Goal-directed fluid removal with furosemide versus placebo in intensive care patients with fluid overload: A randomised,blinded trial (GODIF trial—First version)

Background

Salt and water accumulation leading to fluid overload is associated with increased mortality in intensive care unit (ICU) patients, but diuretics' effects on patient outcomes are uncertain. In this first version of the GODIF trial, we aimed to assess the effects of goal-directed fluid removal with furosemide versus placebo in adult ICU patients with fluid overload.

Methods

We conducted a multicentre, randomised, stratified, parallel-group, blinded, placebo-controlled trial in clinically stable, adult ICU patients with at least 5% fluid overload. Participants were randomised to furosemide versus placebo infusion aiming at achieving neutral cumulative fluid balance as soon as possible. The primary outcome was the number of days alive and out of the hospital at 90 days.

Results

The trial was terminated after the enrolment of 41 of 1000 participants because clinicians had difficulties using cumulative fluid balance as the only estimate of fluid status (32% of participants had their initially registered cumulative fluid balance adjusted and 29% experienced one or more protocol violations). The baseline cumulative fluid balance was 6956 ml in the furosemide group and 6036 ml in the placebo group; on day three, the cumulative fluid balances were 1927 ml and 5139 ml. The median number of days alive and out of hospital at day 90 was 50 days in the furosemide group versus 45 days in the placebo group (mean difference 1 day, 95% CI -19 to 21, p-value .94).

Conclusions

The use of cumulative fluid balance as the only estimate of fluid status appeared too difficult to use in clinical practice. We were unable to provide precise estimates for any outcomes as only 4.1% of the planned sample size was randomised.     

Comprehensively evaluating cancer survival in children with birth defects: a population-based assessment

Cancer Causes & Control - Congenital malformations are strong risk factors for childhood cancer. Our objective was to determine whether cancer survival differs by birth defect status among...     

Pneumococcal meningitis before the introduction of 10-valent pneumococcal conjugate vaccine into the National Childhood Immunization Program in Poland

Background

Poland introduced the 10-valent conjugate pneumococcal vaccine (PCV10) into the childhood immunization program in January 2017. During previous decades, considerable changes had occurred in the surveillance system for invasive pneumococcal disease. Therefore, to provide baseline data on pneumococcal diseases before PCV10 introduction, we evaluated the epidemiology of pneumococcal meningitis (PM), the only syndrome monitored consistently since 1970.

Perinatal and familial risk factors for soft tissue sarcomas in childhood through young adulthood: A population-based assessment in 4 million live births

Perinatal factors have been associated with soft tissue sarcomas (STS) in case-control studies. However, (i) the contributions of factors including fetal growth remain unknown, ( ii ) these factors have not been examined in cohort studies and (iii) few assessments have evaluated risk in specific STS subtypes. We sought to identify the role of perinatal and familial factors on the risk of STS in a large population-based birth cohort. We identified 4,023,436 individuals in the Swedish Birth Registry born during 1973–2012. Subjects were linked to the Swedish Cancer Registry, where incident STS cases were identified. We evaluated perinatal and familial factors obtained from Statistics Sweden, including fetal growth, gestational age, and presence of a congenital malformation. Poisson regression was used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for associations between perinatal factors and STS overall, as well as by common subtypes. There were 673 individuals diagnosed with STS in 77.5 million person-years of follow-up. Having a congenital malformation was associated with STS (IRR = 1.70, 95% CI: 1.23–2.35). This association was stronger (IRR = 2.90, 95% CI: 1.25–6.71) in recent years (2000–2012). Low fetal growth was also associated with STS during the same time period (IRR = 1.86, 95% CI: 1.05–3.29). Being born preterm was associated with rhabdomyosarcoma (IRR = 1.74, 95% CI: 1.08–2.79). In our cohort study, those with congenital malformations and other adverse birth outcomes were more likely to develop a STS compared to their unaffected contemporaries. These associations may point to disrupted developmental pathways and genetic factors influencing the risk of STS.     

Phase I study of lapatinib plus trametinib in patients with KRAS -mutant colorectal,non-small cell lung,and pancreatic cancer

KRAS oncogene mutations cause sustained signaling through the MAPK pathway. Concurrent inhibition of MEK, EGFR, and HER2 resulted in complete inhibition of tumor growth in KRAS-mutant (KRASm) and PIK3CA wild-type tumors, in vitro and in vivo. In this phase I study, patients with advanced KRASm and PIK3CA wild-type colorectal cancer (CRC), non-small cell lung cancer (NSCLC), and pancreatic cancer, were treated with combined lapatinib and trametinib to assess the recommended phase 2 regimen (RP2R). Patients received escalating doses of continuous or intermittent once daily (QD) orally administered lapatinib and trametinib, starting at 750 mg and 1 mg continuously, respectively. Thirty-four patients (16 CRC, 15 NSCLC, three pancreatic cancers) were enrolled across six dose levels and eight patients experienced dose-limiting toxicities, including grade 3 diarrhea (n = 2), rash (n = 2), nausea (n = 1), multiple grade 2 toxicities (n = 1), and aspartate aminotransferase elevation (n = 1), resulting in the inability to receive 75% of planned doses (n = 2) or treatment delay (n = 2). The RP2R with continuous dosing was 750 mg lapatinib QD plus 1 mg trametinib QD and with intermittent dosing 750 mg lapatinib QD and trametinib 1.5 mg QD 5 days on/2 days off. Regression of target lesions was seen in 6 of the 24 patients evaluable for response, with one confirmed partial response in NSCLC. Pharmacokinetic results were as expected. Lapatinib and trametinib could be combined in an intermittent dosing schedule in patients with manageable toxicity. Preliminary signs of anti-tumor activity in NSCLC have been observed and pharmacodynamic target engagement was demonstrated.     

