Perinatal and 2-year neurodevelopmental outcome in late preterm fetal compromise: the TRUFFLE 2 randomised trial protocol

Introduction: Following the detection of fetal growth restriction, there is no consensus about the criteria that should trigger delivery in the late preterm period. The consequences of inappropriate early or late delivery are potentially important yet practice varies widely around the world, with abnormal findings from fetal heart rate monitoring invariably leading to delivery. Indices derived from fetal cerebral Doppler examination may guide such decisions although there are few studies in this area. We propose a randomised, controlled trial to establish the optimum method of timing delivery between 32 weeks and 36 weeks 6 days of gestation. We hypothesise that delivery on evidence of cerebral blood flow redistribution reduces a composite of perinatal poor outcome, death and short-term hypoxia-related morbidity, with no worsening of neurodevelopmental outcome at 2 years. Methods and analysis: Women with non-anomalous singleton pregnancies 32+0 to 36+6 weeks of gestation in whom the estimated fetal weight or abdominal circumference is <10th percentile or has decreased by 50 percentiles since 18-32 weeks will be included for observational data collection. Participants will be randomised if cerebral blood flow redistribution is identified, based on umbilical to middle cerebral artery pulsatility index ratio values. Computerised cardiotocography (cCTG) must show normal fetal heart rate short term variation (≥4.5 msec) and absence of decelerations at randomisation. Randomisation will be 1:1 to immediate delivery or delayed delivery (based on cCTG abnormalities or other worsening fetal condition). The primary outcome is poor condition at birth and/or fetal or neonatal death and/or major neonatal morbidity, the secondary non-inferiority outcome is 2-year infant general health and neurodevelopmental outcome based on the Parent Report of Children's Abilities-Revised questionnaire. Ethics and dissemination: The Study Coordination Centre has obtained approval from London-Riverside Research Ethics Committee (REC) and Health Regulatory Authority (HRA). Publication will be in line with NIHR Open Access policy. Trial registration number: Main sponsor: Imperial College London, Reference: 19QC5491. Funders: NIHR HTA, Reference: 127 976. Study coordination centre: Imperial College Healthcare NHS Trust, Du Cane Road, London, W12 0HS with Centre for Trials Research, College of Biomedical & Life Sciences, Cardiff University. IRAS Project ID: 266 400. REC reference: 20/LO/0031. ISRCTN registry: 76 016 200

Safety of COVID-19 Vaccine in Patients with Cancer in a High-Volume Comprehensive Cancer Center

Background Few data are available on the safety of COVID-19 vaccines in cancer patients undergoing active cancer-directed treatment. Patients and Methods This case series analyzes outcomes in terms of adverse events in 5297 patients undergoing anti-cancer treatment who were vaccinated with anti-SARS-CoV-2 Pfizer-BioNTech vaccine at a single cancer center from March 6, 2021 to May 9, 2021. Adverse events were retrieved from the national Italian pharmacovigilance platform (http://www.vigicovid.it). Results Of the 5297 patients treated for either solid tumors (87%) or onco-hematologic malignancies (13%) who were vaccinated, 8 adverse drug reactions (ADRs) were reported. One was a severe ADR and 7 were non-severe ADRs. Non-severe ADRs resolved within 48 hours. Conclusion BNT162b2 Pfizer-BioNTech vaccine was safely administered in the largest cohort of cancer patients reported to date

First‐line cetuximab + platinum‐based therapy for recurrent/metastatic head and neck squamous cell carcinoma: A real‐world observational study—ENCORE

Abstract Background ENCORE, an observational, prospective, open‐label study, investigated real‐world treatment practices and outcomes with cetuximab plus platinum‐based therapy (PBT) in first‐line (1L) recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). Aims This multinational study aimed to investigate the long‐term use of cetuximab plus PBT for 1L R/M SCCHN in a clinical setting. In particular, this study aimed to explore clinical considerations such as the decision to prescribe cetuximab plus PBT in R/M SCCHN, the mode and duration of treatment, and patient outcomes. Methods and Results Previously untreated patients with R/M SCCHN whose planned treatment was cetuximab plus PBT were enrolled from 6 countries. Among 221 evaluable patients, planned treatments included cetuximab plus carboplatin (31.2%), cisplatin plus 5‐fluorouracil (31.7%), or carboplatin plus 5‐fluorouracil (23.1%); 3.2% included a taxane, and 45.2% did not include 5‐fluorouracil. Cetuximab treatment was planned for a fixed duration (≤24 weeks) in 15 patients (6.8%) and until disease progression in 206 (93.2%). Median progression‐free survival and overall survival were 6.5 and 10.8 months, respectively. Grade ≥3 adverse events occurred in 39.8% of patients. Serious adverse events occurred in 25.8% of patients; 5.4% were cetuximab‐related. Conclusion In patients with R/M SCCHN, first‐line cetuximab plus PBT was feasible and modifiable in a real‐world setting with similar toxicity and efficacy as in the pivotal phase III EXTREME trial. Clinical trial registration number: EMR 062202‐566

