Tridu Huynh

All Publications

• Hemolysis due to anti-IH in a patient with beta-thalassemia and Mycoplasma pneumoniae infection. Immunohematology Chousal, J. N., Sargolzaeiaval, F., Huynh, T. R., Zhao, M., Rodberg, K., Kopko, P. M., Gopal, S., Allen, E. S. 2024; 40 (4): 139-144

  Abstract

  Anti-IH is a common cold agglutinin that is typically clinically insignificant. We present a case that resulted in hemolysis. A 32-year-old male patient with transfusion-independent beta-thalassemia intermedia presented with symptomatic anemia. His blood sample typed as group B, D+ and demonstrated multiple alloantibodies and cold autoantibodies. He was transfused uneventfully, but re-presented 10 days later with recurrent, worsening anemia. At this time, transfusion of group O, phenotype-matched red blood cells (RBCs) resulted in an acute hemolytic reaction. While anemia was initially attributed to drug-mediated bone marrow toxicit y and subsequently to a delayed hemolytic reaction, further evaluation revealed Mycoplasma pneumoniae infection and a cold agglutinin (anti-IH specificity), indicating a likely autoimmune-mediated anemia due to an infectious etiology. Subsequent transfusion of 2 group B, phenotype-matched RBC units using a blood warmer was uneventful. Anti-IH is only rarely associated with hemolytic transfusion reactions, which may be exacerbated when transfusing group O RBC units to group B patients. M. pneumoniae infection likely led to cold agglutinin-mediated hemolysis of endogenous and transfused RBCs. The patient was successfully managed with intravenous immunoglobulin, steroids, rituximab, erythropoietin, hydroxyurea, and amoxicillin clavulanate/azithromycin. This case illustrates the importance of infectious disease evaluation in patients with unexplained anemia, the potential clinical significance of autoanti-IH, and the value of providing type-specific RBC units in these circumstances.

  View details for DOI 10.2478/immunohematology-2024-018

  View details for PubMedID 39740016

• Phase II basket trial of Dual Anti-CTLA-4 and Anti-PD-1 blockade in Rare Tumors (DART) SWOG S1609: adrenocortical carcinoma cohort. Journal for immunotherapy of cancer Patel, S. P., Othus, M., Chae, Y. K., Huynh, T., Tan, B., Kuzel, T., McLeod, C., Lopez, G., Chen, H. X., Sharon, E., Streicher, H., Ryan, C. W., Blanke, C., Kurzrock, R. 2024; 12 (7)

  Abstract

  Multiple common cancers benefit from immunotherapy; however, less is known about efficacy in rare tumors. We report the results of the adrenocortical carcinoma cohort of NCI/SWOG S1609 Dual Anti-CTLA-4 and Anti-PD-1 blockade in Rare Tumors.A prospective, phase 2 clinical trial of ipilimumab plus nivolumab was conducted by the SWOG Early Therapeutics and Rare Cancers Committee for multiple rare tumor cohorts across >1,000 National Clinical Trial Network sites.21 eligible patients were registered. Median age was 53 years (range 26-69); 16 (76%) were women.Ipilimumab 1 mg/kg intravenously every 6 weeks with nivolumab 240 mg intravenously every 2 weeks was administered until disease progression, symptomatic deterioration, treatment delay for any reason >56 days, unacceptable or immune-related toxicity with inability to decrease prednisone to <10 mg daily, or per patient request.The primary endpoint was the overall response rate (ORR) (RECIST V.1.1). Secondary endpoints include clinical benefit rate (CBR) (includes stable disease (SD)>6 months), progression-free survival (PFS), overall survival (OS), and toxicity. Immune-related outcomes included immune ORR (iORR), immune CBR (iCBR), and immune PFS (iPFS). A two-stage design was used assuming: null=5% alternative=30%, n=6 in the first stage, 16 max, one-sided alpha=13%.The median number of prior therapy lines was 2 (range: 1-9). 3 of 21 patients attained confirmed partial response (PR) (ORR=14%). In addition, one patient had an unconfirmed PR; one, stable disease (SD)>6 months; one, immune-related RECIST (iRECIST) PR (iPR); and one patient attained iSD>6 months: clinical benefit rate (response or SD>6 months)=5/21 (24%), iORR=4/21 (19%), iCBR=7/21 (33%). The 6-month PFS was 24%; 6-month iPFS, 33%. The PFS for patients (N=7) with iRECIST clinical benefit were 57, 52, 18, 15, 13, 7, and 7 months. The 6-month OS was 76%; the median OS, was 15.8 months. The most common toxicities were fatigue (62%) and rash (38%), and the most common grade 3/4 immune-related adverse events were hepatic dysfunction (9.5%) and adrenal insufficiency (9.5%). Treatment-related adverse events leading to discontinuation of therapy in four patients (21%). There were no grade 5 adverse events.Ipilimumab plus nivolumab is active in refractory metastatic adrenocortical cancer meeting the primary endpoint of the study, with a 19% iORR and 33% iCBR (includes SD/iSD>6 months) and with the longest PFS/iPFS of 52 and 57 months.NCT02834013 (registered 15 July, 2016; https://clinicaltrials.gov/ct2/show/NCT02834013).

