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Abstract Background Preexisting diabetes (PDM) increases the risk of maternal and perinatal mortality and morbidity. Reduction of maternal hyperglycemia prior to and during pregnancy can reduce these risks. Despite compelling evidence that preconception care (PCC), which includes achieving strict glycemic goals, reduces the risk of congenital malformations and other adverse pregnancy outcomes, only a minority of individuals receive PCC. Suboptimal pregnancy outcomes demonstrated in real-world data highlight the need to further optimize prenatal glycemia. New evolving technology shows promise in helping to achieve that goal. Dysglycemia is not the only driver of poor pregnancy outcomes in PDM. The increasing impact of obesity on pregnancy outcomes underscores the importance of optimal nutrition and management of insulin sensitizing medications during prenatal care for PDM. Objective To provide recommendations for the care of individuals with PDM that lead to a reduction in maternal and neonatal adverse outcomes. Methods The Guideline Development Panel (GDP) composed of a multidisciplinary panel of clinical experts, along with experts in guideline methodology and systematic literature review, identified and prioritized 10 clinically relevant questions related to the care of individuals with diabetes before, during and after pregnancy. The GDP prioritized randomized controlled trials (RCTs) evaluating the effects of different interventions (eg, PCC, nutrition, treatment options, delivery) during the reproductive life cycle of individuals with diabetes, including type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Systematic reviews queried electronic databases for publications related to these 10 clinical questions. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology was used to assess the certainty of evidence and develop recommendations. The approach incorporated perspectives from 2 patient representatives and considered patient values, costs and resources required, acceptability and feasibility, and impact on health equity of the proposed recommendations. Results In individuals with diabetes mellitus who have the possibility of becoming pregnant, we suggest asking a screening question about pregnancy intention at every reproductive, diabetes, and primary care visit. Screening for pregnancy intent is also suggested at urgent care/emergency room visits when clinically appropriate (2 | ⊕OOO). This was suggested based on indirect evidence demonstrating a strong association between PCC and both reduced glycated hemoglobin (HbA1c) at the first prenatal visit and congenital malformations. In individuals with diabetes mellitus who have the possibility of becoming pregnant, we suggest use of contraception when pregnancy is not desired (2 | ⊕⊕OO). This was suggested based on indirect evidence in women with diabetes, where PCC—including contraception as a key component—showed a clinically significant association with improvements in first-trimester HbA1c and the rate of congenital malformations, together with indirect evidence from the general population regarding the reduction of unplanned pregnancies and pregnancy terminations with the use of contraception. In individuals with T2DM, we suggest discontinuation of glucagon-like peptide-1 receptor agonist (GLP-1RA) before conception rather than discontinuation between the start of pregnancy and the end of the first trimester (2 | ⊕OOO). This was suggested based on limited data on risk of exposure to GLP-1RA receptor agonists during pregnancy. In pregnant individuals with T2DM already on insulin, we suggest against routine addition of metformin (2 | ⊕OOO). This was suggested based on the GDP judgment that the benefit of adding metformin to insulin to achieve decrease in rates of large for gestational age infants did not outweigh the potential harm of increasing the risk of small for gestational age infants or adverse childhood outcomes related to changes in body composition. In individuals with PDM, we suggest either a carbohydrate-restricted diet (<175 g/day) or usual diet (>175 g/day) during pregnancy (2 | ⊕OOO). This was suggested based on the GDP judgment that the available evidence was limited and very indirect, resulting in significant uncertainty about the net benefits or harms. As such, the evidence was insufficient to support a recommendation either for or against a carbohydrate intake cutoff of 175 g/day. In pregnant individuals with T2DM, we suggest either the use of a continuous glucose monitor (CGM) or self-monitoring of blood glucose (SMBG) (2 | ⊕OOO). There is lack of direct evidence supporting superiority of CGM use over SMBG for T2DM during pregnancy. There is indirect evidence supporting improved glucometrics with the use of CGM for individuals with T2DM outside of pregnancy, substantial improvements in neonatal outcomes for individuals with T1DM using CGM during pregnancy and the potential for decreasing adverse pregnancy