Thrombotic Events Are Unusual Toxicities of Chimeric Antigen Receptor T-Cell Therapies.

Chimeric antigen receptor (CAR) T-cell therapy has greatly transformed the treatment and prognosis of B-cell hematological malignancies. As CAR T-cell therapy continues to be more readily adopted and indications increase, the field's recognition of emerging toxicities will continue to grow. Among the adverse events associated with CAR T-cell therapy, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) are the most common toxicities, while thrombotic events represent an under-reported, life-endangering complication. To determine thrombosis incidence post CAR T-cell therapy, we performed a multi-center, retrospective study on CAR T-cell therapy adult patients (N = 140) from Indiana University Simon Cancer Center and the University of North Carolina Medical Center treated from 2017 to 2022 for relapsed and refractory B-cell acute lymphoblastic leukemia (B-ALL, N = 3), diffuse large B-cell lymphoma (DLBCL, N = 92), follicular lymphoma (FL, N = 9), mantle cell lymphoma (MCL, N = 2), and multiple myeloma (MM, N = 34). We report 10 (7.14%) thrombotic events related to CAR T-cell therapy (DLBCL: N = 8, FL: N = 1, MM: N = 1) including 9 primary venous events and 1 arterial event that occurred with median time of 23.5 days post CAR T-cell infusion. In search of parameters associated with such events, we performed multivariate analyses of coagulation parameters (i.e., PT, PTT, and D-Dimer), scoring for adverse events (Padua Score and ISTH DIC Score) and grading for CAR T-cell toxicity severity (CRS grade and ICANS grade) and found that D-Dimer peak elevation and ICANS grade were significantly associated with post-CAR T-cell infusion thrombosis. While the pathophysiology of CAR T-cell associated coagulopathy remains unknown, our study serves to develop awareness of these emerging and unusual complications.

Incidence of venous thromboembolism in the setting of hematopoietic cell transplantation.

The underlying risk of venous thromboembolism (VTE) is unclear in patients undergoing hematopoietic cell transplantation (HCT). As such, these patients should still be considered at risk for development of VTE due to factors such as their underlying malignancy and the marked inflammatory state that develops from treatment. The purpose of this study was to characterize the incidence of VTE in patients undergoing HCT. Retrospective chart review of patients from the Indiana University Stem Cell Transplant Unit treated between January 1, 2008, and May 24, 2011. Patients were older than 18 years and had undergone HCT. The primary objective was to analyze the incidence of VTE in patients undergoing autologous HCT versus allogeneic HCT. Secondary objectives included documentation of VTE treatment strategies and time to occurrence of VTE. Of the 567 patients who underwent autologous HCT, 14 developed VTE (2.5%), whereas 5 of the 180 patients who underwent allogeneic HCT developed VTE (2.8%; P = 1.000). The median time to development of VTE from admission for HCT was 12 days in the autologous HCT arm versus 19 days in the allogeneic HCT arm (P = 0.610). The most commonly used VTE treatment strategy was enoxaparin (12 out of 19 VTEs). This study illustrates that VTE does occur rarely in patients who have undergone HCT. The optimal treatment regimen in this population requires further evaluation. Until a reliable protocol for treatment and evidence for risk factors are established, providers should be vigilant for occurrence of VTE in these patients.

CAR T cell Toxicities: Bedside to Bench - How Novel Toxicities Inform Laboratory Investigations.

