Can serum progesterone concentration direct a fresh or freeze-all transfer strategy in the first in vitro fertilisation cycle?

PURPOSE: To examine the interaction between serum progesterone concentration on the trigger day and choice of freeze-all and fresh transfer strategies on live birth in an unselected population as well as in patients over 35 years old. METHODS: We performed a retrospective cohort study of 26,661 patients commencing their first IVF cycle in a large fertility centre between 2015 and 2019, including 4687 patients over 35 years old. We performed a multivariable fractional polynomial interaction analysis within a logistic regression model to investigate the interaction between serum progesterone concentration and the choice of freeze-all or fresh transfer strategy following the first transfer. RESULTS: 15,539 patients underwent a fresh embryo transfer and 11,122 underwent a freeze-all strategy in their first IVF cycle. The freeze-all group had a higher live birth rate compared to the fresh group (43.9% vs 40.3%). After adjusting for confounding factors, there was a positive interaction between serum progesterone concentrations and the choice of a freeze-all versus fresh embryo transfer on live birth (p for interaction 0.0001), with a larger magnitude of effect when progesterone concentration was higher. Such an interaction was also observed in patients over 35 years old (p for interaction 0.01), but the treatment effect curve over progesterone concentrations was almost flat. CONCLUSIONS: In an unselected population, frozen transfer is associated with greater chances of live birth, especially in patients with higher serum progesterone concentration. In patients over 35 years old, the benefit of a freeze-all policy appears small across all serum progesterone concentrations.

Implementation of a Colorectal Surgical Site Infection Prevention Bundle and Checklist: A Quality Improvement Project.

After noting an elevated surgical site infection rate in 2019 associated with colorectal surgeries, leaders at two Central Virginia health system hospitals convened an interdisciplinary team to audit current practices and research infection prevention strategies. After identifying a lack of standardization in care processes for colorectal surgery patients and reviewing the literature on colorectal bundles, the team created a bundle focusing on the use of antibiotics, chlorhexidine gluconate wipes or baths, separate closing instrument trays, nasal decolonization, bowel preparation, and maintaining patient normothermia. After synthesis and stakeholder input, the team implemented the colorectal bundle along with a checklist for all users to complete to ensure compliance and standardization of practice and for auditing purposes. Implementation results were positive: the total number of colorectal infections decreased from nine in 2020 to three in 2021. Education was critical to securing staff member engagement for successful implementation of and compliance with the bundle.

A Simplified Approach to Breast Reduction Using the Medial Pedicle.

Background: Breast reduction is a common procedure for plastic surgery. The authors have adopted a modified technique using the medial pedicle, with markings using a 15-9-9 framework and a methodical step-wise approach. Objectives: This study introduces the 15-9-9 framework as a design for medial pedicle breast reductions that is easy to perform and teach, with favorable outcomes. Methods: Markings using the 15-9-9 framework were used, describing the mosque dome and medial pedicle length and width. The technique was performed in day surgery under general anesthesia. Patients were followed up for 1 year, with photographs taken at each visit and complications recorded. A retrospective review of 80 patients between November 2013 and July 2019 was completed in a single-surgeon's practice. Results: Patients were an average of 49 years (18-72 years) with a BMI of 28 kg/m2 (23-32). The average planned postoperative sternal notch to areola distance was 22 cm (19-26 cm) and sternal notch to nipple distance was 24 cm (21-28 cm). The average duration of the surgical procedure was 3.4 hours. An average of 464 g (90-1210 g) was removed from each breast. Complication rates were low with minor fat necrosis (14%), T-junction breakdown (10%), hematoma (3.8%), dog ear formation (3.8%), junctional necrosis (2.5%), and partial nipple loss (1.3%). One patient had a cerebrovascular accident in the late postoperative period. Aesthetically pleasing results were achieved postoperatively. Conclusions: This technique using the 15-9-9 framework is simple to learn, perform, and teach with overall aesthetically pleasing outcomes.

Scripting Analyses of Genomes in Ensembl Plants.

Ensembl Plants ( http://plants.ensembl.org ) offers genome-scale information for plants, with four releases per year. As of release 47 (April 2020) it features 79 species and includes genome sequence, gene models, and functional annotation. Comparative analyses help reconstruct the evolutionary history of gene families, genomes, and components of polyploid genomes. Some species have gene expression baseline reports or variation across genotypes. While the data can be accessed through the Ensembl genome browser, here we review specifically how our plant genomes can be interrogated programmatically and the data downloaded in bulk. These access routes are generally consistent across Ensembl for other non-plant species, including plant pathogens, pests, and pollinators.

