Radiology of fibrosis. Part I: Thoracic organs.

Sustained injury from factors such as hypoxia, infection, or physical damage may provoke improper tissue repair and the anomalous deposition of connective tissue that causes fibrosis. This phenomenon may take place in any organ, ultimately leading to their dysfunction and eventual failure. Tissue fibrosis has also been found to be central in both the process of carcinogenesis and cancer progression. Thus, its prompt diagnosis and regular monitoring is necessary for implementing effective disease-modifying interventions aiming to reduce mortality and improve overall quality of life. While significant research has been conducted on these subjects, a comprehensive understanding of how their relationship manifests through modern imaging techniques remains to be established. This work intends to provide a comprehensive overview of imaging technologies relevant to the detection of fibrosis affecting thoracic organs as well as to explore potential future advancements in this field.

Radiology of fibrosis part II: abdominal organs.

Fibrosis is the aberrant process of connective tissue deposition from abnormal tissue repair in response to sustained tissue injury caused by hypoxia, infection, or physical damage. It can affect almost all organs in the body causing dysfunction and ultimate organ failure. Tissue fibrosis also plays a vital role in carcinogenesis and cancer progression. The early and accurate diagnosis of organ fibrosis along with adequate surveillance are helpful to implement early disease-modifying interventions, important to reduce mortality and improve quality of life. While extensive research has already been carried out on the topic, a thorough understanding of how this relationship reveals itself using modern imaging techniques has yet to be established. This work outlines the ways in which fibrosis shows up in abdominal organs and has listed the most relevant imaging technologies employed for its detection. New imaging technologies and developments are discussed along with their promising applications in the early detection of organ fibrosis.

Radiology of fibrosis part III: genitourinary system.

Fibrosis is a pathological process involving the abnormal deposition of connective tissue, resulting from improper tissue repair in response to sustained injury caused by hypoxia, infection, or physical damage. It can impact any organ, leading to their dysfunction and eventual failure. Additionally, tissue fibrosis plays an important role in carcinogenesis and the progression of cancer.Early and accurate diagnosis of organ fibrosis, coupled with regular surveillance, is essential for timely disease-modifying interventions, ultimately reducing mortality and enhancing quality of life. While extensive research has already been carried out on the topics of aberrant wound healing and fibrogenesis, we lack a thorough understanding of how their relationship reveals itself through modern imaging techniques.This paper focuses on fibrosis of the genito-urinary system, detailing relevant imaging technologies used for its detection and exploring future directions.

Neuroimaging findings and neurological manifestations in hospitalized COVID-19 patients: Impact of cancer and ventilatory support status.

INTRODUCTION: Coronavirus 2019 (COVID-19) is known to affect the central nervous system. Neurologic morbidity associated with COVID-19 is commonly attributed to sequelae of some combination of thrombotic and inflammatory processes. The aim of this retrospective observational study was to evaluate neuroimaging findings in hospitalized COVID-19 patients with neurological manifestations in cancer versus non-cancer patients, and in patients with versus without ventilatory support (with ventilatory support defined as including patients with intubation and noninvasive ventilation). Cancer patients are frequently in an immunocompromised or prothrombotic state with side effects from chemotherapy and radiation that may cause neurological issues and increase vulnerability to systemic illness. We wanted to determine whether neurological and/or neuroimaging findings differed between patients with and without cancer. METHODS: Eighty adults (44 male, 36 female, 64.5 ±14 years) hospitalized in the Mount Sinai Health System in New York City between March 2020 and April 2021 with reverse-transcriptase polymerase chain reaction-confirmed COVID-19 underwent magnetic resonance imaging (MRI) during their admissions. The cohort consisted of four equal subgroups based on cancer and ventilatory support status. Clinical and imaging data were acquired and analyzed. RESULTS: Neuroimaging findings included non-ischemic parenchymal T2/FLAIR signal hyperintensities (36.3%), acute/subacute infarcts (26.3%), chronic infarcts (25.0%), microhemorrhages (23.8%), chronic macrohemorrhages (10.0%), acute macrohemorrhages (7.5%), and encephalitis-like findings (7.5%). There were no significant differences in neuroimaging findings between cancer and non-cancer subgroups. Clinical neurological manifestations varied. The most common was encephalopathy (77.5%), followed by impaired responsiveness/coma (38.8%) and stroke (26.3%). There were significant differences between patients with versus without ventilatory support. Encephalopathy and impaired responsiveness/coma were more prevalent in patients with ventilatory support (p = 0.02). Focal weakness was more frequently seen in patients without ventilatory support (p = 0.01). DISCUSSION: This study suggests COVID-19 is associated with neurological manifestations that may be visible with brain imaging techniques such as MRI. In our COVID-19 cohort, there was no association between cancer status and neuroimaging findings. Future studies might include more prospectively enrolled systematically characterized patients, allowing for more rigorous statistical analysis.