Multiple chimeric antigen receptor (CAR) T cell therapies are FDA approved, and several are under development. While effective for some cancers, toxicities remain a limitation. The most common toxicities, i.e. cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS), are well described. With increasing utilization, providers worldwide are reporting on other emergent, and often complicated toxicities. Given the evolving toxicity profiles and urgent need to catalogue these emerging and emergent CAR T toxicities and describe management approaches, the American Society of Hematology Subcommittee on Emerging Gene and Cell Therapies organized the first Scientific Workshop on CAR T cell toxicities during the annual society meeting. The workshop functioned to 1) aggregate reports of CAR T emergent toxicities, including movement disorders after BCMA CAR T, coagulation abnormalities, and prolonged cytopenias; 2) disseminate bedside to bench efforts elucidating pathophysiological mechanisms of CAR-T toxicities, including the intestinal microbiota and systemic immune dysregulation; and 3) highlight gaps in the availability of clinical tests such as cytokine measurements, which could be utilized to expand our knowledge around the monitoring of toxicities. Key themes emerged. First, while clinical manifestations may develop before the pathophysiologic mechanisms are understood, these must be studied to aid in the detection and prevention of such toxicities. Second, systemic immune dysregulation appears central to these emergent toxicities and research is needed to elucidate links between tumor, CAR T, and microbiota. Finally, there was consensus around an urgency to create a repository to capture emergent CAR-T toxicities and the real-world management.

Inflammation and autoimmunity are interrelated in patients with sickle cell disease at a steady-state condition: implications for vaso-occlusive crisis, pain, and sensory sensitivity.

This study aimed to comprehensively analyze inflammatory and autoimmune characteristics of patients with sickle cell disease (SCD) at a steady-state condition (StSt) compared to healthy controls (HCs) to explore the pathogenesis of StSt and its impact on patients' well-being. The study cohort consisted of 40 StSt participants and 23 HCs enrolled between July 2021 and April 2023. StSt participants showed elevated white blood cell (WBC) counts and altered hematological measurements when compared to HCs. A multiplex immunoassay was used to profile 80 inflammatory cytokines/chemokines/growth factors in plasma samples from these SCD participants and HCs. Significantly higher plasma levels of 35 analytes were observed in SCD participants, with HGF, IL-18, IP-10, and MCP-2 being among the most significantly affected analytes. Additionally, autoantibody profiles were also altered, with elevated levels of anti-SSA/Ro60, anti-Ribosomal P, anti-Myeloperoxidase (MPO), and anti-PM/Scl-100 observed in SCD participants. Flow cytometric analysis revealed higher rates of red blood cell (RBC)/reticulocyte-leukocyte aggregation in SCD participants, predominantly involving monocytes. Notably, correlation analysis identified associations between inflammatory mediator levels, autoantibodies, RBC/reticulocyte-leukocyte aggregation, clinical lab test results, and pain crisis/sensitivity, shedding light on the intricate interactions between these factors. The findings underscore the potential significance of specific biomarkers and therapeutic targets that may hold promise for future investigations and clinical interventions tailored to the unique challenges posed by SCD. In addition, the correlations between vaso-occlusive crisis (VOC)/pain/sensory sensitivity and inflammation/immune dysregulation offer valuable insights into the pathogenesis of SCD and may lead to more targeted and effective therapeutic strategies. Clinical Trial Registration: ClinicalTrials.gov, Identifier: NCT05045820.

Inflammation and autoimmunity are interrelated in patients with sickle cell disease at a steady-state condition: implications for vaso-occlusive crisis, pain, and sensory sensitivity.

