Biliary cancer brain metastases: a multi-institution case series with case reports.

Background: Biliary cancers are rare, and few reported cases of brain metastases from primary biliary cancers exist, especially describing patients in the United States. This report assesses the proportion and incidence of brain metastases arising from primary biliary cancers [cholangiocarcinoma (CCA) and gallbladder cancer] at Stanford University and the University of California, San Francisco, describes clinical characteristics, and provides a case series. Methods: We queried 3 clinical databases at Stanford and the University of California, San Francisco to retrospectively identify and review the charts of 15 patients with brain metastases from primary biliary cancers occurring between 1990 to 2020. Results: Among patients with brain metastases analyzed at Stanford (3,585), 6 had a primary biliary cancer, representing 0.17% of all brain metastases. Among biliary cancer patients at the University of California, San Francisco (1,055), 9 had brain metastases, representing an incidence in biliary cancer of 0.85%. A total of 15 biliary cancer patients with brain metastases were identified at the two institutions. Thirteen out of 15 patients (86.7%, 95% CI: 59.5-98.3) were female. The median overall survival from primary biliary cancer diagnosis was 214 days (95% CI: 71.69-336.82 days) and subsequent OS from the time of brain metastasis diagnosis was 57 days (95% CI: 13.43-120.64 days). Death within 90 days of brain metastasis diagnosis occurred in 66.67% of patients (95% CI: 38.38-88.17). Conclusions: Brain metastases from primary biliary cancers are rare, with limited survival once diagnosed. This report can aid health care providers in caring for patients with brain metastases from primary biliary cancers.

Quantifying virtual reality pain modulation in healthy volunteers: A randomized, crossover study.

STUDY OBJECTIVE: Virtual reality (VR) is an emerging tool to reduce pain and anxiety during procedures. Although VR's clinical benefits are reported, biometric data quantifying VR's effect on pain tolerance is lacking. We used time-lapse, subjective, and biometric data to evaluate VR's effect on modulating pain. DESIGN: Randomized, controlled crossover within-subject clinical trial. SETTING: This study was conducted in the Chariot Lab at Lucile Packard Children's Hospital and outdoors at Stanford University School of Medicine. PATIENTS: 156 healthy volunteers were included. INTERVENTIONS: Participants underwent pain-inducing ice immersions while connected to biometric sensors. Participants were randomized to immerse their dominant or non-dominant hand with VR or control (no VR) for one immersion, and then crossed-over to the other hand for the second immersion. We instructed participants to submerge their hand until they reached their pain tolerance or until four minutes elapsed. MEASUREMENTS: Outcomes included ice immersion duration, perceived pain scores, and skin conductance response density (SCRD), a marker of sympathetic arousal. We used survival analysis and mixed effects models to compare measurements with and without VR. MAIN RESULTS: 153 participants were included in the analysis. Participants with VR were 64% less likely to remove their hands from the ice bath throughout the immersion's duration compared to control (P < 0.001). Participants with VR reported significantly lower pain scores after controlling for dominant hand treatment assignment, VR vs. no VR treatment order, and gender (P < 0.001). SCRD increased as time progressed for both VR and control groups (P = 0.047 combined), with no significant mean group differences. CONCLUSIONS: Participants with VR were more likely to survive the 4-min ice bath challenge longer and with lower levels of pain perception, supporting VR's effectiveness as a distraction tool during painful procedures. We observed no differences in sympathetic response when comparing VR to no VR.

Radiopaque Recreations of Lung Pathologies From Clinical Computed Tomography Images Using Potassium Iodide Inkjet 3-dimensional Printing: Proof of Concept.

PURPOSE: The purpose of this study was to develop a 3-dimensional (3D) printing method to create computed tomography (CT) realistic phantoms of lung cancer nodules and lung parenchymal disease from clinical CT images. MATERIALS AND METHODS: Low-density paper was used as substrate material for inkjet printing with potassium iodide solution to reproduce phantoms that mimic the CT attenuation of lung parenchyma. The relationship between grayscale values and the corresponding CT numbers of prints was first established through the derivation of exponential fitted equation from scanning data. Next, chest CTs from patients with early-stage lung cancer and coronavirus disease 2019 (COVID-19) pneumonia were chosen for 3D printing. CT images of original lung nodule and the 3D-printed nodule phantom were compared based on pixel-to-pixel correlation and radiomic features. RESULTS: CT images of part-solid lung cancer and 3D-printed nodule phantom showed both high visual similarity and quantitative correlation. R2 values from linear regressions of pixel-to-pixel correlations between 5 sets of patient and 3D-printed image pairs were 0.92, 0.94, 0.86, 0.85, and 0.83, respectively. Comparison of radiomic measures between clinical CT and printed models demonstrated 6.1% median difference, with 25th and 75th percentile range at 2.4% and 15.2% absolute difference, respectively. The densities and parenchymal morphologies from COVID-19 pneumonia CT images were well reproduced in the 3D-printed phantom scans. CONCLUSION: The 3D printing method presented in this work facilitates creation of CT-realistic reproductions of lung cancer and parenchymal disease from individual patient scans with microbiological and pathology confirmation.

Safety of ACE-I and ARB medications in COVID-19: A retrospective cohort study of inpatients and outpatients in California.

