Longitudinal transcriptomic analysis reveals persistent enrichment of iron homeostasis and erythrocyte function pathways in severe COVID-19 ARDS.

Introduction: The acute respiratory distress syndrome (ARDS) is a common complication of severe COVID-19 and contributes to patient morbidity and mortality. ARDS is a heterogeneous syndrome caused by various insults, and results in acute hypoxemic respiratory failure. Patients with ARDS from COVID-19 may represent a subgroup of ARDS patients with distinct molecular profiles that drive disease outcomes. Here, we hypothesized that longitudinal transcriptomic analysis may identify distinct dynamic pathobiological pathways during COVID-19 ARDS. Methods: We identified a patient cohort from an existing ICU biorepository and established three groups for comparison: 1) patients with COVID-19 ARDS that survived hospitalization (COVID survivors, n = 4), 2) patients with COVID-19 ARDS that did not survive hospitalization (COVID non-survivors, n = 5), and 3) patients with ARDS from other causes as a control group (ARDS controls, n = 4). RNA was isolated from peripheral blood mononuclear cells (PBMCs) at 4 time points (Days 1, 3, 7, and 10 following ICU admission) and analyzed by bulk RNA sequencing. Results: We first compared transcriptomes between groups at individual timepoints and observed significant heterogeneity in differentially expressed genes (DEGs). Next, we utilized the likelihood ratio test to identify genes that exhibit different patterns of change over time between the 3 groups and identified 341 DEGs across time, including hemoglobin subunit alpha 2 (HBA1, HBA2), hemoglobin subunit beta (HBB), von Willebrand factor C and EGF domains (VWCE), and carbonic anhydrase 1 (CA1), which all demonstrated persistent upregulation in the COVID non-survivors compared to COVID survivors. Of the 341 DEGs, 314 demonstrated a similar pattern of persistent increased gene expression in COVID non-survivors compared to survivors, associated with canonical pathways of iron homeostasis signaling, erythrocyte interaction with oxygen and carbon dioxide, erythropoietin signaling, heme biosynthesis, metabolism of porphyrins, and iron uptake and transport. Discussion: These findings describe significant differences in gene regulation during patient ICU course between survivors and non-survivors of COVID-19 ARDS. We identified multiple pathways that suggest heme and red blood cell metabolism contribute to disease outcomes. This approach is generalizable to larger cohorts and supports an approach of longitudinal sampling in ARDS molecular profiling studies, which may identify novel targetable pathways of injury and resolution.

Investigating risk factors and treatment options for severe, partially steroid responsive, and steroid-refractory checkpoint inhibitor pneumonitis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized cancer care with incredible reductions in mortality. One of the most devastating complications of treatment is ICI-related pneumonitis (ICI-p). Despite this, little is known regarding risk factors for severe pneumonitis and treatment effectiveness of various therapeutic options for steroid-refractory disease. To address this, we conducted a retrospective study on patients with cancer who developed ICI-p. METHODS: We examined consecutive patients who received ICIs and developed ICI-p. Risk factors of interest for severe disease and steroid-refractory ICI-p, including pre-treatment pulmonary function tests (PFTs) and chest imaging, were compared between patients with severe (grades 3-5) and mild (grades 1-2) pneumonitis. The clinical and treatment courses for patients with steroid-refractory ICI-p were recorded. RESULTS: A total of 132 patients developed ICI-p, with 60 patients having mild and 72 with severe disease. We found that lower forced vital capacity percent predicted (66.24 vs 85.05, P = .05), lower total lung capacity percent predicted (85.23 vs 99.71, P = .13), and specific radiographic patterns on pre-treatment chest imaging were predictors of severe disease. Initial corticosteroid dose of less than 1 milligram per kilogram prednisone equivalent (P = .14) was correlated with partially steroid-responsive or steroid-refractory ICI-p. Ten patients had steroid refractory ICI-p, and those who received IVIG alone as the immune suppressant beyond corticosteroids had improved survival (P = 05). CONCLUSIONS: We are the first to identify pre-treatment PFTs and chest imaging abnormalities as risk factors for severe ICI-p. We also found that lower corticosteroid doses were associated with partially steroid-responsive and steroid-refractory ICI-p. Larger, prospective studies are needed to validate our results.

