Cell Transplantation Group Research Articles

Sinusoidal Obstruction Syndrome/Veno-Occlusive Disease after Unmanipulated Haploidentical Hematopoietic Stem Cell Transplantation with Post-Transplantation Cyclophosphamide: A Study on Behalf of the Spanish Hematopoietic Stem Cell Transplantation and Cellular Therapy Group (GETH)

Sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is a life-threatening complication after both autologous and allogeneic hematopoietic stem cell transplantation (HSCT). However, its characterization after haploidentical HSCT (haplo-HSCT) with post-transplantation cyclophosphamide (PT-Cy) is scarce. This study aimed to describe characteristics and outcomes of patients with SOS/VOD after haplo-HSCT with PT-Cy. We conducted a retrospective study of 797 patients undergoing a haplo-HSCT with PT-Cy between 2007 and 2019 in 9 centers in Spain. SOS/VOD was defined according to modified Seattle, Baltimore, or revised European Society for Blood and Marrow Transplantation (EBMT) criteria. Severity was graded retrospectively according to revised EBMT severity criteria into 4 categories: mild, moderate, severe, and very severe. From a total of 797 haplo-HSCTs performed, 46 patients (5.77%) were diagnosed with SOS/VOD at a median of 19 days (range, 4 to 84 days) after transplantation. Based on revised EBMT severity criteria, the SOS/VOD cases were classified as mild (n = 4; 8.7%), moderate (n = 10; 21.7%), severe (n = 12; 26.1%), and very severe (n = 20; 43.5%). Overall, 30 patients (65%) achieved SOS/VOD complete response, 25 (83%) of whom were treated with defibrotide. Twenty patients (43%) died before day +100 post-HSCT. Death was attributed to SOS/VOD in 11 patients, and 5 patients died of other causes without resolution of SOS/VOD. The incidence of SOS/VOD after haplo-HSCT with PT-Cy was comparable to those reported after HLA-identical HSCT series. Most of the patients developed very severe SOS/VOD according to revised EBMT severity criteria. Despite a promising SOS/VOD complete response (CR) rate (65%), 100-day mortality remained high (43%), indicating that further improvement in the management of this potentially fatal complication is needed.

Simultaneous treatment with cells and rosemary extract ameliorates 6-OHDA-induced toxicity in the hippocampus of mice.

In this study, we delved into the hippocampal region to understand the effects of adipose stem cells (ADSCs) and rosemary extract (RE). Our main objective was to explore how these substances influence spatial memory, neurotrophins, and changes in antioxidant enzymes. Moreover, we meticulously investigated the impact of dopamine deficiency, a notable characteristic linked with Parkinson's disease (PD), on memory impairment. This study comprised five groups of Wistar rats - all male, all selected randomly. We labeled two of these gatherings "lesion" (L) and "sham" (SH). Each got injections in the bilateral form with 6 μg - one group getting saline, while another got 6-OHDA. From couple weeks before the neurotoxin injection to 8 weeks later on, our lesion cohort was treated with rosemary at a dosage rate of 50 mg/kg body weight - let's call it RE for simplicity sake. Moreover, there is also this other lot, designated as cell-transplanted lesion group or catchy exercise (CE) as we prefer to interpret them; they had cell transplants conducted exactly 7 days after receiving their respective injections. Bringing up the rear, we got a group treated with both cell transplant and rosemary (CE+R). We performed spatial memory tests at 4 weeks, then again at 8. At the end of eighth week, the brains were extracted for q-PCR, enzymatic and immunohistochemical studies. Turning our gaze toward a comparison between the CE+R and CE groups versus the L group, we spot an intriguing drop in escape latency time. There is also more time spent in quadrants. Digging deeper into this matter, the CE+R bunch unveiled a clear surge when it comes to the expression of four genes, namely NGF, BDNF, NT3, and NT4! This was notable especially while comparing with both R and even other fellows from its very own broader group - CE. In a bit complex bit related to enzyme activity now, there is some good news as well for those in favor of potent antioxidants such as GPx or SOD. CE + R group, showed a significant increase of GPX and SOD enzymes, compared to the SH and L groups, and a significant decrease of MDA activity as compared to other treated groups. A significant decrease of escape latency and increase of time in quadrant were observed in the CE+R and CE groups compared to L group. What's more, the levels of MDA in the CE+R group plummeted significantly when set up against the SH group. Wrapping things up, a definite downscale was observed in the density of GFAP-positive cells throughout different regions located within the hippocampus; this decline presented itself not solely in treatment groups but gripped onto those falling under SH as well, especially when compared to its comrade - the L group. Using ADSCs and taking RE orally have shown promising results in improving memory issues linked with PD.

Dynamics of Sex Hormones in Men with Diabetes Mellitus After Autologous Mesenchymal Stem Cell Transplant.

