Kristy Robledo

Delayed versus Immediate Cord Clamping in Preterm Infants

Background The preferred timing of umbilical‐cord clamping in preterm infants is unclear. Methods We randomly assigned fetuses from women who were expected to deliver before 30 weeks of gestation to either immediate clamping of the umbilical cord (≤10 seconds after delivery) or delayed clamping (≥60 seconds after delivery). The primary composite outcome was death or major morbidity (defined as severe brain injury on postnatal ultrasonography, severe retinopathy of prematurity, necrotizing enterocolitis, or late‐onset sepsis) by 36 weeks of postmenstrual age. Analyses were performed on an intention‐to‐treat basis, accounting for multiple births. Results Of 1634 fetuses that underwent randomization, 1566 were born alive before 30 weeks of gestation; of these, 782 were assigned to immediate cord clamping and 784 to delayed cord clamping. The median time between delivery and cord clamping was 5 seconds and 60 seconds in the respective groups. Complete data on the primary outcome were available for 1497 infants (95.6%). There was no significant difference in the incidence of the primary outcome between infants assigned to delayed clamping (37.0%) and those assigned to immediate clamping (37.2%) (relative risk, 1.00; 95% confidence interval, 0.88 to 1.13; P=0.96). The mortality was 6.4% in the delayed‐clamping group and 9.0% in the immediate‐clamping group (P=0.03 in unadjusted analyses; P=0.39 after post hoc adjustment for multiple secondary outcomes). There were no significant differences between the two groups in the incidences of chronic lung disease or other major morbidities. Conclusions Among preterm infants, delayed cord clamping did not result in a lower incidence of the combined outcome of death or major morbidity at 36 weeks of gestation than immediate cord clamping. (Funded by the Australian National Health and Medical Research Council [NHMRC] and the NHMRC Clinical Trials Centre; APTS Australian and New Zealand Clinical Trials Registry number, ACTRN12610000633088.)

Response to Cetuximab With or Without Irinotecan in Patients With Refractory Metastatic Colorectal Cancer Harboring the KRAS G13D Mutation: Australasian Gastro-Intestinal Trials Group ICECREAM Study

PURPOSE RAS mutations predict lack of response to epidermal growth factor receptor monoclonal antibody therapy in patients with metastatic colorectal cancer (mCRC), but preclinical studies and retrospective clinical data suggest that patients with tumors harboring the exon 2 KRAS G13D mutation may benefit from cetuximab. We aimed to assess cetuximab monotherapy and cetuximab plus irinotecan in patients with molecularly selected (G13D mutation) chemotherapy-refractory mCRC in a randomized phase II trial of this rare molecular subtype. PATIENTS AND METHODS Patients with chemotherapy-refractory KRAS G13D mutation-positive mCRC who had progressed within 6 months of irinotecan therapy were randomly assigned to cetuximab 400 mg/m(2) loading dose and then 250 mg/m(2) once per week with or without irinotecan 180 mg/m(2) once every 2 weeks. The primary end point was 6-month progression-free survival; secondary end points were response rate, overall survival, quality of life, and toxicity. RESULTS Fifty-one of 53 patients recruited over 2 years were eligible. The 6-month progression-free survival rate was 10% (95% CI, 2% to 26%) for cetuximab versus 23% (95% CI, 9% to 40%) for cetuximab plus irinotecan with a hazard ratio of 0.74 (95% CI, 0.42 to 1.32). Response and stable disease rates were 0% and 58% for monotherapy versus 9% and 70% for combination treatment, respectively. Overall survival and quality of life were similar; toxicities were higher with combination therapy. CONCLUSION In patients with G13D-mutated chemotherapy-refractory mCRC, there was no statistically significant improvement in disease control at 6 months with either cetuximab monotherapy or cetuximab plus irinotecan. No responses were seen with single-agent cetuximab. The responses observed with the combination of cetuximab and irinotecan may reflect true drug synergy or persistent irinotecan sensitivity. The ICECREAM (Irinotecan Cetuximab Evaluation and Cetuximab Response Evaluation Among Patients with a G13D Mutation) study demonstrates the need to prospectively evaluate hypotheses that were previously supported by retrospective analyses and exemplifies the value of international collaboration in trials of rare molecular subtypes.