  View details for DOI 10.1136/jitc-2024-009074

  View details for PubMedID 39067873

  View details for PubMedCentralID PMC11284838

• Effects of antineoplastic and immunomodulating agents on postvaccination SARS-CoV-2 breakthrough infections, antibody response, and serological cytokine profile. Journal for immunotherapy of cancer New, J., Cham, J., Smith, L., Puglisi, L., Huynh, T., Kurian, S., Bagsic, S., Fielding, R., Hong, L., Reddy, P., Eum, K. S., Martin, A., Barrick, B., Marsh, C., Quigley, M., Nicholson, L. J., Pandey, A. C. 2024; 12 (1)

  Abstract

  Despite immunization, patients on antineoplastic and immunomodulating agents have a heightened risk of COVID-19 infection. However, accurately attributing this risk to specific medications remains challenging.An observational cohort study from December 11, 2020 to September 22, 2022, within a large healthcare system in San Diego, California, USA was designed to identify medications associated with greatest risk of postimmunization SARS-CoV-2 infection. Adults prescribed WHO Anatomical Therapeutic Chemical (ATC) classified antineoplastic and immunomodulating medications were matched (by age, sex, race, and number of immunizations) with control patients not prescribed these medications yielding a population of 26 724 patients for analysis. From this population, 218 blood samples were collected from an enrolled subset to assess serological response and cytokine profile in relation to immunization.Prescription of WHO ATC classified antineoplastic and immunomodulatory agents was associated with elevated postimmunization SARS-CoV-2 infection risk (HR 1.50, 95% CI 1.38 to 1.63). While multiple immunization doses demonstrated a decreased association with postimmunization SARS-CoV-2 infection risk, antineoplastic and immunomodulatory treated patients with four doses remained at heightened risk (HR 1.23, 95% CI 1.06 to 1.43). Risk variation was identified among medication subclasses, with PD-1/PD-L1 inhibiting monoclonal antibodies, calcineurin inhibitors, and CD20 monoclonal antibody inhibitors identified to associate with increased risk of postimmunization SARS-CoV-2 infection. Antineoplastic and immunomodulatory treated patients also displayed a reduced IgG antibody response to SARS-CoV-2 epitopes alongside a unique serum cytokine profile.Antineoplastic and immunomodulating medications associate with an elevated risk of postimmunization SARS-CoV-2 infection in a drug-specific manner. This comprehensive, unbiased analysis of all WHO ATC classified antineoplastic and immunomodulating medications identifies medications associated with greatest risk. These findings are crucial in guiding and refining vaccination strategies for patients prescribed these treatments, ensuring optimized protection for this susceptible population in future COVID-19 variant surges and potentially for other RNA immunization targets.

