Considerations for the development of iPSC-derived cell therapies: a review of key challenges by the JSRM-ISCT iPSC Committee.

Since their first production in 2007, human induced pluripotent stem cells (iPSCs) have provided a novel platform for the development of various cell therapies targeting a spectrum of diseases, ranging from rare genetic eye disorders to cancer treatment. However, several challenges must be tackled for iPSC-based cell therapy to enter the market and achieve broader global adoption. This white paper, authored by the Japanese Society for Regenerative Medicine (JSRM) - International Society for Cell Therapy (ISCT) iPSC Committee delves into the hurdles encountered in the pursuit of safe and economically viable iPSC-based therapies, particularly from the standpoint of the cell therapy industry. It discusses differences in global guidelines and regulatory frameworks, outlines a series of quality control tests required to ensure the safety of the cell therapy, and provides details and important considerations around cost of goods (COGs), including the impact of automated advanced manufacturing.

A machine-learning model that incorporates CD45 surface expression predicts hematopoietic progenitor cell recovery after freeze-thaw.

BACKGROUND AIMS: Sufficient doses of viable CD34+ (vCD34) hematopoietic progenitor cells (HPCs) are crucial for engraftment. Additional-day apheresis collections can compensate for potential loss during cryopreservation but incur high cost and additional risk. To aid predicting such losses for clinical decision support, we developed a machine-learning model using variables obtainable on the day of collection. METHODS: In total, 370 consecutive autologous HPCs, apheresis-collected since 2014 at the Children's Hospital of Philadelphia, were retrospectively reviewed. Flow cytometry was used to assess vCD34% on fresh products and thawed quality control vials. The ratio of vCD34% thawed to fresh, which we call "post-thaw index," was used as an outcome measure, with a "poor" post-thaw index defined as <70%. HPC CD45 normalized mean fluorescence intensity (MFI) was calculated by dividing CD45 MFI of HPCs to the CD45 MFI of lymphocytes in the same sample. We trained XGBoost, k-nearest neighbor and random forest models for the prediction and calibrated the best model to minimize falsely-reassuring predictions. RESULTS: In total, 63 of 370 (17%) products had a poor post-thaw index. The best model was XGBoost, with an area under the receiver operator curve of 0.83 evaluated on an independent test data set. The most important predictor for a poor post-thaw index was the HPC CD45 normalized MFI. Transplants after 2015, based on the lower of the two vCD34% values, showed faster engraftment than older transplants, which were based on fresh vCD34% only (average 10.6 vs 11.7 days, P = 0.0006). CONCLUSIONS: Transplants taking into account post-thaw vCD34% improved engraftment time in our patients; however, it came at the cost of unnecessary multi-day collections. The results from applying our predictive algorithm retrospectively to our data suggest that more than one-third of additional-day collections could have been avoided. Our investigation also identified CD45 nMFI as a novel marker for assessing HPC health post-thaw.

Preoperative Anemia is Associated with Increased Intraoperative Mortality in Patients Undergoing Cardiac Surgery.

OBJECTIVES: We sought to investigate the incidence of preoperative anemia in cardiac surgery and its association with outcomes. METHODS: A retrospective review of clinical, laboratory, and transfusion data for all patients who underwent cardiac surgery at Sultan Qaboos University Hospital between 2008 and 2014 was performed. Patients were divided into two groups, anemic and non-anemic, with anemia defined as hemoglobin levels < 13 g/dL (males) and < 12 g/dL (females). Clinical variables were compared using chi-square and independent t-test. Factors influencing preoperative mortality were analyzed using multivariate binary logistics regression. RESULTS: A total of 599 patients (69.9% males and 30.1% females) were included in the study; 69.3% underwent coronary artery bypass surgery. Preoperative anemia was found in 76.1% of females and 26.7% of male patients. Rates of intraoperative red blood cell transfusions were higher among anemic patients (75.9% vs. 52.3%, p < 0.001). Anemic patients had a worse risk profile with higher incidence of diabetes mellitus (53.8% vs. 38.9%, p < 0.001), congestive heart failure (51.4% vs. 28.3%, p < 0.001), arrhythmia (16.5% vs. 8.6%, p = 0.004), and cerebrovascular disease (10.0% vs. 4.9%, p = 0.015). In addition, they had a higher risk of overall mortality (6.4% vs. 2.6%, p = 0.023). Preoperative anemia remained a risk factor for intraoperative mortality after logistic regression (odds ratio = 4.08, 95% confidence interval: 1.43-11.66; p = 0.009). CONCLUSIONS: Preoperative anemia in cardiac surgery is independently associated with increased intraoperative mortality and early readmission rates post-surgery.

