Cardiac time intervals and myocardial performance index for prediction of twin-twin transfusion syndrome

Objectives To explore whether intertwin discordance in myocardial performance index (MPI) or cardiac time intervals enables the prediction of twin-twin transfusion syndrome (TTTS) in monochorionic diamniotic (MCDA) pregnancies with amniotic fluid discordance.Methods Prospective cohort study of MCDA pregnancies with amniotic fluid discordance >= 4 cm. Serial ultrasound examinations consisted of evaluation of amniotic fluid, fetal Dopplers and fetal cardiac function.Results We included 21 "future-TTTS" (group I), 18 selective fetal growth restriction (sFGR; group II) and 20 uncomplicated MCDA twin pairs (group III). Group I had a higher intertwin difference in left ventricle (LV) MPI and right ventricle (RV) MPI compared to group II and III. The intertwin difference in global heart relaxation time was significantly higher in group I compared to group III. Future recipient twins had significantly higher relaxation times of the global heart and RV and lower contraction times of the global heart and RV compared to the "expected recipients" in group II and III.Conclusion Intertwin discordance in LV-MPI and RV-MPI differentiate between TTTS and MCDA pregnancies with transient discordant amniotic fluid volume. Cardiac time intervals identify future recipient twins. The clinical utility of cardiac time intervals and MPI should be investigated in large prospective studies.Research into fetal development and medicin

Temozolomide chemotherapy versus radiotherapy in high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study.

BACKGROUND: Outcome of low-grade glioma (WHO grade II) is highly variable, reflecting molecular heterogeneity of the disease. We compared two different, single-modality treatment strategies of standard radiotherapy versus primary temozolomide chemotherapy in patients with low-grade glioma, and assessed progression-free survival outcomes and identified predictive molecular factors. METHODS: For this randomised, open-label, phase 3 intergroup study (EORTC 22033-26033), undertaken in 78 clinical centres in 19 countries, we included patients aged 18 years or older who had a low-grade (WHO grade II) glioma (astrocytoma, oligoastrocytoma, or oligodendroglioma) with at least one high-risk feature (aged >40 years, progressive disease, tumour size >5 cm, tumour crossing the midline, or neurological symptoms), and without known HIV infection, chronic hepatitis B or C virus infection, or any condition that could interfere with oral drug administration. Eligible patients were randomly assigned (1:1) to receive either conformal radiotherapy (up to 50·4 Gy; 28 doses of 1·8 Gy once daily, 5 days per week for up to 6·5 weeks) or dose-dense oral temozolomide (75 mg/m(2) once daily for 21 days, repeated every 28 days [one cycle], for a maximum of 12 cycles). Random treatment allocation was done online by a minimisation technique with prospective stratification by institution, 1p deletion (absent vs present vs undetermined), contrast enhancement (yes vs no), age (<40 vs ≥40 years), and WHO performance status (0 vs ≥1). Patients, treating physicians, and researchers were aware of the assigned intervention. A planned analysis was done after 216 progression events occurred. Our primary clinical endpoint was progression-free survival, analysed by intention-to-treat; secondary outcomes were overall survival, adverse events, neurocognitive function (will be reported separately), health-related quality of life and neurological function (reported separately), and correlative analyses of progression-free survival by molecular markers (1p/19q co-deletion, MGMT promoter methylation status, and IDH1/IDH2 mutations). This trial is closed to accrual but continuing for follow-up, and is registered at the European Trials Registry, EudraCT 2004-002714-11, and at ClinicalTrials.gov, NCT00182819. FINDINGS: Between Sept 23, 2005, and March 26, 2010, 707 patients were registered for the study. Between Dec 6, 2005, and Dec 21, 2012, we randomly assigned 477 patients to receive either radiotherapy (n=240) or temozolomide chemotherapy (n=237). At a median follow-up of 48 months (IQR 31-56), median progression-free survival was 39 months (95% CI 35-44) in the temozolomide group and 46 months (40-56) in the radiotherapy group (unadjusted hazard ratio [HR] 1·16, 95% CI 0·9-1·5, p=0·22). Median overall survival has not been reached. Exploratory analyses in 318 molecularly-defined patients confirmed the significantly different prognosis for progression-free survival in the three recently defined molecular low-grade glioma subgroups (IDHmt, with or without 1p/19q co-deletion [IDHmt/codel], or IDH wild type [IDHwt]; p=0·013). Patients with IDHmt/non-codel tumours treated with radiotherapy had a longer progression-free survival than those treated with temozolomide (HR 1·86 [95% CI 1·21-2·87], log-rank p=0·0043), whereas there were no significant treatment-dependent differences in progression-free survival for patients with IDHmt/codel and IDHwt tumours. Grade 3-4 haematological adverse events occurred in 32 (14%) of 236 patients treated with temozolomide and in one (<1%) of 228 patients treated with radiotherapy, and grade 3-4 infections occurred in eight (3%) of 236 patients treated with temozolomide and in two (1%) of 228 patients treated with radiotherapy. Moderate to severe fatigue was recorded in eight (3%) patients in the radiotherapy group (grade 2) and 16 (7%) in the temozolomide group. 119 (25%) of all 477 patients had died at database lock. Four patients died due to treatment-related causes: two in the temozolomide group and two in the radiotherapy group. INTERPRETATION: Overall, there was no significant difference in progression-free survival in patients with low-grade glioma when treated with either radiotherapy alone or temozolomide chemotherapy alone. Further data maturation is needed for overall survival analyses and evaluation of the full predictive effects of different molecular subtypes for future individualised treatment choices. FUNDING: Merck Sharpe & Dohme-Merck & Co, Canadian Cancer Society, Swiss Cancer League, UK National Institutes of Health, Australian National Health and Medical Research Council, US National Cancer Institute, European Organisation for Research and Treatment of Cancer Cancer Research Fund

