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.     

Targeting MYC-driven replication stress in medulloblastoma with AZD1775 and gemcitabine

Journal of Neuro-Oncology - MYC-driven medulloblastomas are highly aggressive childhood tumors with dismal outcomes and a lack of new treatment paradigms. We identified that targeting replication...     

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.     

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.     

Economic impacts of care by high-volume providers for non-curative esophagogastric cancer: a population-based analysis

Gastric Cancer - Esophagogastric cancer (EGC) is one of the deadliest and costliest malignancies to treat. Care by high-volume providers can provide better outcomes for patients with EGC. Cost...     

The Added Value of SARC-F to Prescreening Using FRAX for Hip Fracture Prevention in Older Community Adults

Objectives

To examine the potential added value of a simple 5-item questionnaire for sarcopenia screening (SARC-F) to the Fracture Risk Assessment Tool (FRAX) for hip fracture risk prediction, in order to identify at-risk older adults for screening with dual-energy x-ray absorptiometry (DXA).