A case of misdiagnosed arterial thoracic outlet syndrome as primary Raynaud's phenomenon.

Arterial thoracic outlet syndrome (aTOS) is a rare, but potentially, limb-threatening condition that is often misdiagnosed. We present the case of a 29-year-old man who was initially managed under the presumption of primary Raynaud's phenomenon for >1 year before the correct diagnosis of aTOS, and the delay in diagnosis was complicated by substantial distal thromboembolic occlusion. Successful staged treatment included thoracic outlet decompression, subclavian artery aneurysm repair with subclavian-to-axillary bypass, anticoagulation, and an unconventional axillary-to-ulnar artery bypass. This report highlights the diagnostic challenges of aTOS and the importance of considering it in patients with Raynaud's phenomenon and vaso-occlusive symptoms.

Formation of recurring transient Ca2+-based intercellular communities during Drosophila hematopoiesis.

Tissue development occurs through a complex interplay between many individual cells. Yet, the fundamental question of how collective tissue behavior emerges from heterogeneous and noisy information processing and transfer at the single-cell level remains unknown. Here, we reveal that tissue scale signaling regulation can arise from local gap-junction mediated cell-cell signaling through the spatiotemporal establishment of an intermediate-scale of transient multicellular communication communities over the course of tissue development. We demonstrated this intermediate scale of emergent signaling using Ca2+ signaling in the intact, ex vivo cultured, live developing Drosophila hematopoietic organ, the lymph gland. Recurrent activation of these transient signaling communities defined self-organized signaling "hotspots" that gradually formed over the course of larva development. These hotspots receive and transmit information to facilitate repetitive interactions with nonhotspot neighbors. Overall, this work bridges the scales between single-cell and emergent group behavior providing key mechanistic insight into how cells establish tissue-scale communication networks.

Sarcoid-like reactions to immune checkpoint inhibitors: Incidence, treatment course, and impact on cancer progression and survival.

INTRODUCTION: Sarcoid-like reactions (SLRs) to immune checkpoint inhibitors (ICIs) are a rare but increasingly recognized immune-related adverse event of which the clinical significance is unclear. METHODS: We conducted a retrospective cohort study at a tertiary academic center of consecutive patients who received at least one dose of ICI from 2013 to 2020. Patient characteristics, risk factors, and outcomes were compared between patients with and without SLR following ICI treatment. RESULTS: A total of 2963 cancer patients received at least 1 dose of ICI between 2013 and 2020, and 7 patients (0.24 %) developed SLR. There were no significant demographic differences between patients with and without SLR following ICI. SLRs occurred in 5 of 451 (1.07 %) melanoma patients and 2 of 840 (0.24 %) non-small cell lung cancer patients. Two of the 7 patients had multi-organ SLR, and both were symptomatic requiring systemic corticosteroids and permanent ICI discontinuation, while single organ SLR patients did not require immune suppression. Development of SLR did not appear to have negative impact on cancer progression or overall survival; in fact, a trend towards improved progression-free and overall survival was observed (median time: 1363 days vs 127 days, p = 0.091; 1387 days vs 428.5 days, p = 0.19, respectively). CONCLUSIONS: SLRs are a known but understudied complication associated with ICI therapy. Multisystem SLR patients were more symptomatic and required ICI discontinuation and immune suppression. Larger studies are needed to fully evaluate the impact of SLR on cancer outcomes.

The Validity of Patient-Reported Outcome Measures of Quality of Life in Palliative Care: A Systematic Review.