Weight loss in hypertrophic cardiomyopathy: A clinical case series.

Background: Obesity is prevalent among patients with hypertrophic cardiomyopathy (HCM). Obese HCM patients have greater wall thickness, LV mass, worse hemodynamic function and NYHA class. Weight loss may favorably influence the HCM phenotype. Case summary: We describe six patients with hypertrophic cardiomyopathy who lost weight through diet and lifestyle changes (n = 4) or bariatric surgery (n = 2). Radiographic imaging, with cardiac MRI or CT scan, was performed before and after their weight loss. There was a mean decrease in LV mass and indexed LV mass, and a mean numerical decrease in mean wall thickness in up to 14 out of 18 LV segments. There was also NYHA class reduction in symptoms. Discussion: In this case series, we have shown that substantial weight loss in HCM patients can be associated with a decrease in LV mass, wall thickness and improvement in symptoms. These observations indicate the potential for positive remodeling of the heart by weight loss. Prospective studies of the benefits of weight loss in HCM are needed.

Radiographic features of pneumonitis in patients treated with immunotherapy compared to traditional chemotherapy for non-small cell lung cancer.

BACKGROUND: Pneumonitis has been described as a side effect of immunotherapy as well as traditional chemotherapy. Although immune-related adverse event (IRAE) pneumonitis has been extensively characterized, the relationship between IRAE pneumonitis and pneumonitis secondary to chemotherapy is less clear. Here, we present the first analysis of radiographic features of pneumonitis secondary to immunotherapy compared to chemotherapy. METHODS: Using our radiology records system, we searched chest computed tomography (CT) reports for the term "pneumonitis". We evaluated medical records to establish chronicity of pneumonitis occurring after medication administration and excluded cases where radiation therapy appeared to be the cause of pneumonitis. We also obtained information regarding demographic, clinical, and treatment characteristics for comparison. RESULTS: Patients treated with immunotherapy demonstrated more specific features of pneumonitis including consolidation, ground glass opacities, septal thickening, traction bronchiectasis, and pulmonary nodules compared to those treated with chemotherapy. Immunotherapy treatment correlated with the development of pulmonary nodules (p = 0.048), and administration of more than one immunotherapy agent correlated with a greater incidence of development of nodules (p = 0.050). Radiographic features in patients treated with immunotherapy all decreased over time. Conversely, in patients treated with chemotherapy the incidence of ground glass opacities, traction bronchiectasis, pulmonary nodules, and mediastinal/hilar adenopathy increased over time. CONCLUSIONS: IRAE-pneumonitis has distinct features and a distinct clinical course compared to pneumonitis secondary to chemotherapy. Importantly, IRAE-pneumonitis features decreased over time, suggesting that careful consideration of the benefit-risk ratio may allow for continuation of immunotherapy in some patients who develop pneumonitis.

Discovery and characterization of orally bioavailable 4-chloro-6-fluoroisophthalamides as covalent PPARG inverse-agonists.