outcomes with improved glucometrics in individuals with T2DM. In individuals with PDM using a CGM, we suggest against the use of a single 24-hour CGM target <140 mg/dL (7.8 mmol/L) in place of standard-of-care pregnancy glucose targets of fasting <95 mg/dL (5.3 mmol/L), 1-hour postprandial <140 mg/dL (7.8 mmol/L), and 2-hour postprandial < 120 mg/dL (6.7 mmol/L) (2 | ⊕OOO). This was suggested based on indirect evidence that associated adverse pregnancy outcomes with a fasting glucose > 126 mg/dL (7 mmol/L). In individuals with T1DM who are pregnant, we suggest the use of a hybrid closed-loop pump (pump adjusting automatically based on CGM) rather than an insulin pump with CGM (without an algorithm) or multiple daily insulin injections with CGM (2 | ⊕OOO). This was suggested based on a meta-analysis of RCTs which demonstrated improvement in glucometrics with increased time in range (MD +3.81%; CI −4.24 to 11.86) and reduced time below range (MD −0.85%; CI −1.98 to 0.28) with the use of hybrid closed-loop pump technology. In individuals with PDM, we suggest early delivery based on risk assessment rather than expectant management (2 | ⊕OOO). This was suggested based on indirect evidence that risks may outweigh benefits of expectant management beyond 38 weeks gestation and that risk assessment criteria may be useful to inform ideal delivery timing. In individuals with PDM (including those with pregnancy loss or termination), we suggest postpartum endocrine care (diabetes management), in addition to usual obstetric care (2 | ⊕OOO). As the postpartum period frequently overlaps with preconception, this was suggested based on indirect evidence demonstrating a strong association between PCC and both reduced HbA1c at the first prenatal visit and congenital malformations. Conclusion The data supporting these recommendations were of very low to low certainty, highlighting the urgent need for research designed to provide high certainty evidence to support the care of individuals with diabetes before, during, and after pregnancy. Investment in implementation science for PCC is crucial to prevent significant mortality and morbidity for individuals with PDM and their children. RCTs to further define glycemic targets in pregnancy and refinement of emerging technology to achieve those targets can lead to significant reduction of harm and in the burden of diabetes care. Data on optimal nutrition and obesity management in pregnancy are lacking. More research on timing of delivery in women with PDM is also needed.

Abstract Background Preexisting diabetes (PDM) increases the risk of maternal and perinatal mortality and morbidity. Reduction of maternal hyperglycemia prior to and during pregnancy can reduce these risks. Despite compelling evidence that preconception care (PCC), which includes achieving strict glycemic goals, reduces the risk of congenital malformations and other adverse pregnancy outcomes, only a minority of individuals receive PCC. Suboptimal pregnancy outcomes demonstrated in real-world data highlight the need to further optimize prenatal glycemia. New evolving technology shows promise in helping to achieve that goal. Dysglycemia is not the only driver of poor pregnancy outcomes in PDM. The increasing impact of obesity on pregnancy outcomes underscores the importance of optimal nutrition and management of insulin sensitizing medications during prenatal care for PDM. Objective To provide recommendations for the care of individuals with PDM that lead to a reduction in maternal and neonatal adverse outcomes. Methods The Guideline Development Panel (GDP) composed of a multidisciplinary panel of clinical experts, along with experts in guideline methodology and systematic literature review, identified and prioritized 10 clinically relevant questions related to the care of individuals with diabetes before, during and after pregnancy. The GDP prioritized randomized controlled trials (RCTs) evaluating the effects of different interventions (eg, PCC, nutrition, treatment options, delivery) during the reproductive life cycle of individuals with diabetes, including type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Systematic reviews queried electronic databases for publications related to these 10 clinical questions. