177 results on '"Rehan IF"'
Search Results
2. Matched Unrelated Donor Hematopoietic Cell Transplant with Increased Donor Inhibitory KIR Improves Survival in a Pediatric Acute Leukemia: A CIBMTR Cohort Analysis
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Elizabeth Krieger, Rehan Qayyum, and Amir Ahmed Toor
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
3. Endogenous antigen presentation impacts on T-box transcription factor expression and functional maturation of CD8+ T cells
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Smith, Corey, Elhassen, Diah, Gras, Stephanie, Wynn, Katherine K., Dasari, Vijayendra, Tellam, Judy, Tey, Siok-Keen, Rehan, Sweera, Liu, Yu Chih, Rossjohn, Jamie, Burrows, Scott R., and Khanna, Rajiv
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- 2012
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4. Flavopiridol causes early mitochondrial damage in chronic lymphocytic leukemia cells with impaired oxygen consumption and mobilization of intracellular calcium
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Hussain, Syed-Rehan A., Lucas, David M., Johnson, Amy J., Lin, Thomas S., Bakaletz, Alan P., Dang, Vinh X., Viatchenko-Karpinski, Serge, Ruppert, Amy S., Byrd, John C., Kuppusamy, Periannan, Crouser, Elliott D., and Grever, Michael R.
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- 2008
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5. Patient-Specific Metabolism Assessed By Visceral Fat and Diabetes May Alter Prognosis in Relapsed/Refractory Hodgkin Lymphoma
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Pullarkat, Priyanka, primary, Nizamuddin, Rehan, additional, Jaswal, Shama, additional, Watkins, Marcus, additional, Bartlett, Nancy L., additional, Cashen, Amanda F, additional, Ippolito, Joseph, additional, and Mehta-Shah, Neha, additional
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- 2020
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6. Efficacy and Safety Profile of Proteasome Inhibitor Based Drug Regimens for Treatment of Newly Diagnosed AL Amyloidosis: A Systematic Review
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Javed, Saad, primary, Syed, Tariq Iqtidar Sadiq, additional, Fatima, Hejab, additional, Inam, Syed Hashim Ali, additional, Rehan, Tayyab, additional, Abdullah, Syed Maaz, additional, Najmuddin, Mohammed Musa, additional, Haider, Mobeen Zaka, additional, Neupane, Karun, additional, Sana, Muhammad Khawar, additional, Dar, Abdul Jabbar, additional, Jaan, Ali, additional, Mirza, Muhammad Ali, additional, and Anwer, Faiz, additional
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- 2020
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7. Increased Inhibitory KIR-Ligand Interactions Confer Relapse Protection Following HLA Matched Unrelated Donor HCT for AML
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Krieger, Elizabeth, primary, Qayyum, Rehan, additional, and Toor, Amir Ahmed, additional
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- 2020
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8. Efficacy and Safety Profile of Proteasome Inhibitor Based Drug Regimens for Treatment of Newly Diagnosed AL Amyloidosis: A Systematic Review
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Muhammad Ali Mirza, Abdul Jabbar Dar, Mobeen Zaka Haider, Tariq Iqtidar Sadiq Syed, Ali Jaan, Mohammed Musa Najmuddin, Karun Neupane, Tayyab Rehan, Syed Hashim Ali Inam, Saad Javed, Syed Maaz Abdullah, Hejab Fatima, Faiz Anwer, and Muhammad Khawar Sana
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Drug ,Oncology ,medicine.medical_specialty ,business.industry ,media_common.quotation_subject ,Immunology ,Cell Biology ,Hematology ,Newly diagnosed ,medicine.disease ,Biochemistry ,Safety profile ,Internal medicine ,medicine ,AL amyloidosis ,Proteasome inhibitor ,business ,media_common ,medicine.drug - Abstract
Introduction: Light chain amyloidosis (AL) is a plasma cell disorder associated with detrimental manifestations in multiple organ systems of the body. It is estimated that approximately 1275-3200 new cases occur in the United States annually. Proteasome inhibitors (PI), such as bortezomib, carfilzomib, and ixazomib used for multiple myeloma treatment are also used for the treatment of AL amyloidosis. Our aim in this review is to evaluate the efficacy and safety profile of PI-based regimens for the treatment of newly diagnosed AL Amyloidosis (ND-AL). Methods: We conducted a systematic review (following PRISMA guidelines) by completing a comprehensive literature search on PubMed, Cochrane, ClinicalTrials.gov, and Embase on June 23rd, 2020. We were able to identify 901 articles, 325 articles from PubMed, 50 from Cochrane, 23 from Clinical Trials.org, and 253 from Embase. After the screening, we selected 11 published studies (n=436) including 5 phase lll trials, 2 phase I/II trials. Results: Cyclophosphamide, Bortezomib, Dexamethasone (CyBorD) with or without Daratumumab (Dara): In a Phase lll trial (ANDEROMADA study), Palldini et al. (2020) studied the efficacy of Dara+ CyBorD vs CyBorD in ND-AL pts (n=28). The addition of Dara to CyBorD showed an improved overall hematological response (ORR) in 96% with complete response (CR) in 54% pts at a median follow up of 17.6 months (Table 1). In a retrospective study by Lim et al. (2017), CyBorD was given to ND-AL pts (n=39) which showed an ORR in 63% with very good partial response (VGPR) in 50% pts. In a retrospective study by Diaz-Pallares et al. (2020), CyBord was given to ND-AL pts (n=34) which showed an ORR in 91% with CR, VGPR, and partial response (PR) in 26%, 26%, and 38% pts, respectively. Progression-free survival (PFS) and overall survival (OS) were reported at 26.7 months and 22 months (P=0.06) respectively (Table 1). Bortezomib, Melphalan, Dexamethasone (BMD): In a phase III trial (EMN-03 study), Kastritis et al. (2020) studied the efficacy of BMD vs MD in ND-AL pts (n=109). Addition of B to MD showed an improved ORR: 81% vs 56% (p=0.001) with CR/VGPR in 53% vs 28% pts. No significant difference in survival outcome was observed. In a phase III trial, Kastritis et al. (2015) studied the efficacy of BMD vs MD in ND-AL pts (n=69). Addition of B to MD showed an improved ORR: 75% vs 53% (p=0.075) with CR/VGPR in 56% vs 42% pts (p=0.277). OS and PFS were also improved in BMD group as compared to control group: 83% vs 72% (p= 0.295) and 61% vs 49% (p=0.079) at 2 years, respectively (Table 1). Bortezomib, Melphalan, Prednisolone (BMP): In a retrospective study by Lee et al. (2014), BMP was given to ND-AL pts (n=19) which showed an ORR in 84% pts with CR, VGPR and PR in 37%, 21% and 26% pts, respectively (Table 1). Induction with B based regimens for ASCT: In a Phase lll trial (HOVON 104), Minnema et al. (2019), studied the efficacy of BD induction prior to HDM/ASCT in pts (n=35) with ND-AL. At 6 months, BD induction prior to HDM/ASCT vs No BD Induction prior to HDM/ASCT showed an ORR: 80% vs 80% with an improved CR: 43% vs 5% and VGPR: 54% vs 51%. In a Phase I/II trial by Sanchorawala et al. (2015), BD induction followed by B-HDM conditioning for ASCT was done in pts (n=27) with ND-AL. ORR at 6 months post ASCT was observed in 100% pts with CR and VGPR in 63% and 37% pts, respectively (Table 1). Induction with B based regimen prior to ASCT vs Upfront ASCT: In a retrospective analysis by Scharman et al. (2017), 53 pts who received ASCT were categorized into 3 groups i.e. Upfront ASCT, induction with B based regimen and induction with other regimens. ND-AL Patients (n=34/53) receiving B based induction vs no induction showed an improved ORR: 94% vs 69% (p=0.04). OS also improved in B based induction as compared to no induction group: 87% vs 77% (p=0.22) at 3 years. PFS at 3 years was 61% vs 69%, respectively (Table 1). Conclusions: PI-based regimens have shown favorable outcomes in the treatment of ND-AL and are effective therapeutic options. The most promising results are observed with CyBorD+Dara. The adverse events associated with PI-based therapy are peripheral neuropathy, anemia, thrombocytopenia, and infections. Further prospective clinical trials are warranted for a broader understanding of the safety and efficacy profile of PI-based regimens and correlation with individual pts characteristics. Table Caption: Table 1: Comparative efficacy and safety of proteasome-inhibitor based drug regimens in ND-AL Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.
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- 2020
9. Patient-Specific Metabolism Assessed By Visceral Fat and Diabetes May Alter Prognosis in Relapsed/Refractory Hodgkin Lymphoma
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Marcus Watkins, Nancy L. Bartlett, Priyanka Pullarkat, Rehan Nizamuddin, Shama Jaswal, Joseph E. Ippolito, Neha Mehta-Shah, and Amanda F. Cashen
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medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Immunology ,Salvage therapy ,Retrospective cohort study ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Lymphoma ,Refractory ,Internal medicine ,Diabetes mellitus ,Cohort ,medicine ,Hodgkin lymphoma ,business - Abstract
Background: Hodgkin lymphoma (HL) is a rare lymphoma that often affects young people, with a median age of diagnosis of 39. While the 5-year PFS rate for patients after front-line chemotherapy is 94.6%, those who relapse have a 50% to 60% rate of cure (Alinari and Blum, Blood 2016). We recently discovered that increased abdominal visceral fat normalized to subcutaneous fat (rVFA) is associated with poorer outcomes in females, but not males, with diffuse large B-cell lymphoma (DLBCL). (Teja e tal ASH 2018) Interestingly, increased body mass index overall has been found to be associated with favorable prognosis in DLBCL (Carson et al., Journal of Clinical Oncology 2012). The correlation between these findings and elevated fasting blood glucose further supports a relationship between metabolism and prognosis in lymphoma. Since HL patients are generally younger and healthier than DLBCL patients at diagnosis, we sought to determine if rVFA and other metabolic markers had similar prognostic value in relapsed/refractory HL patients. Methods: We conducted a retrospective study of 95 consecutively treated relapsed/refractory HL patients treated at Washington University in St. Louis, who presented with first relapse between 2004 and 2018. We recorded baseline clinical risk factors such as sex, age, BMI, IPI, diabetes status, extranodal sites at relapse, and duration of response to initial therapy. Treatment and response to therapy by PET/CT were also recorded. In 80 patients, pre-treatment CT images were available to determine areas of subcutaneous and visceral fat at the level of the umbilicus. These values were normalized to total fat to calculate rVFA (Nguyen Radiology, 2018). Thresholds for risk stratification and sex differences were obtained using Cutoff Finder (Budczies PLOS One 2012). Data was analyzed with SPSS. Results: Ninety-five patients were eligible for analysis (54M, 41F) and 50 (53%) had refractory disease to initial therapy. (Table 1) The overall response rate to salvage therapy was 77%. There was no significant difference in overall survival (OS) (p = 0.55) or progression-free survival (PFS) (p = 0.49) between males and females in our study. Patients with higher BMI at diagnosis had a trend towards inferior OS and PFS after relapse. Those with BMI Eighty patients had CT images available for rVFA analysis (45M, 35F). Both males and females had a median rVFA of 28%. Patients with rVFA greater than 34% had inferior OS after relapse (HR= 8.85, 95% CI: 2.38-32.93, p Conclusion: In this cohort, elevated rVFA was associated with inferior OS in all patients with relapsed/refractory HL, which is consistent with our findings in DLBCL as well as other solid tumors. Our results also suggest an association between diabetes and HL prognosis. Given the association of increased BMI, rVFA, diabetes and poorer outcomes in our cohort, there may be an association between a patient's metabolism and prognosis in Hodgkin lymphoma. Further studies should be conducted to examine the relationship between metabolism and cancer prognosis in a larger cohort. Disclosures Bartlett: Seattle Genetics: Consultancy, Research Funding; Immune Design: Research Funding; Forty Seven: Research Funding; Millennium: Research Funding; Merck: Research Funding; BTG: Consultancy; Roche/Genentech: Consultancy, Research Funding; BMS/Celgene: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Acerta: Consultancy; Kite, a Gilead Company: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Autolus: Research Funding; ADC Therapeutics: Consultancy; Affimed Therapeutics: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ippolito:Vital Images, Inc: Research Funding. Mehta-Shah:Karyopharm Therapeutics: Consultancy; C4 Therapeutics: Consultancy; Verastem: Research Funding; Celgene: Research Funding; Genetech/Roche: Research Funding; Corvus: Research Funding; Bristol Myers-Squibb: Research Funding; Kyowa Hakko Kirin: Consultancy; Innate Pharmaceuticals: Research Funding.