  View details for DOI 10.1136/jitc-2023-008233

  View details for PubMedID 38296596

  View details for PubMedCentralID PMC10831464

• Neoadjuvant chemotherapy and radiotherapy outcomes in borderline-resectable and locally-advanced pancreatic cancer patients. Cancer medicine Botta, G. P., Huynh, T. R., Spierling-Bagsic, S. R., Agelidis, A., Schaffer, R., Lin, R., Sigal, D. 2023; 12 (7): 7713-7723

  Abstract

  There is no agreed upon standard of care for borderline-resectable pancreatic cancer (BRPC) or locally-advanced pancreatic cancer (LAPC) patients regarding the benefit of chemotherapy or radiation alone or in combination.We completed a retrospective cohort analysis of BRPC and LAPC patients at a cancer center with expertise in multi-disciplinary pancreatic ductal adenocarcinoma (PDAC) treatment over a 5-year period from 03/01/2014 to 03/01/2019 (cut-off date). The total evaluable newly diagnosed, treatment naïve, BRPC, and LAPC patients with adequate organ function and ability to obtain treatment after multidisciplinary review was 52 patients. After analysis, patients were evaluated for rates of resection, extent of resection (R0 or R1), median progression-free survival (mPFS), and median overall survival (mOS).Patients were treated with chemotherapy alone (gemcitabine and nab-paclitaxel = 77% (20/26); FOLFIRINOX = 19% (5/26); single agent gemcitabine 3.8% (1/26)), or chemotherapy followed by chemoradiation (gemcitabine +5 Gy × 5 weeks), or chemoradiation alone prior to re-staging and potential resection. Of the 29% (15/52) of patients who went on to surgical resection, 73% (11/15) achieved R0 resection. An R0 resection was achieved in 35% (9/26) of patients treated with chemotherapy alone, 7.6% (1/13) in a patient treated with chemotherapy followed by radiation, and 7.6% (1/13) with concurrent chemoradiotherapy alone. Chemotherapy alone achieved a mPFS of 16.4 months (p  < 0.0025) and mOS of 26.2 months (p  < 0.0001), chemotherapy followed by chemoradiation was 13.0 months and 14.9 months respectively, while concurrent chemoradiotherapy was 6.9 months and 7.3 months.BRPC and LAPC patients capable of surgery after only receiving neoadjuvant treatment with chemotherapy had higher rates of R0 resection with prolonged median PFS and OS compared with any patient needing combination chemotherapy with radiotherapy.

  View details for DOI 10.1002/cam4.5523

  View details for PubMedID 36478411

  View details for PubMedCentralID PMC10134275

• Human Hematopoietic Stem Cell Engrafted IL-15 Transgenic NSG Mice Support Robust NK Cell Responses and Sustained HIV-1 Infection. Viruses Abeynaike, S. A., Huynh, T. R., Mehmood, A., Kim, T., Frank, K., Gao, K., Zalfa, C., Gandarilla, A., Shultz, L., Paust, S. 2023; 15 (2)

  Abstract

  Mice reconstituted with human immune systems are instrumental in the investigation of HIV-1 pathogenesis and therapeutics. Natural killer (NK) cells have long been recognized as a key mediator of innate anti-HIV responses. However, established humanized mouse models do not support robust human NK cell development from engrafted human hematopoietic stem cells (HSCs). A major obstacle to human NK cell reconstitution is the lack of human interleukin-15 (IL-15) signaling, as murine IL-15 is a poor stimulator of the human IL-15 receptor. Here, we demonstrate that immunodeficient NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice expressing a transgene encoding human IL-15 (NSG-Tg(IL-15)) have physiological levels of human IL-15 and support long-term engraftment of human NK cells when transplanted with human umbilical-cord-blood-derived HSCs. These Hu-NSG-Tg(IL-15) mice demonstrate robust and long-term reconstitution with human immune cells, but do not develop graft-versus-host disease (GVHD), allowing for long-term studies of human NK cells. Finally, we show that these HSC engrafted mice can sustain HIV-1 infection, resulting in human NK cell responses in HIV-infected mice. We conclude that Hu-NSG-Tg(IL-15) mice are a robust novel model to study NK cell responses to HIV-1.

