Adamski, Jill

Abstract Purpose: Naturally occurring tumor-specific T cells derived from peripheral blood (PB) offer a clinically accessible source for adoptive immunotherapy. However, the expansion of these T cells from patients with cancer remains a challenge. We hypothesized that mimicking innate immune activation could optimally stimulate antigen-driven T-cell expansion in vitro, unlocking the therapeutic potential of PB-derived T cells. Patients and Methods: We previously developed an ex vivo culture system that selectively expands tumor antigen–activated T cells from PB mononuclear cells (PBMC), generating multiclonal effector and central memory T cells. In this hypothesis-generating study, we evaluated the therapeutic potential of MUC1-activated T cells in patients with relapsed and/or refractory multiple myeloma (r/rMM) in a phase I clinical trial (NCT05411497). MUC1 is an oncoprotein overexpressed in r/rMM. We translated our small-scale culture into GMP-compliant, large-scale manufacturing, which achieved expansion of T cells from heavily pretreated patients’ PBMCs without exhaustion. Five patients were treated with escalating doses of up to 1 × 1010 T cells. Results: Although the cell infusions were well tolerated, no objective responses occurred. One patient, who received the highest dose, has had stable disease for 2 years after infusion. This patient exhibited transient dermatitis with localized MUC1 and CD3 staining, as potential evidence of on-target, off-tumor T-cell reactivity, perhaps contributing to disease stabilization. T-cell receptor sequencing revealed the T-cell product in four of the patients’ blood, which correlated with the product’s degree of polyfunctionality and MUC1 reactivity. Conclusions: These findings demonstrate the feasibility, safety, and biological activity of PB-derived, MUC1-specific T cells as adoptive immunotherapy. Significance: Expanding tumor antigen–specific T cells for clinical use from the blood of heavily pretreated patients with cancer remains a significant hurdle. We scale up a novel culture method that integrates innate immune signals to stimulate T-cell expansion and demonstrate safety, feasibility, and a case of long-term disease stabilization upon treatment of patients with multiple myeloma in a phase I clinical trial.

ABSTRACT We report a case of fulminant Clostridium perfringens septicemia complicated by massive intravascular hemolysis in a 19‐year‐old male with acute myelogenous leukemia. The patient presented with severe anemia and laboratory evidence of profound hemolysis. Despite the high mortality associated with this condition, the patient was successfully treated with broad‐spectrum antibiotics, including clindamycin, and three consecutive sessions of therapeutic plasma exchange (TPE). TPE was employed to remove circulating α‐toxin and cell‐free hemoglobin, thereby mitigating ongoing hemolysis and organ injury. This case highlights the potential role of TPE, in conjunction with appropriate antimicrobial therapy, as an intervention in C. perfringens septicemia with hemolysis.

Abstract Background: Recombinant activated factor VIIa (rFVIIa, NovoSeven®) is an FDA-approved medication for managing bleeding in patients with hemophilia A or B with inhibitors and for those with congenital factor VII deficiency. Its use has expanded off-label in the perioperative context to manage unexpected bleeding complications. However, there is still a gap in real-world data regarding institutional practices, dosing, and outcomes associated with rFVIIa. Methods: With IRB approval, we identified patients who received rFVIIa in the perioperative period between 2020 to 2024 at Mayo Clinic. A detailed chart review was conducted to gather demographic data, comorbid conditions, bleeding disorders, timing, and dosing of perioperative rFVIIa (pre-, intra-, and postoperative), along with postoperative outcomes. We focused on thrombotic and bleeding events, hospital readmissions, and return to the operating room (OR). Descriptive statistics were used for patient characteristics, rFVIIa dosing patterns, and postoperative complications. Type of surgical interventions were stratified based on UCLA perioperative risk stratifications, with a risk score of 5 equating to very high risk surgery and a score of 1 equating to very low risk surgery. Results: Of the 55 patients included, the median age at surgery was 42.3 years (SD 27.4), and 69% were male. The majority were non-Hispanic white (91%). The most common bleeding diatheses were Factor VII deficiency (54.6%), Factor VIII inhibitor (12.7%), and Glanzmann thrombasthenia (7.3%). Less frequent conditions included Hemophilia A (3.6%) and Hemophilia A with inhibitors (3.6%). Among patients with Factor VII deficiency, mild deficiency accounted for 65.9% of cases, followed by severe (19.5%) and moderate (14.6%) forms. Adjunctive medications to control bleeding included emicizumab, FEIBA, and rituximab. Mean estimated blood loss was 136 mL (SD 211 mL), and mean length of stay was 5.7 days (SD 6.4). Surgical risk strongly correlated with perioperative outcomes: blood loss increased from 19 mL in very low-risk surgeries to 352 mL in very high-risk surgeries, while mean length of stay increased from 4.5 days (risk 1) to 19 days (risk 4) and 11 days (risk 5). Actual rFVIIa dosing ranged from 7.2 to 7211.5 mcg/kg per dose, with a median of 67.4 mcg/kg and a mean of 852.8 mcg/kg, reflecting variability in clinical practice. When stratified by surgical risk, the highest median doses were observed in very low- and low-risk surgeries (84.4 and 86.8 mcg/kg, respectively), while very high-risk surgeries had the lowest median dose (30.0 mcg/kg). In the postoperative period, thrombotic events did not occur in the first 90 days but were documented in 1.8% of patients between 90 and 365 days and in 1.8% after 365 days. Bleeding complications were frequent and demonstrated predominance in the immediate post-op period. Within the first 30 days after surgery, 18.2% of patients experienced bleeding complications, with 3.6% classified as major and 14.5% classified as minor, based on ISTH criteria. Between 30 and 90 days, bleeding complications occurred in 9.1% of patients (3.6% major and 5.5% minor), between 90 and 365 days, bleeding was observed in 10.9% of patients, all of which were minor, and beyond one year, bleeding complications were documented in 23.6% of patients, with 3.6% major and 21.8% minor. Readmissions were also common and followed a similar time distribution. In the first 30 days, 7.3% of patients had readmissions related to the prior surgery, and 3.6% had unrelated readmissions. Between 30 and 90 days, 3.6% of readmissions were related and 3.6% were unrelated. Between 90 and 365 days, 3.6% were related and 14.5% were unrelated to the initial procedure. Returns to the OR occurred in 1.8% of patients between 30 and 90 days and in 1.8% between 90 and 365 days. Conclusions: In conclusion, perioperative rFVIIa was most frequently used for Factor VII deficiency but was also administered to patients with Factor VIII inhibitor and Glanzmann's thrombasthenia, as well as several rare congenital and acquired bleeding disorders. Postoperative thrombotic events were rare, while ISTH-defined bleeding complications and readmissions were common. Most bleeding complications were minor, but their frequency was highest in the early postoperative period and again beyond one year. High-risk surgeries were associated with greater blood loss, prolonged hospitalization, and a higher burden of postoperative complications.