Association of a gene-expression subtype to outcome and treatment response in patients with recurrent/metastatic head and neck squamous cell carcinoma treated with nivolumab

Background Immune checkpoint inhibitors have been approved and currently used in the clinical management of recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC) patients. The reported benefit in clinical trials is variable and heterogeneous. Our study aims at exploring and comparing the predictive role of gene-expression signatures with classical biomarkers for immunotherapy-treated R/M HNSCC patients in a multicentric phase IIIb trial.Methods Clinical data were prospectively collected in Nivactor tiral (single-arm, open-label, multicenter, phase IIIb clinical trial in platinum-refractory HNSCC treated with nivolumab). Findings were validated in an external independent cohort of immune-treated HNSCC patients, divided in long-term and short-term survivors (overall survival >18 and <6 months since the start of immunotherapy, respectively). Pretreatment tumor tissue specimen from immunotherapy-treated R/M HNSCC patients was used for PD-L1 (Tumor Proportion Score; Combined Positive Score (CPS)) and Tumor Mutational Burden (Oncopanel TSO500) evaluation and gene expression profiling; classical biomarkers and immune signatures (retrieved from literature) were challenged in the NIVACTOR dataset.Results Cluster-6 (Cl6) stratification of NIVACTOR cases in high score (n=16, 20%) and low score (n=64, 80%) demonstrated a statistically significant and clinically meaningful improvement in overall survival in the high-score cases (p=0.00028; HR=4.34, 95% CI 1.84 to 10.22) and discriminative ability reached area under the curve (AUC)=0.785 (95% CI 0.603 to 0.967). The association of high-score Cl6 with better outcome was also confirmed in: (1) NIVACTOR progression-free survival (p=4.93E-05; HR=3.71, 95% CI 1.92 to 7.18) and objective-response-rate (AUC=0.785; 95% CI 0.603 to 0.967); (2) long survivors versus short survivors (p=0.00544). In multivariate Cox regression analysis, Cl6 was independent from Eastern Cooperative Oncology Group performance status, PDL1-CPS, and primary tumor site.Conclusions These data highlight the presence of underlying biological differences able to predict survival and response following treatment with immunotherapy in platinum-refractory R/M HNSCC that could have translational implications improving treatment selection.Trial registration number EudraCT Number: 2017-000562-30

MATERNAL HEMODYNAMICS FROM PRECONCEPTION TO DELIVERY: RESEARCH, POTENTIAL DIAGNOSTIC AND THERAPEUTIC IMPLICATIONS Position statement by Italian Association of Pre-Eclampsia and Italian Society of Perinatal Medicine

Objective: The Italian Association of Preeclampsia (AIPE) and of the Italian Society of Perinatal Medicine (SIMP) developed clinical questions on Maternal Hemodynamics state of the art. Study design: AIPE and SIMP Experts were divided in small groups and were invited to propose an overview of the existing literature on specific topics related to the clinical questions proposed, developing, wherever possible, clinical and/or research recommendations based on available evidence, expert opinion, and clinical importance. Draft recommendations with a clinical rationale were submitted to 8 AIPE and SIMP Consensus Expert Panel for consideration and approval, with at least 75% agreement required for individual recommendations to be included in the final version. Results: More and more evidence in literature underlines the relationship between maternal and fetal hemodynamics, as well as the relationship between maternal cardiovascular profile and fetal-maternal adverse outcomes such as fetal growth restriction and hypertensive disorders of pregnancy. Experts agreed on proposing a classification of pregnancy hypertension, complications and cardiovascular states based on three different hemodynamic profiles depending on Total Peripheral Vascular Resistance values: hypodynamic (>1300 dynes·s·cm-5), normo-dynamic and hyperdynamic (<800 dynes·s·cm-5) circulation. This differentiation implies different therapeutical strategies, based drugs characteristics and maternal cardiovascular profile. Finally, the cardiovascular characteristics of the women may be useful for a rational approach to an appropriate follow up, due to the increased cardiovascular risk later in life. Conclusions: Although the evidences might not be conclusive, given the lack of large randomized trials, maternal hemodynamics might have great importance in helping Clinicians in understanding the pathophysiology and chose a rational treatment of patients with or at risk for pregnancy complications