Our goal was to determine levels of sex hormones in men with type 1 diabetes mellitus and type 2 diabetes mellitus after autologous mesenchymal stem cell transplant. We examined 10 male patients (32-56 years old) with type 1 diabetes mellitus and type 2 diabetes mellitus, whom we subsequently divided into 2 groups and examined. Group 1 comprised 5 male patients who received autologous mesenchymal stem cell transplant (cells were obtained from patient's iliac crest and cultured for 3-4 weeks) by intravenous infusion. Group 2 comprised 5 male patients (control group) who were on hypoglycemic tablet therapy or insulin therapy. The quantity of autologous mesenchymal stem cells infused was 95 × 106 to 97 × 106 cells. We analyzed levels of testosterone, luteinizing hormone, estradiol, and glycated hemoglobin in patients both before and 3 months after the autologous mesenchymal stem cell transplant procedure. In men with type 1 diabetes mellitus and type 2 diabetes mellitus, autologous mesenchymal stem cell transplant led to an increase in testosterone levels from 5.31 ± 2.12 to 6.33 ± 2.12 ng/mL (P = .82), a decrease in luteinizing hormone from 8.43 ± 1.25 to 5.94 ± 1.57 mIU/mL (P = .04), and a decrease in glycated hemoglobin from 9.45 ± 1.24% to 8.53 ± 1.08% (P = .25) after 3 months. The increase in testosterone in men with autologous mesenchymal stem cell transplant group of 6.33 ± 2.12 ng/mL was significant compared with men in the control group (3.9 ± 1.18 ng/mL; P = .01). Testosterone level increased and luteinizing hormone level decreased within 3 months after autologous mesenchymal stem cell transplant in men with diabetes mellitus.

Hematopoietic cell transplantation and cellular therapies in Switzerland. Evolution over 25years. A report from the stem cell transplantation and cellular therapies working groups of the SBST 1997-2021.

The Swiss Blood Stem Cell Transplantation and Cellular Therapy Group (SBST) leads a mandatory national registry for all hematopoietic stem cell transplants (HCT) and cellular therapies. After 25years, information was available for 11,226 patients receiving an HCT (4031 allogeneic and 7195 autologous), including 925 pediatric patients. We compared patient characteristics and outcome by quinquennia 1997-2001, 2002-2006, 2007-2011, 2012-2016, and 2017-2021. There were numerous changes over time. Allogeneic transplant recipients became older (median age 33.7 vs. 54.3) and had more frequently unrelated donors and reduced intensity conditioning in later quinquennia. Similarly, age increased for recipients of autologous HCT (median 48.3 vs. 59.9). We did not see a significant drop in transplant activity during the SARS-CoV-2 pandemic. Analysis of outcome showed overall survival (relative risk (RR) of death 0.664 (0.529-0.832) and progression free survival (RR 0.708 (0.577-0.870) being improved over time comparing the latest to the first quinquennium adjusting for risk factors. Non-relapse mortality decreased in recipients of allogeneic HCT (RR: 0.371 (0.270-0.509)) over time but relapse risks did not. Outcome of autologous HCT improved as well across quinquennia, this improvement was mainly due to decreased relapse risks (RR 0.681 (0.597-0.777)), possibly related to maintenance treatment or rescue treatment for relapse mainly in myeloma patients. Cellular therapies other than allogeneic or autologous HCT, particularly chimeric antigen receptor T-cells (CAR-T) treatment have started to increase after 2019, year of approval of the first commercial CAR-T product in Switzerland. Data on chimeric antigen receptor T-cell treatment are too early for comparative analyses. Detailed analyses of changes over time are presented. This study includes all HCTs, and cellular therapies, data useful for quality assurance programs, health care cost estimation and benchmarking. Between 50% and 60% of patients are long-term survivors after both types of HCT, indicating growing populations of surviving patients requiring long-term care.

Phase I / II Study on Infusion of Alloreactive or Ex Vivo il-15 Stimulated Natural Killer Cells after Haploidentical Stem Cell Transplantation in Pediatric Patients with Acute Leukemia (PHINK): A Study of the Spanish Hematopoietic Stem Cell Transplantation Group (GETH)