Randomised controlled trial of first-line tyrosine-kinase inhibitor (TKI) versus intercalated TKI with chemotherapy for EGFR-mutated nonsmall cell lung cancer

Introduction Previous studies have shown interference between epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and chemotherapy in the cell cycle, thus reducing efficacy. In this randomised controlled trial we investigated whether intercalated erlotinib with chemotherapy was superior compared to erlotinib alone in untreated advanced EGFR-mutated nonsmall cell lung cancer (NSCLC). Materials and methods Treatment-naïve patients with an activating EGFR mutation, ECOG performance score of 0–3 and adequate organ function were randomly assigned 1:1 to either four cycles of cisplatin-pemetrexed with intercalated erlotinib (day 2–16 out of 21 days per cycle) followed by pemetrexed and erlotinib maintenance (CPE) or erlotinib monotherapy. The primary end-point was progression-free survival (PFS). Secondary end-points were overall survival, objective response rate (ORR) and toxicity. Results Between April 2014 and September 2016, 22 patients were randomised equally into both arms; the study was stopped due to slow accrual. Median follow-up was 64 months. Median PFS was 13.7 months (95% CI 5.2–18.8) for CPE and 10.3 months (95% CI 7.1–15.5; hazard ratio (HR) 0.62, 95% CI 0.25–1.57) for erlotinib monotherapy; when compensating for number of days receiving erlotinib, PFS of the CPE arm was superior (HR 0.24, 95% CI 0.07–0.83; p=0.02). ORR was 64% for CPE versus 55% for erlotinib monotherapy. Median overall survival was 31.7 months (95% CI 21.8–61.9 months) for CPE compared to 17.2 months (95% CI 11.5–45.5 months) for erlotinib monotherapy (HR 0.58, 95% CI 0.22–1.41 months). Patients treated with CPE had higher rates of treatment-related fatigue, anorexia, weight loss and renal toxicity. Conclusion Intercalating erlotinib with cisplatin-pemetrexed provides a longer PFS compared to erlotinib alone in EGFR-mutated NSCLC at the expense of more toxicity