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology was used to assess the certainty of evidence and develop recommendations. The approach incorporated perspectives from 2 patient representatives and considered patient values, costs and resources required, acceptability and feasibility, and impact on health equity of the proposed recommendations. Results In individuals with diabetes mellitus who have the possibility of becoming pregnant, we suggest asking a screening question about pregnancy intention at every reproductive, diabetes, and primary care visit. Screening for pregnancy intent is also suggested at urgent care/emergency room visits when clinically appropriate (2 | ⊕OOO). This was suggested based on indirect evidence demonstrating a strong association between PCC and both reduced glycated hemoglobin (HbA1c) at the first prenatal visit and congenital malformations. In individuals with diabetes mellitus who have the possibility of becoming pregnant, we suggest use of contraception when pregnancy is not desired (2 | ⊕⊕OO). This was suggested based on indirect evidence in women with diabetes, where PCC—including contraception as a key component—showed a clinically significant association with improvements in first-trimester HbA1c and the rate of congenital malformations, together with indirect evidence from the general population regarding the reduction of unplanned pregnancies and pregnancy terminations with the use of contraception. In individuals with T2DM, we suggest discontinuation of glucagon-like peptide-1 receptor agonist (GLP-1RA) before conception rather than discontinuation between the start of pregnancy and the end of the first trimester (2 | ⊕OOO). This was suggested based on limited data on risk of exposure to GLP-1RA receptor agonists during pregnancy. In pregnant individuals with T2DM already on insulin, we suggest against routine addition of metformin (2 | ⊕OOO). This was suggested based on the GDP judgment that the benefit of adding metformin to insulin to achieve decrease in rates of large for gestational age infants did not outweigh the potential harm of increasing the risk of small for gestational age infants or adverse childhood outcomes related to changes in body composition. In individuals with PDM, we suggest either a carbohydrate-restricted diet (<175 g/day) or usual diet (>175 g/day) during pregnancy (2 | ⊕OOO). This was suggested based on the GDP judgment that the available evidence was limited and very indirect, resulting in significant uncertainty about the net benefits or harms. As such, the evidence was insufficient to support a recommendation either for or against a carbohydrate intake cutoff of 175 g/day. In pregnant individuals with T2DM, we suggest either the use of a continuous glucose monitor (CGM) or self-monitoring of blood glucose (SMBG) (2 | ⊕OOO). There is lack of direct evidence supporting superiority of CGM use over SMBG for T2DM during pregnancy. There is indirect evidence supporting improved glucometrics with the use of CGM for individuals with T2DM outside of pregnancy, substantial improvements in neonatal outcomes for individuals with T1DM using CGM during pregnancy and the potential for decreasing adverse pregnancy outcomes with improved glucometrics in individuals with T2DM. In individuals with PDM using a CGM, we suggest against the use of a single 24-hour CGM target <140 mg/dL (7.8 mmol/L) in place of standard-of-care pregnancy glucose targets of fasting <95 mg/dL (5.3 mmol/L), 1-hour postprandial <140 mg/dL (7.8 mmol/L), and 2-hour postprandial < 120 mg/dL (6.7 mmol/L) (2 | ⊕OOO). This was suggested based on indirect evidence that associated adverse pregnancy outcomes with a fasting glucose > 126 mg/dL (7 mmol/L). In individuals with T1DM who are pregnant, we suggest the use of a hybrid closed-loop pump (pump adjusting automatically based on CGM) rather than an insulin pump with CGM (without an algorithm) or multiple daily insulin injections with CGM (2 | ⊕OOO). This was suggested based on a meta-analysis of RCTs which demonstrated improvement in glucometrics with increased time in range (MD +3.81%; CI −4.24 to 11.86) and reduced time below range (MD −0.88%; 95% CI: −2.04 to 0.27) with the use of hybrid closed-loop pump technology. In individuals with PDM, we suggest early delivery based on risk assessment rather than expectant management (2 | ⊕OOO). This was suggested based on indirect evidence that risks may outweigh benefits of expectant management beyond 38 weeks gestation and that risk assessment criteria may be useful to inform ideal delivery timing. In individuals with PDM (including those with pregnancy loss or termination), we suggest postpartum endocrine care (diabetes management), in addition to usual obstetric care (2 | ⊕OOO). As the postpartum period frequently overlaps with preconception, this was suggested based on indirect evidence demonstrating a strong association between PCC and both reduced HbA1c at the first prenatal visit and congenital malformations. Conclusion The data supporting these recommendations were of very low to low certainty, highlighting the urgent need for research designed to provide high certainty evidence to support the care of individuals with diabetes before, during, and after pregnancy. Investment in implementation science for PCC is crucial to prevent significant mortality and morbidity for individuals with PDM and their children. RCTs to further define glycemic targets in pregnancy and refinement of emerging technology to achieve those targets can lead to significant reduction of harm and in the burden of diabetes care. Data on optimal nutrition and obesity management in pregnancy are lacking. More research on timing of delivery in women with PDM is also needed.