Background: Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is a highly complicated but effective procedure for high-risk pediatric leukemia in the absence of an HLA-identical donor. Post-transplant relapse is the main problem for patient survival. According to literature, Natural Killer (NK) cells play a potent role as inducers of the graft-versus-leukemia (GvL) effect in haplo-HSCT. The presence of alloreactive NK cells correlates with a lower relapse rate, improved engraftment, decreasing graft-versus-recipient disease (GvHD) and viral infection risk. In the absence of donor-recipient NK cell alloreactivity, other NK cell activation strategies are necessary. We propose a phase I/II clinical trial with dose escalation, multicenter, framed in the GETH, to determine dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD) of a single infusion of alloreactive NK cells (Allo-NK) or NK cells stimulated ex vivo with IL-15 (IL15-NK) after haplo-HSCT in pediatric patients with high-risk leukemias. Methods: Eighteen pediatric patients with high-risk leukemia were recruited between September 16, 2020, and May 12, 2023, at 5 hospitals in Spain, Hospital Universitario La Paz, Hospital Universitario Gregorio Marañón, Hospital Universitario Niño Jesús, Hospital Universitario Central of Asturias and Hospital Santa Creu and Sant Pau. Patients were stratified in 2 treatment groups: Allo-NK (n=9) or IL15-NK (n=9), depending on the KIR disparity between donor and recipient. Our phase I/II clinical trial presents a dose-escalation design (3+3). The treatment cohorts are divided into cohort 1 (up to 2x10 7 cells/kg), cohort 2 (2-5x10 7 cells/kg) and cohort 3 (5-10x10 7 cells/kg). We have monitored infections reactivation, as well as, chimerism and engraftment after transplantation. In Allo-NK group, the KIR clone that provides alloreactivity in the NK cell was also tracked. The phenotypic profile and functional capacity of NK cells present in the patient up to 360 days after transplantation have also been analyzed. Results: Nine patients (4 in Allo-NK and 5 in IL-15NK) were included in cohort 1, 7 patients (4 in Allo-NK and 3 in IL-15NK) in cohort 2 and 2 patients (1 in Allo-NK and 1 in IL-15NK) in cohort 3. We were unable to complete the dose escalation design initially proposed due to the high weight of some patients and the unavailability of ex vivo expanded NK cells. In IL15-NK group patients presented a higher prevalence of B-ALL (p=0.018) and had received a previous transplant (p=0.082). NK cell infusions of IL15-NK group showed higher expression of CD25 and CD69 receptors and higher functional capacity. In the Allo-NK group, the most prevalent KIR-reactive clone was KIR2DL1 (55.6%). We also observed a tendency for KIR2DL1 alloreactive clone to increase from 30 (8,18%) to 360 (25,63%) days after transplantation. Regarding clinical outcomes in 2 study arms, the incidence of severe (Grades III-IV) acute GvHD was 22.2% and severe chronic GvHD was only observed in 1 (5.6%) patient (Table 1). The incidence any infection or endothelial vascular complications were 72% and 33% respectively. No statistical differences were observed in GvHD, infections and endothelial vascular complications. We found 2 relapses, 1 in each study arm (11.1%). Five patients died, 1 (5.6%) because of disease progression and 4 (22.2%) because transplant related complications (TRM) (Table 1). Dividing patients into the 3 dose-escalation cohorts, we found no significant differences between cohorts in the primary clinical outcomes analysed. One-years overall survival (OS) and disease-free survival (DFS) was 72.22% (CI95% 51.93-100) and GvHD-free/relapse-free survival (GRSF) was 64.1% (CI95% 44.62-92.1), finding no significant differences between either 2 study arms or the 3 dose-escalation cohorts. Regarding the analysis of the NK phenotype, we observed a tendency to increase the expression of CD16 and CD57 receptors between 30 to 360 days after transplantation in both groups. Conclusions: Two study arms shows similar data respect to clinical outcome. Patients infused with IL-15-stimulated NK cells showed similar toxicity to the alloreactive NK group. According to dose escalation, we observed no association between increased toxicity and increased number of infused NK cells. We were unfortunately unable to complete cohort 3 because of the cells/kg ratio in some patients.

Higher expression of programmed cell death 4 (PDCD4) in acute myeloid leukemia is associated with better prognosis after chemotherapy.

Acute myeloid leukemia (AML) is a common heterogeneous malignancy. Novel molecular markers aid diagnosis, patient sub-categorization, and optimal clinical decisions. Here, we explored the prognostic implications associated with the expression of the programmed cell death (PDCD) family of molecules in AML patients. Based on the findings from the TCGA and OHSU cohorts, we observed that the mRNA abundance of PDCD4 is significantly higher compared to other molecules within the PDCD family. Furthermore, high expression of PDCD4 was associated with predicted long-term patient survival in diagnosed AML patients. In the chemotherapy group, patients with high PDCD4 expression showed a tendency toward longer overall survival (OS) (P = 0.0266) and event-free survival (EFS) (P = 0.0008). High PDCD4 levels served as a favorable independent predictor for both OS and EFS in AML patients. However, subgroup analyses in the hematopoietic stem cell transplantation (HSCT) group revealed no significant difference in OS or EFS between individuals with high and low PDCD4 expression. Furthermore, in the low PDCD4 expression group, AML patients who underwent HSCT experienced improved survival outcomes (P = 0.0015), helping to mitigate the unfavorable prognosis associated with PDCD4 downregulation. Conversely, in the high PDCD4 expression group, HSCT offered a notable short-term survival advantage, while patients with high PDCD4 expression responded favorably to long-term survival through chemotherapy. Biological function enrichment showed that the expression of PDCD4 was correlated with complement and coagulation cascades, cell receptor signaling pathways, and cholesterol metabolism. The findings from this study will aid in better categorizing heterogeneous AML patients and guiding more appropriate clinical decision-making.

Transplantation of Chemical Compound-Induced Cells from Human Fibroblasts Improves Locomotor Recovery in a Spinal Cord Injury Rat Model.

The development of regenerative medicine using cell therapy is eagerly awaited for diseases such as spinal cord injury (SCI), for which there has been no radical cure. We previously reported the direct conversion of human fibroblasts into neuronal-like cells using only chemical compounds; however, it is unclear whether chemical compound-induced neuronal-like (CiN) cells are clinically functional. In this study, we partially modified the method of inducing CiN cells (termed immature CiN cells) and examined their therapeutic efficacy, in a rat model of SCI, to investigate whether immature CiN cells are promising for clinical applications. Motor function recovery, after SCI, was assessed using the Basso, Beattie, and Bresnahan (BBB) test, as well as the CatWalk analysis. We found that locomotor recovery, after SCI in the immature CiN cell-transplanted group, was partially improved compared to that in the control group. Consistent with these results, magnetic resonance imaging (MRI) and histopathological analyses revealed that nerve recovery or preservation improved in the immature CiN cell-transplanted group. Furthermore, transcriptome analysis revealed that immature CiN cells highly express hepatocyte growth factor (HGF), which has recently been shown to be a promising therapeutic agent against SCI. Our findings suggest that immature CiN cells may provide an alternative strategy for the regenerative therapy of SCI.