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- 2020
10. Impact of Novel Agents on Outcomes of Patients with Classical Hodgkin Lymphoma and Primary Treatment Failure
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Epperla, Narendranath, primary, Costa, Luciano J., additional, Vaughn, John L, additional, Hanel, Walter, additional, Raya, Saba, additional, Cashen, Amanda F, additional, Sarmad, Rehan, additional, Badar, Talha, additional, Hamadani, Mehdi, additional, Liu, Yang, additional, Barta, Stefan K., additional, Caimi, Paolo, additional, Sethi, Tarsheen K., additional, Reddy, Nishitha, additional, Burkart, Madelyn, additional, Karmali, Reem, additional, Bello, Celeste, additional, Chavez, Julio C., additional, Kothari, Shalin K., additional, Hernandez-Ilizaliturri, Francisco J., additional, Ballard, Hatcher J., additional, Svoboda, Jakub, additional, Emery, Lukas, additional, Lansigan, Frederick, additional, Glenn, Martha, additional, Churnetski, Michael C., additional, Cohen, Jonathon B., additional, Sorge, Caryn, additional, and Xavier, Ana C., additional
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- 2019
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11. Hematopoietic Cell Transplantation Donor Selection Reimagined: KIR-KIR Ligand Interactions and a Formalized Donor Risk Index Effective at Predicting Survival
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Krieger, Elizabeth, primary, Sivagnanaling, Urmila, additional, Webb, Katherine, additional, Broadway, Dana, additional, Roberts, Catherine, additional, McCarty, John M., additional, Wiedl, Christina M., additional, Romee, Rizwan, additional, Keating, Armand, additional, Qayyum, Rehan, additional, and Toor, Amir Ahmed, additional
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- 2019
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12. Infections Associated with CAR T Therapy for Treatment of Hematological Malignancies
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Syed, Tariq Iqtidar Sadiq, primary, Abdullah, Syed Maaz, additional, Rehan, Tayyab, additional, Ahmad, Muhaddis Ejaz, additional, Batool, Syeda Sabeeka, additional, Yousaf, Muhammad Abdullah, additional, Yusufi, Maaz Ahmed, additional, Rehman, Saif Ur, additional, Kotapati, Sravanthi, additional, Khan, Maimoona, additional, Waheed, Asma, additional, Ijaz, Zainab, additional, Ijaz, Awais, additional, and Anwer, Faiz, additional
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- 2019
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13. Development and Validation of a Functional Status-Based Pain Assessment Tool
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Guy, Margaret, primary, Qayyum, Rehan, primary, Derby, Pamela, primary, Carter, Nicole, primary, Keiser, Jessica, primary, Ulbing, Alexandra, primary, Sop, Daniel, primary, and Smith, Wally R, primary
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- 2019
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14. Variability in Killler Immunglobulin like Receptor Gene Expression As a Periodic Function of Gene Position on Chromosome 19
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Krieger, Elizabeth, primary, Sivagnanaling, Urmila, additional, Webb, Katherine, additional, Qayyum, Rehan, additional, and Toor, Amir Ahmed, additional
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- 2019
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15. Middle East Respiratory Syndrome (MERS) Infection in Hematological and Oncological Patients: A Case Series from a Tertiary Care Center in Saudi Arabia
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Alaskar, Ahmed, primary, Bosaeed, Mohammed, additional, Rehan, Hina, additional, Mendoza, May Anne, additional, Alahmari, Bader, additional, Othman, Adel, additional, Alhejazi, Ayman, additional, Abuelgasim, Khadega, additional, Damlaj, Moussab, additional, Alzahrani, Mohsen, additional, Gmati, Giamal, additional, Salama, Hind, additional, Abolfotouh, Mostafah, additional, and Shaheen, Naila, additional
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- 2019
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16. Hematological Profile in the Saudi Population: Reference Intervals By Gender, Age and Regions
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Alaskar, Ahmed, primary, Rehan, Hina, additional, Mendoza, May Anne, additional, Alsahan, Aljowhara, additional, Immanuel, Anita, additional, Alhejazi, Ayman, additional, Abuelgasim, Khadega, additional, Salama, Hind, additional, Damlaj, Moussab, additional, Gmati, Giamal, additional, Alzahrani, Mohsen, additional, Rather, Mushtaq, additional, Alahmari, Bader, additional, Al Mugairi, Areej, additional, and Ahmed, Anwar, additional
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- 2019
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17. Middle East Respiratory Syndrome (MERS) Infection in Hematological and Oncological Patients: A Case Series from a Tertiary Care Center in Saudi Arabia
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Mohsen Alzahrani, May Anne Mendoza, Bader Alahmari, Moussab Damlaj, Ahmed Alaskar, Hina Rehan, Giamal Gmati, Mostafah Abolfotouh, Hind Salama, Khadega A. Abuelgasim, Naila A. Shaheen, Mohammed Bosaeed, Adel Othman, and Ayman Alhejazi
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Pediatrics ,medicine.medical_specialty ,Middle East respiratory syndrome coronavirus ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease_cause ,medicine.disease ,Biochemistry ,Tertiary care ,Intensive care unit ,law.invention ,Health personnel ,law ,904.Outcomes Research-Non-Malignant Conditions ,medicine ,Middle East respiratory syndrome ,business - Abstract
We present the largest to date of a case series of nine patients with hematological and oncological malignancies who were infected with Middle East Respiratory Syndrome Coronavirus (MERS-CoV). MERS-CoV is a novel beta-coronavirus with a high fatality rate in comorbid patients. The majority of MERS cases globally were reported from Saudi Arabia (1983 cases, including 745 related deaths with a case-fatality rate of 37.5%) according to the WHO update of February 2019. All were clinically stable before acquiring the virus. Most of the cases had an active disease as relapse or refractory with three cases being neutropenic. The clinical presentation and radiological features of the patients were variable and inconsistent (Table 1). Diagnosis was confirmed with RT-PCR assays targeting upstream of the E gene and the open-reading frame gene 1a which had to be done repeatedly and required an average of 3 (with max. of 7) samples for a test to be positive (Table 2). All the patients developed respiratory failure, were admitted to the critical care unit (ICU) and required mechanical ventilation. The length of hospital stay ranged from 15 - 48, with an average of 24 days. Unfortunately, all nine patients died within days after admission to the ICU. In addition, the time from diagnosis to death has an average of 9 days ranging from 2-24 days, respectively. In conclusion, MERS CoV infection in hematology/oncology patients has a very poor prognosis regardless of the status of the underlying disease. The clinical presentation is not distinctive and confirming the diagnosis requires numerous respiratory samples. Measures to prevent nosocomial outbreaks should include proper compliance with personal protection equipment by health-care workers when managing patients with suspected and confirmed MERS-CoV infection and prompt isolation of infected patients. Future research is required to enhance our understanding of the disease and to evaluate superior diagnostic and therapeutic options. Disclosures No relevant conflicts of interest to declare.
- Published
- 2021
18. Increased Inhibitory KIR-Ligand Interactions Confer Relapse Protection Following HLA Matched Unrelated Donor HCT for AML
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Amir A. Toor, Rehan Qayyum, and Elizabeth Krieger
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Oncology ,medicine.medical_specialty ,Donor selection ,business.industry ,KIR Ligand ,Immunology ,Hematopoietic stem cell ,Retrospective cohort study ,Cell Biology ,Hematology ,Human leukocyte antigen ,Biochemistry ,medicine.anatomical_structure ,immune system diseases ,In vivo ,Internal medicine ,Cohort ,medicine ,Receptor ,business - Abstract
Killer immunoglobulin-like receptor (KIR) and KIR-ligand (KIRL) interactions play an important role in natural killer cell-mediated graft versus leukemia effect (GVL) after hematopoietic stem cell transplant (HCT) for AML. There is considerable heterogeneity in the KIR gene and KIRL content of individuals, making it difficult to estimate the full clinical impact of NK cell alloreactivity following HCT. Herein, we validate a mathematical model accounting for KIR-KIRL interactions identifying donors with optimal NK cell-mediated alloreactivity and GVL. This retrospective study was performed on de-identified donor and recipient demographic and clinical outcomes data provided by the Center for International Blood and Marrow Transplant Research (CIBMTR). Donor recipient pairs (DRP) who underwent unrelated donor (URD) HCT for early and intermediate AML were included. KIR-KIRL interaction values were assigned as follows; if an inhibitory KIR (iKIR) on the NK cell encounters a ligand on its target, this will give the NK cell an inhibitory signal and this is scored as a single interaction(Figure 1b), as is the case, if there is no ligand for an inhibitory KIR, i.e., missing KIRL (mKIRL) (Figure 1c). Finally, activating KIR (aKIR) interacting with its ligands is similarly scored(Figure 1a). The absolute values of the iKIR and mKIR scores were summed to calculate the composite inhibitory-missing ligand (IM)-KIR score (Figure 1d). The study cohort was comprised of 2365 donor-recipient pairs (DRP) who underwent URD HCT for early or intermediate AML. Mean age was 53 years; 85% of DRPs were high-resolution 8/8 HLA-matched for HLA-A, -B, -C, and -DRB1. All patients received T cell replete grafts; 42% (n=996) received in vivo T cell depletion, 937 (94%) with anti-thymocyte globulin (ATG); 86% received a graft of mobilized peripheral blood stem cells (PBSC), 59% received myeloablative conditioning. This cohort was primarily of Caucasian descent (89%). When adjusted for recipient age, donor age, CMV status, KPS, GVHD prophylaxis, cytogenetics, disease status, conditioning regimen, in vivo T cell depletion, graft source, and sex match, relapse risk was significantly reduced in donor-recipient pairs (DRP) with higher inhibitory KIR-KIRL interaction and missing KIRL (mKIR) scores, with HR=0.86 (P=0.01) & HR=0.84 (P=0.02) respectively. This effect was not observed with activating KIR-KIRL interactions. Chronic GVHD and TRM were not significantly affected by iKIR, mKIR or aKIR. Given the significant individual impact of iKIR and mKIR, the summed inhibitory-missing ligand (IM-KIR) score was next assessed, and when this score was 5 (as opposed to This large international study confirms that unrelated DRPs with greater magnitude of inhibitory KIR-KIRL interactions confer significant relapse protection after MUD HCT in standard-risk AML. This challenges the notion that KIR are irrelevant to donor selection. Future clinical trials evaluating donor selection for URD HCT should include this measure to evaluate its value prospectively in uniformly treated patient cohorts, with adequate GVHD and antiviral prophylaxis to mitigate TRM. Disclosures No relevant conflicts of interest to declare.