Abstract Background Regorafenib is one of several FDA‐approved cancer therapies targeting multiple tyrosine kinases. However, there are few subtype‐specific data regarding kinase inhibitor activity in sarcomas. We report results of a single arm, phase II trial of regorafenib in advanced Ewing family sarcomas. Methods Patients with metastatic Ewing family sarcomas (age ≥ 18, ECOG 0–2, good organ function) who had received at least one line of therapy and experienced progression within 6 months of registration were eligible. Prior kinase inhibitors were not allowed. The initial dose of regorafenib was 160 mg oral days 1–21 of a 28‐day cycle. The primary endpoint was estimating progression‐free rate (PFR) at 8 weeks employing RECIST 1.1. Results Thirty patients (median age, 32 years; 33% women [10 patients]; bone primary, 40%; extraskeletal primary, 60%) enrolled at 14 sites. The most common grade 3 or higher toxicities were hypophosphatemia (5 grade 3, 1 grade 4), hypertension (2 grade 3), elevated ALT (2 grade 3). Sixteen patients required dose reductions, most often for hypophosphatemia ( n = 7 reductions in 6 patients); two stopped regorafenib for toxicity. There was one death unrelated to treatment in the 30‐day post‐study period. Median progression‐free survival (PFS) was 14.8 weeks (95% CI 7.3–15.9); PFR at 8 weeks by Kaplan–Meier analysis was 63% (95% CI 46–81%). The RECIST 1.1 response rate was 10%. Median OS was 53 weeks (95% CI 37–106 weeks). Conclusions Regorafenib has modest activity in the Ewing family sarcomas. Toxicity was similar to that seen in approval studies.

There is a growing appreciation for differences in epidemiology, treatment, and outcomes of cardiovascular conditions by sex. Historically, cardiovascular clinical trials have under-represented females, but findings have nonetheless been applied to clinical care in a sex-agnostic manner. Thus, much of the collective knowledge about sex-specific cardiovascular outcomes result from post hoc and secondary analyses. In some cases, these investigations have revealed important sex-based differences with implications for optimizing care for female patients with arrhythmias. This review explores the available evidence related to cardiac arrhythmia care among females, with emphasis on areas in which important sex differences are known or suggested. Considerations related to improving female enrollment in clinical trials as a way to establish more robust clinical evidence for the treatment of females are discussed. Areas of remaining evidence gaps are provided, and recommendations for areas of future research and specific action items are suggested. The overarching goal is to improve appreciation for sex-based differences in cardiac arrhythmia care as 1 component of a comprehensive plan to optimize arrhythmia care for all patients.

Shared decision making (SDM) has been advocated to improve patient care, patient decision acceptance, patient-provider communication, patient motivation, adherence, and patient reported outcomes. Documentation of SDM is endorsed in several society guidelines and is a condition of reimbursement for selected cardiovascular and cardiac arrhythmia procedures. However, many clinicians argue that SDM already occurs with clinical encounter discussions or the process of obtaining informed consent and note the additional imposed workload of using and documenting decision aids without validated tools or evidence that they improve clinical outcomes. In reality, SDM is a process and can be done without decision tools, although the process may be variable. Also, SDM advocates counter that the low-risk process of SDM need not be held to the high bar of demonstrating clinical benefit and that increasing the quality of decision making should be sufficient. Our review leverages a multidisciplinary group of experts in cardiology, cardiac electrophysiology, epidemiology, and SDM, as well as a patient advocate. Our goal is to examine and assess SDM methodology, tools, and available evidence on outcomes in patients with heart rhythm disorders to help determine the value of SDM, assess its possible impact on electrophysiological procedures and cardiac arrhythmia management, better inform regulatory requirements, and identify gaps in knowledge and future needs.