Evaluation of combined effects of brief electrical stimulation and Schwann-like cells on sciatic nerve injury model.

Severe nerve injuries can be treated with electrical stimulation and stem cell therapies, but little is known about the potential benefits of combining these two treatments. In an effort to investigate this combination, we conducted a study to evaluate the effectiveness of electrical stimulation and Schwann-like cell transplantation in female Wistar albino rats. Our study consisted of five groups of rats: a sham group, an injury group, an electrical stimulation group, a Schwann-like cell group, and a combination group. The experimental groups received electrical stimulation, Schwann-like cell transplantation, or both. The animals sciatic function index was evaluated during a 6-week recovery period, and nerve conduction velocity, wet muscle mass, and nerve tissues were also analyzed. The results of the study showed that all experimental groups had a faster functional recovery compared to the injury group, although the difference between groups was not statistically significant. Both the combination group and the Schwann-like cell transplantation group had a higher nerve conduction velocity compared to the other experimental groups. However, there was no significant difference between the combination and Schwann-like cell transplantation groups. Nonetheless, histological analysis showed a better axonal reorganization in the combination group. The study provides preliminary evidence of the potential benefits of combining electrical stimulation and Schwann-like cell transplantation in treating severe nerve injuries. However, further studies with larger sample sizes are needed to confirm these findings and optimize the treatment parameters.

Screening of the best time window for MSC transplantation to treat acute myocardial infarction with SDF-1α antibody-loaded targeted ultrasonic microbubbles: An in vivo study in miniswine.

The present study aimed to screen the best time window for the transplantation of bone marrow mesenchymal stem cells (MSCs) after acute myocardial infarction (MI) through targeted ultrasound microbubbles loaded with SDF-1α antibody. Thirty-six MI miniswine were randomly divided into six experimental groups according to the duration after infarction (1 day, 3 days, 1 week, 2 weeks, 3 weeks, and 4 weeks after infarction). MSCs were labeled with BrdU and then injected through the coronary artery in the stem cell transplantation group to detect the number of transplanted MSCs at different time points after MI. Three miniswine were randomly selected as the control group (sham operation: open chest without ligation of the coronary artery). All SDF-1α groups and control groups were injected with a targeted microbubble ultrasound contrast agent. The values of the myocardial perfusion parameters (A, β, and A × β) were determined. A T, β T, and (A × β)T varied with time and peaked 1 week after MI (P < 0.05). The number of transplanted stem cells in the myocardium through coronary injection of MSCs at 1 week was the greatest and consistent with the changing tendency of A T, β T, and (A × β)T (r = 0.658, 0.778, 0.777, P < 0.05). β T(X), (A × β)T(X), and the number of transplanted stem cells was used to establish the regression equation as follows: Y = 36.11 + 17.601X; Y = 50.023 + 3.348X (R 2 = 0.605, 0.604, P < 0.05). The best time window for transplanting stem cells was 1 week after MI. The myocardial perfusion parameters of the SDF-1α targeted contrast agent can be used to predict the number of transplanted stem cells in the myocardial tissue.

Comparison of outcomes of Clostridium difficile infection in autologous stem cell transplant recipients compared to allogenic stem cell transplant recipients.

e19064 Background: Hematopoietic stem cell transplant (HSCT) recipients are at a higher risk of clostridium difficile infection (CDI). The incidence of CDI in allogenic SCT recipients has been shown to be about 2-fold compared to autologous SCT recipients in certain studies. These differences can be attributed to myeloablative chemotherapy and increased duration of immunosuppression in allogenic SCT patients. In this study we evaluate the impact of CDI on in-hospital outcomes in these two groups of patients. Methods: We included all patients with a prior diagnosis or a procedure code for HSCT and CDI using ICD-10 codes from National Inpatient Sample 2016-2019. Patients were stratified into two groups based on the presence or absence of autologous stem cell transfusion. Information was collected regarding patient demographics, Charlson comorbidities, resource utilization (LOS and total hospitalization charges), and outcomes. The outcomes included sepsis, shock, acute kidney injury, ICU admission, and in-hospital mortality. The differences in outcomes between the two groups were studied. Results: The incidence of CDI in autologous stem cell transplant recipients was lower compared to the allogenic HSCT group (5.1% vs. 6.1%, p-0.003). 7,605 patients were included in the study. Of them, 2,460 (32.25%) patients had autologous stem cell transplantation, while the remaining had allogenic stem cell transfusion. A higher proportion of patients in the autologous stem cell transplant group were males (60.7% vs. 54.32%), and patients aged 45-64 years (55.7% vs. 46.4%). Patients who received autologous stem cell transplants had a lower incidence of death (1.6% vs. 7.8%, p &lt; 0.001), sepsis (17.28% vs. 28.18%, p- &lt; 0.001), shock (4.7% vs. 12%, p &lt; 0.001), AKI (15% vs. 31.6%, p &lt; 0.001) and ICU admissions (5.7% vs. 10.7%, p- &lt; 0.001). There was no significant difference in the length of stay between the two groups (21.30 days vs 22.97 days). Patients in the autologous stem cell transplant group had lower hospitalization charges ($318,072.3 vs $402,281.5, p &lt; 0.001) than the allogenic group. Conclusions: Like prior studies, our study is compatible with the lower incidence of CDI in autologous SCT recipients. Our study also suggested a lower in-hospital mortality and better outcomes compared to patients with allogeneic stem cell transplants. Resource utilization was also noted to be lower in autologous stem cell transplant patients. Further research should be conducted to explain the differences and to allow physicians to provide timely treatments to prevent worse outcomes.

