No drug holidays in BRAFV600E glioma patients: An argument for dose reduction of targeted therapies.

Background: Combined BRAF and MEK inhibition is effective for some BRAFV600E-altered gliomas, a cancer for which there are few effective therapies. While recent clinical trials demonstrate objective response rates of 30%-40%, tolerable adverse event rates are 70%-90%, and 12%-15% of patients stop therapy for toxicity. There are no clear guidelines regarding the timing and reinitiation of BRAF-targeted therapies following drug holidays. Here, we describe 4 patients with rapid disease progression during periods of treatment interruption. All patients experienced a response upon resumption of targeted therapy. Methods: This is a multi-institutional, retrospective review of 4 patients. Results: Three patients were diagnosed with BRAFV600E mutated anaplastic pleomorphic xanthoastrocytoma (aPXA) and 1 with epithelioid glioblastoma. The age range was 32 to 46; 3 patients were female and one patient was male. All patients were initially treated with radiation and were subsequently treated with BRAF/MEK inhibitors after disease progression. All patients with aPXA required the targeted therapy to be held due to toxicity and 1 patient held the therapy prior to transitioning to a novel BRAF-targeted agent. All patients were restarted on BRAF/MEK inhibitors after a drug holiday. Three patients required a dose reduction and all improved clinically following reinitiation. Conclusions: Clinical and radiographic progression may occur rapidly upon holding BRAF-targeted therapy, warranting judicious dose reductions and minimization of drug holidays.

Absence of Cerebrospinal Fluid Pleocytosis in Encephalitis.

BACKGROUND: Early diagnosis of encephalitis involves identifying signs of neuroinflammation, including cerebrospinal fluid (CSF) pleocytosis. However, absence of CSF pleocytosis in encephalitis has been described, most notably in autoimmune encephalitis. We examined clinical characteristics and outcomes associated with the absence or presence of CSF white blood cell pleocytosis (≥ 5 cells/µL), to inform timely diagnosis and management of encephalitis. METHODS: This retrospective study compares initial CSF profiles in 597 adult patients with all-cause encephalitis. RESULTS: Of the 597 patients, 446 (74.7%) had CSF pleocytosis while 151 (25.3%) did not. CSF pleocytosis occurred more commonly in infectious cases (200/446, 44.8%), along with 59 (13.2%) autoimmune cases, comprised chiefly of anti-NMDAR encephalitis (37/59, 62.7%). Notably, the group without pleocytosis was comprised of similar proportions of infectious (47/151, 31.1%) and autoimmune (38/151, 25.92%; p>0.05) encephalitis. Among those with infectious encephalitis, 47/247 (19%) had absent pleocytosis, including 18/76 (23.7%) with HSV-1 encephalitis. The absence of pleocytosis was associated with a decreased rate of acyclovir administration (47.7% in patients without pleocytosis vs. 71.1% in patients with pleocytosis, p<0.001). Despite pleocytosis being associated with some measures of clinical severity at admission such as a Full Outline of UnResponsiveness (FOUR) score ≤14, it was not associated with mortality or prolonged hospitalization. CONCLUSION: CSF pleocytosis is an important criterion for encephalitis diagnosis, but 25.3% of patients with all-cause encephalitis and 23.7% of those with HSV-1 encephalitis exhibit absence of pleocytosis on initial LP. Acyclovir initiation should not be delayed in the absence of pleocytosis in patients with suspected encephalitis.

Prevalence and Neurological Outcomes of Comatose Patients With Extracorporeal Membrane Oxygenation.

