Ex vivo lung perfusion in donation after circulatory death: A post hoc analysis of the Normothermic Ex Vivo Lung Perfusion as an Assessment of Extended/Marginal Donors Lungs trial.

OBJECTIVE: Donation after circulatory death (DCD) donors offer the ability to expand the lung donor pool and ex vivo lung perfusion (EVLP) further contributes to this ability by allowing for additional evaluation and resuscitation of these extended criteria donors. We sought to determine the outcomes of recipients receiving organs from DCD EVLP donors in a multicenter setting. METHODS: This was an unplanned post hoc analysis of a multicenter, prospective, nonrandomized trial that took place during 2011 to 2017 with 3 years of follow-up. Patients were placed into 3 groups based off procurement strategy: brain-dead donor (control), brain-dead donor evaluated by EVLP, and DCD donors evaluated by EVLP. The primary outcomes were severe primary graft dysfunction at 72 hours and survival. Secondary outcomes included select perioperative outcomes, and 1-year and 3-years allograft function and quality of life measures. RESULTS: The DCD EVLP group had significantly higher incidence of severe primary graft dysfunction at 72 hours (P = .03), longer days on mechanical ventilation (P < .001) and in-hospital length of stay (P = .045). Survival at 3 years was 76.5% (95% CI, 69.2%-84.7%) for the control group, 68.3% (95% CI, 58.9%-79.1%) for the brain-dead donor group, and 60.7% (95% CI, 45.1%-81.8%) for the DCD group (P = .36). At 3-year follow-up, presence observed bronchiolitis obliterans syndrome or quality of life metrics did not differ among the groups. CONCLUSIONS: Although DCD EVLP allografts might not be appropriate to transplant in every candidate recipient, the expansion of their use might afford recipients stagnant on the waitlist a viable therapy.

Porous Precision-Templated 40 µm Pore Scaffolds Promote Healing through Synergy in Macrophage Receptor with Collagenous Structure and Toll-Like Receptor Signaling.

Porous precision-templated scaffolds (PTS) with uniform, interconnected, 40 µm pores have shown favorable healing outcomes and a reduced foreign body reaction (FBR). Macrophage receptor with collagenous structure (MARCO) and toll-like receptors (TLRs) have been identified as key surface receptors in the initial inflammatory phase of wound healing. However, the role of MARCO and TLRs in modulating monocyte and macrophage phenotypes within PTS remains uncharacterized. In this study, we demonstrate a synergetic relationship between MARCO and TLR signaling in cells inhabiting PTS, where induction with TLR3 or TLR4 agonists to 40 µm scaffold-resident cells upregulates the transcription of MARCO. Upon deletion of MARCO, the prohealing phenotype within 40 µm PTS polarizes to a proinflammatory and profibrotic phenotype. Analysis of downstream TLR signaling shows that MARCO is required to attenuate nuclear factor kappa B (NF-κB) inflammation in 40 µm PTS by regulating the transcription of inhibitory NFKB inhibitor alpha (NFKBIA) and interleukin-1 receptor-associated kinase 3 (IRAK-M), primarily through a MyD88-dependent signaling pathway. Investigation of implant outcome in the absence of MARCO demonstrates an increase in collagen deposition within the scaffold and the development of tissue fibrosis. Overall, these results further our understanding of the molecular mechanisms underlying MARCO and TLR signaling within PTS. Impact statement Monocyte and macrophage phenotypes in the foreign body reaction (FBR) are essential for the development of a proinflammatory, prohealing, or profibrotic response to implanted biomaterials. Identification of key surface receptors and signaling mechanisms that give rise to these phenotypes remain to be elucidated. In this study, we report a synergistic relationship between macrophage receptor with collagenous structure (MARCO) and toll-like receptor (TLR) signaling in scaffold-resident cells inhabiting porous precision-templated 40 µm pore scaffolds through a MyD88-dependent pathway that promotes healing. These findings advance our understanding of the FBR and provide further evidence that suggests MARCO, TLRs, and fibrosis may be interconnected.