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- 2020
19. Hematological Profile in the Saudi Population: Reference Intervals By Gender, Age and Regions
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Areej Al Mugairi, Aljowhara Alsahan, Mushtaq Rather, Anita Immanuel, Ayman Alhejazi, Anwar Ahmed, Giamal Gmati, Ahmed Alaskar, Mohsen Alzahrani, Hina Rehan, May Anne Mendoza, Bader Alahmari, Khadega A. Abuelgasim, Hind Salama, and Moussab Damlaj
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Hematological disorders ,education.field_of_study ,Percentile ,business.industry ,Immunology ,Population ,Reference range ,Mean age ,Cell Biology ,Hematology ,Biochemistry ,Reference intervals ,Reference values ,Medicine ,education ,business ,Screening study ,Demography - Abstract
Background: Although the prevalence of genetic hematological disorders varies widely between geographical regions, region-specific hematological reference ranges have not been defined in Saudi Arabian adults. Methods: A multicenter retrospective cross-sectional study was conducted with 1127 participants who completed their pre-employment screening and recruitment process between January 2013 and December 2016. Data related to the demographic and hematological indices were extracted. Results: The mean age was 28.0±5.2 years (range 19.4-72.8 years) and gender was distributed equally (47.5% female vs. 52.5% male). The WBC reference range was 3.3-11.4 ×109/L; hemoglobin 111-174 gm/l; platelet 163-412 ×109/L; MCV 80-95.7 fl, and neutrophils 1.2-8.8 ×109/L. A robust regression model was used to evaluate the effect of the participant's characteristics on the hematological indices. Except for WBC, the rest of the hematological indices were significantly influenced by gender, region, and age. The 2.5 percentile hemoglobin values were 135 gm/L in males and 104 gm/L in females, while platelet values were 173 x109/L in females and 159 x109/L in males. Conclusion: The study defined local hematological reference ranges, which were mostly lower than reported in international studies used in our center. Hematological values were mainly influenced by gender and region. A community nationwide screening study is required to create reference ranges specifically for the Saudi population. Disclosures No relevant conflicts of interest to declare.
- Published
- 2019
20. Impact of Novel Agents on Outcomes of Patients with Classical Hodgkin Lymphoma and Primary Treatment Failure
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Mehdi Hamadani, Martha Glenn, Stefan K. Barta, Lukas Emery, Narendranath Epperla, Yang Liu, Jakub Svoboda, Nishitha Reddy, Luciano J. Costa, Paolo Caimi, Ana C. Xavier, Tarsheen K. Sethi, Madelyn Burkart, Celeste M. Bello, Julio C. Chavez, Shalin Kothari, Frederick Lansigan, Amanda F. Cashen, Walter Hanel, Caryn E. Sorge, John L Vaughn, Jonathon B. Cohen, Saba Raya, Hatcher J. Ballard, Rehan Sarmad, Michael C. Churnetski, Talha Badar, Francisco J. Hernandez-Ilizaliturri, and Reem Karmali
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Oncology ,medicine.medical_specialty ,Chlorambucil ,business.industry ,medicine.medical_treatment ,Immunology ,Salvage therapy ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Chemotherapy regimen ,Lymphoma ,Novel agents ,Internal medicine ,medicine ,Primary treatment ,business ,Brentuximab vedotin ,health care economics and organizations ,medicine.drug - Abstract
Introduction: The majority of patients with classical Hodgkin lymphoma (cHL) will be cured with anthracycline-containing chemotherapy regimens. However, 10-20% of patients with early-stage disease and 30-40% of patients with advanced-stage cHL will relapse. The standard treatment for patients with relapsed cHL is salvage chemoimmunotherapy followed by high-dose chemotherapy (HDT) and autologous hematopoietic cell transplantation (auto-HCT) in chemotherapy-sensitive patients. Patients with primary treatment failure (PTF), i.e. patients who have progressive disease while on therapy or who fail to achieve complete remission (CR) at the end of initial therapy, or experience early relapse after CR1 are expected to have a worse prognosis than patients with late relapse. Since 2011 newer treatments, namely Brentuximab vedotin and PD1/PDL1 blockers have been introduced for the treatment of relapsed and refractory cHL. It is unknown whether changes in disease monitoring and management, including the availability of new agents, impacted survival of patients with cHL and PTF. Methods: Fifteen US academic medical centers contributed cases to the ECLIPSE study (Evaluation of Classical Hodgkin Lymphoma patients wIth Primary treatment failure and analySis of outcomEs). ECLIPSE retrospectively captured patient, disease and treatment characteristics and treatment response as assessed by treating physicians. Eligible patients were ≥ 15 years diagnosed with cHL on or after 2005, who received treatment with curative intent with anthracycline-containing chemotherapy regimens, and developed one of the 3 patterns of PTF: detection of progressive disease during or within 6 weeks of completion of chemotherapy (PP cohort, primary progression), partial response (PR) or stable disease (SD) by functional imaging at completion of chemotherapy (PR/SD cohort), or disease progression detected within 12 months of completion of chemotherapy after prior documentation of CR (ER cohort, early relapse). Patients were divided into two "eras" based on year of diagnosis, 2005-2010 (era1) and 2011-2018 (era2), with the latter expected to reflect changes in salvage therapy for cHL. Results: Patient characteristics for the 553 cases are summarized in Table. Median follow up of survivors was 58.7 and 31.2 months for patients diagnosed in era1 and era2, respectively. ABVD was the upfront treatment for 97.6% of cases. Nearly all patients (98.5%) received salvage therapy after PTF and 60.9% underwent auto-HCT. Patients who relapsed or progressed post auto-HCT received a median of 1 (range 0 to 3) salvage regimens. Five-year overall survival (OS) from time of PTF was 70.3% (95% CI=63.4-77.2%) for patients diagnosed in era1, and 77.6% (95% CI=70.3-84.8%, p = 0.018) for patients diagnosed in era2 (Figure A). While there was no difference in OS among the PP, PR/SD and ER cohorts in the era1 (Figure B), the PR/SD and ER cohorts had better OS than PP cohort in era2 (Figure C). On comparing the OS for each of the 3 cohorts between era1 and era2, there was an improvement in OS in the PR/SD (Figure E) and ER cohorts (Figure F) but no improvement among the PP cohort (D). Multivariable analysis of patients in era 2 identified only age (HR 1.05, 95% CI=1.03-1.07, P Conclusions: Though there has been an improvement in survival among cHL cases with PTF treated in the most recent years, the outcome of patients with PP did not change significantly across eras. Patients with PP disease should be prioritized for clinical trials incorporating newer agents and innovative cellular therapy to current available effective treatments. Disclosures Epperla: Pharmacyclics: Honoraria; Verastem Oncology: Speakers Bureau. Costa:Abbvie: Consultancy; Karyopharm: Consultancy; Fujimoto Pharmaceutical Corporation Japan: Other: Advisor; Sanofi: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding. Cashen:Novartis: Other: Speaker's Bureau; Seattle Genetics: Other: Speaker's Bureau; Celgene: Other: Speaker's Bureau. Hamadani:Otsuka: Research Funding; Takeda: Research Funding; Pharmacyclics: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Merck: Research Funding; Sanofi Genzyme: Research Funding, Speakers Bureau; Celgene: Consultancy; Janssen: Consultancy; Medimmune: Consultancy, Research Funding. Barta:Mundipharma: Honoraria; Celgene: Research Funding; Takeda: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Research Funding; Bayer: Consultancy, Research Funding; Mundipharma: Honoraria; Merck: Research Funding; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Reddy:Celgene: Consultancy; BMS: Consultancy, Research Funding; Genentech: Research Funding; Abbvie: Consultancy; KITE Pharma: Consultancy. Karmali:Gilead/Kite; Juno/Celgene: Consultancy, Speakers Bureau; Takeda, BMS: Other: Research Funding to Institution; Astrazeneca: Speakers Bureau. Bello:Celgene: Speakers Bureau. Chavez:Novartis: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Svoboda:AstraZeneca: Consultancy; Celgene: Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Research Funding; Kyowa: Consultancy; Merck: Research Funding; BMS: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding. Glenn:BMS: Research Funding; Merck: Research Funding; Genentech: Research Funding. Cohen:Lymphoma Research Foundation: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; ASH: Research Funding; Takeda Pharmaceuticals North America, Inc.: Research Funding; Gilead/Kite: Consultancy; Bristol-Meyers Squibb Company: Research Funding; Genentech, Inc.: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy; LAM Therapeutics: Research Funding; UNUM: Research Funding; Hutchison: Research Funding; Astra Zeneca: Research Funding.
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- 2019
21. Variability in Killler Immunglobulin like Receptor Gene Expression As a Periodic Function of Gene Position on Chromosome 19
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Rehan Qayyum, Katherine Webb, Amir A. Toor, Urmila Sivagnanaling, and Elizabeth Krieger
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Genetics ,Regulation of gene expression ,Immunology ,Haplotype ,hemic and immune systems ,chemical and pharmacologic phenomena ,Locus (genetics) ,Cell Biology ,Hematology ,Biology ,Biochemistry ,Chromosome 19 ,T-Cell Receptor Gene ,Gene cluster ,otorhinolaryngologic diseases ,Gene ,KIR2DS4 - Abstract
Killer Immunoglobulin Like Receptors (KIR) are expressed on natural killer (NK) and T cell surface. KIR interactions with KIR-ligands have been implicated in outcomes of hematopoietic stem cell transplantation, placental implantation, autoimmune disease and viral infections. While these KIR interactions are clearly important our understanding of what governs their expression is lacking. The KIR Locus is made up of a highly polymorphic and homologous set of genes located on Chromosome 19q13.4 within the leukocyte receptor complex. Unique to the KIR Gene Cluster, KIR haplotypes not only vary allelically, but they also differ in the number of KIR genes present in different individuals, ranging from 7 to 12 genes. KIR haplotypes have been divided into 2 broad groups; Haplotypes A & B, based on the number of activating and inhibitory KIR genes they possess; where haplotype A contains only one activating allele KIR2DS4 and haplotype B contains various combinations of activating alleles. Expression of KIR on the NK cell surface stochastic, with some KIR found more commonly then others. In this abstract we aim to explore the relationship of KIR gene expression and the organization of the KIR gene locus using available genomic and tissue expression data. KIR gene coordinates on chromosome 19 were collected using the UCSC Genome Browser GRCh38/hg38 gene assembly and the NCBI gene website gene assembly NC_000019.10. Initial KIR gene nucleotide position along chromosome 19 were obtained and converted to angular distance (A.D. in radians) from reference. This was done to account for the double helical nature of DNA molecules, using the following equation A.D. = 2px/10.4; where x is the initial KIR gene nucleotide coordinate. Haplotype A was utilized as an initial test case as gene expression data are available for the genes in this haplotype. GTEX Portal was used to collect mRNA expression for each of the haplotype A genes, KIR-2DL1, -2DL3, -2DL4, -2DP1, -2DS4, -3DL1, -3DL2, -3DL3 & -3DP1, including total (median), splenic and whole blood expression in Reads/Kilobase of transcript/million mapped reads (RPKM). Gene expression was determined via RNA-seq of 53 tissues from 570 donors. KIR haplotype A is located along chromosome 19 between nucleotide position 55,236,713 and 55,370,584 which corresponded with an A.D. of 33,354,476 to 33,435,314 radians. When the KIR gene expression was aligned with the coordinates of the corresponding gene on the KIR locus a distinct periodic pattern of variation in expression levels was observed across the KIR genes comprising Haplotype A (Figure 1). This was true for total KIR expression from across various organs, as well as in blood and splenic tissue. This is borne out by expression data on several Haplotype A KIR genes reported in the literature (Figure 1, yellow curve). These observations suggesting that KIR gene expression may be a periodic function of the gene coordinates on the chromosome are analogous to the periodicity observed in T cell receptor VDJ recombination (Meier et al, BBMT 2019 25(5);868). This observation supports the idea that the spiral structure of the helical DNA molecules coiled around the histone molecules and their arrangement on chromosomes may have a fundamental influence on the expression of different genes, perhaps in conjunction with known epigenetic influence of DNA methylation and histone acetylation. This may also point to a role for the non-coding DNA in regulation of gene expression. We posit that the helical DNA chromosome structure may have a fundamental role in determining gene expression, as exemplified by the KIR and T cell receptor gene loci. This knowledge may allow an improved understanding of variability in global gene expression. Disclosures No relevant conflicts of interest to declare.