Importance: A recent systematic review and meta-analysis found that palliative care was not associated with improvement in quality of life (QOL) in terminal noncancer illness. Among potential reasons for a null effect, it is unclear if patient-reported outcome measures (PROMs) measuring QOL were derived or validated among populations with advanced life-limiting illness (ALLI). Objective: To systematically review the derivation and validation of QOL PROMs from a recent meta-analysis of randomized controlled trials (RCT) of palliative care interventions in people with terminal noncancer illness. Evidence Review: EMBASE, MEDLINE, and PsycINFO were searched from inception to January 8, 2023 for primary validation studies of QOL PROMs in populations with ALLI, defined as adults with a progressive terminal condition and an estimated median survival of less than or equal to one year. The primary outcome was the proportion of PROMs that were derived or validated in ≥1 ALLI population. Findings: Twenty-one unique studies of derivation (n = 13) and validation (n = 11, 3 studies evaluated both) provided data on 9657 participants (mean age 63 years, 50% female) across 15 unique QOL PROMs and subscales. Among studies of validation, 9 were in people with cancer (n = 2289, n = 5 PROMs), 1 in neurodegenerative disease (n = 23, n = 1 PROM), and 1 with mixed diseases (n = 248, n = 1 PROM). Across 15 QOL PROMs and subscales, 47% (n = 7) were derived or validated in an ALLI population. The majority of these seven PROMs were exclusively derived or validated among people with cancer (57%, n = 4). QOL PROMs such as Quality of Life at End of Life, EuroQoL-5 Dimension 5-level, and 36-item Short Form Survey demonstrated validity in more than one terminal noncancer illness. Conclusions: Most QOL PROMs that measured the effect of palliative care on QOL in RCTs were neither derived nor validated in an ALLI population. These findings raise questions about the inferences that palliative care does not improve QOL among people with terminal noncancer illness.

Performance of cognitive vs. image-guided fusion biopsy for detection of overall and clinically significant prostate cancer in a multiethnic population.

PURPOSE: Transrectal ultrasound-guided prostate biopsy remains the most used method for the detection of prostate cancer. We recently reported that detection of clinically significant prostate cancer (cs-CaP) using image-guided fusion biopsies (IGFB) varied by race/ethnicity, which calls for further comparison between cognitive fusion biopsy (CFB) and IGFB among non-Hispanic black and Hispanic populations. Therefore, the aim of our study is to compare the rates of detection of cs-CaP and overall CaP by CFB and IGFB in a multiethnic community. MATERIAL AND METHODS: We performed a retrospective, cross-sectional review of men who underwent MRI-transrectal ultrasound-guided prostate biopsy at our diverse, urban academic medical center. Agreement and discordance between fusion biopsies and systematic biopsies for detection of cs-CaP and overall CaP were determined using Kappa statistics. Univariate and multivariate mixed-effects logistic regression models were used to find associations between fusion modalities and prostate cancer detection. RESULTS: In total, 710 men underwent fusion prostate biopsies between December 2015 and June 2021. Upon univariate and multivariate logistic regression analysis, there was no significant association between IGFB vs. CFB and risk of overall CaP (OR = 0.66, 95% CI: 0.36-1.21, P = 0.18) or cs-CaP (OR = 0.57, 95% CI: 0.30-1.08, P = 0.09). We found moderate agreement between fusion and systematic biopsies for both CFB (κ = 0.56) and IGFB (κ = 0.52) in cs-CaP. CONCLUSIONS: CFB and IGFB offer similar detection rates of cs-CaP in a multiethnic population. CFB represents an effective and accessible means of accurately diagnosing prostate cancer.