Establishing a balloon pulmonary angioplasty program for chronic thromboembolic pulmonary hypertension: A United States single-center experience.

INTRODUCTION: Balloon pulmonary angioplasty (BPA) is a less invasive treatment alternative for patients with chronic thromboembolic pulmonary hypertension (CTEPH) who are unable to move forward with pulmonary thromboendarterectomy. This report describes a single-center experience with a nascent BPA program in the United States (US). METHODS: All patients who underwent BPA between August 2018-2021 were included in this retrospective, single-center observational cohort. Pre- and post-procedure clinical information was collected, along with procedural characteristics. RESULTS: Thirty patients began their BPA series during the study period. The majority of patients had segmental disease (n = 25, 83.3%). A total of 135 BPA procedures were performed on 417 segments. On average, patients completed 4.5 sessions and the majority of patients (n = 23, 76.7%) underwent more than 2. There were 24 episodes of hemoptysis and 20 procedural events that required treatment, typically with either heparin reversal or balloon tamponade. Of 26 participants with completed series, mean PA pressure (-6 mmHg, 95% CI -9 to -4 mmHg, p = 0.0001), PVR (-1.9 Wood units, 95% CI -2.9 to -1.0, p = 0.0002), and pulmonary compliance (-1.0 mL/mmHg, 95% CI -1.5 to -0.5, p = 0.0002) improved. Improvement was also seen in NYHA functional classification and walk distance (p = 0.01). Two deaths occurred, with one death peri-procedurally. CONCLUSION: This paper describes an early experience with BPA at a single US center. Improvement in non-invasive and invasive metrics were seen without adding a significant morbidity to an already high-risk patient population.

Paraneoplastic musculoskeletal disorders: review and update for radiologists.

Rheumatic paraneoplastic syndromes are rare syndromes that occur at distant sites from the underlying tumor and may involve the bones, joints, fasciae, muscles, or vessels. In the absence of a known tumor, early recognition of a rheumatic syndrome as paraneoplastic permits dedicated work-up for, and potentially early treatment of an occult malignancy. Although there is a continuously growing list of paraneoplastic rheumatic disorders, not all of these disorders have a well-established association with a neoplastic process. The goals of this article are to review the clinical characteristics, diagnostic work-up, and imaging findings of well-documented rheumatic paraneoplastic disorders.

Diagnosis and treatment of right ventricular dysfunction in patients with COVID-19 on veno-venous extra-corporeal membrane oxygenation.

BACKGROUND: Veno-venous (VV) extracorporeal membrane oxygenation (ECMO) is an effective, but highly resource intensive salvage treatment option in COVID patients with acute respiratory distress syndrome (ARDS). Right ventricular (RV) dysfunction is a known sequelae of COVID-19 induced ARDS, yet there is a paucity of data on the incidence and determinants of RV dysfunction on VV ECMO. We retrospectively examined the determining factors leading to RV failure and means of early identification of this phenomenon in patients on VV ECMO. METHODS: The data was extracted from March 2020 to March 2021 from the regional University of Washington Extracorporeal Life Support database. The inclusion criteria included patients > 18 years of age with diagnosis of COVID-19. All had already been intubated and mechanically ventilated prior to VV ECMO deployment. Univariate analysis was performed to identify risk factors and surrogate markers for RV dysfunction. In addition, we compared outcomes between those with and without RV dysfunction. RESULTS: Of the 33 patients that met inclusion criteria, 14 (42%) had echocardiographic evidence of RV dysfunction, 3 of whom were placed on right ventricular assist device support. Chronic lung disease was an independent risk factor for RV dysfunction (p = 0.0002). RV dysfunction was associated with a six-fold increase in troponin I (0.07 ng/ml vs. 0.44 ng/ml, p = 0.039) and four-fold increase in brain natriuretic peptide (BNP) (158 pg/ml vs. 662 pg/ml, p = 0.037). Deep vein thrombosis (DVT, 21% vs. 43%, p = 0.005) and pulmonary embolism (PE, 11% vs. 21%, p = 0.045) were found to be nearly twice as common in the RV dysfunction group. Total survival rate to hospital discharge was 39%. Data trended towards shorter duration of hospital stay (47 vs. 65.6 days, p = 0.15), shorter duration of ECMO support (21 days vs. 36 days, p = 0.06) and improved survival rate to hospital discharge (42.1% vs. 35.7%, p = 0.47) for those with intact RV function compared to the RV dysfunction group. CONCLUSIONS: RV dysfunction in critically ill patients with COVID-19 pneumonia in common. Trends of troponin I and BNP may be important surrogates for monitoring RV function in patients on VV ECMO. We recommend echocardiographic assessment of the RV on such patients.