Interobserver agreement and image quality of functional cardiac ultrasound measures used in a randomised trial of delayed cord clamping in preterm infants

Objective Functional cardiac ultrasound measures are used clinically and in trials for assessing the haemodynamic status of newborn infants. Superior vena cava (SVC) flow and right ventricular output (RVO) are established measures of systemic blood flow on the first postnatal day. The objective was to assess image quality and interobserver agreement of these measures in preterm infants enrolled in a randomised trial of immediate versus delayed cord clamping. Design and setting Image quality and interobserver agreement for SVC flow, RVO and ductus arteriosus (DA) size were assessed on measurements taken at 3–6, 6–12 and 20–28 hours for the first 10 infants enrolled at each of four sites (total 40). Bland-Altman plots were constructed; mean difference (bias) and limits of agreement (LOA) were calculated. Potential sources of variation were explored. Results Quality was judged satisfactory for >97% of images. The mean difference and LOA between the observers were 5.4 mL/kg/min and −49.0 to 59.8 mL/kg/min for SVC flow, −26.6 mL/kg/min and −131.4 to 78.2 mL/kg/min for RVO, and 0 mm and −0.8 to 0.8 mm for DA diameter, respectively. The principal source of measurement error for SVC flow was diameter, and for RVO, diameter and velocity time integral. The difference between observers for both SVC and RVO was significantly associated with site. Conclusion Interobserver variability for SVC flow is consistent with that previously reported, but higher for RVO. The findings should be incorporated into clinical practice, training, accreditation and trial design.

D-dimer Predicts Long-Term Cause-Specific Mortality, Cardiovascular Events and Cancer in Stable Coronary Heart Disease Patients: The LIPID Study

Background: D-dimer, a degradation product of cross-linked fibrin, is a marker for hypercoagulability and thrombotic events. Moderately elevated levels of D-dimer are associated with the risk of venous and arterial events in patients with vascular disease. We assessed the role of D-dimer levels in predicting long-term vascular outcomes, cause-specific mortality, and new cancers in the LIPID trial (Long-Term Intervention with Pravastatin in Ischaemic Disease) in the context of other risk factors. Methods: LIPID randomized patients to placebo or pravastatin 40 mg/d 5 to 38 months after myocardial infarction or unstable angina. D-dimer levels were measured at baseline and at 1 year. Median follow-up was 6.0 years during the trial and 16 years in total. Results: Baseline D-dimer levels for 7863 patients were grouped by quartile (⩽112, 112–173, 173–273, >273 ng/mL). Higher levels were associated with older age, female sex, history of hypertension, poor renal function, and elevated levels of B-natriuretic peptide, high-sensitivity C-reactive protein, and sensitive troponin I (each P<0.001). During the first 6 years, after adjustment for up to 30 additional risk factors, higher D-dimer was associated with a significantly increased risk of a major coronary event (quartile 4 versus 1: hazard ratio [HR], 1.45; 95% confidence interval, 1.21–1.74), major cardiovascular disease (CVD) event (HR, 1.45; 95% confidence interval, 1.23–1.71) and venous thromboembolism (HR, 4.03; 95% confidence interval, 2.31–7.03; each P<0.001). During the 16 years overall, higher D-dimer was an independent predictor of all-cause mortality (HR, 1.59), CVD mortality (HR, 1.61), cancer mortality (HR, 1.54), and non-CVD noncancer mortality (HR, 1.57; each P<0.001), remaining significant for deaths resulting from each cause occurring beyond 10 years of follow-up (each P⩽0.01). Higher D-dimer also independently predicted an increase in cancer incidence (HR, 1.16; P=0.02).The D-dimer level increased the net reclassification index for all-cause mortality by 4.0 and venous thromboembolism by 13.6. Conclusions: D-dimer levels predict long-term risk of arterial and venous events, CVD mortality, and non-CVD noncancer mortality independent of other risk factors. D-dimer is also a significant predictor of cancer incidence and mortality. These results support an association of D-dimer with fatal events across multiple diseases and demonstrate that this link extends beyond 10 years’ follow-up.