Endometrial thickness in the prediction of neonatal adverse outcomes in frozen cycles for singleton pregnancies.

RESEARCH QUESTION: Does endometrial thickness (EMT) predict adverse neonatal outcomes in singleton pregnancies after in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) frozen embryo transfer (FET)? DESIGN: This retrospective study involved 13,383 women undergoing IVF/ICSI FET cycles between January 2010 and December 2018 in Women's Hospital of Zhejiang University. The primary outcome was preterm delivery (PTD). The secondary outcomes were small for gestational age (SGA), large for gestational age (LGA) and low birthweight (LBW). RESULTS: A total of 13,383 FET cycles resulting in 5220 singleton live births and 8163 failed cycles were included. Multiple spline regression visualization showed an increasing risk of PTD and LBW for a thin EMT. By comparing multiple cut-off points using area under the curve, a cut-off point of 8 mm was identified, which was used to categorize EMT. A reference point of EMT greater than 8 mm was used; after adjusting for covariates, individuals with EMT less than 8 mm had an adjusted odds ratio of 1.75 (95% CI 1.30 to 2.34) for PTD, 1.57 (95% CI 1.09 to 2.26) for LBW, 0.97 (95% CI 0.63 to 1.50) for SGA and 1.04 (95% CI 0.79 to 1.37) for LGA. Additional analyses showed similar increasing risk with a thin endometrium for both PTD with and without caesarean section, and PTD with low and normal birthweight percentiles. CONCLUSION: A clinical cut-off point of 8 mm has been identified, below which risk of PTD and LBW increases in women undergoing IVF/ICSI.

Efficacy and Toxicity of Pegaspargase and Calaspargase Pegol in Childhood Acute Lymphoblastic Leukemia: Results of DFCI 11-001.

PURPOSE: Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia (ALL) Consortium Protocol 11-001 assessed efficacy and toxicity of calaspargase pegol (calaspargase), a novel pegylated asparaginase formulation with longer half-life, compared with the standard formulation pegaspargase. METHODS: Patients age 1 to ≤ 21 years with newly diagnosed ALL or lymphoblastic lymphoma were randomly assigned to intravenous pegaspargase or calaspargase, 2,500 IU/m2/dose. Patients received one induction dose. Beginning week 7, pegaspargase was administered every 2 week for 15 doses and calaspargase every 3 week for 10 doses (30 weeks). Serum asparaginase activity (SAA) (≥ 0.1 IU/mL considered therapeutic) was assessed 4, 11, 18, and 25 days after the induction dose and before each postinduction dose. RESULTS: Between 2012 and 2015, 239 eligible patients enrolled (230 ALL, nine lymphoblastic lymphoma); 120 were assigned to pegaspargase and 119 to calaspargase. After the induction dose, SAA was ≥ 0.1 IU/mL in ≥ 95% of patients on both arms 18 days after dosing. At day 25, more patients had SAA ≥ 0.1 IU/mL with calaspargase (88% v 17%; P ˂ .001). Postinduction, median nadir SAAs were similar (≥ 1.0 IU/mL) for both arms. Of 230 evaluable patients, 99% of pegaspargase and 95% of calaspargase patients achieved complete remission (P = .12), with no difference in frequency of high end-induction minimal residual disease among evaluable patients with B acute lymphoblastic leukemia (B-ALL). There were no differences in frequencies of asparaginase allergy, pancreatitis, thrombosis, or hyperbilirubinemia. With 5.3 years median follow-up, 5-year event-free survival for pegaspargase was 84.9% (SE ± 3.4%) and 88.1% (± SE 3.0%) for calaspargase (P = .65). CONCLUSION: Every 3-week calaspargase had similar nadir SAA, toxicity, and survival outcomes compared with every 2-week pegaspargase. The high nadir SAA observed for both preparations suggest dosing strategies can be further optimized.

GnRH agonist and hCG (dual trigger) versus hCG trigger for follicular maturation: a systematic review and meta-analysis of randomized trials.