Retrospective analysis of diagnosis and therapeutic strategies for patients with hepatosplenic T cell lymphoma.

Hepatosplenic T cell lymphoma (HSTCL) is a rare and aggressive lymphoma with no standard treatment and poor treatment response. From 2001-2021, 20 from a lymphoma cohort of 7247 patients (0.27%) were diagnosed with HSTCL at Samsung Medical Center. The median age at the time of diagnosis was 37.5 (range, 17-72) years, and 75.0% of patients were male. Most patients had B symptoms, hepatomegaly, and splenomegaly. Lymphadenopathy was found in only 31.6% of patients, and increased PET-CT uptake was found in 21.1% of patients. Thirteen patients (68.4%) expressed T cell receptor (TCR) γδ, and 6 patients (31.6%) expressed TCRαβ. The median progression-free survival (PFS) for the entire cohort was 7.2 months (95% CI, 2.9-12.8), and the median overall survival (OS) was 25.7 months (95% CI, not calculated). In subgroup analysis, the overall response rate (ORR) was 100.0% in the ICE/Dexa group and 53.8% in the anthracycline-based group, and the complete response rate was 83.3% in the ICE/Dexa group and 38.5% in the anthracycline-based group. The ORR was 50.0% in the TCRαβ group and 83.3% in the TCRγδ group. The OS was not reached in the autologous hematopoietic stem cell transplantation (HSCT) group and was 16.0 months (95% CI, 15.1-16.9) in the non-transplant group at the data cutoff time (P value 0.015). In conclusion, HSTCL is rare but has a very poor prognosis. The optimal treatment strategy is not defined. More genetic and biological information is needed.

Efficacy and prognostic factors of allogeneic hematopoietic stem cell transplantation treatment for T lymphoblastic leukemia/lymphoma

Objective: To analyze the efficacy and prognostic factors of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for treating T lymphoblastic leukemia/lymphoma (T-ALL/LBL) . Methods: This study retrospectively evaluated 119 adolescent and adult patients with T-ALL/LBL from January 2006 to January 2020 at Peking University Third Hospital and Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences. Patients were divided into chemotherapy-only, chemotherapy followed by allo-HSCT, and chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT) groups according to the consolidation regimen, and the 5-year overall survival (OS) and progression-free survival (PFS) rates of each group were compared. Results: Among 113 patients with effective follow-up, 96 (84.9%) patients achieved overall response (ORR), with 79 (69.9%) having complete response (CR) and 17 (15.0%) having partial response (PR), until July 2022. The analysis of the 96 ORR population revealed that patients without transplantation demonstrated poorer outcomes compared with the allo-HSCT group (5-year OS: 11.4% vs 55.6%, P=0.001; 5-year PFS: 8.9% vs 54.2%, P<0.001). No difference was found in 5-year OS and 5-year PFS between the allo-HSCT and auto-HSCT groups (P=0.271, P=0.197). The same results were achieved in the CR population. Allo-HSCT got better 5-year OS (37.5% vs 0) for the 17 PR cases (P=0.064). Different donor sources did not affect 5-year OS, with sibling of 61.1% vs hap-haploidentical of 63.6% vs unrelated donor of 50.0% (P>0.05). No significant difference was found in the treatment response in the early T-cell precursor acute lymphoblastic leukemia/lymphoma (ETP) and non-ETP populations. The ETP group demonstrated lower 5-year OS compared with the non-ETP group in the chemotherapy alone group (0 vs 12.6%, P=0.045), whereas no significant difference was found between the ETP and non-ETP groups in the allo-HSCT group (75.0% vs 62.9%, P=0.852). Multivariate analysis revealed that high serum lactate dehydrogenase level, without transplantation, and no CR after chemotherapy induction were independently associated with inferior outcomes (P<0.05) . Conclusion: Allo-HSCT could be an effective consolidation therapy for adult and adolescent patients with T-ALL/LBL. Different donor sources did not affect survival. Allo-HSCT may overcome the adverse influence of ETP-ALL/LBL on OS.

Treatment pattern and clinical outcomes in multiple myeloma patients in Japan using the Medical Data Vision claims database.

Multiple myeloma therapy has made remarkable progress with the advent of new drugs. We explored the treatment pattern and outcomes in Japanese patients with multiple myeloma using the Medical Data Vision database. Patients were categorized as per the initial diagnosis period (2003-2015 and 2016-2020), considering the adoption of these new agents and then based on stem cell transplantation. Overall, 6438 patient data were extracted as eligible for data analysis, and the median age at the index diagnosis date was 72.0 years. Bortezomib/dexamethasone was the most common regimen for induction therapy in patients requiring stem cell transplantation from 2003-2015, and the use of bortezomib/lenalidomide/dexamethasone increased from 2016-2020. Lenalidomide/dexamethasone was the most commonly used post-transplant therapy. In the non-stem cell transplantation group, bortezomib/dexamethasone was mainly used for both periods, while lenalidomide/dexamethasone was primarily used from 2016-2020. There was a trend toward shorter first-line treatment duration and a shift to additional treatment patterns with new drugs at the following lines. The time to inpatient death period suggested an improvement between the two periods. Thus, this study revealed that recent diversification of treatment options is preferred and contributes to improved outcomes in the clinical practice of multiple myeloma in Japan.

