Autologous HER2-specific CAR T cells after lymphodepletion for advanced sarcoma: a phase 1 trial.

In this prospective, interventional phase 1 study for individuals with advanced sarcoma, we infused autologous HER2-specific chimeric antigen receptor T cells (HER2 CAR T cells) after lymphodepletion with fludarabine (Flu) ± cyclophosphamide (Cy): 1 × 108 T cells per m2 after Flu (cohort A) or Flu/Cy (cohort B) and 1 × 108 CAR+ T cells per m2 after Flu/Cy (cohort C). The primary outcome was assessment of safety of one dose of HER2 CAR T cells after lymphodepletion. Determination of antitumor responses was the secondary outcome. Thirteen individuals were treated in 14 enrollments, and seven received multiple infusions. HER2 CAR T cells expanded after 19 of 21 infusions. Nine of 12 individuals in cohorts A and B developed grade 1-2 cytokine release syndrome. Two individuals in cohort C experienced dose-limiting toxicity with grade 3-4 cytokine release syndrome. Antitumor activity was observed with clinical benefit in 50% of individuals treated. The tumor samples analyzed showed spatial heterogeneity of immune cells and clustering by sarcoma type and by treatment response. Our results affirm HER2 as a CAR T cell target and demonstrate the safety of this therapeutic approach in sarcoma. ClinicalTrials.gov registration: NCT00902044 .

Physiologic measurements of cognitive load in clinical reasoning.

OBJECTIVES: Cognitive load is postulated to be a significant factor in clinical reasoning performance. Monitoring physiologic measures, such as heart rate variability (HRV) may serve as a way to monitor changes in cognitive load. The pathophysiology of why HRV has a relationship to cognitive load is unclear, but it may be related to blood pressure changes that occur in a response to mental stress. METHODS: Fourteen residents and ten attendings from Internal Medicine wore Holter monitors and watched a video depicting a medical encounter before completing a post encounter form used to evaluate their clinical reasoning and standard psychometric measures of cognitive load. Blood pressure was obtained before and after the encounter. Correlation analysis was used to investigate the relationship between HRV, blood pressure, self-reported cognitive load measures, clinical reasoning performance scores, and experience level. RESULTS: Strong positive correlations were found between increasing HRV and increasing mean arterial pressure (MAP) (p=0.01, Cohen's d=1.41). There was a strong positive correlation with increasing MAP and increasing cognitive load (Pearson correlation 0.763; 95 % CI [; 95 % CI [-0.364, 0.983]). Clinical reasoning performance was negatively correlated with increasing MAP (Pearson correlation -0.446; 95 % CI [-0.720, -0.052]). Subjects with increased HRV, MAP and cognitive load were more likely to be a resident (Pearson correlation -0.845; 95 % CI [-0.990, 0.147]). CONCLUSIONS: Evaluating HRV and MAP can help us to understand cognitive load and its implications on trainee and physician clinical reasoning performance, with the intent to utilize this information to improve patient care.

Neonatal Hyperbilirubinemia Admissions Following Clinical Practice Guideline Implementation.

INTRODUCTION: Treatment of neonatal hyperbilirubinemia remains one of the most common reasons for readmission following delivery. Revised clinical practice guidelines (CPGs) for the treatment of neonatal hyperbilirubinemia were published on August 5, 2022. This report describes the preliminary outcomes following implementation of the new CPGs at Tripler Army Medical Center. MATERIALS AND METHODS: A retrospective chart review was performed for the 12 months prior to implementation and the 5 months post implementation. RESULTS: Bilirubin admissions decreased from 15.6% of total admissions during the 12 months prior to the new guidelines (69/441) to 4.1% of admissions (8/194) during the 5 months after implementation of the new guidelines (P < 0.001). This corresponds to a 74% reduction (risk ratio = 0.26, 95% confidence interval [CI] 0.13 to 0.54). The decrease in admissions was found to correlate to greater than $140,000 in annual savings. CONCLUSION: Adhering to the revised CPGs has the potential to increase resource availability at a time when nursing shortages and financial instability are impacting health care systems nationwide. No short-term adverse events were noted; however, long-term follow up will be needed.

Recognizing a Mediastinal Mass: A Case of Primary Mediastinal Large B-Cell Lymphoma With Pruritus in a 23-Year-Old Adult Male Sailor.