CT Scan versus Saline Load Test for Detection of Traumatic Wrist Arthrotomy.

Background Traumatic arthrotomy of the wrist is most commonly detected using the saline load test (SLT); however, little data exists on the effectiveness of the SLT to this specific joint. The use of computed tomography (CT) scan has been validated as an alternative method to detect traumatic arthrotomy of the knee, as the presence of intra-articular air can be seen when there is violation of the joint capsule. Question/Purpose The purpose of this study was to determine the ability of CT scan to identify arthrotomy of the wrist capsule and compare the diagnostic performance of CT versus traditional SLT. Materials and Methods Ten fresh frozen cadavers which had undergone transhumeral amputation were initially used in this study. A baseline CT scan was performed to ensure no intra-articular air existed prior to intervention. After baseline CT, an arthrotomy was created at the 6R radiocarpal portal site. The wrists then underwent a postarthrotomy CT to identify the presence or absence of intra-articular air. Following CT, the wrists were subjected to the SLT to detect the presence of extravasation from the arthrotomy. Results Nine cadavers were included following baseline CT scan. Following arthrotomy, intra-articular air was visualized in eight of the nine cadavers in the postarthrotomy CT scan. Air was seen in the radiocarpal joint in eight of the nine wrists; midcarpal joint in seven of the nine wrists; and distal radioulnar joint in six of the nine wrists. All wrists (nine of the nine) demonstrated extravasation during the SLT. The mean volume of extravasation occurred at 3.7 mL (standard deviation = 2.6 mL), with a range of 1 to 7 mL. Conclusion CT scan correctly identified eight of the nine simulated traumatic arthrotomies. Injection of 7 mL during the SLT was necessary to identify 100% of the arthrotomies. Clinical Relevance CT scan is a sensitive modality for detection of traumatic arthrotomy of the wrist in a cadaveric model.

Revisiting the Case of Sarah Newbury's Death from Mollities Ossium.

Multiple myeloma and its precursor and variant types represent some of the most common hematologic malignancies in adults. These plasma cell dyscrasias are well-known in modern medicine. There are well-established clinical, laboratory, and pathologic criteria for diagnosis and staging. There is debate about the diagnosis of some of the earliest cases of myeloma described in the literature. We present a critical review of one such case.

Society of Skeletal Radiology- white paper. Guidelines for the diagnostic management of incidental solitary bone lesions on CT and MRI in adults: bone reporting and data system (Bone-RADS).

The purpose of this article is to present algorithms for the diagnostic management of solitary bone lesions incidentally encountered on computed tomography (CT) and magnetic resonance (MRI) in adults. Based on review of the current literature and expert opinion, the Practice Guidelines and Technical Standards Committee of the Society of Skeletal Radiology (SSR) proposes a bone reporting and data system (Bone-RADS) for incidentally encountered solitary bone lesions on CT and MRI with four possible diagnostic management recommendations (Bone-RADS1, leave alone; Bone-RADS2, perform different imaging modality; Bone-RADS3, perform follow-up imaging; Bone-RADS4, biopsy and/or oncologic referral). Two algorithms for CT based on lesion density (lucent or sclerotic/mixed) and two for MRI allow the user to arrive at a specific Bone-RADS management recommendation. Representative cases are provided to illustrate the usability of the algorithms.

Activators of the Anticipatory Unfolded Protein Response with Enhanced Selectivity for Estrogen Receptor Positive Breast Cancer.