  View details for DOI 10.3390/v15020365

  View details for PubMedID 36851579

  View details for PubMedCentralID PMC9960100

• 6 month serologic response to the Pfizer-BioNTech COVID-19 vaccine among healthcare workers. PloS one Cham, J., Pandey, A. C., New, J., Huynh, T., Hong, L., Orendain, N., Topol, E. J., Nicholson, L. J. 2022; 17 (4): e0266781

  Abstract

  Healthcare workers (HCWs) were among the first group of people vaccinated with the Pfizer-BioNTech Covid-19 vaccine (BNT162b2). Characterization of the kinetics of antibody response to vaccination is important to devise future vaccination strategies. To better characterize the antibody response to BNT162b2, we analyzed the kinetics of IgG and IgM antibody response to 5 different SARS-CoV-2 epitopes over a period of 6 months.An observational single-centered study was conducted to evaluate the temporal dynamics of anti-SARS-CoV-2 antibodies following immunization with two doses of BNT162b2. Anti-SARS-CoV-2 antibodies were assessed using the Maverick SARS-CoV-2 multi-antigen panel (Genalyte Inc.). Healthcare workers aged ≥18 receiving BNT162b2 vaccination who self-reported no prior symptoms of COVID-19 nor prior COVID-19 PCR test positivity, were included in this study. HCWs developed an IgG antibody response to SARS-CoV-2 Spike S1, Spike S1 receptor binding domain (RBD), Spike S1S2 and Spike S2 after vaccination. IgG response was observed at two weeks following immunization in most participant samples and continued to increase at week 4, but subsequently decreased significantly starting at 3 months and up to 6 months. In contrast, IgM response to respective epitopes was minimal.Multiplex results demonstrate that, contrary to natural infection, immunization with BNT162b2 produces minimal anti-Spike IgM response. Polyclonal IgG response to Spike declined at 3 months and continued to do so up to 6 months.

  View details for DOI 10.1371/journal.pone.0266781

  View details for PubMedID 35436296

  View details for PubMedCentralID PMC9015132

• Natural killer cells and cytotoxic T lymphocytes are required to clear solid tumor in a patient-derived xenograft. JCI insight Le, D. T., Huynh, T. R., Burt, B., Van Buren, G., Abeynaike, S. A., Zalfa, C., Nikzad, R., Kheradmand, F., Tyner, J. J., Paust, S. 2021; 6 (13)

  Abstract

  Existing patient-derived xenograft (PDX) mouse models of solid tumors lack a fully tumor donor-matched, syngeneic, and functional immune system. We developed a model that overcomes these limitations by engrafting lymphopenic recipient mice with a fresh, undisrupted piece of solid tumor, whereby tumor-infiltrating lymphocytes (TILs) persisted in the recipient mice for several weeks. Successful tumor engraftment was achieved in 83% to 89% of TIL-PDX mice, and these were seen to harbor exhausted immuno-effector as well as functional immunoregulatory cells persisting for at least 6 months postengraftment. Combined treatment with interleukin-15 stimulation and immune checkpoint inhibition resulted in complete or partial tumor response in this model. Further, depletion of cytotoxic T lymphocytes and/or natural killer cells before combined immunotherapy revealed that both cell types were required for maximal tumor regression. Our TIL-PDX model provides a valuable resource for powerful mechanistic and therapeutic studies in solid tumors.

