Molecular profiling of tumors of the brainstem by sequencing of CSF-derived circulating tumor DNA

Abstract

Brainstem gliomas are molecularly heterogeneous diseases, many of which are difficult to safely surgically resect and have limited treatment options due to their eloquent location. These constraints pose challenges to biopsy, which limits the use of routine molecular profiling and identification of personalized therapies. Here, we explored the potential of sequencing of circulating tumor DNA (ctDNA) isolated from the cerebrospinal fluid (CSF) of brainstem glioma patients as a less invasive approach for tumor molecular profiling. CSF was obtained from patients either intraoperatively (91.2%, 52/57), from ventricular-peritoneal shunt (3.5%, 2/57), or by lumbar puncture (5.3%, 3/57), all prior to surgical manipulation of the tumor. Deep sequencing of glioma-associated genes was performed on CSF-derived ctDNA and, where available, matched blood and tumor DNA from 57 patients, including nine medullary and 23 diffuse intrinsic pontine gliomas (DIPG). At least one tumor-specific mutation was detected in over 82.5% of CSF ctDNA samples (47/57). In cases with primary tumors harboring at least one mutation, alterations were identified in the CSF ctDNA of 97.3% of cases (36/37). In over 83% (31/37) of cases, all primary tumor alterations were detected in the CSF, and in 91.9% (34/37) of cases, at least half of the alterations were identified. Among ten patients found to have primary tumors negative for mutations, 30% (3/10) had detectable somatic alterations in the CSF. Finally, mutation detection using plasma ctDNA was less sensitive than sequencing the CSF ctDNA (38% vs. 100%, respectively). Our study indicates that deep sequencing of CSF ctDNA is a reliable technique for detecting tumor-specific alterations in brainstem tumors. This approach may offer an alternative approach to stereotactic biopsy for molecular profiling of brainstem tumors.

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Quantitative analysis of multi-element synergy stabilizing performance: comparison of three methods with respect to their use in clinical studies

Abstract

A number of analyses associated with the uncontrolled manifold (UCM) hypothesis have been used recently to investigate stability of actions across populations. We explored whether some of those methods have an advantage for clinical studies because they require fewer trials to achieve consistent findings. We compared the number of trials needed for the analysis of inter-trial variance, analysis of motor equivalence, and analysis in the space of referent coordinates. Young healthy adults performed four-finger accurate force production tasks under visual feedback with the right (dominant) and left hand over three days. Three methods [analytical (M1), experimental (M2), and cumulative mean (M3) methods] were used to define the minimal number of trials required to reach certain statistical criteria. Two of these methods, M1 and M2, showed qualitatively similar results. Fewer trials (M1: 5–13, M2: 4–10) were needed for analysis of motor equivalence compared to inter-trial variance analysis (M1: 14–24, M2: 10–14). The third method (M3) showed no major differences among the outcome variables. The index of synergy in the inter-trial variance analysis required a very small number of trials (M1, M2: 2–4). Variables related to referent coordinates required only a few trials (under 3), whereas the synergy index in this analysis required the largest number of trials (M1: 24–34, M2: 12–16). This is the first study to quantify the number of trials needed for UCM-based methods of assessing motor coordination broadly used in clinical studies. Clinical studies can take advantage of specific recommendations based on the current data regarding the number of trials needed for each analysis thus allowing minimizing the test session duration without compromising data reliability.

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Contents

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Editorial Board

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Evaluation of Surrogate End Points for Progression to ESKD: Necessary and Challenging

Chronic kidney disease (CKD) is recognized as a global health problem and is associated with significant morbidity and mortality, in particular, progression to kidney failure. There is a paucity of therapies to slow kidney disease progression.1 In part, this is because CKD often progresses slowly, requiring randomized controlled trials (RCTs) of long duration, or restricting enrollment to patients with rapidly progressive or more severe forms of the disease. The use of surrogate end points can increase the number of patients with events, thereby allowing for clinical studies of shorter duration or the enrollment of patients in early stages of CKD for whom therapeutic benefits may be larger.

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A Simple Case of Hyponatremia?

A 58-year-old man with a history of hypertension, hepatitis C virus infection previously treated with ledipasvir/sofosbuvir, and cirrhosis (MELD [Model for End Stage Liver Disease] score, 20) presented to an outside hospital with jaundice. His cirrhosis had been complicated by encephalopathy, and several years earlier, he underwent transarterial chemoembolization for hepatocellular carcinoma. He was found to have stigmata of advanced liver disease, including marked ascites and peripheral edema. Computed tomography showed a mass obstructing the biliary tree, and a biliary drain was placed.

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Masthead

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