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e15118 Background: Melanoma, non-small cell lung cancer (NSCLC), colorectal adenocarcinoma and thyroid tumors frequently harbor BRAF mutations and are tumor types eligible for treatment with FDA-approved BRAF inhibitors. Although there are many ongoing clinical trials with BRAF inhibitors in various advanced tumor types, currently eligibility requires both tumor type identification and BRAF mutation confirmation. The 92-gene assay (CancerTYPE ID) is a gene expression-based classifier of 50 tumor types and subtypes for metastatic patients with diagnostic ambiguity. Multimodal biomarker testing, including NGS, IHC and FISH, enables identification of actionable biomarkers to guide targeted therapy selection. Here, a database of metastatic cases integrating tumor type with biomarker analysis was used to identify patients eligible for BRAF inhibitor treatment. Methods: MOSAIC (Molecular Synergy to Advance Individualized Cancer Care) is an IRB-approved, de-identified database of diagnostically ambiguous cases submitted for CancerTYPE ID testing with tumor type-guided multimodal biomarker testing (Neogenomics). In this study, metastatic cancers of various tumor types with BRAF mutations were identified. Results: CancerTYPE ID determined 27 different tumor types in 2929 (92.5%) of 3168 cases. BRAF mutations were identified in 87 cases across 18 tumor types and subtypes. Out of the 87 cases, 22 (25.3%) had BRAF mutations in a tumor type eligible for FDA-approved BRAF inhibitor treatment, including melanoma, NSCLC, colorectal adenocarcinoma and thyroid cancer. Another 26 (29.9%) BRAF-mutated cases were detected in a tumor type with ongoing BRAF inhibitor clinical trials, including lymphoma, pancreaticobiliary and ovarian cancer (Table). Conclusions: This analysis identified patients with metastatic cancer with actionable BRAF mutations eligible for FDA-approved therapy, and patients who may be eligible for investigational BRAF inhibitors based on tumor type and mutation status. Notably, cancer type identification is critical given that FDA-approved BRAF inhibitor treatment regimens vary based on the tumor-specific indication. These findings support the clinical utility of molecular tumor type classification by CancerTYPE ID combined with biomarker profiling to identify additional treatment options for patients with metastatic cancer.[Table: see text]

Abstract Cellular senescence contributes to tissue homeostasis and age-related pathologies. However, how senescence is initiated in damaged cells remains vague. Here, we discover that irreparable stresses induce transient biogenesis of cilia, which are used by stressed cells to directly communicate with the promyelocytic leukemia nuclear bodies (PML-NBs), the validated stress signaling hub, to initiate senescence responses. Mechanistically, a ciliary ARL13B-ARL3 GTPase cascade negatively regulates the association of transition fiber protein FBF1 and SUMO-conjugating enzyme UBC9. Irreparable stresses downregulate the ciliary ARLs to release UBC9, which SUMOylates FBF1 at the ciliary base. SUMOylated FBF1 then translocates to PML-NBs to promote PML-NB-dependent senescence initiation. Remarkably, Fbf1 suppression effectively subdues global senescence burden and prevents associated health-span decline in irradiation-treated mice. Collectively, our findings assign primary cilia a central role in inducing senescence program and identify them as promising targets to dampen senescence-associated detrimental damage in future senotherapy strategies.

Importance The rise of novel, more infectious SARS-CoV-2 variants has made clear the need to rapidly deploy large-scale testing for COVID-19 to protect public health. However, testing remains limited due to shortages of personal protective equipment (PPE), naso- and oropharyngeal swabs, and healthcare workers. Simple test methods are needed to enhance COVID-19 screening. Here, we describe a simple, and inexpensive spit-test for COVID-19 screening called Patient Self-Collection of Sample-CoV2 (PSCS-CoV2). Objective To evaluate an affordable and convenient test for COVID-19. Methods The collection method relies on deep throat sputum (DTS) self-collected by the subject without the use of swabs, and was hence termed the Self-Collection of Sample for SARS-CoV-2 (abbreviated PSCS-CoV2). We used a phenol-chloroform extraction method for the viral RNA. We then tested for SARS-CoV-2 using real-time reverse transcription polymerase chain reaction with primers against at least two coding regions of the viral nucleocapsid protein (N1 and N2 or E) of SARS-CoV-2. We evaluted the sensitivity and specificity of our protocol. In addition we assess the limit of detection, and efficacy of our Viral Inactivating Solution. We also evaluated our protocol, and pooling strategy from volunteers on a local college campus. Results We show that the PSCS-CoV2 method accurately identified 42 confirmed COVID-19 positives, which were confirmed through the nasopharyngeal swabbing method of an FDA approved testing facility. For samples negative for COVID-19, we show that the cycle threshold for N1, N2, and RP are similar between the PSCS-CoV2 and nasopharynx swab collection method (n = 30). We found a sensitivity of 100% (95% Confidence Interval [CI], 92-100) and specifity of 100% (95% CI, 89-100) for our PSCS-CoV2 method. We determined our protocol has a limit of detection of 1/10,000 for DTS from a COVID-19 patient. In addition, we show field data of the PSCS-CoV2 method on a college campus. Ten of the twelve volunteers (N1 < 30) that we tested as positive were subsequently tested positive by an independent laboratory. Finally, we show proof of concept of a pooling strategy to test for COVID-19, and recommend pool sizes of four if the positivity rate is less than 15%. Conclusion and Relevance We developed a DTS-based protocol for COVID-19 testing with high sensitivity and specificity. This protocol can be used by non-debilitated adults without the assistance of another adult, or by non-debilitated children with the assistance of a parent or guardian. We also discuss pooling strategies based on estimated positivity rates to help conserve resources, time, and increase throughput. The PSCS-CoV2 method can be a key component of community-wide efforts to slow the spread of COVID-19.