Purpose: Autologous serum tears (ASTs) are produced from serum obtained by blood draw and used to treat severe dry eye diseases. Multiple cases of failed AST production occurred due to serum becoming a solidified, gel-like substance after centrifugation. The aim of this study was to identify risk factors associated with inability to compound AST. Methods: From January 2019 to December 2022, 99 patients received AST produced at Mayo Clinic in Arizona. Patient demographics, medical diagnoses, medications, laboratory results, and events surrounding blood draws were obtained through an IRB-approved retrospective chart review. The laboratory and pharmacy protocol procedures were observed in person after the occurrence of the last production issue. Results: Ten total clotted serum episodes occurred in 4 patients, each with multiple occurrences. The indication for AST was chronic ocular graft-vs-host disease (n = 3) and Sjögren syndrome (n = 1). Eighty percent of episodes were associated with either a systemic infection (n = 7) or pulmonary embolism (n = 1) within the prior month. At the time of blood draw, all 4 patients were treated with antiplatelet and/or anticoagulation medications, including rivaroxaban, apixaban, aspirin, and low–molecular-weight heparin. Conclusions: The AST protocol was increased from 30 to 60 minutes of resting time to allow clotting before centrifugation. Inadequate clotting during this stasis period likely resulted in fibrinogen remaining suspended in the serum, leading to solidified plasma instead of liquid serum. We hypothesize risk of inadequate clotting would be increased in patients taking anticoagulation or antiplatelet medications. Our recommendations include ensuring 60-minute collection tube resting time for all patients, including those on anticoagulation medication.

The use of normothermic machine perfusion (NMP) over static cold storage in liver transplantation has been shown to reduce posttransplant risks of early allograft dysfunction, primary nonfunction, and ischemic cholangiopathy, and its increasing use has played a role in the expanded utilization of marginal livers. While studies have demonstrated improved clinical outcomes using NMP over static cold storage preservation, real-time intraoperative data reflecting the quality and viability of NMP livers is limited. This retrospective, single-center study compared NMP versus static cold storage livers in first-time recipients of liver transplants through the evaluation of synthetic coagulation function as measured by thromboelastography and conventional coagulation testing. Secondarily, transfusion utilization between the 2 cohorts was reviewed. One hundred eighty-six recipients of liver transplants receiving allografts from donors after circulatory death were included in the study, of which 99 (53%) allografts were preserved in static cold storage, and 87 (47%) allografts were placed on the TransMedics Organ Care System. Study findings showed NMP livers supported with the TransMedics Organ Care System were associated with increased synthetic coagulation function and less excess fibrinolysis in the postreperfusion period compared to static cold storage livers, and that these findings were better reflected in real-time with thromboelastography monitoring versus conventional coagulation testing. Following reperfusion, there was a significant decrease in the transfusion of blood products in the NMP group compared with that in the static cold storage group. Overall, we determined that the use of intraoperative thromboelastography can provide real-time data to assess one aspect of reperfusion liver quality and viability.

