our experience with carboplatin is promising and provides an alternative regimen for methotrexate-resistant low-risk disease that avoids alopecia and in-patient treatment., (Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.)