Association Between Pretreatment Chest Imaging and Immune Checkpoint Inhibitor Pneumonitis Among Patients With Lung Cancer.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are a first-line and perioperative treatment for lung cancer. Pneumonitis is a potentially life-threatening complication of ICI treatment in 2% to 5% of patients; however, risk factors for developing ICI pneumonitis (ICI-p) remain undefined. METHODS: We conducted a retrospective cohort study of consecutive patients with lung cancer who received at least one dose of ICI from 2015 through 2020 at The Ohio State University. Pneumonitis cases were documented by the treating oncologist and retrospectively evaluated for agreement between an oncologist and a pulmonologist. Patient demographic and clinical characteristics were recorded and summarized between those with and without pneumonitis for the overall cohort. Univariate and multivariable survival analyses using the Fine-Gray competing risk model were used to examine the associations. RESULTS: A total of 471 patients with lung cancer were included, of which 402 had non-small cell lung cancer and 69 had small cell lung cancer; 39 (8%) patients in the overall cohort developed ICI-p. Preexisting interstitial abnormalities and prior chest radiation were both significantly associated with ICI-p on univariate analysis (hazard ratio [HR], 8.91; 95% CI, 4.69-16.92; P<.001; and HR, 2.81; 95% CI, 1.50-5.28; P=.001). On multivariable analyses, interstitial abnormalities remained a strong independent risk factor for ICI-p when controlling for chest radiation and type of immunotherapy (HR, 9.77; 95% CI, 5.17-18.46; P<.001). Among patients with ICI-p (n=39), those with severe (grade 3-5) pneumonitis had worse overall survival compared with those with mild (grade 1 or 2) pneumonitis (P=.001). Abnormal pulmonary function test results at both 12 and 18 months prior to ICI initiation were not significantly associated with ICI-p. CONCLUSIONS: Preexisting interstitial abnormalities on chest CT and prior chest radiation are independent risk factors that are strongly associated with ICI-p in patients with lung cancer. These findings highlight a potential need for closer observation for ICI-p among patients with these risk factors.

Unsupervised domain adaptation for automated knee osteoarthritis phenotype classification.

Background: Osteoarthritis (OA) is a global healthcare problem. The increasing population of OA patients demands a greater bandwidth of imaging and diagnostics. It is important to provide automatic and objective diagnostic techniques to address this challenge. This study demonstrates the utility of unsupervised domain adaptation (UDA) for automated OA phenotype classification. Methods: We collected 318 and 960 three-dimensional double-echo steady-state magnetic resonance images from the Osteoarthritis Initiative (OAI) dataset as the source dataset for phenotype cartilage/meniscus and subchondral bone, respectively. Fifty three-dimensional turbo spin echo (TSE)/fast spin echo (FSE) MR images from our institute were collected as the target datasets. For each patient, the degree of knee OA was initially graded according to the MRI Knee Osteoarthritis Knee Score before being converted to binary OA phenotype labels. The proposed four-step UDA pipeline included (I) pre-processing, which involved automatic segmentation and region-of-interest cropping; (II) source classifier training, which involved pre-training a convolutional neural network (CNN) encoder for phenotype classification using the source dataset; (III) target encoder adaptation, which involved unsupervised adjustment of the source encoder to the target encoder using both the source and target datasets; and (IV) target classifier validation, which involved statistical analysis of the classification performance evaluated by the area under the receiver operating characteristic curve (AUROC), sensitivity, specificity and accuracy. We compared our model on the target data with the source pre-trained model and the model trained with the target data from scratch. Results: For phenotype cartilage/meniscus, our model has the best performance out of the three models, giving 0.90 [95% confidence interval (CI): 0.79-1.02] of the AUROC score, while the other two model show 0.52 (95% CI: 0.13-0.90) and 0.76 (95% CI: 0.53-0.98). For phenotype subchondral bone, our model gave 0.75 (95% CI: 0.56-0.94) at AUROC, which has a close performance of the source pre-trained model (0.76, 95% CI: 0.55-0.98), and better than the model trained from scratch on the target dataset only (0.53, 95% CI: 0.33-0.73). Conclusions: By utilising a large, high-quality source dataset for training, the proposed UDA approach enhances the performance of automated OA phenotype classification for small target datasets. As a result, our technique enables improved downstream analysis of locally collected datasets with a small sample size.

Maintenance of hematopoietic stem cell niche homeostasis requires gap junction-mediated calcium signaling.

Regulation of stem cells requires coordination of the cells that make up the stem cell niche. Here, we describe a mechanism that allows communication between niche cells to coordinate their activity and shape the signaling environment surrounding resident stem cells. Using the Drosophila hematopoietic organ, the lymph gland, we show that cells of the hematopoietic niche, the posterior signaling center (PSC), communicate using gap junctions (GJs) and form a signaling network. This network allows PSC cells to exchange Ca2+ signals repetitively which regulate the hematopoietic niche. Disruption of Ca2+ signaling in the PSC or the GJ-mediated network connecting niche cells causes dysregulation of the PSC and blood progenitor differentiation. Analysis of PSC-derived cell signaling shows that the Hedgehog pathway acts downstream of GJ-mediated Ca2+ signaling to modulate the niche microenvironment. These data show that GJ-mediated communication between hematopoietic niche cells maintains their homeostasis and consequently controls blood progenitor behavior.