  View details for DOI 10.1172/jci.insight.140116

  View details for PubMedID 34081628

  View details for PubMedCentralID PMC8410059

• Lateral medullary infarction with cardiovascular autonomic dysfunction: an unusual presentation with review of the literature. Clinical autonomic research : official journal of the Clinical Autonomic Research Society Huynh, T. R., Decker, B., Fries, T. J., Tunguturi, A. 2018; 28 (6): 569-576

  Abstract

  We report an unusual case of lateral medullary infarction presenting with orthostatic hypotension with pre-syncope without vertigo or Horner's syndrome.Case report with review of the literature.A 67-year-old man presented with pre-syncope and ataxia without vertigo. Initial brain CT and MRI were normal. Neurological evaluation revealed right-beating nystagmus with left gaze, vertical binocular diplopia, right upper-extremity dysmetria, truncal ataxia with right axial lateropulsion, and right-facial and lower extremity hypoesthesia. Bedside blood pressure measurements disclosed orthostatic hypotension. He had normal sinus rhythm on telemetry and normal ejection fraction on echocardiogram. A repeat brain MRI disclosed an acute right dorsolateral medullary infarct. Autonomic testing showed reduced heart rate variability during paced deep breathing, attenuated late phase II and phase IV overshoot on Valsalva maneuver, and a fall of 25 mmHg of blood pressure at the end of a 10-min head-up tilt with no significant change in heart rate. These results were consistent with impaired sympathetic and parasympathetic cardiovascular reflexes. He was discharged to acute rehabilitation a week later with residual right dysmetria and ataxia.Lateral medullary infarctions are usually reported as partial presentations of classical lateral medullary syndrome with accompanying unusual symptoms ranging from trigeminal neuralgias to hiccups. Pre-syncope from orthostatic hypotension is a rare presentation. In the first 3-4 days, absence of early DWI MRI findings is possible in small, dorsolateral medullary infarcts with sensory disturbances. Physicians should be aware of this presentation, as early diagnosis and optimal therapy are associated with good prognosis.

  View details for DOI 10.1007/s10286-018-0502-6

  View details for PubMedID 29368226

• Myxopapillary ependymoma with anaplastic features: A case report with review of the literature. Surgical neurology international Huynh, T. R., Lu, C., Drazin, D., Lekovic, G. 2018; 9: 191

  Abstract

  Myxopapillary ependymoma (MPE) with anaplastic features is extremely rare, with only three case reports in the literature.We report the case of a MPE with anaplastic features in a 24-year-old female who presented with a dominant lumbar mass along with intracranial and sacral metastases. Upon gross total resection of the dominant tumor located at L2-L3, it appeared to arise from the filum terminale, and had a solid component in addition to soft or necrotic areas. Histologically, the tumor was composed of the two classic components of MPE: (1) low-grade ependymal cells surrounding blood vessels, producing the papillary appearance and (2) perivascular myxoid material between blood vessels and ependymal cells, creating the myxopapillary appearance. The high-grade anaplastic component showed hypercellularity, brisk mitotic rate, and vascular proliferation, with frequent pleomorphic cells and atypical mitotic figures. It was positive for vimentin and glial fibrillary acidic protein (GFAP); negative for epithelial membrane antigen (EMA), CAM5.2, creatine kinase 7 (CK7), CK20; and the MIB-1 index (Ki-67) was 8-38%. Ten months after initial resection, follow-up magnetic resonance imaging revealed new lesions in (1) the hypothalamus, (2) the left pons, and (3) the left medial temporal lobe, which were treated with radiosurgery. Eight months later (18 months from initial surgery), the patient underwent thoracic laminectomy for a large leptomeningeal metastasis at T6 and T8.The present case of MPE with anaplastic features is the fourth case on record in the medical literature.