BACKGROUND: Traditionally, final follicular maturation is triggered by a single bolus of human chorionic gonadotropin (hCG). This acts as a surrogate to the naturally occurring luteinizing hormone (LH) surge to induce luteinization of the granulosa cells, resumption of meiosis and final oocyte maturation. More recently, a bolus of gonadotropin-releasing hormone (GnRH) agonist in combination with hCG (dual trigger) has been suggested as an alternative regimen to achieve final follicular maturation. METHODS: This study was a systematic review and meta-analysis of randomized trials evaluating the effect of dual trigger versus hCG trigger for follicular maturation on pregnancy outcomes in women undergoing in vitro fertilization (IVF). The primary outcome was the live birth rate (LBR) per started cycle. RESULTS: A total of 1048 participants were included in the analysis, with 519 in the dual trigger group and 529 in the hCG trigger group. Dual trigger treatment was associated with a significantly higher LBR per started cycle compared with the hCG trigger treatment (risk ratio (RR) = 1.37 [1.07, 1.76], I2 = 0%, moderate evidence). There was a trend towards an increase in both ongoing pregnancy rate (RR = 1.34 [0.96, 1.89], I2 = 0%, low evidence) and implantation rate (RR = 1.31 [0.90, 1.91], I2 = 76%, low evidence) with dual trigger treatment compared with hCG trigger treatment. Dual trigger treatment was associated with a significant increase in clinical pregnancy rate (RR = 1.29 [1.10, 1.52], I2 = 13%, low evidence), number of oocytes collected (mean difference (MD) = 1.52 [0.59, 2.46), I2 = 53%, low evidence), number of mature oocytes collected (MD = 1.01 [0.43, 1.58], I2 = 18%, low evidence), number of fertilized oocytes (MD = 0.73 [0.16, 1.30], I2 = 7%, low evidence) and significantly more usable embryos (MD = 0.90 [0.42, 1.38], I2 = 0%, low evidence). CONCLUSION: Dual trigger treatment with GnRH agonist and HCG is associated with an increased live birth rate compared with conventional hCG trigger. TRIAL REGISTRATION: CRD42020204452 .

Retrospective evaluation of single patient investigational new drug (IND) requests in pediatric oncology.

BACKGROUND: Single patient Investigational New Drug (IND) applications are one mechanism through which experimental therapies are accessed for children with cancer. The landscape of use, outcomes, and toxicity from single patient INDs remains unknown in pediatric oncology. METHODS: We performed a retrospective analysis of all single patient INDs requested and prescribed at a single institution between 1/1/2007 and 5/1/2019. We report aggregate data from the US Food and Drug Administration (FDA) on single patient IND applications over the final two years of the study (2017-2019). We report an overview of all IND applications, as well as clinical descriptions of patients, treatments, outcomes, and toxicity. RESULTS: Over the 2-year period, the FDA approved all 171 submitted single patient IND requests for pediatric oncology. We identified 56 requests from our center during the 12-year study period, and all were approved (median time from FDA submission to approval: 1 day (range 0-12)). 71% of requests were based on disease histology. Lack of pediatric clinical trial (65%) was the most common reason for use. 48 approved requests were ultimately administered. The median duration of treatment was 84 days (range: 4-1590), with 3 patients remaining on treatment at time of analysis. Only 7% discontinued treatment due to toxicity. Three-year overall survival was 50% (95% CI, 35-64). CONCLUSIONS: Single patient INDs in pediatric oncology were universally approved in our national and single-center analysis. In our cohort, single patient INDs were primarily utilized based on disease histology, rather than genomics, for agents that lacked a clinical trial.

Identification of prognostic factors in childhood T-cell acute lymphoblastic leukemia: Results from DFCI ALL Consortium Protocols 05-001 and 11-001.