Abstract Early implantable epilepsy therapy devices provided open-loop electrical stimulation without brain sensing, computing, or an interface for synchronized behavioural inputs from patients. Recent epilepsy stimulation devices provide brain sensing but have not yet developed analytics for accurately tracking and quantifying behaviour and seizures. Here we describe a distributed brain co-processor providing an intuitive bi-directional interface between patient, implanted neural stimulation and sensing device, and local and distributed computing resources. Automated analysis of continuous streaming electrophysiology is synchronized with patient reports using a handheld device and integrated with distributed cloud computing resources for quantifying seizures, interictal epileptiform spikes and patient symptoms during therapeutic electrical brain stimulation. The classification algorithms for interictal epileptiform spikes and seizures were developed and parameterized using long-term ambulatory data from nine humans and eight canines with epilepsy, and then implemented prospectively in out-of-sample testing in two pet canines and four humans with drug-resistant epilepsy living in their natural environments. Accurate seizure diaries are needed as the primary clinical outcome measure of epilepsy therapy and to guide brain-stimulation optimization. The brain co-processor system described here enables tracking interictal epileptiform spikes, seizures and correlation with patient behavioural reports. In the future, correlation of spikes and seizures with behaviour will allow more detailed investigation of the clinical impact of spikes and seizures on patients.

AbstractOraxol consists of an oral dosage form of the chemotherapeutic agent paclitaxel administered with a novel P‐glycoprotein inhibitor encequidar methanesulfonate monohydrate (formerly named HM30181A), which allows oral treatment of cancers that would otherwise be treated with intravenous paclitaxel. Here we describe the population pharmacokinetics (popPK) analyses for oral paclitaxel in patients with advanced/metastatic solid tumors to characterize pharmacokinetic (PK) profiles and quantify sources of PK variability. The best fit popPK model for oral paclitaxel, based on data from seven clinical studies (197 patients with advanced/metastatic solid tumors), involves a linear two‐compartment structural model containing first‐order absorption with a short lag time and first‐order elimination as well as a log additive error. In this popPK model, lower population estimates of central volume for Asian patients versus Caucasian patients did not translate into clinical meaningful differences in oral paclitaxel exposure. Age, sex, body weight or surface area, mild hepatic impairment, and mild to moderate renal impairment had no clinically meaningful effects on the systemic exposure of oral paclitaxel. Simulations were performed on clinical therapeutic dose (oral paclitaxel 205 mg/m2 once daily ×3 days per week) to predict exposure of oral paclitaxel and to support treatment benefits observed in a pivotal phase III trial.

Background: Cranial dural arteriovenous fistulas with cortical venous drainage are rare lesions that can present with hemorrhage. A high rate of rebleeding in the early period following hemorrhage has been reported, but published long-term rates are much lower. No study has examined how risk of rebleeding changes over time. Our objective was to quantify the relative incidence of rebleeding in the early and later periods following hemorrhage. Methods: Patients with dural arteriovenous fistula and cortical venous drainage presenting with hemorrhage were identified from the multinational CONDOR (Consortium for Dural Fistula Outcomes Research) database. Natural history follow-up was defined as time from hemorrhage to first treatment, rebleed, or last follow-up. Rebleeding in the first 2 weeks and first year were compared using incidence rate ratio and difference. Results: Of 1077 patients, 250 met the inclusion criteria and had 95 cumulative person-years natural history follow-up. The overall annualized rebleed rate was 7.3% (95% CI, 3.2–14.5). The incidence rate of rebleeding in the first 2 weeks was 0.0011 per person-day; an early rebleed risk of 1.6% in the first 14 days (95% CI, 0.3–5.1). For the remainder of the first year, the incidence rate was 0.00015 per person-day; a rebleed rate of 5.3% (CI, 1.7–12.4) over 1 year. The incidence rate ratio was 7.3 (95% CI, 1.4–37.7; P , 0.026). Conclusions: The risk of rebleeding of a dural arteriovenous fistula with cortical venous drainage presenting with hemorrhage is increased in the first 2 weeks justifying early treatment. However, the magnitude of this increase may be considerably lower than previously thought. Treatment within 5 days was associated with a low rate of rebleeding and appears an appropriate timeframe.