Approximately 75% of breast cancers are estrogen receptor alpha-positive (ERα+), and targeting ERα directly with ERα antagonists/degraders or indirectly with aromatase inhibitors is a successful therapeutic strategy. However, such treatments are rarely curative and development of resistance is universal. We recently reported ErSO, a compound that induces ERα-dependent cancer cell death through a mechanism distinct from clinically approved ERα drugs, via hyperactivation of the anticipatory unfolded protein response. ErSO has remarkable tumor-eradicative activity in multiple ERα+ tumor models. While ErSO has promise as a new drug, it has effects on ERα-negative (ERα-) cells in certain contexts. Herein, we construct modified versions of ErSO and identify variants with enhanced differential activity between ERα+ and ERα- cells. We report ErSO-DFP, a compound that maintains antitumor efficacy, has enhanced selectivity for ERα+ cancer cells, and is well tolerated in rodents. ErSO-DFP and related compounds represent an intriguing new class for the treatment of ERα+ cancers.

Myeloma Response Assessment and Diagnosis System (MY-RADS): strategies for practice implementation.

Structured reporting systems have been developed for many organ systems and disease processes beginning with BI-RADS in 1993. Numerous reports indicate that referring health care providers prefer structured reports. Reducing variability of reports from one radiologist to another helps referring physician and patient confidence. Changing radiologists practice habits from completely free text to structured reports can be met with some resistance, but most radiologists quickly find that structured reports make their job easier. Whole-body MR studies are recommended as first-line imaging, by the International Myeloma Working Group (IMWG), for all patients with suspected diagnosis of asymptomatic myeloma and/or initial diagnosis of solitary plasmacytoma. Whole-body MR imaging (WBMRI) has been shown to have equal or greater sensitivity and specificity compared to PET/CT for detection of bone marrow involvement. Changing to WBMRI from other imaging modalities can be difficult for referring providers. Patient acceptance is high. MY-RADS is for myeloma patients who have WBMRI studies done. The intent of the system is to promote uniformity in MR imaging acquisition, diagnostic criteria, and response assessment and to diminish differences in the subsequent interpretation and reporting. A secondary benefit is a report template that provides a guide for interpretation for radiologists who may not have previously dictated these difficult studies. The characterization of bone marrow abnormalities in myeloma patients usually is fairly straightforward. To date, there is no standardized scoring or risk stratification of abnormalities nor is there an imaging atlas of abnormalities.

Updates and Ongoing Challenges in Imaging of Multiple Myeloma: AJR Expert Panel Narrative Review.

Advances in the understanding and treatment of multiple myeloma have led to the need for more sensitive and accurate imaging of intramedullary and extramedullary disease. This role of imaging is underscored by recently revised imaging recommendations of the International Myeloma Working Group (IMWG). This narrative review discusses these recommendations from the IMWG for different disease stages, focusing on advanced whole-body modalities, and addresses related challenges and controversies. In the recommendations, whole-body low-dose CT is central in initial patient assessment, replacing the conventional skeletal survey. Although the recommendations favor MRI for diagnosis because of its superior sensitivity and utility in identifying myeloma-defining events, FDG PET/CT is recommended as the modality of choice for assessing treatment response. Consensus opinions are offered regarding the role of imaging in multiple myeloma for characterization of disease distribution, determination of prognosis, and response evaluation.

Transcriptional analysis of cystic fibrosis airways at single-cell resolution reveals altered epithelial cell states and composition.

Cystic fibrosis (CF) is a lethal autosomal recessive disorder that afflicts more than 70,000 people. People with CF experience multi-organ dysfunction resulting from aberrant electrolyte transport across polarized epithelia due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CF-related lung disease is by far the most important determinant of morbidity and mortality. Here we report results from a multi-institute consortium in which single-cell transcriptomics were applied to define disease-related changes by comparing the proximal airway of CF donors (n = 19) undergoing transplantation for end-stage lung disease with that of previously healthy lung donors (n = 19). Disease-dependent differences observed include an overabundance of epithelial cells transitioning to specialized ciliated and secretory cell subsets coupled with an unexpected decrease in cycling basal cells. Our study yields a molecular atlas of the proximal airway epithelium that will provide insights for the development of new targeted therapies for CF airway disease.