剪切波成像对乳腺BI-RADS 4类肿块分类影响的研究

目的:探讨剪切波成像（shear wave elastography，SWE）对乳腺BI-RADS 4类肿块分类影响。方法:收集2017年9月至2019 年3月就诊于我院肿瘤科且常规超声定为BI-RADS 4类的乳腺肿瘤患者139例，共 157个病灶，在手术或穿刺活检前均进行SWE检查，以病理结果作为金标准，评估常规超声及SWE对乳腺肿块诊断的敏感度、特异度和准确性。结果:常规超声诊断4a类73个，4b类35个，4c类49个，常规超声诊断乳腺肿块的敏感性86.1%，特异性74.1%，准确性76.9%；SWE参数最大杨氏模量值（Emax）诊断乳腺良恶性病灶的临界值为94.15 kPa，以该值为诊断良恶性肿块的依据，SWE校正BI-RADS分类后诊断的敏感性87.5%，特异性90.6%，准确性90.4%。结论:SWE通过硬度信息评估，在常规超声的基础上矫正BI-RADS 4类肿块的亚分类，降低了误诊率，提高了诊断的准确性，有一定临床应用价值。     

miR-145调控肝癌腹水模型Th9细胞升高的机制研究

目的:探讨miR-145调控肝癌腹水模型Th9细胞升高的作用机制。方法:构建小鼠H22肝癌腹水模型。造模两周后处死小鼠并分离出脾脏组织，流式细胞术分析肝癌腹水组（MA组）与正常对照组（Control 组）小鼠脾脏Th9细胞表达水平。ELISA法检测脾脏IL-9表达水平。RT-PCR法检测脾脏miR-145表达水平。Western Blot法检测脾脏中PI3K/Akt/mTOR/P70S6K/HIF-1α相关蛋白表达水平。分选小鼠脾脏CD4+T细胞，随机分为miR-145 mimics组和NC组，分别应用miR-145-5P mimics、阴性对照寡核苷酸（negative control，NC）进行转染，RT-PCR检测各组miR-145、HIF-1α mRNA及IL-9 mRNA表达水平。结果:与Control 组相比，MA组Th9细胞及其细胞因子IL-9表达均升高（P<0.05），miR-145表达降低（P<0.05），p-PI3K、p-Akt、mTOR、p-mTOR、p-P70S6K、HIF-1α蛋白均升高（P<0.05）。与NC组相比，miR-145 mimics组miR-145显著升高，HIF-1α mRNA及IL-9 mRNA表达下降。结论:肝癌腹水中Th9细胞升高可能与miR-145下降导致的PI3K/Akt/mTOR/P70S6K/HIF-1α通路激活有关。     

Executive summary from American Radium Society’s appropriate use criteria on neurocognition after stereotactic radiosurgery for multiple brain metastases

BackgroundThe American Radium Society (ARS) Appropriate Use Criteria brain malignancies panel systematically reviewed (PRISMA [Preferred Reporting Items for Systematic Reviews and Meta-Analyses]) published literature on neurocognitive outcomes after stereotactic radiosurgery (SRS) for patients with multiple brain metastases (BM) to generate consensus guidelines.MethodsThe panel developed 4 key questions (KQs) to guide systematic review. From 11 614 original articles, 12 were selected. The panel developed model cases addressing KQs and potentially controversial scenarios not addressed in the systematic review (which might inform future ARS projects). Based upon quality of evidence, the panel confidentially voted on treatment options using a 9-point scale of appropriateness.ResultsThe panel agreed that SRS alone is usually appropriate for those with good performance status and 2–10 asymptomatic BM, and usually not appropriate for >20 BM. For 11–15 and 16–20 BM there was (between 2 case variants) agreement that SRS alone may be appropriate or disagreement on the appropriateness of SRS alone. There was no scenario (among 6 case variants) in which conventional whole-brain radiotherapy (WBRT) was considered usually appropriate by most panelists. There were several areas of disagreement, including: hippocampal sparing WBRT for 2–4 asymptomatic BM; WBRT for resected BM amenable to SRS; fractionated versus single-fraction SRS for resected BM, larger targets, and/or brainstem metastases; optimal treatment (WBRT, hippocampal sparing WBRT, SRS alone to all or select lesions) for patients with progressive extracranial disease, poor performance status, and no systemic options.ConclusionsFor patients with 2–10 BM, SRS alone is an appropriate treatment option for well-selected patients with good performance status. Future study is needed for those scenarios in which there was disagreement among panelists.