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- 2019
22. Development and Validation of a Functional Status-Based Pain Assessment Tool
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Pamela Derby, Daniel Sop, Wally R. Smith, Margaret Guy, Jessica Keiser, Rehan Qayyum, Nicole Carter, and Alexandra Ulbing
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medicine.medical_specialty ,business.industry ,Nurse practitioners ,Immunology ,Cell Biology ,Hematology ,Pain scale ,Numeric Pain Scale ,Physical function ,medicine.disease ,Biochemistry ,Nursing care ,Physical medicine and rehabilitation ,Pain assessment ,Fibromyalgia ,Medicine ,Functional status ,business - Abstract
Introduction: Sickle cell disease (SCD) vaso-occlusive crisis (VOC) often requires hospitalization, but SCD pain may be present prior to admission and persist past discharge, similar to many acute-on-chronic painful conditions. In practice, readiness for discharge during VOC is a judgment and/or negotiation between patients and their caregivers. Subjective pain intensity, rated on a unidimensional continuous or numeric rating scale, communicates neither readiness for discharge, nor patients' multidimensional pain experience. Inpatient multidimensional pain scales that incorporate concepts like physical function may require too much time and/or impose a high, daily respondent burden on uncomfortable SCD respondents. We found no well-established brief daily adult inpatient multidimensional assessment scale for SCD, but found a pediatric daily function SCD scale, as well as scales used in systemic lupus erythematous and fibromyalgia. We therefore developed and validated the functional status-based pain-assessment (FSPA) survey meant to improve evaluation of readiness for discharge during VOC. Methods: FSPA was created using concepts from the above scales, plus input from inpatient management experts familiar with SCD, including physicians, nurse practitioners, pharmacists, and bedside nurses. FSPA helps assess the full spectrum of a patient's functional limitations due to pain. FSPA consists of tasks that are recorded using the patient's self-reported ability (5 point Likert scale ranging from "very easy" to "very difficult") to complete activities including sleeping, watching TV, walking around the room, or eating a meal in a chair. FPSA was designed to be on a health literacy grade of one. Patients were asked to complete FSPA daily at approximately the same time of day. Concurrently, they were asked to rate their pain using a Numeric Rating Scale (NRS, 0-10). Surveys were administered on a preselected nursing unit from January 2018 to June of 2019. Means (standard deviations) or frequencies were used to summarize data. Pearson's correlation was used to examine the relationship between the two continuous variables. Believing readiness for discharge to be a single factor, we performed confirmatory factor analysis (CFA) using structural equation modeling for determining the empirical validity of having a one-factor solution for the FSPA tool. We used item response theory analysis to determine the characteristics of each item using graded response model within a 2-parameter framework. All analyses were performed using Stata 14.0. Results: During the study period, 504 assessments from 86 unique patients over 170 distinct admissions were completed. Of the 86 unique patients, 54% were females with mean age of 31.5 (SD8.0) years. The length of stay was 7.1 (SD6.9) days; minimum 0 days, max 38 days. NRS mean was 6.8 ±1.9 and FSPA mean was 27±8.0. Correlation was moderate and highly significant (Pearson's r = -.4342, p Conclusions: Development and validation of FPSA, while not complete, has yielded a brief assessment tool which may be used daily to improve communication between adult SCD VOC patients and their inpatient clinicians. FPSA may aid the judgment and negotiation of readiness for discharge of these patients, in order to prevent unnecessarily short or long hospital lengths of stay as well as improve patient and provider satisfaction. Future validation could compare FSPA to other longer-term pain and functional assessment tools, determine its ability to predict VOC discharge, and determine whether its use changes VOC discharge behavior. Figure Disclosures Smith: Novartis: Consultancy, Honoraria.
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- 2019
23. Hematopoietic Cell Transplantation Donor Selection Reimagined: KIR-KIR Ligand Interactions and a Formalized Donor Risk Index Effective at Predicting Survival
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Dana Broadway, Catherine H. Roberts, Rizwan Romee, Armand Keating, Amir A. Toor, Elizabeth Krieger, John M. McCarty, Rehan Qayyum, Urmila Sivagnanaling, Christina M. Wiedl, and Katherine Webb
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Hematopoietic cell ,Donor selection ,medicine.medical_treatment ,KIR Ligand ,Immunology ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,Human leukocyte antigen ,Hematologic Neoplasms ,Biology ,Biochemistry ,Transplantation ,Risk index ,medicine ,Cancer research - Abstract
Background When selecting a human leukocyte antigen (HLA) matched unrelated donor (URD) for hematopoietic cell transplantation (HCT) it is generally accepted that donor age, sex, ABO blood group and viral serologic status should be considered. However, the inter-relationship among these variables is not well established and a consensus on how strongly to consider each variable has not been reached. Selection of the optimal donor gets more complicated as new donor recipient pair (DRP) selection parameters, including killer immunoglobulin-like receptors (KIR) haplotypes are included. In this study we seek to develop a logic-based method to reduce the inconsistencies in donor selection in the HLA matched HCT. Methods VCU IRB approval was obtained for a retrospective review of eligible subjects who were adults with known KIR genotyping receiving HLA-A, B, C & DRB1 allelically matched URD HCT for hematologic malignancy between 2014 and 2017. Donor recipient pairs were selected based on donor age, sex match, CMV sero-status match, and ABO compatibility when possible; KIR genotype was not considered in DRP selection. KIR-KIR ligand interactions were calculated for each DR pair and interaction unit values were ascribed as follows; -1, when the donor possessed an inhibitory KIR (iKIR) and the recipient the corresponding HLA; +1, when the donor possessed iKIR and recipient lacked corresponding HLA (mKIR score, missing ligand). A novel inhibitory-missing KIR (IM-KIR) score was calculated for each HLA matched DRP by summing the interaction values as in equation 1. IM KIR Score = |iKIR| + |mKIRL| ………. [1] Univariate and multivariate analysis using Cox regression methods were utilized to evaluate donor parameters associated with overall survival. Weights of each donor risk variable (age, sex, CMV & ABO match) contribution were ascribed and summed up to determine donor risk parameter. Donor risk parameters and reciprocal-IM-KIR were finally combined into a donor risk index. Receiver operating characteristic curve- area under the curve (ROC-AUC) analysis was utilized to compare indices. Results Ninety-eight DRP with known HLA & KIR genotyping were studied. Median follow up at the time of analysis was 583 days. A higher IM-KIR score describes a DRP with increased iKIR-KIR ligand interactions and missing KIR ligand interactions; which was associated with a favorable survival after HCT, HR of 0.44 (95%CI: 0.26 to 0.73; P=0.002). Further analyses were performed using a reciprocal of this score. Univariate analysis of overall survival for donor age, sex match, ABO compatibility and CMV status were all statistically insignificant (p>0.05). However, the donor risk parameter was predictive of mortality with a hazard ratio (HR) of 2.76 (95% CI: 1.22-6.18, p=0.014). Covariate analysis of the donor risk parameter and reciprocal IM-KIR score were both predictive of survival independent of each other with HR 2.41 (1.05-5.54, p=0.038) and 2.35 (1.18-4.70, p=0.016) respectively. Combining the two into a donor risk index was predictive of survival with a HR of 2.38 (1.44-3.92, p=0.001). ROC-AUC comparison of survival for IM-KIR score and donor risk parameter showed statistically significant AUCs of 0.63 and 0.67 respectively. Further, the combined donor risk index shows improved sensitivity and specificity over the donor risk parameter with AUCs of 0.72 and 0.67 respectively. Conclusions A novel KIR-HLA interaction score, the IM-KIR score independently predicts survival in HLA matched DRP, as does a formalized donor risk parameter which includes non-HLA donor characteristics. Moreover, the addition of IM-KIR score to the donor risk parameter enhanced the specificity and sensitivity of predicting survival in these patients. If validated in a larger exploration and validation cohort this method of donor selection may improve the donor selection process, decreasing variability in clinical outcomes and improve overall survival. Disclosures No relevant conflicts of interest to declare.
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- 2019
24. Early Prediction of Moderate-Severe Chronic GvHD By Immunity Related Transcriptome
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Kalra, Amit, primary, Dharmani-Khan, Poonam, additional, Patel, Stuti, additional, Faridi, Rehan Mujeeb, additional, Lewis, Victor A., additional, Daly, Andrew, additional, Mansoor, Adnan, additional, Shabani-Rad, Meer-Taher, additional, Storek, Jan, additional, and Khan, Faisal M, additional
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- 2018
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25. Outcomes of Acute Myeloid Leukemia Patients with Indeterminate Day 14 Bone Marrow Results Treated with and without Re-Induction Chemotherapy
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Jamy, Omer, primary, Bodine, Charles, additional, Sarmad, Rehan, additional, Chadha, Awal, additional, Vachhani, Pankit, additional, Costa, Luciano J, additional, Saad, Ayman, additional, Papadantonakis, Nikolaos, additional, Erba, Harry P., additional, and Di Stasi, Antonio, additional
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- 2018
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26. All Itching Is Not Benign; A Case of Refractory Hypereosinophilic Syndrome Treated with Off Label CD52 Inhibitor-Alemtuzumab
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Ansari, Rehan, primary, Osuna Salazar, Elva Nora, additional, Sarhill, Nabeel, additional, Garcia, Laura E, additional, and Hanley, James, additional
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- 2018
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27. The Healthcare Burden of Emergency Department Utilization for Multiple Myeloma: A Five Years U.S. Nationwide Study
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Bakr, Mohamed Mokhtar, primary, Zahid, Umar, additional, Tenneti, Pavan, additional, Farooqi, Rehan, additional, and Anwer, Faiz, additional
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- 2018
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28. All Itching Is Not Benign; A Case of Refractory Hypereosinophilic Syndrome Treated with Off Label CD52 Inhibitor-Alemtuzumab
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James Hanley, Elva Nora Osuna Salazar, Nabeel Sarhill, Rehan Ansari, and Laura Garcia
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medicine.medical_specialty ,CD52 ,business.industry ,Hypereosinophilic syndrome ,Chronic lymphocytic leukemia ,Immunology ,Hypereosinophilia ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Gastroenterology ,Leukemia ,Imatinib mesylate ,Internal medicine ,medicine ,Alemtuzumab ,Eosinophilia ,medicine.symptom ,business ,medicine.drug - Abstract
INTRODUCTION Usually attributed to allergies or parasites (Seifert et. al Medline 2008) eosinophila is often overlooked. However hypereosinophilia (absolute eosinophil count >1.5 X 109/L on two separate exams one month apart or with pathologic confirmation) can have serious manifestations. When hypereosinophilia is associated with eosinophil-mediated organ damage or dysfunction, a hypereosinophilic syndrome (HES) exists. With an unpredictable course, eosinophilic infiltration commonly affects the skin (eczema), lung (dyspnea), & GIT (gastritis). However life-threatening damage to the CVS (myocarditis) or the CNS may occur. Clinically HES is subdivided into: myeloid variants (M-HES), T lymphocytic variants (L-HES), Familial HES, Idiopathic HES, Organ-restricted, and specific/defined syndromes associated with hypereosinophilia (Roufosse et. al Respiration 2016). Treatment is based upon symptoms and the molecular presence of Fip1-like1-platelet-derived growth factor receptor alpha. If present, patients are initially treated with imatinib mesylate, while those with other types are given a trial of steroids (Cools et. al N Engl J Med 2003). Regrettably complete remissions are rare and long term corticosteroid uses are infamous. Corticosteroid-refractory HES can be fatal with a reported 10 year survival of CASE A 71y/o M with a history of COPD complained of localized pruritus to his back that improved with antihistamines and topical steroids. After a few years he started to experience deterioration in his symptoms and was found to have eosinophilia. Any attempts to taper his oral steroids lead to a widespread manifestation of pruritus and lichenification. At the Mayo Clinic a comprehensive workup was performed including a bone marrow and skin biopsy that revealed perivascular and interstitial mixed dermal inflammation with eosinophils. He had an absolute eosinophil count of 6.92 X 109/L (N Between mepolizumab, an anti IL-5 humanized monoclonal antibody used in severe eosinophilic asthmatics and alemtuzumab, insurance approved of the latter. After 12 treatments he reached complete remission and resolution of symptoms with a normal blood eosinophil level of 0.1 X 103/uL. A repeat bone marrow biopsy did not reveal any primary hematolymphoid neoplasm. DISCUSSION Alemtuzumab is a monoclonal antibody that targets CD 52, a cell surface glycoprotein present on T and B lymphocytes, monocytes and eosinophils. Approved for use on B-cell chronic lymphocytic leukemia and relapsing multiple sclerosis, the use of alemtuzumab on HES is justified by the evidence that CD52 is highly expressed on eosinophils but is notably absent on neutrophils and bone marrow precursors (Verstovsek, S et. al Clinical Cancer Res 2009). Prior studies have been promising regarding the efficacy of alemtuzumab and HES. Out of 12 patients that were followed for 3 years, 10 achieved complete hematologic response - defined as normalization of the absolute eosinophil count (Strati, P. et. al Clinical Lymphoma, Myeloma & Leukemia 2012). Adverse effects have been related to the infusion (fever), and lymphopenia. There is an increased risk of opportunistic infections, especially CMV. Late complications such as secondary lymphomas may also develop. Close follow up and appropriate prophylaxis can be used to mitigate these complications. CONCLUSION Our patient responded well to alemtuzumab, without any notable side effects. Therapy should be reserved due to early and late adverse affects but this agent has proved to be an effective treatment for HES in terms of both complete hematologic response and duration (Strati, P. et. al Clinical Lymphoma, Myeloma & Leukemia 2012). Moreover resistance is not seen, as patients with relapse were able to achieve a second remission. Data about efficacy and safety in the long-term remains lacking, but for treatment resistant and refractory HES, Alemtuzmab may be a suitable choice. Disclosures No relevant conflicts of interest to declare.
