Browsing by Author "Mehta, Rakesh"
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Item CAR T-cell toxicities: from bedside to bench, how novel toxicities inform laboratory investigations(American Society of Hematology, 2024) Perna, Fabiana; Parekh, Samir; Diorio, Caroline; Smith, Melody; Subklewe, Marion; Mehta, Rakesh; Locke, Frederick L.; Shah, Nirali N.; Medicine, School of MedicineMultiple chimeric antigen receptor (CAR) T-cell therapies are US Food and Drug Administration-approved, and several are under development. Although effective for some cancers, toxicities remain a limitation. The most common toxicities, that is, cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, are well described. With increasing utilization, providers worldwide are reporting other emergent and often complicated toxicities. Given the evolving toxicity profiles and urgent need to catalog these emerging and emergent CAR T-cell 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-cell emergent toxicities, including movement disorders after B-cell maturation antigen CAR T cell, coagulation abnormalities, and prolonged cytopenia; (2) disseminate bedside-to-bench efforts elucidating pathophysiological mechanisms of CAR T-cell 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 used to expand our knowledge around the monitoring of toxicities. Key themes emerged. First, although clinical manifestations may develop before the pathophysiologic mechanisms are understood, they must be studied to aid in the detection and prevention of such toxicities. Second, systemic immune dysregulation appears to be central to these emergent toxicities, and research is needed to elucidate the links between tumors, CAR T cells, and microbiota. Finally, there was a consensus around the urgency to create a repository to capture emergent CAR T-cell toxicities and the real-world management.Item Cerebral fat embolism syndrome mimicking thrombotic thrombocytopenic purpura in a patient with Hemoglobin SC disease(Wiley, 2016-05) Kammeyer, Ryan; Devnani, Rohit; Mehta, Rakesh; Department of Medicine, IU School of MedicineCase Presentation A 54 year‐old man with hemoglobin SC disease (HbSC) and a history of substance abuse presented to the Emergency Department from a nursing home with two days of progressive weakness, shortness of breath, and lower back pain. He developed a fever, hypoxia, and tachycardia on the day of admission. He did not have any recent changes in medications, and his family as well as the nursing home staff denied any access to illicit drugs.Item Cerebral Vein Thrombosis in Concomitant Combination Oral Contraceptive Pill Use and COVID-19(2023-03) Owusu, Raiven; Bode, Leah; Jansen, Nicole; Libke, Megan; Mehta, RakeshCase Description: Patient is a 27-year-old female who presented with confusion, fever, and chills and was found to have a cerebral vein thrombosis (CVT) on MRI. She had a seven-year history of combination oral contraceptive pill (OCP) use and prior to onset of symptoms tested positive for COVID-19. After CVT diagnosis, she started apixaban, which was discontinued 6 months later. She decided to discontinue her OCP and had a copper intrauterine device (IUD) placed. Clinical Significance: CVT is a rare form of stroke that most commonly affects young women. Pregnancy, puerperium, and OCP all use induce a hypercoagulable state which increases risk for CVT. Estrogen causes increased circulating procoagulant factors in the plasma, and combined OCP users are often found to have an acquired resistance to activated protein C6, which both contribute to a hypercoagulable state. COVID-19-associated coagulopathy also induces concurrent hyper-inflammatory response, hypercoagulability, and vascular endothelial cell dysfunction. These pathologic mechanisms are believed to be linked to elevated plasma levels of coagulation factors and reduced fibrinolysis, resulting in prothrombotic events. COVID-19 infection is thought to exacerbate existing prothrombotic states like OCP use. Conclusion: Concomitant hypercoagulable states, such as combination OCP use and COVID-19 coagulopathy, increase overall risk for thrombotic events. Patients with risk factors for hypercoagulability presenting with headache, visual changes, and confusion should be evaluated for CVT. Following a thrombotic event in a patient on