BACKGROUND/OBJECTIVES: While outcomes for pediatric T-cell acute lymphoblastic leukemia (T-ALL) are favorable, there are few widely accepted prognostic factors, limiting the ability to risk stratify therapy. DESIGN/METHODS: Dana-Farber Cancer Institute (DFCI) Protocols 05-001 and 11-001 enrolled pediatric patients with newly diagnosed B- or T-ALL from 2005 to 2011 and from 2012 to 2015, respectively. Protocol therapy was nearly identical for patients with T-ALL (N = 123), who were all initially assigned to the high-risk arm. End-induction minimal residual disease (MRD) was assessed by reverse transcription polymerase chain reaction (RT-PCR) or next-generation sequencing (NGS), but was not used to modify postinduction therapy. Early T-cell precursor (ETP) status was determined by flow cytometry. Cases with sufficient diagnostic DNA were retrospectively evaluated by targeted NGS of known genetic drivers of T-ALL, including Notch, PI3K, and Ras pathway genes. RESULTS: The 5-year event-free survival (EFS) and overall survival (OS) for patients with T-ALL was 81% (95% CI, 73-87%) and 90% (95% CI, 83-94%), respectively. ETP phenotype was associated with failure to achieve complete remission, but not with inferior OS. Low end-induction MRD (<10-4 ) was associated with superior disease-free survival (DFS). Pathogenic mutations of the PI3K pathway were mutually exclusive of ETP phenotype and were associated with inferior 5-year DFS and OS. CONCLUSIONS: Together, our findings demonstrate that ETP phenotype, end-induction MRD, and PI3K pathway mutation status are prognostically relevant in pediatric T-ALL and should be considered for risk classification in future trials. DFCI Protocols 05-001 and 11-001 are registered at www.clinicaltrials.gov as NCT00165087 and NCT01574274, respectively.

Using Deprescribing Practices and the Screening Tool of Older Persons' Potentially Inappropriate Prescriptions Criteria to Reduce Harm and Preventable Adverse Drug Events in Older Adults.

OBJECTIVES: Approximately 98% of older Americans are simultaneously taking 5-or more-medications to manage at least 2 chronic conditions. Polypharmacy and the use of potentially inappropriate medications (PIMs) are a concern for older adults because they pose a risk for adverse drug events (ADEs), which are associated with emergency department visits and hospitalizations and are an important patient safety priority. We sought to review the evidence of patient safety practices aimed at reducing preventable ADEs in older adults, specifically (i) deprescribing interventions to reduce polypharmacy and (ii) use of the Screening Tool of Older Persons' Potentially Inappropriate Prescriptions (STOPP) to reduce PIMs. METHODS: We conducted a systematic review of literature published between 2008 and 2018 that studied examined the effect of these interventions to reduce preventable ADEs in older adults. RESULTS: Twenty-six studies and 1 systematic review were included (14 for deprescribing and 12 for STOPP and the systematic review). The deprescribing interventions involved decision support tools, educational interventions, and medication reviews by pharmacists and/or providers. Deprescribing studies primarily examined the effect of interventions on process outcomes and observed reductions in polypharmacy, often significantly. A few studies also examined clinical and economic outcomes. Studies of the use of the STOPP screening criteria most commonly reported changes in PIMs, as well as some economic outcomes. CONCLUSIONS: Deprescribing interventions and interventions using the STOPP criteria seem effective in reducing polypharmacy and PIMs in older adults, respectively. Future research on the effectiveness of these approaches on clinical outcomes, the comparative effectiveness of different multicomponent interventions using these approaches, and how to most effectively implement them to improve uptake and evidence-based care is needed.

Assessment of female fertility in the general practice setting.

BACKGROUND: An assessment of female fertility may be undertaken in the general practice setting for a variety of reasons. These include concerns about future fertility when pregnancy is not immediately planned, a desire to consider elective oocyte cryopreservation and difficulty conceiving. OBJECTIVE: The aim of this article is to summarise indications, rationale and components of a comprehensive female fertility assessment in a primary care setting. DISCUSSION: The primary care physician has an essential role in providing women with guidance, counselling and assessment regarding fertility concerns. A complete initial assessment includes pre-pregnancy screening and counselling, and assessment of ovulation, ovarian reserve and pelvic anatomy to guide further investigation and management.

A plugin for the Ensembl Variant Effect Predictor that uses MaxEntScan to predict variant spliceogenicity.

SUMMARY: Assessing the pathogenicity of genetic variants can be a complex and challenging task. Spliceogenic variants, which alter mRNA splicing, may yield mature transcripts that encode non-functional protein products, an important predictor of Mendelian disease risk. However, most variant annotation tools do not adequately assess spliceogenicity outside the native splice site and thus the disease-causing potential of variants in other intronic and exonic regions is often overlooked. Here, we present a plugin for the Ensembl Variant Effect Predictor that packages MaxEntScan and extends its functionality to provide splice site predictions using a maximum entropy model. The plugin incorporates a sliding window algorithm to predict splice site loss or gain for any variant that overlaps a transcript feature. We also demonstrate the utility of the plugin by comparing our predictions to two mRNA splicing datasets containing several cancer-susceptibility genes. AVAILABILITY AND IMPLEMENTATION: Source code is freely available under the Apache License, Version 2.0: https://github.com/Ensembl/VEP_plugins. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Refining risk classification in childhood B acute lymphoblastic leukemia: results of DFCI ALL Consortium Protocol 05-001.

Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocol 05-001 tested a new risk stratification system in children and adolescents with newly diagnosed acute lymphoblastic leukemia (ALL). At study entry, B-ALL patients were classified as standard risk (SR) or high risk (HR) based on age, white blood cell (WBC) count, and central nervous system status. After achieving complete remission (CR), patients with high end-induction minimal residual disease (MRD) (≥10-3 by polymerase chain reaction analysis of patient-specific antigen receptor rearrangements) and/or adverse cytogenetics (KMT2A rearrangement or hypodiploidy) were reclassified as very high risk (VHR) and received intensified therapy. IKZF1 deletion status was retrospectively evaluated by multiplex ligation-dependent probe amplification. Between 2005 and 2011, 678 Philadelphia chromosome-negative B-ALL patients aged 1 to 18 years enrolled; 651 achieved CR and 648 received a final risk group. Among all 678 patients, 5-year event-free survival (EFS) was 87% (95% confidence interval [CI], 84-89) and overall survival 93% (95% CI, 90-94). Five-year disease-free survival of SR patients (N = 407) was 94% (95% CI, 91-96), HR (N = 176) was 84% (95% CI, 77-88), and VHR (N = 65) was 79% (95% CI, 67-87). IKZF1 deletion was present in 62 of 385 (16%) assessed patients and was associated with inferior 5-year EFS (63%; 95% CI, 49%-74% vs 88%; 95% CI, 84%-91%; P < .001), and higher 5-year cumulative incidence of relapse, including among those with low MRD (24% vs 8%, P = .001). In multivariable analysis, age ≥15 years, WBC ≥50 × 109/L, IKZF1 deletion, and MRD ≥10-4 was each associated with inferior outcome. In conclusion, risk-stratified therapy on DFCI 05-001 resulted in favorable outcomes for B-ALL patients, including those with VHR features. IKZF1 deletion was an independent predictor of inferior outcome. This trial was registered at www.clinicaltrials.gov as #NCT00400946.

Phase I trial of the mTOR inhibitor everolimus in combination with multi-agent chemotherapy in relapsed childhood acute lymphoblastic leukemia.

BACKGROUND: We sought to determine the feasibility of co-administering everolimus with a four-drug reinduction in children and adolescents with acute lymphoblastic leukemia (ALL) experiencing a first marrow relapse. PROCEDURE: This phase I study tested everolimus with vincristine, prednisone, pegaspargase and doxorubicin in patients with marrow relapse occurring >18 months after first complete remission (CR). The primary aim was to identify the maximum tolerated dose of everolimus. Three dose levels (DLs) were tested during dose escalation (2, 3, and 5 mg/m2 /day). Additional patients were enrolled at the 3- and 5 mg/m2 /day DLs to further evaluate toxicity (dose expansion). RESULTS: Thirteen patients enrolled during dose escalation and nine during dose expansion. During dose escalation, one dose-limiting toxicity occurred (grade 4 hyperbilirubinemia) in six evaluable patients at DL3 (5 mg/m2 /day). The most common grade ≥3 adverse events were febrile neutropenia, infections, transaminitis, hyperbilirubinemia, and hypophosphatemia. Two of the 12 patients treated at DL3 developed Rothia mucilaginosa meningitis. Nineteen patients (86%) achieved a second CR (CR2). Of those, 13 (68%) had a low end-reinduction minimal residual disease (MRD) level (≤10-3 by polymerase chain reaction-based assay). The CR2 rate for patients with B-cell ALL treated at DL3 (n = 12) was 92%; 82% of these patients had low MRD. CONCLUSIONS: Everolimus combined with four-drug reinduction chemotherapy was generally well tolerated and associated with favorable rates of CR2 and low end-reinduction MRD. The recommended phase 2 dose of everolimus given in combination with a four-drug reinduction is 5 mg/m2 /day. This promising combination should be further evaluated in a larger patient cohort.