PPAR gamma (PPARG) is a ligand activated transcription factor that regulates genes involved in inflammation, bone biology, lipid homeostasis, as well as a master regulator of adipogenesis and a potential lineage driver of luminal bladder cancer. While PPARG agonists lead to transcriptional activation of canonical target genes, inverse agonists have the opposite effect through inducing a transcriptionally repressive complex leading to repression of canonical target gene expression. While many agonists have been described and tested clinically, inverse agonists offer an underexplored avenue to modulate PPARG biology in vivo. Current inverse agonists lack favorable in vivo properties; herein we describe the discovery and characterization of a series of orally bioavailable 4-chloro-6-fluoroisophthalamides as covalent PPARG inverse-agonists, BAY-5516, BAY-5094, and BAY-9683. Structural studies of this series revealed distinct pre- and post-covalent binding positions, which led to the hypothesis that interactions in the pre-covalent conformation are primarily responsible for driving affinity, while interactions in the post-covalent conformation are more responsible for cellular functional effects by enhancing PPARG interactions with its corepressors. The need to simultaneously optimize for two distinct states may partially explain the steep SAR observed. Exquisite selectivity was achieved over related nuclear receptors in the subfamily due in part to a covalent warhead with low reactivity through an SNAr mechanism in addition to the specificity gained through covalent binding to a reactive cysteine uniquely positioned within the PPARG LBD. BAY-5516, BAY-5094, and BAY-9683 lead to pharmacodynamic regulation of PPARG target gene expression in vivo comparable to known inverse agonist SR10221 and represent new tools for future in vivo studies to explore their potential utility for treatment of disorders of hyperactivated PPARG including luminal bladder cancer and other disorders.

A 52-Year-Old Man With Chest Pain and Dyspnea.

CASE PRESENTATION: A 52-year-old man came to the cardiac surgery clinic for pulmonary thromboendarterectomy (PTE) evaluation. He had initially appeared at an outside hospital 1 year earlier, with chest pain and shortness of breath. He had no known chronic conditions. A CT pulmonary angiogram (CTPA) at that time showed a filling defect at the bifurcation of the main pulmonary artery. A transthoracic echocardiogram revealed mild mitral valve regurgitation, but otherwise the results were normal. As he was hemodynamically stable and not hypoxemic, he was treated solely by anticoagulation. Despite adhering to prescribed apixaban, he developed progressive dyspnea and reduced exercise tolerance over the subsequent year. A repeat CTPA performed 12 months after the initial presentation showed a persistent filling defect at the level of the pulmonary artery bifurcation, with a new extension now completely occluding the right main pulmonary artery. A pulmonary angiogram confirmed this complete occlusion, and right heart catheterization revealed precapillary pulmonary hypertension, with a mean pulmonary artery pressure of 50 mm Hg. His anticoagulation was transitioned to enoxaparin for presumed apixaban treatment failure, and an investigation for hypercoagulable conditions was initiated. His lupus anticoagulant test result was positive, but he did not meet the criteria for antiphospholipid syndrome because he was negative for anticardiolipin and ß2-glycoprotein antibodies. Assays for antithrombin III, protein C, prothrombin gene, and factor V Leiden mutations produced normal results.

Discovery and Structure-Based Design of Potent Covalent PPARγ Inverse-Agonists BAY-4931 and BAY-0069.

The ligand-activated nuclear receptor peroxisome-proliferator-activated receptor-γ (PPARG or PPARγ) represents a potential target for a new generation of cancer therapeutics, especially in muscle-invasive luminal bladder cancer where PPARγ is a critical lineage driver. Here we disclose the discovery of a series of chloro-nitro-arene covalent inverse-agonists of PPARγ that exploit a benzoxazole core to improve interactions with corepressors NCOR1 and NCOR2. In vitro treatment of sensitive cell lines with these compounds results in the robust regulation of PPARγ target genes and antiproliferative effects. Despite their imperfect physicochemical properties, the compounds showed modest pharmacodynamic target regulation in vivo. Improvements to the in vitro potency and efficacy of BAY-4931 and BAY-0069 compared to those of previously described PPARγ inverse-agonists show that these compounds are novel tools for probing the in vitro biology of PPARγ inverse-agonism.