Potential role of exosome-based allorecognition pathways involved in lung transplant rejection.

Innate and adaptive immunity both contribute to allorecognition mechanisms that drive rejection after lung transplantation. Classic allorecognition pathways have been extensively described, but there continues to be several unanswered questions. Exosome research appears to be a novel and potentially significant area of allorecognition research and could be the missing link that answers some existing questions. This article reviews literature that is associated with allorecognition pathways and the role of exosomes in alloreactivity.

Uniform 40-µm-pore diameter precision templated scaffolds promote a pro-healing host response by extracellular vesicle immune communication.

Implanted porous precision templated scaffolds (PTS) with 40-µm spherical pores reduce inflammation and foreign body reaction (FBR) while increasing vascular density upon implantation. Larger or smaller pores, however, promote chronic inflammation and FBR. While macrophage (MØ) recruitment and polarization participates in perpetuating this pore-size-mediated phenomenon, the driving mechanism of this unique pro-healing response is poorly characterized. We hypothesized that the primarily myeloid PTS resident cells release small extracellular vesicles (sEVs) that induce pore-size-dependent pro-healing effects in surrounding T cells. Upon profiling resident immune cells and their sEVs from explanted 40-µm- (pro-healing) and 100-µm-pore diameter (inflammatory) PTS, we found that PTS pore size did not affect PTS resident immune cell population ratios or the proportion of myeloid sEVs generated from explanted PTS. However, quantitative transcriptomic assessment indicated cell and sEV phenotype were pore size dependent. In vitro experiments demonstrated the ability of PTS cell-derived sEVs to stimulate T cells transcriptionally and proliferatively. Specifically, sEVs isolated from cells inhabiting explanted 100 µm PTS significantly upregulated Th1 inflammatory gene expression in immortalized T cells. sEVs isolated from cell inhabiting both 40- and 100-µm PTS upregulated essential Treg transcriptional markers in both primary and immortalized T cells. Finally, we investigated the effects of Treg depletion on explanted PTS resident cells. FoxP3+ cell depletion suggests Tregs play a unique role in balancing T cell subset ratios, thus driving host response in 40-µm PTS. These results indicate that predominantly 40-µm PTS myeloid cell-derived sEVs affect T cells through a distinct, pore-size-mediated modality.

Incidental long bone cartilage lesions: is any further imaging workup needed?

OBJECTIVE: To determine the rate of chondrosarcoma in incidentally discovered painless long bone cartilage lesions and to determine if any further imaging is needed. MATERIALS AND METHODS: A cartilage lesion was said to be an enchondroma when it had characteristic matrix mineralization and no aggressive features. Search of all imaging reports and tumor board files for keywords enchondroma, cartilage lesion, chondroid, and chondrosarcoma. Retrospective review of medical records and imaging studies from 4.5-year period. Data points collected included patient age, sex, lesion site, size, symptoms, type of imaging, imaging appearance, and length of follow-up. Only patients with no pain were included as enchondroma. Patients with final diagnosis of chondrosarcoma were included for comparison of all features. RESULTS: Only 1/73 (1.4%) patients with an initial incidentally discovered painless lesion was later diagnosed, with new symptoms, as atypical cartilage tumor. Average age was 59.4 years. Bones involved were the femur (n = 33), humerus (n = 30), tibia (n = 7), fibula (n = 2), and ulna (n = 1). Average enchondroma size was 3.9 cm (range 1.4-11.5). Average follow-up was 47 months (range 2-196 months). Eleven long bone chondrosarcomas were identified. All chondrosarcoma patients had pain and aggressive imaging findings. CONCLUSION: Our study reveals that the rate of chondrosarcoma in incidentally found painless chondroid lesions without aggressive features in long bones is low. Imaging follow-up may be needed only in the setting of new symptoms.

Distribution of Femoral Metastases; Potential Role for Extended FDG PET/CT Scanning.