combined OCPs, finding an alternative contraceptive that meets the patient’s reproductive goals and lowers their risk of repeat thromboembolic events is important. Progesterone-only and non-hormonal contraceptive options, such as IUDs, have a decreased risk of thrombosis compared to combined OCPs and can provide alternative contraceptive methods.Item Experiences of Female and Male Medical Students With Death, Dying, and Palliative Care: One Size Does Not Fit All(Sage, 2018-06) Hoffman, Leslie A.; Mehta, Rakesh; Vu, T. Robert; Frankel, Richard M.; Anatomy and Cell Biology, School of MedicineBackground: 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.Item 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(Frontiers Media, 2024-02-01) Li, Wei; Pucka, Andrew Q.; Debats, Candice; Reyes, Brandon A.; Syed, Fahim; O’Brien, Andrew R. W.; Mehta, Rakesh; Manchanda, Naveen; Jacob, Seethal A.; Hardesty, Brandon M.; Greist, Anne; Harte, Steven E.; Harris, Richard E.; Yu, Qigui; Wang, Ying; Microbiology and Immunology, School of MedicineThis 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.Item Oral Iron Replacement Normalizes Fibroblast Growth Factor 23 in Iron Deficient Patients with Autosomal Dominant Hypophosphatemic Rickets(Wiley, 2020-02) Imel, Erik A.; Liu, Ziyue; Coffman, Melissa; Acton, Dena; Mehta, Rakesh; Econs, Michael J.; Medicine, School of MedicineAutosomal 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.Item Physicians in Postgraduate Training Characteristics and Support of Palliative Sedation for Existential Distress(Sage, 2017-09) Cripe, Larry D.; Perkins, Susan M.; Cottingham, Ann; Tong, Yan; Kozak, Mary Ann; Mehta, Rakesh; Medicine, School of MedicineIntroduction: 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.Item Postpartum Hepatic Infarction in Antiphospholipid Syndrome Patients(2021-03) Joseph, Sophia; Hardman, Sara; Zeh, Janie; Sivamohan, Anjali; Mehta, RakeshCASE: Our patient is a 31-year-old woman with a complicated past medical history of Systemic Lupus Erythematosus (SLE) and Antiphospholipid Ayndrome (APS). She originally presented several years ago when she was found to have Libman-Sacks endocarditis. She was diagnosed with SLE and APS at the time and was subsequently anticoagulated with warfarin. When she became pregnant, warfarin was discontinued and she was managed with a low molecular weight heparin (LMWH). She was continued on LMWH post-partum, but was noncompliant. For a few weeks following delivery, she presented to the hospital on several occasions with acute right upper quadrant pain. CT imaging confirmed several hepatic infarcts and she was treated with steroids, fondaparinux, and plaquenil. CONCLUSIONS: APS poses several risks during and after pregnancy due to susceptibility to venous and arterial thrombosis1. There is an increased risk of thrombosis up to 12 weeks postpartum. Continuation of anticoagulation following delivery is essential in APS women who have a high baseline risk of thrombosis2. Non-compliance with medications may have contributed to this presentation. This case is unique in that hepatic infarcts rarely occur due to the dual blood supply of the liver. Moreover, the diagnosis of hepatic infarction can be difficult as it may present similarly to HELLP, possibly contributing to her multiple admissions with RUQ pain3,4. CLINICAL SIGNIFICANCE: This case is significant because it demonstrates the rare, but life-threatening risk of postpartum hepatic infarction in APS patients. Proper postpartum management and compliance with anticoagulation medications are essential to mitigating risk. Furthermore, providers may face challenges in diagnosing hepatic infarction as it could mimic other diseases.Item Thrombocytopenia and disseminated histoplasmosis in immunocompetent adults(Wiley, 2017-10-18) Kutkut, Issa; Vater, Laura; Goldman, Mitchell; Czader, Magdalena; Swenberg, Jessica; Fulkerson, Zachary; Mehta, Rakesh; Medicine, School of MedicineDisseminated 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.Item Thrombotic Events Are Unusual Toxicities of Chimeric Antigen Receptor T-Cell Therapies(MDPI, 2023-05-06) Schorr, Christopher; Forindez, Jorge; Espinoza-Gutarra, Manuel; Mehta, Rakesh; Grover, Natalie; Perna, Fabiana; Medicine, School of MedicineChimeric 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.