High expression of miR-107 and miR-17 predicts poor prognosis and guides treatment selection in acute myeloid leukemia.

The prognostic significance of miR-107 and miR-17 in patients with acute myeloid leukemia (AML) remains unclear. A total of 173 patients with de novo AML from the Cancer Genome Atlas database were enrolled in this study and further divided into a chemotherapy group (98 cases) and an allogeneic hematopoietic stem cell transplantation (allo-HSCT) group (75 cases) according to their therapy regimen. In the chemotherapy cohort, high miR-107 or miR-17 expression was associated with poorer overall survival (OS) and event-free survival (EFS). On the other hand, there were no significant differences in OS and EFS between the high- and low-expression subgroups in the allo-HSCT group. Next, we stratified the total number of patients with AML into high- and low-expression groups according to the median expression levels of miR-107 or miR-17. In the high miR-107 or miR-17 expression group, patients treated with allo-HSCT had longer OS than those treated with chemotherapy. In the low miR-107 or miR-17 expression group, no significant differences in OS and EFS were observed between the two therapy subgroups. When patients were further clustered into three groups (both low miR-107 and low miR-17, either high miR-107 or high miR-17, and both high miR-107 and high miR-17), patients with both high miR-107 and high miR-17 expression had the worst OS and EFS of the entire group and of the chemotherapy group. On the other hand, there were no significant differences in OS and EFS among the three subgroups in the allo-HSCT group. Cox regression confirmed the concurrence of high expression of miR-107 and miR-17 might act as an independent prognostic factor for EFS and OS in the entire group and the chemotherapy group. Bioinformatics analysis showed differentially expressed genes (DEGs) associated with miR-107 and miR-17 expression were mainly enriched in multiple metabolic processes. The combination of miR-107 and miR-17 provides prognostic significance for patients with AML and should be considered in the clinical selection of the optimal treatment regimen when deciding between chemotherapy and allo-HSCT.

Risk of Secondary Malignancies in Hematopoietic Stem Cell Transplantation Recipients: A Nationwide Population-Based Study in Taiwan

The improvement of survival after hematopoietic stem cell transplantation has brought about a need to evaluate long-term complications, for instance, secondary malignancies. The risk of subsequent malignancies after hematopoietic stem cell transplantation must be clarified in a large population. To estimate the risk of secondary malignancies in hematopoietic stem cell transplantation survivors and compare it with the risk in patients without hematopoietic stem cell transplantation history. We conducted a population-based retrospective cohort study of 3,059 hematopoietic stem cell transplantation recipients from the National Health Insurance Research Database of Taiwan, containing 1,378 autologous, 1,641 allogeneic, and 40 cord blood stem cell transplantation recipients between 2000 and 2013. A control group of 12,236 patients without an hematopoietic stem cell transplantation history was identified. The covariates included age, sex, comorbidities, stem cell source, facility level of care, and history of total body irradiation. Comorbidities were estimated by the revised Charlson comorbidity index, and a higher score suggested more severe comorbidity. Adjusted hazard ratios were determined by adjusting for age, sex, comorbidity, and facility level of care. Overall, hematopoietic stem cell transplantation recipients had a higher risk of secondary malignancies with an adjusted hazard ratios of 1.348 (p = 0.017). Being male and female (adjusted hazard ratios 1.395, p = 0.009 and adjusted hazard ratios 1.291, p = 0.042, respectively) and pre-hematopoietic stem cell transplantation total body irradiation (adjusted hazard ratios 1.591, p < 0.001) were correlated with a high risk of secondary malignancies. Among the subsequent neoplasms, bone cancer showed the highest risk (adjusted hazard ratios 27.899, p < 0.001), followed by laryngeal (adjusted hazard ratios 6.643, p < 0.001), kidney (adjusted hazard ratios 5.580, p < 0.001), esophageal, pancreatic, thyroid (adjusted hazard ratios 1.993, p < 0.001), and skin (adjusted hazard ratios 1.992, p < 0.001) cancers. The median follow-up duration was 2.16 years in the hematopoietic stem cell transplantation group and 2.57 years in the control group, and the overall median follow-up duration was 2.21 years. Medical practitioners should be aware of the high risk of secondary malignancies in hematopoietic stem cell transplantation recipients later in life. These recipients should be informed about the importance of regular follow-up and photoprotective measures. Lifelong surveillance is recommended.