OBJECTIVES: To investigate prevalence, risk factors, and in-hospital outcomes of comatose extracorporeal membrane oxygenation (ECMO) patients. DESIGN: Retrospective observational. SETTING: Tertiary academic hospital. PARTICIPANTS: Adults received venoarterial (VA) or venovenous (VV) ECMO support between November 2017 and April 022. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We defined 24-hour off sedation as no sedative infusion (except dexmedetomidine) or paralytics administration over a continuous 24-hour period while on ECMO. Off-sedation coma (comaoff) was defined as a Glasgow Coma Scale score of ≤8 after achieving 24-hour off sedation. On-sedation coma (comaon) was defined as a Glasgow Coma Scale score of ≤8 during the entire ECMO course without off sedation for 24 hours. Neurological outcomes were assessed at discharge using the modified Rankin scale (good, 0-3; poor, 4-6). We included 230 patients (VA-ECMO 143, 65% male); 24-hour off sedation was achieved in 32.2% VA-ECMO and 26.4% VV-ECMO patients. Among all patients off sedation for 24 hours (n = 69), 56.5% VA-ECMO and 52.2% VV-ECMO patients experienced comaoff. Among those unable to be sedation free for 24 hours (n = 161), 50.5% VA-ECMO and 17.2% VV-ECMO had comaon. Comaoff was associated with poor outcomes (p < 0.05) in VA-ECMO and VV-ECMO groups, whereas comaon only impacted the VA-ECMO group outcomes. In a multivariable analysis, requirement of renal replacement therapy was an independent risk factor for comaoff after adjusting for ECMO configuration, after adjusting for ECMO configuration, acute brain injury, pre-ECMO partial pressure of oxygen in arterial blood, partial pressure of carbon dioxide in arterial blood, pH, and bicarbonate level (worst value within 24 hours before cannulation). CONCLUSIONS: Comaoff was common and associated with poor outcomes at discharge. Requirement of renal replacement therapy was an independent risk factor.

Plasma biomarkers for brain injury in extracorporeal membrane oxygenation.

Extracorporeal membrane oxygenation (ECMO) is a life-saving intervention for patients with refractory cardiorespiratory failure. Despite its benefits, ECMO carries a significant risk of neurological complications, including acute brain injury (ABI). Although standardized neuromonitoring and neurological care have been shown to improve early detection of ABI, the inability to perform neuroimaging in a timely manner is a major limitation in the accurate diagnosis of neurological complications. Therefore, blood-based biomarkers capable of detecting ongoing brain injury at the bedside are of great clinical significance. This review aims to provide a concise review of the current literature on plasma biomarkers for ABI in patients on ECMO support.

Large-scale contractions of Friedreich's ataxia GAA repeats in yeast occur during DNA replication due to their triplex-forming ability.

Friedreich's ataxia (FRDA) is a human hereditary disease caused by the presence of expanded (GAA)n repeats in the first intron of the FXN gene [V. Campuzano et al., Science 271, 1423-1427 (1996)]. In somatic tissues of FRDA patients, (GAA)n repeat tracts are highly unstable, with contractions more common than expansions [R. Sharma et al., Hum. Mol. Genet. 11, 2175-2187 (2002)]. Here we describe an experimental system to characterize GAA repeat contractions in yeast and to conduct a genetic analysis of this process. We found that large-scale contraction is a one-step process, resulting in a median loss of ∼60 triplet repeats. Our genetic analysis revealed that contractions occur during DNA replication, rather than by various DNA repair pathways. Repeats contract in the course of lagging-strand synthesis: The processivity subunit of DNA polymerase δ, Pol32, and the catalytic domain of Rev1, a translesion polymerase, act together in the same pathway to counteract contractions. Accumulation of single-stranded DNA (ssDNA) in the lagging-strand template greatly increases the probability that (GAA)n repeats contract, which in turn promotes repeat instability in rfa1, rad27, and dna2 mutants. Finally, by comparing contraction rates for homopurine-homopyrimidine repeats differing in their mirror symmetry, we found that contractions depend on a repeat's triplex-forming ability. We propose that accumulation of ssDNA in the lagging-strand template fosters the formation of a triplex between the nascent and fold-back template strands of the repeat. Occasional jumps of DNA polymerase through this triplex hurdle, result in repeat contractions in the nascent lagging strand.