Surgical accuracy of image-free versus image-based robotic-assisted total knee arthroplasty.

BACKGROUND: This study investigated the accuracy in achieving proper lower limb alignment and component positions after total knee replacement (TKR) with image-free and image-based robotic-assisted TKR. METHODS: A total of 129 patients (166 knees) suffering from end-stage knee arthritis who underwent TKA operated by robotic-assisted surgery between the years 2018 and mid-2021 were recruited. Radiological outcomes were compared between image-free and image-based robotic-assisted surgical systems. RESULTS: There were significant differences between the two robotic systems when comparing the mean planned component alignment and the mean measured alignment on radiographs, in which the image-free robotic-assisted system was more varus, whereas the image-based robotic-assisted system was more valgus for both the mean femoral and tibial component coronal alignment (p < 0.001). For tibial component sagittal alignment, the image-based group had a larger deviation from the planned posterior slope (p < 0.001). CONCLUSION: Image-free and image-based robotic assisted TKR had differing accuracy in femoral and tibial alignment.

Discovery of quinazoline HPK1 inhibitors with high cellular potency.

Hematopoietic progenitor kinase 1 (HPK1) is regarded as a highly validated target in pre-clinical immune oncology. HPK1 has been described as regulating multiple critical signaling pathway in both adaptive and innate cells. In support of this role, HPK1 KO T cells show enhanced sensitivity to TCR activation and HPK1 KO mice display enhanced anti-tumor activity. Taken together, inhibition of HPK1 has the potential to induce enhanced anti-tumor immune response. Herein, we described the discovery of highly potent HPK1 inhibitors starting form a weak HTS hit. Using a structure-based drug design, HPK1 inhibitors exhibiting excellent cellular single-digit nanomolar potency in both proximal (pSLP76) and distal (IL-2) biomarkers along with sustained elevation of IL-2 cytokine secretion were discovered.

Does pharyngoplasty work? Outcomes of 100 consecutive operations over 10 years.

BACKGROUND: Velopharyngeal insufficiency is a commonly encountered problem in Cleft Surgery, with pharyngoplasty being the mainstay of surgical management. In this study we aim to investigate the indications and outcomes of a single institution's experience and compare to international literature. METHODS: A retrospective review was performed looking at over 100 consecutive primary pharyngoplasty operations for velopharyngeal dysfunction over a 10-year period at a single institution. Aetiology, peri-operative course and speech outcomes for the cohort between January 2010 through January 2020 were assessed. A comprehensive literature review was performed for comparison and analysis of the studies' data. RESULTS: Ninety-seven consecutive patients were included in the study on which 103 operations were performed. Average age at time of surgery was 7.25 years old. Approximately 37% of the patients had a diagnosed syndrome, sequence or chromosomal abnormality. Ninety-seven of the 103 operations were primary pharyngoplasties, 4 were revision pharyngoplasties and 2 return to theatre procedures. Regarding speech outcomes, 51% of the patients that had formal speech assessments were found to have a significant improvement, 42% moderate improvement and 7% had no improvement. 93% of the patients that underwent pharyngoplasty in this study had significant or moderate improvement in speech outcomes. These speech outcomes and post-operative complications such as obstructive sleep apnoea are analysed. CONCLUSION: This study demonstrates that pharyngoplasty is a safe procedure for velopharyngeal insufficiency with a good overall success rate. The major outcomes assessed including complications & safety, revision rate and speech outcomes are comparative to previous international studies.

Single use Negative Pressure Wound Therapy (NPWT) system in the management of knee arthroplasty.