Treatment Options for Relapsed Acute Lymphoblastic Leukemia Study

This study aims to analyze the treatment options for relapsed acute lymphoblastic leukemia (ALL). ALL is a type of cancer that affects the white blood cells, and can often recur after initial treatment. The focus of this study is to evaluate the efficacy of various treatments for relapsed ALL, including chemotherapy, radiation therapy, bone marrow transplantation, and targeted therapies. Results from a systematic review of the literature indicate that treatment options for relapsed ALL are often effective, but can vary depending on the stage of the disease. Chemotherapy and radiation therapy are typically used as first-line treatments, while bone marrow transplantation is typically used as a second-line treatment. Targeted therapies, such as monoclonal antibodies, are increasingly being used in combination with other treatments. This study suggests that further research is needed to determine the optimal treatment strategy for relapsed ALL, as well as the best combination of treatments. Objectives: To investigate the current treatments for relapsed acute lymphoblastic leukemia (ALL) Methodology: This study conducted in department of pediatric Hematology and oncology CMH Rawalpindi From jan 2020 to jan 2023 Comprised 100 pediatric patients with relapsed ALL. Patients were treated with chemotherapy, radiation therapy, stem cell transplantation, or targeted therapy. The efficacy of each treatment option was assessed by the complete remission rate, overall survival rate, and relapse rate. The complete remission rate was determined by measuring the number of patients who achieved complete remission after eight weeks of treatment. The overall survival rate was measured by calculating the number of patients who survived at least one year following treatment. Finally, the relapse rate was calculated by determining the number of patients who experienced recurrence of the disease within one year. Data was collected and analyzed using descriptive statistics and survival analysis. Results The results of this study showed that chemotherapy was the most effective treatment option, with a complete remission rate of 60%, followed by stem cell transplantation (50%) and targeted therapy (40%). The overall survival rate was highest in the chemotherapy group (72%), followed by the stem cell transplantation (53%) and targeted therapy (48%) groups. Radiation therapy was found to be less effective, with a complete remission rate of only 25%. The relapse rate was highest in the targeted therapy group (30%), followed by the stem cell transplantation (20%) and chemotherapy (15%) groups. Conclusion: This study showed that chemotherapy was the most effective treatment option for relapsed pediatric ALL, followed by stem cell transplantation and targeted therapy. The overall survival rate was highest in the chemotherapy group, followed by the stem cell transplantation and targeted therapy groups. Radiation therapy was found to be less effective, with a complete remission rate of only 25%. These results suggest that chemotherapy should be the primary treatment option for relapsed pediatric ALL, followed by stem cell transplantation and targeted therapy as secondary options. Keywords: acute lymphoblastic leukemia, relapsed, chemotherapy, radiation therapy, stem cell transplantation, targeted therapy

Regenerative Potential of Bone Morphogenetic Protein 7-Engineered Mesenchymal Stem Cells in Ligature-Induced Periodontitis.

Periodontitis is an oral disease caused by bacterial infection that has stages according to the severity of tissue destruction. The advanced stage of periodontitis presents irreversible destruction of soft and hard tissues, which finally results in loss of teeth. When conventional treatment modalities show limited results, tissue regeneration therapy is required in patients with advanced periodontitis. In the present study, we aimed to evaluate the effect of bone marrow-derived mesenchymal stem cells (BM-MSCs) delivering bone morphogenetic protein 7 (BMP7) on tissue regeneration in a periodontitis model. BMP7 is a member of the BMP family that shows bone-forming ability; however, BMPs rapid clearing and degradation and unproven efficacy make it difficult to apply it in clinical dentistry. To overcome this, we established BMP7-expressing engineered BM-MSCs (BMP7-eBMSCs) that showed superior osteogenic differentiation potential when subcutaneously transplanted with a biphasic calcium phosphate scaffold into immunocompromised mice. Furthermore, the efficacy of BMP7-eBMSC transplantation for periodontal tissue regeneration was evaluated in a rat ligature-induced periodontitis model. Upon measuring two-dimensional and three-dimensional amounts of regenerated alveolar bone using microcomputed tomography, the amounts were found to be significantly higher in the BMP7-eBMSC transplantation group than in the eBMSC transplantation group. Most importantly, fibrous periodontal ligament (PDL) tissue regeneration was also achieved upon BMP7-eBMSC transplantation, which was evaluated by calculating the modified relative connective tissue attachment. The amount of connective tissue attachment in the BMP7-eBMSC transplantation group was significantly higher than that in the ligature-induced periodontitis group, although the increase was comparable between the BMP7-eBMSC and human PDL stem cell transplantation groups. Taken together, our results suggested that sustainable release of BMP7 induces periodontal tissue regeneration and that transplantation of BMP7-eBMSCs is a feasible treatment option for periodontal regeneration. Impact Statement Periodontitis is the second most common human dental disease affecting chronic systemic diseases. Despite the tremendous efforts trying to cure the damaged periodontal tissues using tissue engineering technologies, a definitive regenerative method has not been in consensus. Researchers are seeking more feasible and abundant source of mesenchymal stem cells (MSCs), and furthermore, how to use reliable growth factors under more efficient control are the issues to be solved. In this study, we aimed to evaluate the effect of bone morphogenetic protein 7 (BMP7) gene delivering bone marrow-derived MSCs on periodontal tissue regeneration to evaluate the efficacy of BMP7 and engineered BMSCs for periodontal tissue regeneration.