Abstract This manuscript describes a novel approach for treating patients with long‐term sequelae from hemoglobin Evans (Hb Evans). After instituting conservative therapies for approximately 2 years, our patient's symptoms continually worsened. Therefore, we performed red blood cell exchange (RBCx) to reduce his Hb Evans percentage and his co‐existing elevation of methemoglobin. Our assumptions of clinical benefit were based on our collective experience performing RBCx for patients with sickle cell disease. After the first exchange, pre‐ and post‐laboratory results supported our approach and the patient experienced marked improvement in his clinical signs and symptoms. This report provides preliminary proof of principle for the use of RBCx to treat Hb Evans and other non‐Hb S hemoglobinopathies.

ImportanceDirect oral anticoagulant (DOAC)–associated intracranial hemorrhage (ICH) has high morbidity and mortality. The safety and outcome data of DOAC reversal agents in ICH are limited.ObjectiveTo evaluate the safety and outcomes of DOAC reversal agents among patients with ICH.Data SourcesPubMed, MEDLINE, The Cochrane Library, Embase, EBSCO, Web of Science, and CINAHL databases were searched from inception through April 29, 2022.Study SelectionThe eligibility criteria were (1) adult patients (age ≥18 years) with ICH receiving treatment with a DOAC, (2) reversal of DOAC, and (3) reported safety and anticoagulation reversal outcomes. All nonhuman studies and case reports, studies evaluating patients with ischemic stroke requiring anticoagulation reversal or different dosing regimens of DOAC reversal agents, and mixed study groups with DOAC and warfarin were excluded.Data Extraction and SynthesisPreferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were used for abstracting data and assessing data quality and validity. Two reviewers independently selected the studies and abstracted data. Data were pooled using the random-effects model.Main Outcomes and MeasuresThe primary outcome was proportion with anticoagulation reversed. The primary safety end points were all-cause mortality and thromboembolic events after the reversal agent.ResultsA total of 36 studies met criteria for inclusion, with a total of 1832 patients (967 receiving 4-factor prothrombin complex concentrate [4F-PCC]; 525, andexanet alfa [AA]; 340, idarucizumab). The mean age was 76 (range, 68-83) years, and 57% were men. For 4F-PCC, anticoagulation reversal was 77% (95% CI, 72%-82%; I2 = 55%); all-cause mortality, 26% (95% CI, 20%-32%; I2 = 68%), and thromboembolic events, 8% (95% CI, 5%-12%; I2 = 41%). For AA, anticoagulation reversal was 75% (95% CI, 67%-81%; I2 = 48%); all-cause mortality, 24% (95% CI, 16%-34%; I2 = 73%), and thromboembolic events, 14% (95% CI, 10%-19%; I2 = 16%). Idarucizumab for reversal of dabigatran had an anticoagulation reversal rate of 82% (95% CI, 55%-95%; I2 = 41%), all-cause mortality, 11% (95% CI, 8%-15%, I2 = 0%), and thromboembolic events, 5% (95% CI, 3%-8%; I2 = 0%). A direct retrospective comparison of 4F-PCC and AA showed no differences in anticoagulation reversal, proportional mortality, or thromboembolic events.Conclusions and RelevanceIn the absence of randomized clinical comparison trials, the overall anticoagulation reversal, mortality, and thromboembolic event rates in this systematic review and meta-analysis appeared similar among available DOAC reversal agents for managing ICH. Cost, institutional formulary status, and availability may restrict reversal agent choice, particularly in small community hospitals.

AbstractConvalescent plasma, collected from donors who have recovered from a pathogen of interest, has been used to treat infectious diseases, particularly in times of outbreak, when alternative therapies were unavailable. The COVID‐19 pandemic revived interest in the use of convalescent plasma. Large observational studies and clinical trials that were executed during the pandemic provided insight into how to use convalescent plasma, whereby high levels of antibodies against the pathogen of interest and administration early within the time course of the disease are critical for optimal therapeutic effect. Several studies have shown outpatient administration of COVID‐19 convalescent plasma (CCP) to be both safe and effective, preventing clinical progression in patients when administered within the first week of COVID‐19. The United States Food and Drug Administration expanded its emergency use authorization (EUA) to allow for the administration of CCP in an outpatient setting in December 2021, at least for immunocompromised patients or those on immunosuppressive therapy. Outpatient transfusion of CCP and infusion of monoclonal antibody therapies for a highly transmissible infectious disease introduces nuanced challenges related to infection prevention. Drawing on our experiences with the clinical and research use of CCP, we describe the logistical considerations and workflow spanning procurement of qualified products, infrastructure, staffing, transfusion, and associated management of adverse events. The purpose of this description is to facilitate the efforts of others intent on establishing outpatient transfusion programs for CCP and other antibody‐based therapies.