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- 2018
29. Early Prediction of Moderate-Severe Chronic GvHD By Immunity Related Transcriptome
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Jan Storek, Amit Kalra, Andrew Daly, Poonam Dharmani-Khan, Stuti Patel, Faisal Khan, Rehan M. Faridi, Meer-Taher Shabani-Rad, Victor Lewis, and Adnan Mansoor
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Oncology ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,T cell ,Immunology ,Cell Biology ,Hematology ,Human leukocyte antigen ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Transcriptome ,Transplantation ,Graft-versus-host disease ,Immune system ,medicine.anatomical_structure ,immune system diseases ,Internal medicine ,medicine ,CD5 ,business - Abstract
Introduction:Graft versus host disease (GvHD) is the most common and debilitating complication of allogeneic hematopoietic cell transplantation (HCT). Among the two clinically significant forms, moderate-severe chronic GvHD (cGvHD) is more difficult to treat than grade 2-4 acute GvHD (aGvHD). Chronic GvHD rarely shows a sustained complete response to immunosuppressive drugs and non-responders either die or suffer long-term. However, if an early and accurate prediction of ensuing cGvHD is posiible, then the high risk patients can be identified and treated preemptively. In the present investigation, we retrospectively analyzed the transcriptome of immunity related genes at one month post-transplant with the aim to identify a potential early and accurate predictor of clinically significant cGvHD. Methods:A cohort of 73 HLA matched first allogeneic HCT recipients with moderate-severe cGvHD (n = 31) and no chronic GvHD (n = 42) were included in the study. All patients received similar myeloablative conditioning regimens along with 4.5 mg/kg antithymocyte globulin as GvHD prophylaxis. The diagnosis of cGvHD was based on National Institutes of Health consensus criteria and median day of diagnosis in our cohort was 126 days. Total RNA was extracted from cryopreserved peripheral blood mononuclear cells (PBMNCs) at one month post-transplant. Gene expression CodeSet profiling of 594 immunity related genes including 15 internal reference genes was performed using Nano string Technology Immunology panel. Differential gene expression and receiver operating characteristic (ROC) analyses was performed using R statistical packages and GraphPad PRISM software. Benjamini Hochberg procedure was used to calculate the P value and the false discovery rate (FDR). Differentially expressed genes with a Benjamini Hochberg P value (BHP) of Results:A gene panel consisting of immunity related 12 genes was identified at one month post-transplant whose transcriptome profile was significantly different between patients that developed moderate-severe cGvHD compared to the patients who did not develop cGvHD. The identified gene panel included highly upregulated T cell activation and proliferation markers like CD3D (BHP=0.005), CD3E (BHP=0.01), CCR7 (BHP=0.005), CD5 (BHP=0.006); TNF receptor superfamily markers like B- and T-lymphocyte attenuator-BTLA (BHP=0.004), CD27 (BHP=0.004), CD40LG (BHP=0.005); and Costimulatory signaling molecules like Inducible T-cell Co-stimulator ICOS (BHP=0.001), CD28 (BHP=0.006) in patients with cGVHD. A gene score of >7 in this panel of 12 genes was able to differentiate patients with high risk of developing mod-severe cGvHD with a sensitivity of 79% and specificity of 88% (AUC = 0.88, P Conclusions:The cGvHD gene panel consisting of 12 genes from multiple immune regulatory pathways identified in the present study provided an early prediction of moderate-severe cGvHD (one month) with high sensitivity and specificity. The robust and rapid technique of nanostring based transcriptome profiling has the potential to be implemented in the clinic. Differentiating patients at high risk of mod-severe cGvHD can help develop new strategies for preemptive therapy and pave the way towards precision medicine leading to improved outcomes of HCT. Disclosures No relevant conflicts of interest to declare.
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- 2018
30. The Healthcare Burden of Emergency Department Utilization for Multiple Myeloma: A Five Years U.S. Nationwide Study
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Rehan Farooqi, Faiz Anwer, Mohamed Mokhtar Bakr, Umar Zahid, and Pavan Tenneti
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medicine.medical_specialty ,Univariate analysis ,education.field_of_study ,Multivariate analysis ,business.industry ,Incidence (epidemiology) ,Immunology ,Population ,Cell Biology ,Hematology ,Emergency department ,medicine.disease ,Biochemistry ,Statistical significance ,Emergency medicine ,Health care ,medicine ,business ,education ,Multiple myeloma - Abstract
Introduction: Multiple myeloma is comparatively uncommon cancer, but among blood malignancies it is still the second most common cancer after non-Hodgkin lymphoma. Patients with complications of multiple myeloma (MM) frequently present to the emergency department. There is a lack of data about the health care burden and trends of utilization of emergency department services by MM patients. The objective of this study is to investigate the recent trends in resource utilization in the emergency departments for MM. Furthermore, we aimed to look for the demographic characteristics associated with the subsequent hospitalization of MM patients. We hypothesized that there has been an increase in the utilization of emergency department services for the management of MM patients in recent years. We further hypothesized that subsequent hospitalization rate may be decreasing with the availability of more efficacious and potentially less toxic drugs. Methods: For this study we obtained the data from United States National Emergency Department Sample (NEDS) years 2010-2014. For categorical variables, frequencies and proportions were generated and statistical significance was tested using a chi-squared test. Rate of myeloma associated emergency department visits were estimated by using US census population. Patients and hospital characteristics were entered in univariate analysis to predict in-patient admissions from the ED. Multivariable logistic regression was used to predict in-patient admissions for the variables that were found statistically significant in univariate analysis. All tests were two-sided with the statistical significance set at p < 0.05. All analyses were conducted using STATA 14.2v and no missing data was imputed. Results: Between 2010 to 2014, approximately 443,214 patients visited emergency departments (ED) with the diagnosis of MM, that accounted for 0.06 % of all emergency department visits. There was an absolute increase of 22% in MM related visits from 80,466 in 2010 to 98,279 in 2014. While the rate of emergency department service utilization by myeloma patient increased significantly by 19% (p=0.04). Overall 73% of myeloma related visits resulted in hospitalization, but over the study period trend of hospitalization decreased. The percentage of patients treated and discharged to home increased from 23% to 29% between 2010 to 2014. Total charges associated with myeloma related visits increased significantly from $315 million to $626 million during 2010 to 2014, with an annual increase in the rate (19.26%: p Conclusion: Multiple myeloma related emergency department service utilization and total charges are increasing over the observed time limit. While the incidence of hospitalization from emergency department is decreasing overtime. These findings can be explained on the basis of few facts. MM patients are living longer with the availability of newer drugs but remain uncured. Most patients will face relapse after the initial disease control, at which point they may need to utilize ED services more frequently. As better oral or intravenous drugs are available through oncology out-patient offices, limited MM drug choices are available in the hospital, majority of MM patients are discharged sooner from the hospitals resulting in reduced hospital admission rates as well as shorter hospital stay. Disclosures No relevant conflicts of interest to declare.
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- 2018
31. Outcomes of Acute Myeloid Leukemia Patients with Indeterminate Day 14 Bone Marrow Results Treated with and without Re-Induction Chemotherapy
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Ayman Saad, Omer Jamy, Charles Bodine, Awal Chadha, Rehan Sarmad, Antonio Di Stasi, Pankit Vachhani, Harry P. Erba, Nikolaos Papadantonakis, and Luciano J. Costa
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medicine.medical_specialty ,business.industry ,Immunology ,Significant difference ,Complete remission ,Induction chemotherapy ,Cell Biology ,Hematology ,Institutional review board ,Biochemistry ,Consolidation therapy ,Transplantation ,Regimen ,High dose cytarabine ,Family medicine ,medicine ,business ,health care economics and organizations - Abstract
Introduction: The initial response to standard induction chemotherapy for acute myeloid leukemia (AML) is commonly assessed with day 14 bone marrow evaluation; patients with residual disease may receive re-induction chemotherapy. The benefit of re-induction chemotherapy in patients with indeterminate day 14 bone marrow results (defined in our study as ≤ 20% cellularity and 5-20% blasts) remains unclear. We report our experience of AML patients with indeterminate day 14 bone marrow treated with and without re-induction chemotherapy. Methods: A retrospective chart review was performed to evaluate adult patients with newly diagnosed AML treated with and without re-induction chemotherapy for indeterminate day 14 bone marrow results between January 2010 and April 2018 at our institution. All patients included in the analysis received induction chemotherapy with cytarabine and an anthracycline. Approval for the study was obtained from the Institutional Review Board. Results: We identified 50 patients with indeterminate day 14 bone marrow results (Table 1). Twenty five patients (50%) received re-induction therapy and 25 (50%) did not. Flow cytometry data on day 14 bone marrow samples were available for 15 patients (60%) who received re-induction and 18 (72%) who did not. All flow cytometry samples, when performed, were reported as persistent/residual disease. The median age at diagnosis was 56 years (range 19-70) in patients who received re-induction and 59 years (range 23-73) in those who did not. There were 12 patients (48%) with poor risk disease, both in the re-induction arm (10 abnormal karyotype, 2 normal karyotype with molecular abnormalities) as well as in the no re-induction arm (6 abnormal karyotype, 6 normal karyotype with molecular abnormalities). FLT3-ITD mutation was positive at diagnosis in 2 cases (8%) in the re-induction arm and in 8 cases (32%) not receiving re-induction. The most commonly used chemotherapy regimen in the re-induction arm was fludarabine, high dose cytarabine and granulocyte-colony stimulating factor (FLAG, 56%). Fifteen patients (60%) in the re-induction arm and 17 (68%) in the no re-induction arm received post-remission consolidation therapy. High-dose cytarabine was the preferred consolidation regimen (96%). The overall response rate [complete remission (CR) + CR with incomplete count recovery (CRi)] was similar in both arms (80% vs. 80%). There was no statistically significant difference in median overall survival (OS) and relapse free survival (RFS) between the re-induction and no re-induction arms (Figure 1). In univariate analysis, no statistically significant difference in OS was found for age at diagnosis (≥ 60 years vs. < 60 years; p=0.06), white blood cell count at diagnosis (≥ 50,000 vs. < 50,000; p=0.48), disease risk status (poor risk vs. favorable/intermediate risk; p=0.81) and performance of transplant (yes vs. no; p=0.13) in the entire population. Conclusion: Our study did not find a statistically significant difference in overall response rates, as well as for OS and RFS in AML patients with indeterminate day 14 bone marrow receiving re-induction or not. Our findings question the utility of immediate re-induction chemotherapy and raise the concern for over treatment in this patient population. Larger studies investigating similar outcomes are warranted to validate these clinical findings. Table 1. Table 1. Disclosures Costa: Celgene: Honoraria, Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding; Janssen: Research Funding; Karyopharm: Research Funding; Sanofi: Honoraria; BMS: Research Funding. Saad:Actinium: Consultancy. Papadantonakis:Agios pharmaceuticals: Honoraria, Other: advisory board. Erba:Janssen: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; MacroGenics: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Incyte: Consultancy, Speakers Bureau; Juno: Research Funding; Amgen: Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Daiichi Sankyo: Consultancy, Research Funding; Agios: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Astellas: Research Funding; Takeda/Millenium: Research Funding; Janssen: Research Funding; Celgene: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Juno: Research Funding; Amgen: Research Funding; Immunogen: Consultancy, Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Pfizer: Consultancy, Other: grant; Astellas: Research Funding; Agios: Consultancy, Speakers Bureau; MacroGenics: Consultancy; Immunogen: Consultancy, Research Funding; Juno: Research Funding; Celgene: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Takeda/Millenium: Research Funding; Astellas: Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Takeda/Millenium: Research Funding; Amgen: Research Funding; Amgen: Research Funding; Novartis: Consultancy, Speakers Bureau; Janssen: Research Funding; Jazz: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Takeda/Millenium: Research Funding; Janssen: Research Funding; Immunogen: Consultancy, Research Funding; MacroGenics: Consultancy; Pfizer: Consultancy, Other: grant; Agios: Consultancy, Speakers Bureau; Juno: Research Funding; MacroGenics: Consultancy; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy, Other: grant; Celgene: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Pfizer: Consultancy, Other: grant; Jazz: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; Astellas: Research Funding; Incyte: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau.