This study aimed to comprehensively analyze inflammatory and autoimmune characteristics of patients with sickle cell disease (SCD) at a steady-state condition (StSt) compared to healthy controls (HCs) to explore the pathogenesis of StSt and its impact on patients' well-being. The study cohort consisted of 40 StSt participants and 23 HCs enrolled between July 2021 and April 2023. StSt participants showed elevated white blood cell (WBC) counts and altered hematological measurements when compared to HCs. A multiplex immunoassay was used to profile 80 inflammatory cytokines/chemokines/growth factors in plasma samples from these SCD participants and HCs. Significantly higher plasma levels of 37 analytes were observed in SCD participants, with HGF, IL-18, IP-10, and MCP-2 being among the most significantly affected analytes. Additionally, autoantibody profiles were also altered, with elevated levels of anti-SSA/Ro60, anti-Ribosomal P, anti-Myeloperoxidase (MPO), and anti-PM/Scl-100 observed in SCD participants. Flow cytometric analysis revealed higher rates of red blood cell (RBC)/reticulocyte-leukocyte aggregation in SCD participants, predominantly involving monocytes. Notably, correlation analysis identified associations between inflammatory mediator levels, autoantibodies, RBC/reticulocyte-leukocyte aggregation, clinical lab test results, and pain crisis/sensitivity, shedding light on the intricate interactions between these factors. The findings underscore the potential significance of specific biomarkers and therapeutic targets that may hold promise for future investigations and clinical interventions tailored to the unique challenges posed by SCD. In addition, the correlations between vaso-occlusive crisis (VOC)/pain/sensory sensitivity and inflammation/immune dysregulation offer valuable insights into the pathogenesis of SCD and may lead to more targeted and effective therapeutic strategies.

Oral Iron Replacement Normalizes Fibroblast Growth Factor 23 in Iron-Deficient Patients With Autosomal Dominant Hypophosphatemic Rickets.

Autosomal dominant hypophosphatemic rickets (ADHR) is caused by mutations impairing cleavage of fibroblast growth factor 23 (FGF23). FGF23 gene expression increases during iron deficiency. In humans and mice with the ADHR mutation, iron deficiency results in increased intact FGF23 concentrations and hypophosphatemia. We conducted a prospective open label pilot clinical trial of oral iron replacement over 12 months in ADHR patients to test the hypothesis that oral iron administration would normalize FGF23 concentrations. Eligibility criteria included: FGF23 mutation; and either serum iron <50 µg/dL; or serum iron 50 to 100 µg/dL combined with hypophosphatemia and intact FGF23 >30 pg/mL at screening. Key exclusion criteria were kidney disease and pregnancy. Oral iron supplementation started at 65 mg daily and was titrated based on fasting serum iron concentration. The primary outcome was decrease in fasting intact FGF23 by ≥20% from baseline. Six adults (three male, three female) having the FGF23-R176Q mutation were enrolled; five completed the 12-month protocol. At baseline three of five subjects had severely symptomatic hypophosphatemia (phosphorus <2.5 mg/dL) and received calcitriol with or without phosphate concurrent with oral iron during the trial. The primary outcome was met by 4 of 5 (80%) subjects all by month 4, and 5 of 5 had normal intact FGF23 at month 12. Median (minimum, maximum) intact FGF23 concentration decreased from 172 (20, 192) pg/mL at baseline to 47 (17, 78) pg/mL at month 4 and 42 (19, 63) pg/mL at month 12. Median ferritin increased from 18.6 (7.7, 82.5) ng/mL at baseline to 78.0 (49.6, 261.0) ng/mL at month 12. During iron treatment, all three subjects with baseline hypophosphatemia normalized serum phosphorus, had markedly improved symptoms, and were able to discontinue calcitriol and phosphate. Oral iron repletion normalized FGF23 and phosphorus in symptomatic, iron-deficient ADHR subjects. Thus, the standard approach to ADHR should include recognition, treatment, and prevention of iron deficiency. © 2019 American Society for Bone and Mineral Research.

Single Image Super-Resolution Based on Wiener Filter in Similarity Domain.

Single image super-resolution (SISR) is an ill-posed problem aiming at estimating a plausible high-resolution (HR) image from a single low-resolution image. Current state-of-the-art SISR methods are patch-based. They use either external data or internal self-similarity to learn a prior for an HR image. External data-based methods utilize a large number of patches from the training data, while self-similarity-based approaches leverage one or more similar patches from the input image. In this paper, we propose a self-similarity-based approach that is able to use large groups of similar patches extracted from the input image to solve the SISR problem. We introduce a novel prior leading to the collaborative filtering of patch groups in a 1D similarity domain and couple it with an iterative back-projection framework. The performance of the proposed algorithm is evaluated on a number of SISR benchmark data sets. Without using any external data, the proposed approach outperforms the current non-convolutional neural network-based methods on the tested data sets for various scaling factors. On certain data sets, the gain is over 1 dB, when compared with the recent method A+. For high sampling rate (x4), the proposed method performs similarly to very recent state-of-the-art deep convolutional network-based approaches.