BACKGROUND: Wound complication, skin blister formation in particular, causes devastating consequences after total knee arthroplasty (TKA). Negative Pressure Wound Therapy (NPWT) tries to improve wound management leading to decrease length of hospital stay and better clinical outcomes. Low body mass index (BMI) could play a part in wound recovery management although lacking evidence. This study compared length of hospital stay and clinical outcomes between NPWT and Conventional groups, and factors affected and how BMI affected. METHODS: This was a retrospective clinical record review of 255 (160 NPWT and 95 Conventional) patients between 2018 and 2022. Patient demographics including body mass index (BMI), surgical details (unilateral or bilateral), length of hospital stay, clinical outcomes including skin blisters occurrence, and major wound complications were investigated. RESULTS: Mean age of patients at surgery was 69.95 (66.3% were female). Patients treated with NPWT stayed significantly longer in the hospital after joint replacement (5.18 days vs. 4.55 days; p = 0.01). Significantly fewer patients treated with NPWT found to have blisters (No blisters: 95.0% vs. 87.4%; p = 0.05). In patients with BMI < 30, percentage of patients requiring dressing change was significantly lower when treated with NPWT than conventional (0.8% vs. 33.3%). CONCLUSION: Percentage of blisters occurrence in patients who underwent joint replacement surgery is significantly lower using NPWT. Patients using NPWT stayed significantly longer in the hospital after surgery because significant proportion received bilateral surgery. NPWT patients with BMI < 30 were significantly less likely to change wound dressing.

Selective Wee1 Inhibitors Led to Antitumor Activity In Vitro and Correlated with Myelosuppression.

Wee1 is a tyrosine kinase that is highly expressed in several cancer types. Wee1 inhibition can lead to suppression of tumor cell proliferation and sensitization of cells to the effects of DNA-damaging agents. AZD1775 is a nonselective Wee1 inhibitor for which myelosuppression has been observed as a dose-limiting toxicity. We have applied structure-based drug design (SBDD) to rapidly generate highly selective Wee1 inhibitors that demonstrate better selectivity than AZD1775 against PLK1, which is known to cause myelosuppression (including thrombocytopenia) when inhibited. While selective Wee1 inhibitors described herein still achieved in vitro antitumor efficacy, thrombocytopenia was still observed in vitro.

Long-term survivorship and results in lower limb arthroplasty: a registry-based comparison study.

INTRODUCTION: Popularity of joint replacement surgery due to ever aging population surges the demand for a proper national joint registry. Our Chinese University of Hong Kong - Prince of Wales Hospital (CUHK-PWH) joint registry has passed the 30th year. The aims of this study are 1) summarize our territory-wide joint registry which has passed the 30th year since establishment and 2) compare our statistics with other major joint registries. METHODS: Part 1 was to review the CUHK-PWH registry. Demographic characteristics of our patients who underwent knee and hip replacements had been summarized. Part 2 was a series of comparisons with registries from Sweden, UK, Australia and New Zealand. RESULTS: CUHK-PWH registry captured 2889 primary total knee replacements (TKR) (110 (3.81%) revision) and 879 primary total hip replacements (THR) (107 (12.17%) revision). Median Surgery time of TKR was shorter than THR. Clinical outcome scores were much improved after surgery in both. Uncemented of hybrid in TKR were most popular in Australia (33.4%) and 40% in Sweden and UK. More than half of TKR and THR patients showed the highest percentage with ASA grade 2. New Zealand reflected the best cumulative percentage survival 20 years after surgery of 92.2%, 76.0%, 84.2% survivorship 20 years after TKR, unicompartmental knee replacement (UKR) and Hip. CONCLUSION: A worldwide accepted patient-reported outcome measure (PROM) is recommended to develop to make comparisons among registries and studies feasible. Completeness of registry data is important and useful to improve surgical performance through data comparisons from different regions. Funding from government on sustaining registries is reflected. Registries from Asian countries have yet to be grown and reported.

Surgical accuracy and clinical outcomes of image-free robotic-assisted total knee arthroplasty.