INTRODUCTION: There is significant interest in the use of angiotensin converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARB) in coronavirus disease 2019 (COVID-19) and concern over potential adverse effects since these medications upregulate the severe acute respiratory syndrome coronavirus 2 host cell entry receptor ACE2. Recent studies on ACE-I and ARB in COVID-19 were limited by excluding outpatients, excluding patients by age, analyzing ACE-I and ARB together, imputing missing data, and/or diagnosing COVID-19 by chest computed tomography without definitive reverse transcription polymerase chain reaction (RT-PCR), all of which are addressed here. METHODS: We performed a retrospective cohort study of 1023 COVID-19 patients diagnosed by RT-PCR at Stanford Hospital through April 8, 2020 with a minimum follow-up time of 14 days to investigate the association between ACE-I or ARB use with outcomes. RESULTS: Use of ACE-I or ARB medications was not associated with increased risk of hospitalization, intensive care unit admission, or death. Compared to patients with charted past medical history, there was a lower risk of hospitalization for patients on ACE-I (odds ratio (OR) 0.43; 95% confidence interval (CI) 0.19-0.97; P = 0.0426) and ARB (OR 0.39; 95% CI 0.17-0.90; P = 0.0270). Compared to patients with hypertension not on ACE-I or ARB, patients on ARB medications had a lower risk of hospitalization (OR 0.09; 95% CI 0.01-0.88; P = 0.0381). CONCLUSIONS: These findings suggest that the use of ACE-I and ARB is not associated with adverse outcomes and may be associated with improved outcomes in COVID-19, which is immediately relevant to care of the many patients on these medications.

Hepatocellular Carcinoma Brain Metastases: A Single-Institution Experience.

BACKGROUND: Brain metastases (BMs) from hepatocellular carcinoma (HCC) are rare, with a paucity of reported cases. In the present retrospective cohort report, we assessed the proportion of BMs arising from HCC and characterized the related details, including patient demographics, clinical characteristics, treatment modalities, and survival outcomes. METHODS: We retrospectively identified and reviewed the medical records of 14 patients with BMs from HCC seen at our institution from 2008 to 2018. RESULTS: Among all patients with BMs, the proportion originating from primary liver cancer was 0.39%. In every case (n = 14), the liver cancer was HCC. The median age at the BM diagnosis was 64 years (range, 37-82 years). The median alpha-fetoprotein level at the diagnosis of BM was 540 ng/mL (range, 3-10,000 ng/mL). The median interval from the HCC diagnosis to the development of BMs was 31.1 months (range, 3.17-107 months). Of the 14 patients, 8 (57%) had had metastases to the brain parenchyma and 6 had had skull or dural metastases. For patients with brain parenchymal metastases, the median number of metastases was 1 (range, 1-5). Of the 14 patients, 13 have died, with a median overall survival after the BM diagnosis of 2.83 months (range, 0.430-24.0 months). At the latest follow-up examination, the survival for the 14th patient was 142 months after the BM diagnosis. Resection of BMs with radiosurgery was associated with increased survival compared with radiosurgery alone (10.9 months vs. 2.8 months; P = 0.04). CONCLUSIONS: HCC BMs are rare and constitute a small fraction of the total incidence of BMs. The prognostic data we have provided can aid medical providers in caring for patients with HCC BMs.

Clinical characteristics associated with COVID-19 severity in California.

Given the rapidly progressing coronavirus disease 2019 (COVID-19) pandemic, this report on a US cohort of 54 COVID-19 patients from Stanford Hospital and data regarding risk factors for severe disease obtained at initial clinical presentation is highly important and immediately clinically relevant. We identified low presenting oxygen saturation as predictive of severe disease outcomes, such as diagnosis of pneumonia, acute respiratory distress syndrome, and admission to the intensive care unit, and also replicated data from China suggesting an association between hypertension and disease severity. Clinicians will benefit by tools to rapidly risk stratify patients at presentation by likelihood of progression to severe disease.

Familial knockin mutation of LRRK2 causes lysosomal dysfunction and accumulation of endogenous insoluble α-synuclein in neurons.

Missense mutations in the multi-domain kinase LRRK2 cause late onset familial Parkinson's disease. They most commonly with classic proteinopathy in the form of Lewy bodies and Lewy neurites comprised of insoluble α-synuclein, but in rare cases can also manifest tauopathy. The normal function of LRRK2 has remained elusive, as have the cellular consequences of its mutation. Data from LRRK2 null model organisms and LRRK2-inhibitor treated animals support a physiological role for LRRK2 in regulating lysosome function. Since idiopathic and LRRK2-linked PD are associated with the intraneuronal accumulation of protein aggregates, a series of critical questions emerge. First, how do pathogenic mutations that increase LRRK2 kinase activity affect lysosome biology in neurons? Second, are mutation-induced changes in lysosome function sufficient to alter the metabolism of α-synuclein? Lastly, are changes caused by pathogenic mutation sensitive to reversal with LRRK2 kinase inhibitors? Here, we report that mutation of LRRK2 induces modest but significant changes in lysosomal morphology and acidification, and decreased basal autophagic flux when compared to WT neurons. These changes were associated with an accumulation of detergent-insoluble α-synuclein and increased neuronal release of α-synuclein and were reversed by pharmacologic inhibition of LRRK2 kinase activity. These data demonstrate a critical and disease-relevant influence of native neuronal LRRK2 kinase activity on lysosome function and α-synuclein homeostasis. Furthermore, they also suggest that lysosome dysfunction, altered neuronal α-synuclein metabolism, and the insidious accumulation of aggregated protein over decades may contribute to pathogenesis in this late-onset form of familial PD.