Experiences of Female and Male Medical Students With Death, Dying, and Palliative Care: One Size Does Not Fit All.

BACKGROUND: Medical students learn about death, dying, and palliative care (DDPC) through formal curricular offerings and informal clinical experiences; however, the lessons learned in the clinic may be at odds with the formal curriculum. Reflective writing is a means for students to "bracket" their DDPC experiences and reconcile conflicts between the formal and informal curriculum. OBJECTIVES: The aim of this study is to compare the level of reflection demonstrated in medical students' narratives on DDPC with other experiences and to examine the domains of professionalism that students perceive to be prevalent in their DDPC experiences. METHODS: Third-year medical students submitted professionalism narratives during their internal medicine clerkship. We identified a subset of narratives related to DDPC (n = 388) and randomly selected control narratives (n = 153). We assessed the level of reflection demonstrated in the narratives using a validated rubric and analyzed the professionalism domains that students identified as relevant to their experience. RESULTS: There was no difference in reflective level between DDPC and control narratives. Within the DDPC group, female students demonstrated higher reflection (2.24 ± 0.71) than male students (2.01 ± 0.77; P < .001). Caring, compassion and communication, and honor and integrity were prominent among DDPC narratives. More females identified caring, compassion, and communication as relevant to their DDPC experiences, whereas more males identified altruism. CONCLUSION: Males and females have different perceptions of DDPC experiences, and female students appear to be more deeply impacted. These findings can help clinical faculty engage students more effectively with this challenging topic.

Thrombocytopenia and disseminated histoplasmosis in immunocompetent adults.

Disseminated histoplasmosis among immunocompetent patients is rare, but may be associated with clinically significant refractory thrombocytopenia. Platelet counts often return to normal levels following antifungal therapy. Therefore, the most important management of this refractory thrombocytopenia is the recognition and treatment of histoplasmosis infection.

Physicians in Postgraduate Training Characteristics and Support of Palliative Sedation for Existential Distress.

INTRODUCTION: Palliative sedation for refractory existential distress (PS-ED) is ethically troubling but potentially critical to quality end-of-life (EOL) care. Physicians' in postgraduate training support toward PS-ED is unknown nor is it known how empathy, hope, optimism, or intrinsic religious motivation (IRM) affect their support. These knowledge gaps hinder efforts to support physicians who struggle with patients' EOL care preferences. METHODS: One hundred thirty-four postgraduate physicians rated their support of PS for refractory physical pain (PS-PP) or PS-ED, ranked the importance of patient preferences in ethically challenging situations, and completed measures of empathy, hope, optimism, and IRM. Predictors of PS-ED and PS-PP support were examined using binary and multinomial logistic regression. RESULTS: Only 22.7% of residents were very supportive of PS-ED, and 82.0% were very supportive of PS-PP. Support for PS-PP or PS-ED did not correlate with levels of empathy, hope, optimism, or IRM; however, for residents with lower IRM, greater optimism was associated with greater PS-ED support. In contrast, among residents with higher IRM, optimism was not associated with PS-ED support. CONCLUSIONS: Comparing current results to published surveys, a similar proportion of residents and practicing physicians support PS-ED and PS-PP. In contrast to practicing physicians, however, IRM does not directly influence residents' supportiveness. The interaction between optimism and IRM suggests residents' beliefs and characteristics are salient to their EOL decisions. End-of-life curricula should provide physicians opportunities to reflect on the personal and ethical factors that influence their support for PS-ED.

Texture Classification Using Dense Micro-Block Difference.