Cetuximab Alone or With Irinotecan for Resistant KRAS-, NRAS-, BRAF- and PIK3CA-wild-type Metastatic Colorectal Cancer: The AGITG Randomized Phase II ICECREAM Study

Micro‐Abstract Most unresectable metastatic colon cancer remains incurable, with a median survival of less than 3 years. Molecularly targeted therapies have recently been developed; in particular, monoclonal antibodies against the epidermal growth factor receptor, which are efficacious in 40% to 60% of chemotherapy‐resistant patients with wild‐type KRAS. This study shows that cetuximab plus irinotecan, compared with cetuximab alone, increases the response rate and delays progression in irinotecan‐resistant RAS wild‐type colorectal cancer. Background The Irinotecan Cetuximab Evaluation and Cetuximab Response Evaluation (ICECREAM) study assessed the efficacy of cetuximab monotherapy compared with cetuximab combined with chemotherapy for quadruple wild‐type (KRAS, NRAS, BRAF, or P13KCA exon 20) metastatic colorectal cancer. Patients and Methods Patients were enrolled in an open‐label, multicenter, phase II trial and randomly assigned to cetuximab 400 mg/m2, then 250 mg/m2 cetuximab weekly, with or without irinotecan 180 mg/m2 every 2 weeks. The primary endpoint was 6‐month progression‐free survival; secondary endpoints were response rate, overall survival, toxicity, and quality of life. Results From 2012 to 2016, 48 patients were recruited. Two were ineligible, and 2 were not evaluable for response. Characteristics were balanced, except gender (male, 62% vs. 72%) and primary sidedness (left, 95% vs. 68%). For cetuximab compared with cetuximab‐irinotecan, progression‐free survival was 14% versus 41% (hazard ratio, 0.39; 95% confidence interval, 0.20‐0.78; P = .008); response rate was 10% (2 partial responses) versus 38% (1 complete, 8 partial); P = .04. Grade 3 to 4 toxicities were less with cetuximab monotherapy (23% vs. 50%); global and specific quality of life scores did not differ. Conclusion In comparison with cetuximab alone, cetuximab plus irinotecan increases the response rate and delays progression in irinotecan‐resistant RAS wild‐type colorectal cancer. This echoes data from molecularly unselected patients.

A novel evaluation of density differences in subcutaneous abdominal adipose tissue layers in pregnancy using elastography

Chronic inflammation leads to adipose tissue (AT) fibrosis through excessive accumulation of extracellular matrix proteins. An increasing degree of fibrosis in AT is associated with increasing body mass index (BMI) and insulin resistance. Anecdotally AT has been observed to vary with ease of ultrasound penetration on medical examinations. Ultrasound strain elastography (SE) is a useful tool in assessing fibrosis in liver disease but has not previously been used to assess AT fibrosis. This study assesses the variance in density of the two anatomical layers of subcutaneous AT, superficial subcutaneous adipose tissue (SSAT) and deep subcutaneous adipose tissue (DSAT) in pregnancy using SE.

Does continuous infusion of local anaesthesia improve pain control and walking distance after coronary artery bypass graft surgery? A randomised controlled trial

OBJECTIVES To evaluate the effects of continuous infusion of ropivacaine compared to sham infusion or usual care on pain scores before and after physiotherapy treatment, distance walked and time to discharge from physiotherapy, after coronary artery bypass graft (CABG) surgery. DESIGN Prospective, randomised, double blind controlled trial. SETTING AND PARTICIPANTS Seventy-five participants who underwent CABG surgery with left internal mammary artery grafts were allocated, to the ropivacaine group (n=26), the sham group (n=25), or usual care group (n=24). Participants in the ropivacaine group received 0.5% ropivacaine and participants in the sham group received normal saline, both as continuous infusions via two parasternally tunnelled catheters for 96hours continuously. The usual care group did not receive a device. All groups had patient-controlled analgesia and/or oral analgesia. RESULTS Seventy-two participants completed the study. There was no significant between-group differences in pain scores, distance walked on any post operative day (POD) or number of participants discharged from physiotherapy by POD 4. For the group as a whole there was a significant linear decrease in pain score from mean (SD) 42 (24) mm on POD1 to 15 (16) mm on POD4 (p<0.001), (MD 27mm, 95% CI 22 to 32) and walking distance increased from 1 (5) m on POD1 to 183 (239) m on POD4 (p<0.001) MD 181m, 95% CI 126 to 236). CONCLUSION Infusion of ropivacaine post CABG surgery was unable to reduce pain, increase distance walked or reduce time to physiotherapy discharge compared to sham or usual care. Trial registration number ACTRN12612001243808.