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- 2018
32. Imaging flow cytometry documents incomplete resistance of human sickle F-cells to ex vivo hypoxia-induced sickling
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J. Philip McCoy, Eduard J. van Beers, James S. Nichols, Gregory J. Kato, Rehan Saiyed, Kleber Yotsumoto Fertrin, Christine A. Brantner, David A. Hepp, Leigh Samsel, Mathew P. Daniels, and Laurel Mendelsohn
- Subjects
medicine.diagnostic_test ,Immunology ,Anemia, Sickle Cell ,Cell Biology ,Hematology ,Venous blood ,Hypoxia (medical) ,Biology ,medicine.disease ,Biochemistry ,Sickle cell anemia ,Flow cytometry ,Andrology ,Red blood cell ,medicine.anatomical_structure ,hemic and lymphatic diseases ,Fetal hemoglobin ,medicine ,Humans ,Hemoglobin ,medicine.symptom ,Fetal Hemoglobin ,Ex vivo - Abstract
To the editor: We have read with great interest the “Perspectives” article by Steinberg et al in the January 23, 2014, edition of Blood.1 The authors present a mathematical model that implies that the critical content of fetal hemoglobin (HbF) required to prevent polymerization of sickle hemoglobin is higher than the threshold HbF content that renders an erythrocyte detectable as an “F-cell” on immunofluorescent staining by flow cytometry. This would lead to a hypothesis that only a subset of F-cells are resistant to hypoxia-induced sickling. We obtained data from a new imaging flow cytometry assay that can qualitatively support this general principle, although with clear assay limitations that don’t permit us to address quantitatively the predictions of Steinberg et al in detail. These new results show that intracellular HbF is a major factor influencing sickling, but it is clearly not the only factor. We investigated the influence of HbF content on sickling at the individual cell level through our recently developed Sickle Imaging Flow Cytometry Assay (SIFCA), a robust, reproducible sickling assay.2 We developed an enhanced version of SIFCA that allows simultaneous analysis of both intracellular expression of HbF and morphological features of each red blood cell (RBC). Peripheral venous blood samples were collected with written consent from 22 adult sickle cell anemia (SCA) patients (8 off and 14 on hydroxyurea, median HbF 10.7% and 18.3%, respectively) with a wide HbF range (1.5% to 33.0%). We subjected 1% RBC suspensions to deoxygenation for 2 hours at 2% oxygen followed by fluorescent labeling against HbF. Images from 20 000 cells were obtained by imaging flow cytometry (ImageStreamX Mk II; Amnis Corporation), allowing combined analysis of shape change and HbF expression for each RBC. We confirmed previous observations3 using conventional flow cytometry that F-cell count significantly correlates with percent HbF determined by HPLC (Figure 1A). F-cell count by SIFCA correlated highly with conventional F-cell flow cytometry by an independent Clinical Laboratory Improvement Amendments–certified facility (r2 = 0.9976, 95% CI 0.9861-0.9996, P < .0001, data not shown). SIFCA yields automated determination of the percentage of “normal cells,” which remain biconcave discs, and of “abnormal cells,” which change their shape on hypoxic incubation, including the majority of sickled cells. As expected, the HbF percentage correlated positively and negatively with the percentage of normal and abnormal cells, respectively (Figure 1B-C). Figure 1 Imaging flow cytometry documents incomplete resistance of human sickle F-cells to ex vivo hypoxia-induced sickling. (A) HbF in the hemolysate correlates positively with the percentage of F-cells detected by SIFCA. HbF protective effect against sickling ... Fluorescent labeling of HbF allowed us to discriminate non-F-cells (Figure 1Di-ii) from F-cells (Figure 1Diii-iv), and analyze their shape as captured in the brightfield images. The images confirmed the prediction that some RBCs with detectable HbF content still sickle (Figure 1Div), and also identified RBCs that are resistant to sickling despite no detectable HbF (Figure 1Dii). The percentage of non-F-cells sickling on deoxygenation was significantly higher than among F-cells (20.08% [95% CI 15.56-24.60] vs 13.44% [95% CI 10.21-16.68], P < .0001). This difference was statistically significant both in patients not taking HU and in treated patients (Figure 1F). F-cells from patients on HU sickled significantly less than F-cells from patients off HU, and the same difference was borderline significant when comparing non-F-cells from patients on HU with those off HU. Our observations support that the threshold used for detection of F-cells is not the same threshold that defines protection against sickling. Similar to previous investigators, we also have found that the very high concentration of intraerythrocytic hemoglobin poses a difficult challenge in achieving the antigen saturation with anti-γ-globin antibody that is necessary to measure accurately the amount of HbF per F-cell,4 which will be needed ultimately to test fully the mathematical modeling predictions of Steinberg et al. Differential RBC susceptibility of non-F-cells to sickling between patients on or off HU also supports the existence of additional beneficial mechanisms of HU other than HbF induction.4 The identification of factors besides HbF that modulate sickle hemoglobin polymerization may help in the design of novel therapies for HU-resistant SCA patients.
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- 2014
33. The Hedgehog receptor Patched1 regulates myeloid and lymphoid progenitors by distinct cell-extrinsic mechanisms
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David J. Curtis, Brandon J. Wainwright, Sumitha Vasudevan, Nhu-Y N Nguyen, Rehan Villani, Stephen M. Jane, Matthew P. McCormack, and Sarah L. Siggins
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Male ,Patched Receptors ,Myeloid ,Thymic stromal lymphopoietin ,Immunology ,Kruppel-Like Transcription Factors ,Mice, Transgenic ,Receptors, Cell Surface ,Biology ,Biochemistry ,Receptors, G-Protein-Coupled ,Mice ,Mice, Congenic ,Thymic Stromal Lymphopoietin ,medicine ,Animals ,Cell Lineage ,Hedgehog Proteins ,Myeloid Cells ,Lymphocytes ,Bone Marrow Transplantation ,Myelopoiesis ,Osteoblasts ,Lymphopoiesis ,Gene Expression Regulation, Developmental ,Cell Biology ,Hematology ,Smoothened Receptor ,Hedgehog signaling pathway ,Cell biology ,Mice, Inbred C57BL ,Patched-1 Receptor ,Haematopoiesis ,medicine.anatomical_structure ,Radiation Chimera ,Cytokines ,Female ,Bone marrow ,Signal transduction ,Stem cell ,Smoothened - Abstract
Hedgehog (Hh) ligands bind to the Patched1 (Ptch1) receptor, relieving repression of Smoothened, which leads to activation of the Hh signaling pathway. Using conditional Ptch1 knockout mice, the aim of this study was to determine the effects of activating the Hh signaling pathway in hematopoiesis. Surprisingly, hematopoietic-specific deletion of Ptch1 did not lead to activation of the Hh signaling pathway and, consequently, had no phenotypic effect. In contrast, deletion of Ptch1 in nonhematopoietic cells produced 2 distinct hematopoietic phenotypes. First, activation of Hh signaling in epithelial cells led to apoptosis of lymphoid progenitors associated with markedly elevated levels of circulating thymic stromal lymphopoietin. Second, activation of Hh signaling in the bone marrow cell niche led to increased numbers of lineage-negative c-kit+ Sca-1+ bone marrow cells and mobilization of myeloid progenitors associated with a marked loss of osteoblasts. Thus, deletion of Ptch1 leads to hematopoietic effects by distinct cell-extrinsic mechanisms rather than by direct activation of the Hh signaling pathway in hematopoietic cells. These findings have important implications for therapeutics designed to activate the Hh signaling pathway in hematopoietic cells including hematopoietic stem cells.
- Published
- 2009
34. IL-21 mediates apoptosis through up-regulation of the BH3 family member BIM and enhances both direct and antibody-dependent cellular cytotoxicity in primary chronic lymphocytic leukemia cells in vitro
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Syed-Rehan A. Hussain, Carolyn Cheney, David Jarjoura, Julie M. Roda, Wayne R. Kindsvogel, William E. Carson, Susheela Tridandapani, Michael A. Caligiuri, Xiaoli Zhang, Trupti Joshi, Amy Lehman, Susan E Schmidt, Natarajan Muthusamy, John C. Byrd, Asha Ramanunni, and Aruna Gowda
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Cytotoxicity, Immunologic ,medicine.medical_treatment ,Chronic lymphocytic leukemia ,Immunology ,Apoptosis ,Biology ,Biochemistry ,Antibodies, Monoclonal, Murine-Derived ,chemistry.chemical_compound ,Interleukin 21 ,Proto-Oncogene Proteins ,hemic and lymphatic diseases ,STAT5 Transcription Factor ,medicine ,Humans ,Cytotoxic T cell ,Antibody-dependent cell-mediated cytotoxicity ,Bcl-2-Like Protein 11 ,Interleukins ,Antibody-Dependent Cell Cytotoxicity ,Antibodies, Monoclonal ,Membrane Proteins ,Tyrosine phosphorylation ,Cell Biology ,Hematology ,medicine.disease ,Up-Regulation ,Fludarabine ,STAT1 Transcription Factor ,Cytokine ,chemistry ,Cancer research ,Apoptosis Regulatory Proteins ,Rituximab ,Vidarabine ,medicine.drug - Abstract
Interleukin-21 (IL-21) is a recently identified γ-chain receptor cytokine family member that promotes B-cell apoptosis as well as activation of innate immune system. Based on this, we hypothesized that IL-21 might enhance the apoptosis induced by fludarabine and rituximab and also play a role in augmenting immune-mediated clearance of the chronic lymphocytic leukemia (CLL) cells. Our studies demonstrate that the majority of CLL patients have surface IL-21 receptor-α, and its expression correlates with apoptosis, tyrosine phosphorylation of STAT1, and up-regulation of the proapoptotic BH3 domain protein BIM. IL-21–induced BIM up-regulation is critical for apoptosis because inhibition of BIM expression using small interfering RNA prevented IL-21–induced apoptosis. IL-21 treatment of CLL cells but not normal T cells with fludarabine or rituximab additively enhanced the direct cytotoxic effect of these therapies. In addition to its proapoptotic effect, IL-21 promoted STAT1 and STAT5 phosphorylation in natural killer cells with concurrent enhanced antibody-dependent cellular cytotoxicity against rituximab-coated CLL cells in vitro. These data provide justification for combination studies of IL-21 with fludarabine and rituximab in CLL and suggest that BIM up-regulation might serve as relevant pharmacodynamic end point to measure biologic effect of this cytokine in vivo.