This study investigates the distribution of femoral metastases in cancer patients, specifically addressing the incidence of distal femoral metastases. PET/CT examinations routinely extend only to mid-thigh level, precluding detection of distal metastases. We found a total of 208 femoral metastases in 112 patients. 30% had distal femoral metastases in addition to other areas of involvement. 7% of patients with femoral metastases had only distal femur disease. 6 patients had distal pathologic fractures. Exclusion of the distal femur during PET/CT may result in a missed or delayed diagnosis that could contribute to the development of a pathologic fracture with increased morbidity.

Dual energy CT can aid in the emergent differentiation of acute traumatic and pathologic fractures of the pelvis and long bones.

PURPOSE: To determine whether dual energy CT (DECT) scanning can aid in the differentiation between acute traumatic and pathologic fractures of the pelvis and long bones. METHODS: Retrospective review of 11 patients with 15 pathologic fractures proven by biopsy and/or other advanced imaging modalities. Age- and sex-matched patients with non-pathologic traumatic fractures were used as controls. Studies were reviewed by two readers on syngo.via software before and after the creation of virtual bone marrow color maps. Hounsfield units (HU) of the marrow space at the level of the fracture were recorded on both reviews. Differences between the HU of the bone marrow of traumatic and pathologic fractures were compared using two-tailed unpaired t-test. RESULTS: A statistically significant difference was found in the HU of the affected bone marrow on DECT virtual noncalcium bone marrow color maps between the pathologic group (mean HU:4.89) and the non-pathologic group (mean HU: - 286.2) (p = 0.0177). HU measurements on the mixed kVp images were 150.4 for the pathologic and 94.1 for the non-pathologic fracture groups, respectively, with no statistical significance (p = 0.272). CONCLUSIONS: DECT scanning can aid in the differentiation between hematoma at acute traumatic fracture sites and neoplasm at pathologic fracture sites. HU of the bone marrow is higher for pathologic fractures, and the difference in bone marrow attenuation is more evident on the virtual bone marrow color maps.

Underweight Patients With Cystic Fibrosis Have Acceptable Survival Following Lung Transplantation: A United Network for Organ Sharing Registry Study.

BACKGROUND: Reduced BMI is an absolute contraindication for lung transplantation (LTx) at most centers in the United States. The objective of this study was to quantify post-LTx survival of moderate to severely underweight patients with cystic fibrosis (CF) (BMI < 17 kg/m2) in the United States relative to normal-weight recipients with CF and other frequently transplanted patient cohorts. METHODS: Using United Network for Organ Sharing Registry data (undergoing transplant from June 2005-November 2015), Kaplan-Meier estimates of median posttransplant survival were calculated for all patients with CF, COPD, and idiopathic pulmonary fibrosis (IPF), as well as low and normal weight CF subgroups. Cox regression modeling stratified according to transplant center assessed risk of posttransplant mortality in recipients with CF and a BMI < 17 kg/m2 compared with recipients with COPD (reference). RESULTS: Median posttransplant survival (95% CI) for CF, COPD, and IPF was 7.9 (7.2-8.6), 5.9 (5.6-6.2), and 5.5 (5.2-5.8) years, respectively. Although an absolute decrease was noted in posttransplant survival for recipients with CF and a BMI < 17 kg/m2, compared with those with CF and a BMI ≥ 17 kg/m2 (7.0 years [4.5-7.9] vs 8.2 years [7.3-9.0]), Cox modeling found no increased mortality risk (adjusted hazard ratio, 1.09; 95% CI, 0.90-1.32; P = .38). There was no difference in posttransplant mortality between patients with CF and a BMI < 17 kg/m2 and recipients with COPD and all BMIs (adjusted hazard ratio, 1.04; 95% CI, 0.86-1.25; P = .71). CONCLUSIONS: Transplant recipients with CF and a BMI < 17 kg/m2 had posttransplant survival rates comparable to those of other groups frequently undergoing transplantation. BMI < 17 kg/m2 as a single risk factor in the CF population should not be treated as an absolute contraindication to LTx.