Abstract Trial Information Click here to access other published clinical trials. Lessons Learned The results from the liposarcoma cohort of SARC024 confirm previously published data and do not support the routine use of regorafenib in this patient population. Continued exploration of novel therapies, including combination approaches, is warranted for a patient population in whom limited treatment options exist. Background Regorafenib is a multitargeted kinase inhibitor with a kinase profile overlapping, but distinct from, pazopanib, an agent approved for recurrent and metastatic non-gastrointestinal stromal tumor (GIST), non-adipocytic soft tissue sarcoma. We conducted a randomized, phase II study of regorafenib versus placebo in refractory liposarcoma patients. Methods Patients with advanced or metastatic, treatment-refractory liposarcoma were randomized 1:1 to receive regorafenib 160 mg or placebo once daily (3 weeks on, 1 week off). Patients with well-differentiated liposarcoma only were excluded. Crossover for placebo was allowed upon progression. The primary endpoint was progression-free survival (PFS), according to RECIST version 1.1. Results Forty-eight subjects with liposarcoma (34 dedifferentiated, 12 myxoid/round cell, 2 pleomorphic) were enrolled. Median PFS was 1.87 (95% confidence interval [CI], 0.92–3.67) months for regorafenib versus 2.07 (95% CI, 1.64–3.44) months for placebo; stratified hazard ratio [HR], 0.85 (95% CI, 0.46, 1.58), p = .62. No responses were seen on regorafenib. One PR was observed on placebo. Median overall survival was 6.46 (95% CI, 4.16–23.48) months for regorafenib and 4.89 (95% CI, 3.02–9.77) months for placebo, stratified HR, 0.66 (95% CI, 0.31–1.40), p = .28). Treatment-related adverse events were similar to the known safety profile of regorafenib. Conclusion Regorafenib did not appear to improve PFS in treatment-refractory liposarcoma. No new significant safety signals were observed.

11005 Background: Pazopanib is approved for soft tissue sarcoma pts after failure of other therapy, but there are few subtype-specific data regarding kinase inhibitor activity. We report on a single arm, phase II trial of REGO in advanced EWS. Methods: EWS pts (age > 18, ECOG 0-2, good organ function) who had at least 1 line of therapy and had PD within 6 mo were eligible. Prior oral kinase inhibitors were not allowed. Initial REGO dose was 160 mg PO QD x21 q28d. Dose reductions were employed for toxicity and AEs. The primary endpoint was PFS at 8 weeks (PFS8w) employing RECIST 1.1. Sample size of 30 allowed determination of the difference between PFS8w of 50% vs 25% with alpha = 0.05 and power of 91%. Results: 30 pts (median age 32, range 19-65; M/F = 20/10; ECOG 0/1/2 = 16/13/1; bone, 12; soft tissue, 18; median prior treatments 5, range 1-10) enrolled at 14 US sites (09/2014-03/2016). Most common grade (G3) toxicities were hypophosphatemia (6), hypertension (2), high ALT (2) and 1 each: fatigue, abd pain, diarrhea, hypokalemia, oral mucositis, neutropenia and rash; no G4 toxicities were noted. 13 pts required ≥1 dose reduction, most commonly hypophosphatemia (n = 7); 2 stopped REGO for toxicity. There was 1 death in the 30 day post study period, not REGO related. Median dose at study end: 140 mg (3.5 tabs, range 80-160 mg) 3 wks on/1wk off. 18/30 pts were without PD at 8 wks. Median PFS: 3.6 mo (95%CI 2.8-3.8 mo). PFS8w by KM was 73% (95%CI 57-89%). Best responses: PR/SD/PD/not evaluable of 3/18/7/2, for RECIST RR 10%. Two pts with PR had EWSR1 translocation by FISH; a third had CIC-DUX4. Median duration of response: 5.5 mo (95%CI 2.9-8.0). Median OS is not reached. Conclusions: The substudy met its primary endpoint. REGO toxicity was similar to that seen previously. Enrollment continues in LPS and OGS cohorts, and is being expanded to further study variant EWS without EWSR1-FLI1 fusion. Study of the existing tissue may elucidate which EWS patients may benefit from REGO. Clinical trial information: NCT02048371.