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- 2008
35. Differential Expression of Immunity Related Genes and Early Prediction of Severe Graft Versus Host Disease after Allogeneic Hematopoietic Cell Transplantation
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Dharmani-Khan, Poonam, primary, Faridi, Rehan Mujeeb, additional, Akhter, Ariz, additional, Kalra, Amit, additional, Storek, Jan, additional, and Khan, Faisal M, additional
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- 2016
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36. SEC61B Regulates Calcium Flux and Platelet Hyperactivity in Diabetes Mellitus
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Kong, Yvonne X, Rehan, Rajan, Moreno, Cesar L, Zhao, Huiwen, James, David, Cielesh, Michelle, Morahan, Grant, Cartland, Sian, Kavurma, Mary, Neely, Greg, Rondina, Matthew T., Weaver, James, Larance, Mark, and Passam, Freda H
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Background/Aim
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- 2023
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37. Hairy Cell Leukemia with Severe Leukocytosis
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Almakadi, Mohammed, Akram, Muhammad Rehan, Aldhafeeri, Dalal, Alrajjal, Ahmed, Elazony, Ahmed, Nawaz, Azhar, Alruwaythi, Mohammed, Althubyani, Hamoud, Albeihany, Amal, and Ahmed, Liju
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Introduction
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- 2023
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38. Differential Expression of Immunity Related Genes and Early Prediction of Severe Graft Versus Host Disease after Allogeneic Hematopoietic Cell Transplantation
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Jan Storek, Amit Kalra, Poonam Dharmani-Khan, Rehan M. Faridi, Ariz Akhter, and Faisal Khan
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Oncology ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,T cell ,Immunology ,BTLA ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Transplantation ,surgical procedures, operative ,Graft-versus-host disease ,medicine.anatomical_structure ,Immune system ,immune system diseases ,Internal medicine ,Medicine ,CD5 ,business ,Complication - Abstract
Background: Allogeneic hematopoietic cell transplantation (HCT) is curative for hematological malignancies. However, Graft versus host disease (GVHD) is the most common and debilitating complication of HCT as 10-15% HCT recipients die and 25% suffer long-term due to GVHD. Effective but toxic prophylaxes for GVHD (e.g., anti-thymocyte globulin) exist that can be given preemptively to patients with high risk of GVHD. However, an early and accurate identification of patients who are at a high risk of developing severe GVHD is the prerequisite for any preemptive therapy. The 'onset' of symptoms associated with GVHD is the final manifestation of a series of cellular and molecular perturbations that take place when host epithelial cells are attacked by the donor immune cells. With the aim of identifying potential functional biomarkers for early prediction of severe GVHD, a comprehensive panel of 594 genes shared among 24 immunology-related gene networks were retrospectively analyzed at different posttransplant time points prior to the onset of GVHD . Methods: Two hundred and two RNA specimens from 117 first allogeneic HCT recipients with (n=49) or without (n=68) clinically significant GVHD were analyzed. RNA was extracted from cryopreserved peripheral blood mononuclear cells (PBMNCs) collected at three early post-transplant time points: one week (n=32), one month (n=85) and two months (n=80) after transplantation. Messenger RNA counts for 594 human genes with immunity related functions and 15 internal reference genes were obtained using Nanostring based gene expression CodeSet profiling. Empirical Bayes statistics for differential gene expression, receiver operating characteristic (ROC) and principle component analyses were performed using R statistical packages to identify the gene sets with highest sensitivity and specificity for early prediction of clinically significant GVHD. Results: A 'GVHD transcript panel' comprising of highly upregulated 6 genes with T cell related pro-inflammatory functions was identified at one month post transplantation in patients with clinically significant GVHD (grade II-IV acute GVHD (median day of onset = 34 days) and/or chronic GVHD requiring systemic therapy, median day of onset = 108 days). The panel consists of CD27 (AUC=0.93; p=3.4X10-8); B- and T-lymphocyte attenuator, BTLA ((AUC=0.92; p=3.4X10-8),Inducible T-cell Co-stimulator, ICOS (AUC=0.90; p=3.5X10-7), CD5 (AUC=0.87; p=8.5X10-7), CD3D (AUC=0.88; p=8.8X10-7) and CD28 (AUC=0.91; p=9.9X10-7). The GVHD transcript panel predicted clinically significant GVHD with sensitivity of 85% and specificity of 95%. Conclusions: The findings strongly favor the early prediction of clinically significant GVHD made possible by differential expression profile of genes associated with T cell related pro-inflammatory functions The identified 'GVHD transcript panel' is highly sensitive and specific in identifying patients at a high risk of developing GVHD and can pave the way to precision HCT medicine. Disclosures No relevant conflicts of interest to declare.
- Published
- 2016
39. Copies of Donor Killer Immunoglobulin-like Receptor Genes and Motifs Titrate Natural Killer (NK) Cells' Functional Response to Epstein - Barr Virus Infections and Influence the Risk of Developing Post-Transplant Lymphoproliferative Disease (PTLD) after Allogeneic Hematopoietic Cell Transplantation
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Faridi, Rehan Mujeeb, primary, Kemp, Taylor J, additional, Dharmani, Poonam, additional, Lewis, Victor A., additional, Berka, Noureddine, additional, Storek, Jan, additional, and Khan, Faisal M, additional
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- 2015
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40. Endogenous antigen presentation impacts on T-box transcription factor expression and functional maturation of CD8+ T cells
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Stephanie Gras, Yu Chih Liu, Katherine K Wynn, Vijayendra Dasari, Corey Smith, Rajiv Khanna, Scott R. Burrows, Jamie Rossjohn, Sweera Rehan, Judy Tellam, Diah Elhassen, and Siok-Keen Tey
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Immunology ,Antigen presentation ,Eomesodermin ,Cytomegalovirus ,chemical and pharmacologic phenomena ,CD8-Positive T-Lymphocytes ,Major histocompatibility complex ,Lymphocyte Activation ,Biochemistry ,Granzymes ,Major Histocompatibility Complex ,Interleukin 21 ,Interferon-gamma ,Antigen ,Cytotoxic T cell ,Humans ,Antigen-presenting cell ,Antigens, Viral ,Cells, Cultured ,Antigen Presentation ,biology ,Perforin ,Cell Differentiation ,Cell Biology ,Hematology ,Flow Cytometry ,Cell biology ,Granzyme B ,Cytomegalovirus Infections ,biology.protein ,Cytokines ,T-Box Domain Proteins ,T-Lymphocytes, Cytotoxic - Abstract
T-box transcription factors T-bet (Tbx21) and Eomesodermin (Eomes) are critical players in CD8+ cytotoxic T lymphocyte effector function and differentiation, but how the expression of these transcription factors is regulated remains poorly defined. Here we show that dominant T cells directed toward human CMV, expressing significantly higher levels of T-bet with graded loss of Eomes expression (T-bethiEomeshi/lo), are more efficient in recognizing endogenously processed peptide-major histocompatibility complexes (pMHC) compared with subdominant virus-specific T cells expressing lower levels of T-bet and high levels of Eomes (T-betintEomeshi). Paradoxically, the T-bethiEomeshi/lo dominant populations that efficiently recognized endogenous antigen demonstrated lower intrinsic avidity for pMHC, whereas T-betintEomeshi subdominant populations were characterized by higher pMHC avidity and less efficient recognition of virus-infected cells. Importantly, differential endogenous viral antigen recognition by CMV-specific CD8+ T cells also correlated with the differentiation status and expression of perforin, granzyme B and K. Furthermore, we demonstrate that the expression of T-bet correlates with clonal expansion, differentiation status, and expression of perforin, granzyme B and K in antigen-specific T cells. These findings illustrate how endogenous viral antigen presentation during persistent viral infection may influence the transcriptional program of virus-specific T cells and their functional profile in the peripheral blood of humans.
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- 2012
41. Copies of Donor Killer Immunoglobulin-like Receptor Genes and Motifs Titrate Natural Killer (NK) Cells' Functional Response to Epstein - Barr Virus Infections and Influence the Risk of Developing Post-Transplant Lymphoproliferative Disease (PTLD) after Allogeneic Hematopoietic Cell Transplantation
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Jan Storek, Victor Lewis, Noureddine Berka, Poonam Dharmani, Taylor J. Kemp, Faisal Khan, and Rehan M. Faridi
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Immunology ,Viral transformation ,Cell Biology ,Hematology ,Biology ,Biochemistry ,Virology ,Virus ,Transplantation ,Immune system ,hemic and lymphatic diseases ,Receptor ,KIR3DL1 ,Gene ,KIR2DS4 - Abstract
BACKGROUND: Recipientsof allogeneic HCT remain vulnerable to a heightened risk of reactivation of otherwise latent viral infections owing to a compromised immune system early after transplantation. Uncontrolled reactivation of Epstein-Barr virus (EBV) leading to post-transplant lymphoproliferative disorder (PTLD) is one of such major complications after T-cell depleted HCT. Recovering within weeks after transplantation and being first in line of defense against viral infections, natural killer (NK) cells are deemed important in the immunopathogenesis of EBV complications. Their role however remains elusive. NK cell responses are regulated by a series of activating and inhibitory cell surface receptors, central to which are the Killer Immunoglobulin-like Receptors (KIR). Through these receptors NK cells discriminate healthy cells from 'altered' self-cells by scaling the perturbations in HLA expression after viral transformation of the target cell. Here, we set out to determine whether and how KIR gene and motifs' content of HCT donors and/or recipients influences the development of PTLD after allo-HCT. STUDY DESIGN: Hypothesizing that diverse NK cell receptor repertoires can titrate NK cell functional responses to EBV infections/reactivation and can potentially modify the risk of developing PTLD, we determined the KIR gene repertoires of 356 HLA-matched donor-recipient pairs of first allo-HCT and 50 healthy donors through Next Generation Sequencing of the KIR locus on the Illumina MiSeq platform. Based on the presence/absence and number of copies of individual genes, the KIR genotypes were determined and classified into four common centromeric (cA01, cB01, cB02 and cB03) and two telomeric (tA01 and tB01) motifs along with their variants. PBMNCs from KIR typed healthy volunteers were stimulated with EBV-transformed target cells to enumerate NK cell response to EBV (degranulation and/or IFNγ production) as a function of KIR gene content and motifs' distribution using a multicolor flow cytometry-based assay. Effect of KIR gene profile on development of PTLD was analyzed using binomial competing risks regression statistics. Distribution of NK cell functional response across various KIR characterized groups was analyzed using Mann-Whitney U statistics. RESULTS: Donor telomeric A motifs (tA01, KIR3DL1+ve KIR2DS4+ve; KIR3DS1/2DS1+/-ve), strongly protected against PTLD (p=0.0001, SHR=0.17; Figure 1). An increased protection against PTLD with increasing number of tA01 was noted with at least one copy required for a significant protective effect (Figure 1B). Copy number analysis of tA01 gene contents yielded similar associations. Further, the number of EBV induced functional NK cell subsets were significantly higher in individuals with than without KIR genotypes containing tA01 motifs (Figure 2 A-C) and was found to be increasing with an increasing number of tA01 copies (Figure 2 A'-C'). There was no influence of recipients' KIR repertoire on the risk of developing PTLD CONCLUSIONS: NK cell responsiveness, a function of KIR gene repertoire has a profound effect on the development of PTLD. Appropriately characterized KIR gene profile based identification of HCT recipients at high risk of developing PTLD will enable closer monitoring of EBV DNAemia and facilitate prompt therapy. Figure 1. Donor KIR telomeric A motif (tA01) protects against the risk of developing PTLD (A). Presence of at least one copy of donor KIR tA01 motif confers significant protection from PTLD (B) Figure 1. Donor KIR telomeric A motif (tA01) protects against the risk of developing PTLD (A). Presence of at least one copy of donor KIR tA01 motif confers significant protection from PTLD (B) Figure 2. KIR telomeric A motifs (tA01) titrate NK cells' functional response to Epstein-Barr virus infected cells (A-C), with and increasing %functional NK cells and subsets (measures as expressing CD107a, IFN-γ, or both) are observed with increasing tA01 motifs' copies (A'-C') Figure 2. KIR telomeric A motifs (tA01) titrate NK cells' functional response to Epstein-Barr virus infected cells (A-C), with and increasing %functional NK cells and subsets (measures as expressing CD107a, IFN-γ, or both) are observed with increasing tA01 motifs' copies (A'-C') Disclosures No relevant conflicts of interest to declare.