OBJECTIVE Cervical spondylotic myelopathy (CSM) is a common progressive spine disorder affecting predominantly middle-aged and elderly populations. With increasing life expectancy, the incidence of CSM is expected to rise further. The outcomes of elderly patients undergoing CSM surgery and especially their quality of life (QOL) postoperatively remain undetermined. This study retrospectively reviewed patients to identify baseline differences and validated postoperative patient-reported outcome (PRO) measures in elderly patients undergoing CSM surgery. METHODS The multi-institutional, neurosurgery-specific NeuroPoint Quality Outcomes Database was queried to identify CSM patients treated surgically at the 14 highest-volume sites from January 2016 to December 2018. Patients were divided into three groups: young (< 65 years), early elderly (65–74 years), and late elderly (≥ 75 years). Demographic and PRO measures (Neck Disability Index [NDI] score, modified Japanese Orthopaedic Association [mJOA] score, EQ-5D score, EQ-5D visual analog scale [VAS] score, arm pain VAS, and neck pain VAS) were compared among the groups at baseline and 3 and 12 months postoperatively. RESULTS A total of 1151 patients were identified: 691 patients (60%) in the young, 331 patients (28.7%) in the early elderly, and 129 patients (11.2%) in the late elderly groups. At baseline, younger patients presented with worse NDI scores (p < 0.001) and lower EQ-5D VAS (p = 0.004) and EQ-5D (p < 0.001) scores compared with early and late elderly patients. No differences among age groups were found in the mJOA score. An improvement of all QOL scores was noted in all age groups. On unadjusted analysis at 3 months, younger patients had greater improvement in arm pain VAS, NDI, and EQ-5D VAS compared with early and late elderly patients. At 12 months, the same changes were seen, but on adjusted analysis, there were no differences in PROs between the age groups. CONCLUSIONS The authors’ results indicate that elderly patients undergoing CSM surgery achieved QOL outcomes that were equivalent to those of younger patients at the 12-month follow-up.

Background This phase I multicenter study was designed to evaluate the safety, tolerability, efficacy, and translational effects on the tumor microenvironment of itacitinib (Janus-associated kinase 1 (JAK1) inhibitor) in combination with epacadostat (indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor) or parsaclisib (phosphatidylinositol 3-kinase δ (PI3Kδ) inhibitor). Methods Patients with advanced or metastatic solid tumors were enrolled and received itacitinib (100–400 mg once a day) plus epacadostat (50–300 mg two times per day; group A), or itacitinib (100–400 mg once a day) plus parsaclisib or parsaclisib monotherapy (0.3–10 mg once a day; group B). Results A total of 142 patients were enrolled in the study. The maximum tolerated dose was not reached for either the combination of itacitinib plus epacadostat (n=47) or itacitinib plus parsaclisib (n=90). One dose-limiting toxicity of serious, grade 3 aseptic meningitis was reported in a patient receiving itacitinib 300 mg once a day plus parsaclisib 10 mg once a day, which resolved when the study drugs were withdrawn. The most common treatment-related adverse events among patients treated with itacitinib plus epacadostat included fatigue, nausea, pyrexia, and vomiting, and for patients treated with itacitinib plus parsaclisib were fatigue, pyrexia, and diarrhea. In the itacitinib plus epacadostat group, no patient had an objective response. Among patients receiving itacitinib 100 mg once a day plus parsaclisib 0.3 mg once a day, three achieved partial response for an objective response rate (95% CI) of 7.1% (1.50 to 19.48). Treatment with itacitinib plus epacadostat demonstrated some increase in tumor CD8+ T cell infiltration and minor changes in six plasma proteins, whereas treatment with itacitinib plus high-dose parsaclisib resulted in downregulation of 20 plasma proteins mostly involved in immune cell function, with no observed change in intratumoral CD8+ T cell infiltration. Conclusion Adverse events with JAK1 inhibition combined with either IDO1 or PI3Kδ inhibition were manageable, but the combinations demonstrated limited clinical activity or enhancement of immune activation in the tumor microenvironment. Trial registration number NCT02559492.