Virtual screening for small-molecule pathway regulators by image-profile matching.

Identifying the chemical regulators of biological pathways is a time-consuming bottleneck in developing therapeutics and research compounds. Typically, thousands to millions of candidate small molecules are tested in target-based biochemical screens or phenotypic cell-based screens, both expensive experiments customized to each disease. Here, our uncustomized, virtual, profile-based screening approach instead identifies compounds that match to pathways based on the phenotypic information in public cell image data, created using the Cell Painting assay. Our straightforward correlation-based computational strategy retrospectively uncovered the expected, known small-molecule regulators for 32% of positive-control gene queries. In prospective, discovery mode, we efficiently identified new compounds related to three query genes and validated them in subsequent gene-relevant assays, including compounds that phenocopy or pheno-oppose YAP1 overexpression and kill a Yap1-dependent sarcoma cell line. This image-profile-based approach could replace many customized labor- and resource-intensive screens and accelerate the discovery of biologically and therapeutically useful compounds.

An International Perspective on Preceding Infections in Guillain-Barré Syndrome: The IGOS-1000 Cohort.

BACKGROUND AND OBJECTIVES: Infections play a key role in the development of Guillain-Barré syndrome (GBS) and have been associated with specific clinical features and disease severity. The clinical variation of GBS across geographical regions has been suggested to be related to differences in the distribution of preceding infections, but this has not been studied on a large scale. METHODS: We analyzed the first 1,000 patients included in the International GBS Outcome Study with available biosamples (n = 768) for the presence of a recent infection with Campylobacter jejuni, hepatitis E virus, Mycoplasma pneumoniae, cytomegalovirus, and Epstein-Barr virus. RESULTS: Serologic evidence of a recent infection with C. jejuni was found in 228 (30%), M. pneumoniae in 77 (10%), hepatitis E virus in 23 (3%), cytomegalovirus in 30 (4%), and Epstein-Barr virus in 7 (1%) patients. Evidence of more than 1 recent infection was found in 49 (6%) of these patients. Symptoms of antecedent infections were reported in 556 patients (72%), and this proportion did not significantly differ between those testing positive or negative for a recent infection. The proportions of infections were similar across continents. The sensorimotor variant and the demyelinating electrophysiologic subtype were most frequent across all infection groups, although proportions were significantly higher in patients with a cytomegalovirus and significantly lower in those with a C. jejuni infection. C. jejuni-positive patients were more severely affected, indicated by a lower Medical Research Council sum score at nadir (p = 0.004) and a longer time to regain the ability to walk independently (p = 0.005). The pure motor variant and axonal electrophysiologic subtype were more frequent in Asian compared with American or European C. jejuni-positive patients (p < 0.001, resp. p = 0.001). Time to nadir was longer in the cytomegalovirus-positive patients (p = 0.004). DISCUSSION: Across geographical regions, the distribution of infections was similar, but the association between infection and clinical phenotype differed. A mismatch between symptom reporting and serologic results and the high frequency of coinfections demonstrate the importance of broad serologic testing in identifying the most likely infectious trigger. The association between infections and outcome indicates their value for future prognostic models.

Identification of ADAR1 adenosine deaminase dependency in a subset of cancer cells.

Systematic exploration of cancer cell vulnerabilities can inform the development of novel cancer therapeutics. Here, through analysis of genome-scale loss-of-function datasets, we identify adenosine deaminase acting on RNA (ADAR or ADAR1) as an essential gene for the survival of a subset of cancer cell lines. ADAR1-dependent cell lines display increased expression of interferon-stimulated genes. Activation of type I interferon signaling in the context of ADAR1 deficiency can induce cell lethality in non-ADAR1-dependent cell lines. ADAR deletion causes activation of the double-stranded RNA sensor, protein kinase R (PKR). Disruption of PKR signaling, through inactivation of PKR or overexpression of either a wildtype or catalytically inactive mutant version of the p150 isoform of ADAR1, partially rescues cell lethality after ADAR1 loss, suggesting that both catalytic and non-enzymatic functions of ADAR1 may contribute to preventing PKR-mediated cell lethality. Together, these data nominate ADAR1 as a potential therapeutic target in a subset of cancers.