BACKGROUND: The development of total knee arthroplasty (TKA) for knee osteoarthritis (OA) has a good reputation for its effectiveness in reducing joint pain and improving range of motion. We aimed to review our early results using the image-free robotic-assisted technology in knee arthroplasty. METHODS: A total of 71 patients suffering from end-stage OA knee receiving TKA operated by robotic-assisted surgery between the years 2018 and mid-2021 were recruited. Clinical and radiological outcomes were compared with age and sex-matched control group (conventional TKA). RESULTS: The radiological outcome showed significantly more postoperative lower limb alignment outliers in conventional side than robotic-assisted sides. Postoperative knee scores were similar among both groups. Robotic-assisted TKA required a longer implantation time but a shorter hospital stay. CONCLUSION: Robotic-assisted TKA achieved a lower rate of mechanical axis Outlier in the coronal and sagittal plane with a shorter hospital stay. Yet both methods achieve a similar functional outcome.

Association between pre-treatment chest imaging and pulmonary function abnormalities and immune checkpoint inhibitor pneumonitis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are a first-line treatment for various metastatic solid tumors. Pneumonitis is a potentially devastating complication of ICI treatment and a leading cause of ICI-related mortality. Here, we evaluate whether abnormal pre-treatment pulmonary function tests (PFTs) or interstitial abnormalities on computed tomography of the chest (CT chest) prior to ICI are associated with the development of ICI-pneumonitis (ICI-p). METHODS: We conducted a retrospective cohort study of consecutive patients who received at least one dose of ICI from 2011 to 2017 at The Ohio State University. Potential risk factors for ICI-p, including abnormal PFTs and CT chest, were recorded. These risk factors were compared between patients with and without pneumonitis. RESULTS: In total, 1097 patients were included, 46 with ICI-p and 1051 without. Ninety percent of patients had pre-treatment chest imaging, while only 10% had pre-treatment PFTs. On multivariable analysis, interstitial abnormalities and reduced total lung capacity (TLC) were significantly associated with development of ICI-p (hazard ratio of 42.42 [95% CI; 15.04-119.67] and hazard ratio of 4.04 [95% CI; 1.32-12.37]), respectively. No other PFT abnormality was associated with increased risk of ICI-p. There was no significant difference in overall survival in patients who did or did not develop ICI-p (p = 0.332). CONCLUSIONS: Pre-existing interstitial abnormalities on CT chest and reduced TLC were strongly associated with developing ICI-p. Prospective studies are warranted to further explore the role of PFTs as a potential tool for identifying patients at highest risk for developing ICI-p.

Automated in vivo compound screening with zebrafish and the discovery and validation of PD 81,723 as a novel angiogenesis inhibitor.

Angiogenesis is a critical process in tumor progression. Inhibition of angiogenesis by blocking VEGF signaling can impair existing tumor vessels and halt tumor progression. However, the benefits are transient, and most patients who initially respond to these therapies develop resistance. Accordingly, there is a need for new anti-angiogenesis therapeutics to delay the processes of resistance or eliminate the resistive effects entirely. This manuscript presents the results of a screen of the National Institutes of Health Clinical Collections Libraries I & II (NIHCCLI&II) for novel angiogenesis inhibitors. The 727 compounds of the NIHCCLI&II library were screened with a high-throughput drug discovery platform (HTP) developed previously with angiogenesis-specific protocols utilizing zebrafish. The screen resulted in 14 hit compounds that were subsequently narrowed down to one, with PD 81,723 chosen as the lead compound. PD 81,723 was validated as an inhibitor of angiogenesis in vivo in zebrafish and in vitro in human umbilical vein endothelial cells (HUVECs). Zebrafish exposed to PD 81,723 exhibited several signs of a diminished endothelial network due to the inhibition of angiogenesis. Immunochemical analysis did not reveal any significant apoptotic or mitotic activity in the zebrafish. Assays with cultured HUVECs elucidated the ability of PD 81,723 to inhibit capillary tube formation, migration, and proliferation of endothelial cells. In addition, PD 81,723 did not induce apoptosis while significantly down regulating p21, AKT, VEGFR-2, p-VEGFR-2, eNOS, and p-eNOS, with no notable change in endogenous VEGF-A in cultured HUVECs.