- Published
- 2015
42. Survival of Chronic Myeloid Leukemia Patients in Comparison to General Population in the Tyrosine Kinase Inhibitors Era: A US Population Based Study
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Sarmad, Rehan, Jamy, Omer, and Costa, Luciano J.
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- 2017
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43. Risk and Outcomes of Second Malignant Neoplasms in Chronic Myeloid Leukemia Survivors
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Jamy, Omer, Sarmad, Rehan, and Costa, Luciano J.
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- 2017
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44. Influence of Production Affecting Cytokine Genetic Variants on Allogeneic Hematopoietic Cell Transplantation Outcomes
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Tripathi, Gaurav, primary, Khan, Poonam D, additional, Faridi, Rehan M, additional, Lewis, Victor, additional, Berka, Noureddine, additional, Storek, Jan, additional, and Khan, Faisal M, additional
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- 2014
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45. End-Alveolar Carbon Monoxide As a Measure of Erythrocyte Survival and Hemolytic Severity in Sickle Cell Disease
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Minniti, Caterina P., primary, Baird, John H., additional, Xu, Dihua, additional, Mendelsohn, Laurel, additional, Saiyed, Rehan, additional, Jackson, Mary, additional, Nichols, James, additional, Kim-Shapiro, Daniel, additional, Xia, Yang, additional, and Kato, Gregory J., additional
- Published
- 2014
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46. Influence of Production Affecting Cytokine Genetic Variants on Allogeneic Hematopoietic Cell Transplantation Outcomes
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Noureddine Berka, Faisal Khan, Gaurav Tripathi, Victor Lewis, Poonam D. Khan, Jan Storek, and Rehan M. Faridi
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Donor selection ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Human leukocyte antigen ,Hematopoietic stem cell transplantation ,Biology ,medicine.disease ,Biochemistry ,Cytokine Receptor Gene ,Interleukin 10 ,Cytokine ,Graft-versus-host disease ,medicine ,Genetic predisposition - Abstract
Introduction: High resolution human leukocyte antigen (HLA) matching is regarded as a prerequisite for the clinical success of allogeneic haematopoietic cell transplantation (HCT). However, studies have reported immunogenetic factors other than HLA also plays an important role in preventing and controlling post HCT complications, in particular graft-versus-host disease (GVHD) and infections. Cytokines and cytokine receptors, which are the key regulators of the immune surveillance against infections and/or allo-immune responses, are important candidates. The genetic control of cytokine production is evidenced by polymorphisms in cytokine gene regulatory regions resulting in low, moderate, or high cytokine production. Here, we evaluated the prognostic significance of cytokine genetic variants known to impact cytokine production on different outcomes of allogeneic HCT. Materials and Methods: A total of 793 subjects were accrued, including 360 adult allo-HCT donors (discovery cohort; n=240, and validation cohort; n=120), 382 HCT allo- recipients and 50 healthy individuals. All subjects of the discovery cohort and healthy individuals were analyzed for 22 single nucleotide variants located in the regulatory and/or exonic regions of 13 cytokine or cytokine receptor gene using sequence-specific primer based assay. All subjects of the validation cohort were genotyped SNPs located in the IL10 and IL1R gene promoter region by direct sequencing. . CMV specific immune response was assessed by stimulating PBMNCs from healthy individuals with CMV lysate and CMV peptide-pp65 followed by enumeration of IFN-g producing and CD107a expressing (degranulating) MNCs, T cells and their subsets. Results: Cytokine gene variants of donors and not that of recipients appear to influence post HCT complications. Two of these variant system- SNPs leading to low production of IL10 and high production of IL1R showed strong correlation with GVHD and posttransplant CMV infections respectively. Allo-HCT recipients who have received graft from donors carrying low IL-10 producing gene variants (AA) at IL-10 -1082G/A and (ATA/ATA at IL-10 -1082G/A, -819C/T and -592C/A) have high incidence of significant GVHD (defined as grade II-IV acute GVHD and/or chronic GVHD requiring systemic immunotherapy) (P=0.008, HR= 2.8, Figure 1; and P=0.03, HR= 1.8 respectively) compared to recipients who have received graft from donors carrying high producer IL-10 gene variants. Allo-HCT recipients who have received graft from donors carrying low IL-1R producing genotype (-1970 CC) showed high incidence of CMV reactivation (p=0.01; HR=2.1, Figure 2) in comparison to the HCT recipients receiving grafts from donors carrying high IL1-R producing genotype (-1970 GG). Further, the in-vitro culture analysis in healthy individuals showed that IL1R+ cells have 3-5 fold stronger anti-CMV immune responses (IFNg+ and/or CD107a+ cells) in comparison to IL1R- cells. Conclusions: Genetic predisposition to low IL-10 production is a strong predictor of GVHD while that tohigh production of IL-1R confers strong protection against CMV reactivation after allogeneic HCT. Thefindings implicate the importance of prospective assessment of cytokine gene variants to improve allogeneic HCT donor selection. Figure 1: Figure 1:. High incidence of significant GVHD in HCT recipients receiving grafts from donors carrying low IL-10 producing genotypes (-1082 AA) than donors carrying high IL-10 producing genotype (-1082 GG). Figure 2: Figure 2:. High incidence of CMV reactivation in HCT recipients receiving grafts from donors carrying low IL-1R producing genotype (-1970 CC) than donors carrying high IL-1R producing genotype Disclosures No relevant conflicts of interest to declare.
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- 2014
47. End-Alveolar Carbon Monoxide As a Measure of Erythrocyte Survival and Hemolytic Severity in Sickle Cell Disease
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Yang Xia, Laurel Mendelsohn, Dihua Xu, John H. Baird, Mary Jackson, Gregory J. Kato, James S. Nichols, Caterina P. Minniti, Daniel B. Kim-Shapiro, and Rehan Saiyed
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medicine.medical_specialty ,Pathology ,Red Cell ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease_cause ,medicine.disease ,Biochemistry ,Gastroenterology ,Hemolysis ,Nitric oxide ,chemistry.chemical_compound ,Red blood cell ,medicine.anatomical_structure ,chemistry ,Internal medicine ,medicine ,Prospective cohort study ,business ,Oxidative stress ,Blood sampling ,Blood drawing - Abstract
Introduction: In sickle cell disease, polymerization of sickle hemoglobin gives rise to changes in the integrity and viability of the erythrocyte, leading to both extravascular and intravascular hemolysis and shortened life-span. Current gold standard techniques to estimate RBC survival require that a label be placed on the cells that can be followed while the RBCs age in the circulation. These studies are infrequently employed in practice, due to the need for multiple blood draws and an extended period of observation (6 weeks) in order to obtain the necessary time points. Endogenous CO is a technique that has been used in multiple studies to assess RBC survival, based upon the principal that virtually all CO produced in human beings results from cleavage of the α-methene bond of heme and is completely excreted via the lungs. Because RBC destruction accounts for approximately 80% of heme turnover in the body, endogenous CO production can be used as a quantitative indicator of RBC life span. Furne has reported on the development of a simple, rapid, and noninvasive method for determining RBC life span based on gas chromatography measurement of exhaled alveolar CO (EACO) concentration immediately upon awakening corrected for atmospheric CO, as determined with a device that simulates the body's equilibration with CO. We set up to investigate the use of early morning end-alveolar CO (EACO) concentration as a quantitative measure of RBC life span and correlate it to indirect measurements of hemolytic rate in subjects with sickle cell disease. Material and methods: EACO was measured within 24 hours of breath collection in 67 SCD adult patients (67 HbSS, 4 HbSC and 1 HbSb-Thalassemia) and 14 HbAA race matched controls on an Ametrek TA 7000 Gas Purity Monitor. Subjects were at steady state, at least 30 days from transfusion or acute exacerbations. Breath samples were collected immediately upon awakening the same day as blood sampling for additional tests. EACO groups were compared using the Mann-Whitney test. EACO values were used to calculate the red blood cell lifespan by the method of Furne (PMID 12878986), using the calculation: RBC survival (days) = 1,380 · [Hb]/EACO. Correlation analyses are reported using Pearson's correlation coefficient. The statistical significance was set at a two-side p < .05. Analyses were performed with R version 2.13.1 (2011-07-08). Results: EACO was nearly four-fold higher in patients than controls (median 2.25 vs. 0.58 ppm, p Conclusions: Our results confirm the usefulness of exhaled CO measurement as a marker of hemolysis and red cell survival and in substantial, prospective cohort of adult patients with SCD, confirming and considerably extending results of other investigators. EACO-derived RBC survival can be used to update estimates from Crosby in 1955 regarding the proportion of overall hemolysis falling into the extravascular and intravascular categories, the latter related to oxidative stress and scavenging of nitric oxide. This assay may be a useful biomarker in clinical trials of therapeutic interventions aimed at improving red cell life-span in SCD and other hemolytic anemias. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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- 2014
48. Imaging flow cytometry documents incomplete resistance of human sickle F-cells to ex vivo hypoxia-induced sickling
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Fertrin, Kleber Yotsumoto, primary, van Beers, Eduard J., additional, Samsel, Leigh, additional, Mendelsohn, Laurel G., additional, Saiyed, Rehan, additional, Nichols, James S., additional, Hepp, David A., additional, Brantner, Christine A., additional, Daniels, Mathew P., additional, McCoy, J. Philip, additional, and Kato, Gregory J., additional
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- 2014
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49. Phase 1 Clinical Trial Of The Candidate Anti-Sickling Agent Aes-103 In Adults With Sickle Cell Anemia
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Kato, Gregory J., primary, Lawrence, Marlene Peters, additional, Mendelsohn, Laurel G., additional, Saiyed, Rehan, additional, Wang, Xunde, additional, Conrey, Anna K., additional, Starling, Judith M., additional, Grimes, George, additional, Taylor, James G, additional, McKew, John, additional, Minniti, Caterina P., additional, and Stern, Warren, additional
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- 2013
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50. The Anti-Sickling Agent Aes-103 Decreases Sickle Erythrocyte Fragility, Hypoxia-Induced Sickling and Hemolysis In Vitro
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Mendelsohn, Laurel G., primary, Pedoeim, Leah, additional, Wang, Yekai Kevin, additional, Saiyed, Rehan, additional, Brantner, Christine A., additional, Daniels, Mathew P., additional, Nichols, James S., additional, Wang, Xunde, additional, van Beers, Eduard J., additional, and Kato, Gregory J., additional
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- 2013
- Full Text
- View/download PDF
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