Genomic Activation of PPARG Reveals a Candidate Therapeutic Axis in Bladder Cancer.

The PPARG gene encoding the nuclear receptor PPARγ is activated in bladder cancer, either directly by gene amplification or mutation, or indirectly by mutation of the RXRA gene, which encodes the heterodimeric partner of PPARγ. Here, we show that activating alterations of PPARG or RXRA lead to a specific gene expression signature in bladder cancers. Reducing PPARG activity, whether by pharmacologic inhibition or genetic ablation, inhibited proliferation of PPARG-activated bladder cancer cells. Our results offer a preclinical proof of concept for PPARG as a candidate therapeutic target in bladder cancer. Cancer Res; 77(24); 6987-98. ©2017 AACR.

Durability of the Rituximab Response in Acetylcholine Receptor Autoantibody-Positive Myasthenia Gravis.

IMPORTANCE: Myasthenia gravis (MG), an autoimmune disorder of neuromuscular transmission, is treated by an array of immunotherapeutics, many of which are nonspecific. Even with current therapies, a subset of patients has medically refractory MG. The benefits of B-cell-targeted therapy with rituximab have been observed in MG; however, the duration of these benefits after treatment is unclear. OBJECTIVE: To evaluate the durability of response to rituximab in the treatment of acetylcholine receptor autoantibody-positive (AChR+) generalized MG. DESIGN, SETTING AND PARTICIPANTS: This retrospective case series study included 16 patients with AChR+ MG referred to an MG clinic from January 1, 2007, to December 31, 2015. The patients were treated with rituximab and followed up for 18 to 84 months after treatment. MAIN OUTCOMES AND MEASURES: Assessment of long-term clinical response, durability of response and/or relapse rate, AChR autoantibody levels, adverse effects, and inflammatory markers. RESULTS: In the 16 patients (6 men and 10 women; median age, 42 [range, 18-69] years), clinical improvement was observed in parallel with complete withdrawal or reduction of other immunotherapies, with all patients achieving complete stable remission, pharmacologic remission, or minimal manifestations based on the Myasthenia Gravis Foundation of America postintervention status criteria. Nine patients (56%) had a relapse during a mean follow-up of 36 (range, 24-47) months. Seven patients (44%) remained relapse free with a mean follow-up of 47 (range, 18-81) months since the last rituximab treatment. All values were normalized to a pretreatment anti-AChR antibody level of 100% and the mean levels after each rituximab cycle were calculated. A 33% decrease was seen after cycle 1 of rituximab treatment (100% vs 67%; P = .004); 20% after cycle 2 (compared with cycle 1) (67% vs 47%; P = .008); and 17% after cycle 3 (compared with cycle 2) (47% vs 30%; P = .02). However, the serum cytokine levels measured were found to be unchanged. CONCLUSIONS AND RELEVANCE: Rituximab therapy appears to be an effective option in patients with refractory AChR+ MG, who were observed to have a durable response after treatment. Identification of markers of disease relapse and sustained remission are critical next steps in the development of pathophysiology-relevant, evidence-based practice parameters for rituximab in the treatment of MG.

The Cost and Outcome Effectiveness of Total Hip Replacement: Technique Choice and Volume-Output Effects Matter.