Impact of Blood Transfusion on Troponin I Levels and Outcomes after Cardiac Surgery: A Cohort Study.

OBJECTIVES: Increased cardiac troponin I (TI) has been suggested to be a sensitive indicator of intraoperative myocardial injury. We investigated the association of transfusion on TI levels post-surgery and outcomes in patients undergoing elective cardiac surgeries. METHODS: We conducted a retrospective review of 542 patients. Patients were divided into two groups based on TI levels at 24 hours (TI24) (> 6.5 µg/L vs. ≤ 6.5 µg/L). The impact of transfusion on TI levels was estimated using logistic regression and adjusted for using a multivariable model that included aortic cross-clamp time and preoperative ejection fraction. The effect of TI on the clinical outcomes was examined. RESULTS: Red blood cell (RBC) transfusion was found to be associated with high TI levels (odds ratio (OR) = 2.33, p = 0.007, 95% confidence interval (CI): 1.30-4.30). A trend was observed when aortic cross-clamp time and preoperative ejection fraction were adjusted for (OR = 2.06, p = 0.080, 95% CI: 0.90-4.70). An association was found between aortic cross-clamp time and high TI levels in the multivariable model (OR = 1.01, p = 0.028, 95% CI: 1.00-1.02). Elevated TI levels was associated with higher mortality (OR = 4.15, p = 0.017, 95% CI: 1.29-13.08), renal failure (OR = 2.99, p = 0.004, 95% CI: 1.41-6.32), and increased length of stay in-hospital (OR = 4.50, p = 0.020, 95% CI: 0.69-8.30). CONCLUSIONS: RBC transfusion is associated with increased TI24 post-cardiac surgery and worse outcomes, albeit a confounding effect cannot be excluded. Larger studies are required to confirm these findings.

Unusual Indolent Course of a Chronic Active Epstein-Barr Virus-Associated Natural Killer Cell Lymphoproliferative Disorder.

Natural killer (NK) cell lymphoproliferative disorders are uncommon and the Epstein-Barr virus (EBV) plays an important aetiological role in their pathogenesis. We report a 20-year-old male with a chronic active EBV infection associated with a NK cell lymphoproliferative disorder which had an unusual indolent course. He presented to the Sultan Qaboos University Hospital in Muscat, Oman, in December 2011 with a history of intermittent fever and coughing. Examinations revealed generalised lymphadenopathy, hepatosplenomegaly, leukocytosis, transaminitis, diffuse bilateral lung infiltrates and bone marrow lymphocyte involvement. A polymerase chain reaction (PCR) test revealed a high EBV viral load in the peripheral blood cells. The patient received a course of piperacillin-tazobactam for Klebsiella pneumoniae, but no active treatment for the lymphoproliferative disorder. However, his lymphocyte count, serum lactate dehydrogenase and liver enzymes dropped spontaneously. In addition, EBV PCR copies fluctuated and then decreased significantly. He remained clinically asymptomatic over the following four years.

Discriminatory power of the intraoperative cell salvage use in the prediction of platelet and plasma transfusion in patients undergoing cardiac surgery.

INTRODUCTION: We aim to assess the discrimination of transfused salvaged blood in predicting perioperative platelet and plasma transfusion. METHODS: Retrospective review was performed on all patients undergoing cardiac surgery with cell saver (CS) support. The area under the receiver operating characteristics curve was calculated. RESULTS: The discrimination achieved by transfused CS volumes in predicting perioperative platelet and plasma transfusion was poor (AUC 0.642 and 0.613 respectively). None of the covariates included (preoperative platelets, cardiopulmonary bypass use and time, aortic cross clamp time and use of aspirin or clopidogrel within 7 days of surgery) were statistically significant predictors. CONCLUSION: Volumes of transfused CS blood have poor discrimination in predicting platelet and plasma transfusion.

Cerebral sinus thrombosis following IV immunoglobulin therapy of immune thrombocytopenia purpura.

We present a pediatric patient treated with high dose intravenous immunoglobulin (IVIG) for acute immune thrombocytopenic purpura (ITP), who developed cerebral sinus thrombosis in the absence of any identifiable hypercoagulable state. This report describes the successful management of this rare complication in this challenging setting. This report shows IVIG induced cerebral sinus thrombosis in ITP.