Sacral neuromodulation for faecal incontinence - 10 years' experience at a Scottish tertiary centre.

INTRODUCTION: Sacral nerve stimulation (SNS) is increasingly popular in the management of faecal incontinence. This paper reports the first 10-year experience of SNS in the management of faecal incontinence at a tertiary referral centre. Data was collected in a prospectively maintained database. RESULTS: In total 130 patients were referred. The majority were women (94%) under 75-year-old (98%). Seven patients were found to have full-thickness rectal prolapse at the initial work-up and proceeded to rectopexy. Eighty-three patients underwent temporary SNS testing with 73.5% positive outcome, of which 52 patients had permanent implant insertion. There were four failures of SNS (7%) following implantation despite successful temporary testing, seven infection, one lead migration and three post-operative pain/numbness. One patient subsequently developed colorectal cancer requiring SNS removal. A higher frequency of episodes of incontinence was associated with positive SNS outcome (p = 0.007). There was no significant association between age, sex, type of faecal incontinence, previous anorectal/pelvic surgery, colonoscopic or USS findings and the likelihood of successful SNS. Of the 52 patients with SNS implants, 27 patients were seen only once for follow-up; the remaining 25 patients were seen more than once - five of these were part of our initial cases of routine 6- and 12-monthly follow-up, 6 patients were seen for adjustment of voltages, whereas the remaining 14 patients were seen for complications of the implants. If the initial five patients were excluded, only 38% of patients would have been seen more frequently on an as-required basis. CONCLUSION: SNS is a safe and effective option in the management of faecal incontinence. Of the initial work-up, endoscopy and examination-under-anaesthesia (EUA) or proctogram are essential and more likely to influence the likelihood of suitability of SNS testing. A patient-led drop-in approach to follow-up is feasible to allow patients to be seen on an as-required basis.

Splicing arrays reveal novel RBM10 targets, including SMN2 pre-mRNA.

BACKGROUND: RBM10 is an RNA binding protein involved in message stabilization and alternative splicing regulation. The objective of the research described herein was to identify novel targets of RBM10-regulated splicing. To accomplish this, we downregulated RBM10 in human cell lines, using small interfering RNAs, then monitored alternative splicing, using a reverse transcription-PCR screening platform. RESULTS: RBM10 knockdown (KD) provoked alterations in splicing events in 10-20% of the pre-mRNAs, most of which had not been previously identified as RBM10 targets. Hierarchical clustering of the genes affected by RBM10 KD revealed good conservation of alternative exon inclusion or exclusion across cell lines. Pathway annotation showed RAS signaling to be most affected by RBM10 KD. Of particular interest was the finding that splicing of SMN pre-mRNA, encoding the survival of motor neuron (SMN) protein, was influenced by RBM10 KD. Inhibition of RBM10 resulted in preferential expression of the full-length, exon 7 retaining, SMN transcript in four cancer cell lines and one normal skin fibroblast cell line. SMN protein is expressed from two genes, SMN1 and SMN2, but the SMN1 gene is homozygously disrupted in people with spinal muscular atrophy; as a consequence, all of the SMN that is expressed in people with this disease is from the SMN2 gene. Expression analyses using primary fibroblasts from control, carrier and spinal muscle atrophy donors demonstrated that RBM10 KD resulted in preferential expression of the full-length, exon 7 retaining, SMN2 transcript. At the protein level, upregulation of the full-length SMN2 was also observed. Re-expression of RBM10, in a stable RBM10 KD cancer cell line, correlated with a reversion of the KD effect, demonstrating specificity. CONCLUSION: Our work has not only expanded the number of pre-mRNA targets for RBM10, but identified RBM10 as a novel regulator of SMN2 alternative inclusion.

Management of non-tubal ectopic pregnancies at a large tertiary hospital.

There are limited data on the management of non-tubal ectopic pregnancies (NTEP). We reviewed the management of these cases at a tertiary centre with a dedicated institutional protocol. All cases of confirmed NTEP were retrospectively identified from 2006 to 2014. Records were reviewed for presenting features, mode and success of initial management, preservation of fertility and length of hospital stay. The main outcome measure was the success rate of medical management with methotrexate. The 60 cases identified included 34 cornual, 14 Caesarean section scar, nine cervical and three cervical involving previous Caesarean scar. Primary surgical management was performed in 22 patients. Thirty-eight patients received medical therapy with single or multidose methotrexate. Successful medical management was observed in 33 (87%); however, length of stay was significantly longer compared with surgical patients (mean 14 ± 12 days versus 5 ± 2 days, P < 0.01). Hysterectomy was performed in three patients (one surgical group, two medical group). There was one case of methotrexate toxicity with no long-term adverse outcome. Medical management of NTEP is a safe first-line therapy for clinically stable patients desiring preservation of fertility despite a longer period of inpatient monitoring and follow-up.