BACKGROUND: Total hip replacement (THR) must be managed in a more sustainable manner. More cost-effective surgical techniques and the centralization/regionalization of services are two solutions. The former requires an assessment of newer minimally invasive and muscle-sparing surgical techniques. The latter necessitates an effective volume-outcome (VO) relationship. Prior studies have failed to evaluate and control for the VO relation. OBJECTIVE: The objective of this study was to evaluate the relative cost and outcome effectiveness of two minimally invasive and one muscle-sparing techniques while evaluating and controlling for a potentially endogenous VO relation. METHODS: An all payer claims database for all THR performed in Maine in 2011 was used. The cost and outcome effectiveness of newer minimally invasive (modified Hardinge) and muscle-sparing (modified Watson-Jones) techniques were compared with the standard bearer posterior minimally invasive method. Using regression analysis, the outcomes analyzed were as follows: total costs, length of hospital stay, nursing care and home discharges, and use of physical therapy. Regression analysis was also used to evaluate and control for VO effects. RESULTS: (1) Newer muscle-sparing and minimally invasive approaches are substantially more effective; (2) irrespective of technique, higher volume surgeons are more effective; (3) technique-specific VO effects for more complex techniques exist and show substantial savings when yearly volume exceeds 30-50; and (4) the anterolateral muscle-sparing technique is accessible to the average surgeon. CONCLUSION: Reliance on newer surgical techniques and centralization/regionalization of THR services can reduce costs.

Clinical characteristics of refractory myasthenia gravis patients.

BACKGROUND: A subset of myasthenia gravis (MG) patients is refractory to standard therapies. Identifying the characteristics of this population is essential as newer treatment strategies emerge that may be more effective in this group. OBJECTIVE: The aim of our study is to describe the clinical features of refractory MG patients and compare them to those of non-refractory patients. METHODS: A retrospective chart review was completed of 128 MG patients referred to a tertiary neuromuscular clinic from 2003 to 2011. Patients were classified as refractory or non-refractory based on predefined criteria, and clinical features were compared. RESULTS: Nineteen out of 128 patients were classified as refractory (14.8 percent). Compared to the non-refractory patients, the refractory patients were more likely to be younger at onset, female, thymomatous, and MuSK-antibody positive. CONCLUSION: Refractory MG patients represent a small but distinct group for whom exploring newer therapeutic approaches and immunopathologic differences is warranted.

Defective leukocyte GM-CSF receptor (CD116) expression and function in inflammatory bowel disease.

BACKGROUND & AIMS: Inflammatory bowel disease (IBD) refers to 2 chronic inflammatory diseases of the intestine, ie, ulcerative colitis and Crohn's disease. IBD results from environmental factors (eg, bacterial antigens) triggering a dysregulated immune response in genetically predisposed hosts. Although the basis of IBD is incompletely understood, a number of recent studies have implicated defective innate immune responses in the pathogenesis of IBD. In this regard, there is much interest in therapies that activate innate immunity (eg, recombinant granulocyte-macrophage colony-stimulating factor). METHODS: In this study, we screened expression and function of circulating leukocyte granulocyte-macrophage colony-stimulating factor receptor (CD116) messenger RNA and surface protein in 52 IBD patients and 52 healthy controls. RESULTS: Our results show that both granulocyte and monocyte CD116 levels, but not CD114 or interleukin-3Rα, were significantly decreased in IBD compared to control (P<.001) and disease controls (irritable bowel syndrome; P<.001; rheumatoid arthritis; P<.025). IBD-associated CD116 repression was more prominent in patients with ulcerative colitis compared to Crohn's disease (P<.05), was independent of disease activity (P>.05), and was not influenced by current medications (P>.05). Receiver operating characteristic curve analysis revealed that leukocyte CD116 expression is a sensitive (85%) and specific (92%) biomarker for IBD. Moreover, granulocyte CD116-mediated function (phosphorylation of signal transducers and activators of transcription 3) paralleled decreased expression of CD116 in IBD granulocytes compared to control (P<.001). CONCLUSIONS: These studies identify defective expression and function of CD116 as a distinguishing feature of IBD and implicate an associated defect in innate immune responses toward granulocyte-macrophage colony-stimulating factor.