  View details for DOI 10.4103/sni.sni_422_17

  View details for PubMedID 30294495

  View details for PubMedCentralID PMC6169347

• Pediatric spondylolysis/spinal stenosis and disc herniation: national trends in decompression and discectomy surgery evaluated through the Kids' Inpatient Database. Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery Huynh, T. R., Lagman, C., Sweiss, F., Shweikeh, F., Nuño, M., Drazin, D. 2017; 33 (9): 1563-1570

  Abstract

  The purpose of this study is to describe national trends in spinal decompression without fusion and discectomy procedures in the US pediatric inpatient population.The Kids' Inpatient Database (KID) was queried for pediatric patients with primary diagnoses of spinal spondylolysis/stenosis or disc herniation and having undergone spinal decompression without fusion or discectomy over more than a decade (2000 to 2012). The primary (indirect) outcomes of interest were in-hospital complication rates, length of stay (LOS), total costs, and discharge dispositions.A total of 7315 patients, comprised of pediatric spinal spondylolysis/stenosis (n = 287, 3.92%) and pediatric disc herniation (n = 7028, 96.1%) patients, were included in the study. During the years 2000 to 2012, diagnoses of pediatric spondylolysis/spinal stenosis increased from 61 to 90 diagnoses per 3-year period, while diagnoses of pediatric disc herniation decreased from 2133 to 1335 diagnoses per 3-year period. Spinal decompression was associated with higher in-hospital complication rates (18.1 vs 5.3%, p < 0.0001), longer hospital stays (5 vs 1.69 days, p < 0.0001), higher mean total charges ($49,186 vs $19,057, p < 0.0001), and higher non-routine discharge rates (12.3 vs 2.5%, p < 0.0001) versus discectomy.Spinal decompression is associated with longer hospital stays, more complications, higher costs, and more non-routine discharges when compared to discectomy. The data supports the disparate nature of these disease processes and elucidates basic clinical trends in uncommon spinal disorders affecting children.

  View details for DOI 10.1007/s00381-017-3471-5

  View details for PubMedID 28643037

• Cutting Edge: The Orphan Nuclear Receptor Nr4a1 Regulates CD8+ T Cell Expansion and Effector Function through Direct Repression of Irf4. Journal of immunology (Baltimore, Md. : 1950) Nowyhed, H. N., Huynh, T. R., Thomas, G. D., Blatchley, A., Hedrick, C. C. 2015; 195 (8): 3515-9

  Abstract

  The transcription factor IFN regulatory factor (IRF)4 was shown to play a crucial role in the protective CD8(+) T cell response; however, regulation of IRF4 expression in CD8(+) T cells remains unclear. In this article, we report a critical role for Nr4a1 in regulating the expansion, differentiation, and function of CD8(+) T cells through direct transcriptional repression of Irf4. Without Nr4a1, the regulation of IRF4 is lost, driving an increase in Irf4 expression and, in turn, resulting in a faster rate of CD8 T cell proliferation and expansion. Nr4a1-deficient mice show increases in CD8 T cell effector responses with improved clearance of Listeria monocytogenes. Our data support a novel and critical role for Nr4a1 in the regulation of CD8(+) T cell expansion and effector function through transcriptional repression of Irf4.

  View details for DOI 10.4049/jimmunol.1403027

  View details for PubMedID 26363057

  View details for PubMedCentralID PMC4592102

• The nuclear receptor nr4a1 controls CD8 T cell development through transcriptional suppression of runx3. Scientific reports Nowyhed, H. N., Huynh, T. R., Blatchley, A., Wu, R., Thomas, G. D., Hedrick, C. C. 2015; 5: 9059

  Abstract

  The NR4A nuclear receptor family member Nr4a1 is strongly induced in thymocytes undergoing selection, and has been shown to control the development of Treg cells; however the role of Nr4a1 in CD8(+) T cells remains undefined. Here we report a novel role for Nr4a1 in regulating the development and frequency of CD8(+) T cells through direct transcriptional control of Runx3. We discovered that Nr4a1 recruits the corepressor, CoREST to suppress Runx3 expression in CD8(+) T cells. Loss of Nr4a1 results in increased Runx3 expression in thymocytes which consequently causes a 2-fold increase in the frequency and total number of intrathymic and peripheral CD8(+) T cells. Our findings establish Nr4a1 as a novel and critical player in the regulation of CD8 T cell development through the direct suppression of Runx3.

  View details for DOI 10.1038/srep09059

  View details for PubMedID 25762306

  View details for PubMedCentralID PMC4356985