This paper is devoted to the problem of texture classification. Motivated by recent advancements in the field of compressive sensing and keypoints descriptors, a set of novel features called dense micro-block difference (DMD) is proposed. These features provide highly descriptive representation of image patches by densely capturing the granularities at multiple scales and orientations. Unlike most of the earlier work on local features, the DMD does not involve any quantization, thus retaining the complete information. We demonstrate that the DMD have dimensionality much lower than Scale Invariant Feature Transform (SIFT) and can be computed using integral image much faster than SIFT. The proposed features are encoded using the Fisher vector method to obtain an image descriptor, which considers high-order statistics. The proposed image representation is combined with the linear support vector machine classifier. Extensive experiments are conducted on five texture data sets (KTH-TIPS, UMD, KTH-TIPS-2a, Brodatz, and Curet) using standard protocols. The results demonstrate that our approach outperforms the state-of-the-art in texture classification.

Chronic myeloid leukemia within a year of kidney transplant with elevated alkaline phosphatase correlated with imatinib therapy.

The incidence of certain malignancies is significantly higher after organ transplant. However, there are rare reports of chronic myeloid leukemia in the posttransplant setting. The average reported interval between a transplant and the diagnosis of chronic myeloid leukemia is 44 months (range, 10- 96 mo). We report 2 patients with chronic myeloid leukemia within 1 year of a kidney transplant, which is significantly shorter than those previously reported. Both patients were receiving mycophenolate mofetil and tacrolimus for immunosuppression. They were treated with imatinib for chronic myeloid leukemia, and both patients demonstrated an isolated elevation of serum alkaline phosphatase that was directly correlated with imatinib. Despite a potential interaction between the 2 drugs, blood levels of tacrolimus and imatinib were not elevated during the course of treatment. Isolated elevation of alkaline phosphatase in this particular setting has not been reported previously.

Update on anticoagulant medications for the interventional radiologist.

For many years, available anticoagulant medications were limited to vitamin K antagonists, unfractionated heparin, and aspirin. However, in the past 20 years, several new agents have been developed for the treatment of thrombosis, and even more are being developed. This increasing number of medications has led to more specific treatment algorithms for the care of venous and arterial thrombotic events. As more agents become available, treatment guidelines are rapidly changing. With increasing frequency, interventional radiologists encounter patients already taking anticoagulant medications prophylactically or therapeutically, or they need to determine which anticoagulant medications need to be initiated for a particular procedure. Therefore, it has become increasingly important to understand the mechanisms, risks, and benefits of anticoagulant medications. A review of the traditional anticoagulants, their new counterparts, and their places in the medication repertoire of interventional radiology will be discussed herein.

Molecular and clinical spectrum of type I plasminogen deficiency: A series of 50 patients.

Severe type I plasminogen (PLG) deficiency has been causally linked to a rare chronic inflammatory disease of the mucous membranes that may be life threatening. Here we report clinical manifestations, PLG plasma levels, and molecular genetic status of the PLG gene of 50 patients. The most common clinical manifestations among these patients were ligneous conjunctivitis (80%) and ligneous gingivitis (34%), followed by less common manifestations such as ligneous vaginitis (8%), and involvement of the respiratory tract (16%), the ears (14%), or the gastrointestinal tract (2%). Four patients showed congenital occlusive hydrocephalus, 2 with Dandy-Walker malformation of cerebellum. Venous thrombosis was not observed. In all patients, plasma PLG levels were markedly reduced. In 38 patients, distinct mutations in the PLG gene were identified. The most common genetic alteration was a K19E mutation found in 34% of patients. Transient in vitro expression of PLG mutants R134K, delK212, R216H, P285T, P285A, T319_N320insN, and R776H in transfected COS-7 cells revealed significantly impaired secretion and increased degradation of PLG. These results demonstrate impaired secretion of mutant PLG proteins as a common molecular pathomechanism in type I PLG deficiency.