Primary mediastinal large B-cell lymphoma (PMBCL) is a rare, non-Hodgkin, B-cell lymphoma thought to originate from thymic B cells, which occurs primarily in young adults such as in the active duty population. Primary mediastinal large B-cell lymphoma (PMBCL) presents as a large mediastinal mass, posing risks to the cardiopulmonary safety of patients and challenging the routine approach to diagnosis. We describe a case of a 23-year-old male sailor who presented to sick call on his ship while in port with shortness of breath, night sweats, 50-pound weight loss, and pruritic punched-out lesions on all extremities. An initial chest X-ray showed a large consolidation. After being seen in the pulmonary medicine clinic 5 weeks after his initial presentation, the patient was admitted to the intensive care unit after computed tomography of his chest revealed a mediastinal mass, causing compression of both the right bronchus and superior vena cava with a large pericardial effusion. Empiric high-dose dexamethasone was initiated before a formal diagnosis due to his significant risk for cardiopulmonary compromise. Following diagnosis and two cycles of chemotherapy, the patient was transferred to a medical oncology facility in the continental USA. This case demonstrates the need to educate all military providers to recognize the presentation of mediastinal masses in active duty service members and the importance of urgently escalating these patients to higher levels of care in order to avoid life-threatening complications.

Progressive, refractory macrophage activation syndrome as the initial presentation of anti-MDA5 antibody positive juvenile dermatomyositis: a case report and literature review.

BACKGROUND: Macrophage activation syndrome (MAS) is a severe and under-recognized complication of rheumatologic diseases. We describe a patient who presented with rapidly progressive, refractory MAS found to have anti-MDA5 antibody Juvenile Dermatomyositis (JDM) as her underlying rheumatologic diagnosis. CASE PRESENTATION: We describe a 14-year-old female who at the time of admission had a history of daily fevers for 6 weeks and an unintentional sixteen-pound weight loss. Review of systems was significant for cough, shortness of breath, chest pain, headaches, sore throat, muscle aches, rash, nausea, and loss of appetite. An extensive initial workup revealed findings consistent with an autoimmune process. While awaiting results of her workup she had clinical decompensation with multi-organ system involvement including pancytopenias, interstitial lung disease, hepatitis, cardiac involvement, gastrointestinal distension and pain, feeding intolerance, extensive mucocutaneous candidiasis, and neuropsychiatric decline. Due to her decompensation, significant interstitial lung disease, and likely underlying rheumatologic condition she was started on high dose pulse steroids and mycophenolate. An MRI was performed due to her transaminitis and shoulder pain revealing significant myositis. Intravenous immunoglobulin was then initiated. The myositis antibody panel sent early in her workup was significant for anti-MDA5 and anti-SSA-52 antibodies. Despite high dose pulse steroids, mycophenolate, and IVIG, her disease progressed requiring escalating therapies. Ultimately, she responded with resolution of her MAS as well as significant and steady improvement in her feeding intolerance, interstitial lung disease, cardiac dysfunction, myositis, arthritis, and cutaneous findings. CONCLUSIONS: JDM in the pediatric patient is rare, as is MAS. In patients with complex rheumatologic conditions and lack of response to treatment, it is important to continually assess the patient's clinical status with MAS in mind, as this may change the treatment approach. Without proper recognition of this complication, patients can have a significant delay in diagnosis leading to life-threatening consequences.

Role of anticoagulation in the management of tumor thrombus: A 10-year single-center experience.

BACKGROUND: Children with cancer diagnosis are overall at a higher risk of thrombosis. For a newly diagnosed blood clot, patients are commonly started on anticoagulants to prevent further extension and embolization of the clot. In the rare instance that a pediatric patient has a tumor thrombus, role of anticoagulation is less clear. PROCEDURE/METHODS: Patients under 21 years of age with a finding of tumor thrombus on imaging from 2010 to 2020 at Texas Children's Hospital were identified and their medical records were reviewed. RESULTS: A total of 50 patients were identified. Most thrombi were incidental findings at diagnosis; however, two patients presented with pulmonary embolism (PE). Inferior vena cava extension was noted in 36% of the patients, and 24% patients had an intracardiac tumor thrombus. Anticoagulation was initiated in 10 patients (20%). There was no difference in the rate of bland thrombus formation and/or embolization in patients who did or did not receive anticoagulation. However, three of the six patients with asymptomatic tumor thrombus who were started on anticoagulation had bleeding complications compared to only two patients in the no anticoagulation cohort (p < .05). CONCLUSION: Children with intravascular extension of solid tumors were not commonly started on anticoagulation at the time of diagnosis, irrespective of the extent of tumor thrombus. Furthermore, we observed a significant trend toward higher incidence of bleeding complications after initiation of anticoagulation for asymptomatic tumor thrombus. There is inadequate evidence at this time to support routine initiation of anticoagulation in pediatric patients with intravascular extension of solid tumors.

Megaloblastic Anemia Progressing to Severe Thrombotic Microangiopathy in Patients with Disordered Vitamin B12 Metabolism: Case Reports and Literature Review.

We describe 2 children with cobalamin G disease, a disorder of vitamin B12 metabolism with normal serum B12 levels. They presented with megaloblastic anemia progressing rapidly to severe thrombotic microangiopathy. In infants presenting with acute thrombotic microangiopathy, cobalamin disorders should be considered early as diagnosis and targeted treatment can be lifesaving.