Non-IDH1-R132H IDH1/2 mutations are associated with increased DNA methylation and improved survival in astrocytomas, compared to IDH1-R132H mutations

Somatic mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 occur at high frequency in several tumour types. Even though these mutations are confined to distinct hotspots, we show that gliomas are the only tumour type with an exceptionally high percentage of IDH1(R132H) mutations. Patients harbouring IDH1(R132H) mutated tumours have lower levels of genome-wide DNA-methylation, and an associated increased gene expression, compared to tumours with other IDH1/2 mutations ("non-R132H IDH1/2 mutations"). This reduced methylation is seen in multiple tumour types and thus appears independent of the site of origin. For 1p/19q non-codeleted glioma (astrocytoma) patients, we show that this difference is clinically relevant: in samples of the randomised phase III CATNON trial, patients harbouring tumours with IDH mutations other than IDH1(R132H) have a better outcome (hazard ratio 0.41, 95% CI [0.24, 0.71], p = 0.0013). Such non-R132H IDH1/2-mutated tumours also had a significantly lower proportion of tumours assigned to prognostically poor DNA-methylation classes (p < 0.001). IDH mutation-type was independent in a multivariable model containing known clinical and molecular prognostic factors. To confirm these observations, we validated the prognostic effect of IDH mutation type on a large independent dataset. The observation that non-R132H IDH1/2-mutated astrocytomas have a more favourable prognosis than their IDH1(R132H) mutated counterpart indicates that not all IDH-mutations are identical. This difference is clinically relevant and should be taken into account for patient prognostication.MTG6Molecular tumour pathology - and tumour genetic

The value of echocardiography and Doppler in the prediction of fetal demise after laser coagulation for TTTS: A systematic review and meta‐analysis

Obstetric

Cardiac time intervals and myocardial performance index for prediction of twin‐twin transfusion syndrome

Objectives To explore whether intertwin discordance in myocardial performance index (MPI) or cardiac time intervals enables the prediction of twin-twin transfusion syndrome (TTTS) in monochorionic diamniotic (MCDA) pregnancies with amniotic fluid discordance.Methods Prospective cohort study of MCDA pregnancies with amniotic fluid discordance >= 4 cm. Serial ultrasound examinations consisted of evaluation of amniotic fluid, fetal Dopplers and fetal cardiac function.Results We included 21 "future-TTTS" (group I), 18 selective fetal growth restriction (sFGR; group II) and 20 uncomplicated MCDA twin pairs (group III). Group I had a higher intertwin difference in left ventricle (LV) MPI and right ventricle (RV) MPI compared to group II and III. The intertwin difference in global heart relaxation time was significantly higher in group I compared to group III. Future recipient twins had significantly higher relaxation times of the global heart and RV and lower contraction times of the global heart and RV compared to the "expected recipients" in group II and III.Conclusion Intertwin discordance in LV-MPI and RV-MPI differentiate between TTTS and MCDA pregnancies with transient discordant amniotic fluid volume. Cardiac time intervals identify future recipient twins. The clinical utility of cardiac time intervals and MPI should be investigated in large prospective studies.Research into fetal development and medicin

The value of echocardiography and Doppler in the prediction of fetal demise after laser coagulation for TTTS: A systematic review and meta-analysis

Obstetric

Early postnatal cardiac follow-up of survivors of twin-twin transfusion syndrome treated with fetoscopic laser coagulation

Research into fetal development and medicin

Perioperative fetal hemodynamic changes in twin-twin transfusion syndrome and neurodevelopmental outcome at two years of age

Research into fetal development and medicin

POCUS series: ultrasound during cardiopulmonary resuscitation

This article is part of the point-of-care ultrasound (POCUS) series. During cardiopulmonary resuscitation, bedside ultrasound has important clinical value for confirming a diagnosis, establishing a prognosis and in therapeutic decision-making. In this article we provide a practical review on how to implement and apply POCUS during cardiopulmonary resuscitation and discuss its merits and pitfalls.Perioperative Medicine: Efficacy, Safety and Outcome (Anesthesiology/Intensive Care