Intravenous pegylated asparaginase versus intramuscular native Escherichia coli L-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001): a randomised, open-label phase 3 trial.

BACKGROUND: l-asparaginase is a universal component of treatment for childhood acute lymphoblastic leukaemia, and is usually administered intramuscularly. Pegylated Escherichia coli asparaginase (PEG-asparaginase) has a longer half-life and is potentially less immunogenic than the native Escherichia coli (E coli) preparation, and can be more feasibly administered intravenously. The aim of the Dana-Farber Cancer Institute Acute Lymphoblastic Leukaemia Consortium Protocol 05-001 (DFCI 05-001) was to compare the relative toxicity and efficacy of intravenous PEG-asparaginase and intramuscular native E colil-asparaginase in children with newly diagnosed acute lymphoblastic leukaemia. METHODS: DFCI 05-001 enrolled patients aged 1-18 years with newly diagnosed acute lymphoblastic leukaemia from 11 consortium sites in the USA and Canada. Patients were assigned to an initial risk group on the basis of their baseline characteristics and then underwent 32 days of induction therapy. Those who achieved complete remission after induction therapy were assigned to a final risk group and were eligible to participate in a randomised comparison of intravenous PEG-asparaginase (15 doses of 2500 IU/m(2) every 2 weeks) or intramuscular native E colil-asparaginase (30 doses of 25 000 IU/m(2) weekly), beginning at week 7 after study entry. Randomisation (1:1) was unmasked, and was done by a statistician-generated allocation sequence using a permuted blocks algorithm (block size of 4), stratified by final risk group. The primary endpoint of the randomised comparison was the overall frequency of asparaginase-related toxicities (defined as allergy, pancreatitis, and thrombotic or bleeding complications). Predefined secondary endpoints were disease-free survival, serum asparaginase activity, and quality of life during therapy as assessed by PedsQL surveys. All analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00400946. FINDINGS: Between April 22, 2005, and Feb 12, 2010, 551 eligible patients were enrolled. 526 patients achieved complete remission after induction, of whom 463 were randomly assigned to receive intramuscular native E colil-asparaginase (n=231) or intravenous PEG-asparaginase (n=232). The two treatment groups did not differ significantly in the overall frequency of asparaginase-related toxicities (65 [28%] of 232 patients in the intravenous PEG-asparaginase group vs 59 [26%] of 231 patients in the intramuscular native E colil-asparaginase group, p=0·60), or in the individual frequency of allergy (p=0·36), pancreatitis (p=0·55), or thrombotic or bleeding complications (p=0·26). Median follow-up was 6·0 years (IQR 5·0-7·1). 5-year disease-free survival was 90% (95% CI 86-94) for patients assigned to intravenous PEG-asparaginase and 89% (85-93) for those assigned to intramuscular native E colil-asparaginase (p=0·58). The median nadir serum asparaginase activity was significantly higher in patients who received intravenous PEG-asparaginase than in those who received intramuscular native E colil-asparaginase. Significantly more anxiety was reported by both patients and parent-proxy in the intramuscular native E colil-asparaginase group than in the intravenous PEG-asparaginase group. Scores for other domains were similar between the groups. The most common grade 3 or worse adverse events were bacterial or fungal infections (47 [20%] of 232 in the intravenous PEG-asparaginase group vs 51 [22%] of 231 patients in the intramuscular E colil-asparaginase group) and asparaginase-related allergic reactions (14 [6%] vs 6 [3%]). INTERPRETATION: Intravenous PEG-asparaginase was not more toxic than, was similarly efficacious to, and was associated with decreased anxiety compared with intramuscular native E colil-asparaginase, supporting its use as the front-line asparaginase preparation in children with newly diagnosed acute lymphoblastic leukaemia. FUNDING: National Cancer Institute and Enzon Pharmaceuticals.