Whole-exome sequencing identifies FANC heterozygous germline mutation as an adverse factor for immunosuppressive therapy in Chinese aplastic anemia patients aged 40 or younger: a single-center retrospective study

Acquired aplastic anemia (AA) is a bone marrow failure disorder characterized by pancytopenia, and immunosuppressive therapy (IST) is the optional first-line management. Several studies identified the influencing factors on IST response; however, there are still a considerable number of patients suffering from poor prognoses. In this study, we enrolled 61 AA patients aged ≤ 40 years old, and whole-exome sequencing (WES) found unexpected high FANC heterozygous germline mutations (28/61, 45.9%). Patients with FANC mutations have a significantly lower absolute reticulocyte count and CD34+ % in the bone marrow and also lower 3-, 6-, and 9-month IST response than that without mutation, which were 0% vs. 25% (P = 0.017), 26.3% vs. 42.1% (P = 0.495), and 29.4% vs. 72.2% (P = 0.011), especially in anti-thymocyte globulin combined with the cyclosporin A (ATG + CsA) group, which were 0% vs.33.4% (P = 0.143), 25% vs.83.3% (P = 0.103), and 25% vs. 100% (P = 0.003), respectively. The event-free survival in the FANCwt group was also better than that in the FANCmut group (P = 0.016) and also showed in patients who received ATG + CsA treatment (P = 0.045). In addition, all the adverse effects of FANC germline mutation were not significant in stem cell–transplanted group. Our result indicated that the WES-based detection of FANC heterozygous germline mutations may have a great meaning in predicting IST response of acquired AA. This study was registered at chictr.org.cn (# ChiCTR2100054992).

Stability and biosafety of human epidermal stem cell for wound repair: preclinical evaluation

BackgroundCell therapy is a key technology to prevent sacrificing normal skin. Although some studies have shown the promise of human epidermal stem cells (EpiSCs), the efficacy, biosafety and quality control of EpiSC therapy have not been systematically reported.MethodsThe biosafety, stemness maintenance and wound repair of EpiSC were systematically verified by in vitro and in vivo experiments. EpiSC were prepared from the foreskin using a collagen type IV rapid adherence method. The EpiSCs were identified by flow cytometry, immunofluorescence staining and cell morphology. The well-growing passage 1 (P1) EpiSCs were used to determine the proliferation curve (counting method). EpiSC clone formation assay was performed by Giemsa staining. Nude mice were used to prepare a full-thickness skin defect wound model to detect the repair effect of EpiSCs. The biosafety of EpiSCs was double tested in vitro and in vivo.ResultsThe results showed that the expression of specific markers and clone formation efficiency was stable when passage 1 (P1) to P8 cells were cultured, and the stemness rate of P8 cells was close to 85.1%. EpiSCs were expanded in vitro for 25 days, the number of cells reached 2.5 × 108, and the transplantable area was approximately 75% of the total body surface area (TBSA). At 45 days, the total number of cells was approximately 30 billion, and the transplantable area was approximately the size of a volleyball court. A nude mouse wound model indicated that EpiSCs could rapidly close a wound. On postinjury day 7, the wound epithelialization rate in the cell transplantation group was significantly higher than that in the NaCl group (P < 0.05). In vitro, cell senescence increased, and telomerase activity decreased in P1 to P8 EpiSCs. In vivo, there were no solid tumors or metastatic tumors after EpiSC (P8) transplantation. In addition, the quality control of cultured cells met the clinical application criteria for cell therapy.ConclusionThis preclinical study showed the stability and biosafety of human EpiSC therapy for wound repair.Graphical

Clinical Outcomes by Consolidation of Bone Marrow Stem Cell Therapy and Coronary Artery Bypass Graft in Patients With Heart Failure With Reduced Ejection Fraction: A Meta-analysis

Bone marrow stem cell (BMSC) transplantation during coronary artery bypass graft (CABG) is an innovative treatment for ischemic heart disease (IHD). We conduct a meta-analysis to examine whether patients with IHD presenting heart failure with reduced ejection fraction (HFrEF) can be beneficent from CABG with additional BMSC transplantation. Electronic searches were performed on PubMed, EMBASE, Cochrane Library, and ClinicalTrials.gov from their inception to July 2021. The efficacy was based on left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), left ventricular end-diastolic volume (LVEDV), left ventricular end-diastolic volume index (LVEDVi), left ventricular end-systolic volume index (LVESVi), and 6-min walk test (6MWT) change after treatment. Eight randomized-controlled trials (RCTs) were included in this meta-analysis, with a total of 350 patients. Results showed BMSC transplantation significantly improved the LVEF [mean difference (MD) = 6.23%, 95% confidence interval (CI): 3.22%–9.24%, P < 0.0001], LVEDVi (MD = −20.15 ml/m2, 95% CI: −30.49 to −9.82 ml/m2, P < 0.00001), and LVESVi (MD = −17.69 ml/m2, 95% CI: −25.24 to −10.14 ml/m2, P < 0.00001). There was no statistically significant difference in the improvement of LVEDD, LVEDV, and 6MWT between the cell transplantation group and control groups. Subgroup analysis revealed that the intervention for control group could affect the efficacy of BMSC transplantation. Sensitivity analysis found the conclusion of LVEDD, LVEDV, and 6MWT changes was not stable. Therefore, among patients with IHD presenting HFrEF, BMSC transplantation during CABG is promising to be beneficial for postoperative left ventricular (LV) function improvement. However, according to the unstable results of the sensitivity analysis, it cannot be concluded whether the extra step has a positive effect on left ventricular remodeling and exercise capacity. RCTs with larger cohorts and more strict protocols are needed to validate these conclusions.