Phosphatidylserine and Tyro3-Axl-Mertk Receptor Tyrosine Kinase level detection in plasma and on plasma-derived extracellular vesicle surface in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is a chronic lymphoproliferative disorder characterized by monoclonal B cell proliferation. Studies carried out in recent years suggest that extracellular vesicles (EVs) may be a potential biomarker in cancer. Tyro3-Axl-Mertk (TAM) Receptor Tyrosine Kinases (RTKs) and Phosphatidylserine (PS) have crucial roles in macrophage-mediated immune response under normal conditions. In the tumor microenvironment, these molecules contribute to immunosuppressive signals and prevent the formation of local and systemic antitumor immune responses. Based on this, we aimed to evaluate the amount of PS and TAM RTK in plasma and on the surface of EVs in CLL patients and healthy volunteers in this study. In this study, 25 CLL (11 F/14 M) patients in the Rai (O-I) stage, newly diagnosed or followed up without treatment, and 15 healthy volunteers (11 F/4 M) as a control group were included. For all samples, PS and TAM RTK levels were examined first in the plasma and then in the EVs obtained from the plasma. We detected a significant decrease in plasma PS, and TAM RTK levels in CLL patients compared to the control. Besides, we determined a significant increase in TAM RTK levels on the EV surface in CLL, except for PS. In conclusion, these receptor levels measured by ELISA in plasma may not be effective for the preliminary detection of CLL. However, especially TAM RTKs on the surface of EVs may be good biomarkers and potential targets for CLL therapies.

A Novel Hypothesis: Certain KIR/Cognate Ligand Containing Genotypes Differ in Frequency Among Patients With Myeloma and Have an Effect on Age of Disease Onset.

BACKGROUND: Natural killer (NK) cells are known to have cytotoxic effects mediated through killer immunoglobulin-like receptors (KIRs) and their cognate ligands. Role of KIRs in myeloma is yet unresolved. PATIENTS AND METHODS: KIR genotypes and ligands of 204 newly diagnosed MM patients are compared with 424 healthy subjects. Statistical analysis included t-test, chi-square and binary logistic regression. RESULTS: KIR ligands were significantly more (C2C2: 27.5% vs 15.1%; OR 2.128; 95% CI, 1.417-3.196; P < .001) or less (C1C2: 40.2% vs 51.9%; OR 0.623; 95% CI, 0.444-0.874; P = .006) frequent among MM. Co-occurrence of genotype AA with C2C2 was also higher in frequency among MM (OR 2.509; 95% CI, 1.171-5.378; P = .015) likewise cAB1 with C1C2 was less frequent (OR 0.553; 95% CI, 0.333-0.919; P = .021). Genotypes AA with C1C1, cAB1 with C1C2 or C1C2 alone were associated with a delay (median age: 61 [48-73]; P = .044; 62 [31-81]; P = .030 or 59 [31-85]; P = .028), but AA with C2C2 with an earlier age of onset (48 [29-77]; P = .042). In multivariate analysis including R-ISS, light chain, KIR genotype/ligands; ligand C1C2 (P = .02) and genotype AA-C1C1 (P = .037) were independently associated with age of onset ≥60. CONCLUSION: C1C2 and C2C2 alone or in combination with KIR genotype (cAB1 and AA, respectively), is observed in less or higher frequency among MM cases and associated with delayed/earlier age of onset, respectively. Genotype AA-C1C1 although in similar frequency between patients and healthy subjects, is also associated with delay. To our knowledge, this is the first study demonstrating an association between KIR and MM onset age, independent from R-ISS or light chain type.

Allogeneic Hematopoietic Stem Cell Transplantation for Primary Myelofibrosis: A 20-year Experience in a Single Center

Background: Allogeneic hematopoietic stem cell transplantation is a well-established approach for patients diagnosed with primary myelofibrosis and remains the only potentially curative treatment. Aims: To present the overall outcome of patients with myelofibrosis treated with allogeneic hematopoietic stem cell transplantation. Study Design: A retrospective cross-sectional study. Methods: This study is a retrospective analysis of 26 consecutive patients with primary myelofibrosis who underwent transplantation at our center between January 2002 and January 2022. Disease and transplant variables contributing to outcomes were analyzed. Results: The median age at the time of transplantation was 52.5 (range, 32-63) years and the median time from diagnosis to allogeneic hematopoietic stem cell transplantation was 25 (range, 3.1-156.8) months. Myeloablative conditioning and reduced-intensity conditioning regimens were used in 8 (30.8%) and 18 (69.2%) transplantations, respectively. Neutrophil and platelet engraftment was achieved in 23 patients at a median follow-up of 21.2 months (range, 12 days to 234.8 months). Primary graft failure occurred in 1 of 23 patients (4.3%). Neutrophil and platelet engraftment occurred at a median of 16 (range, 12-39) days and 20 (range, 11-78) days, respectively. Acute graft-versus-host disease was seen in 11 of 22 patients engrafted allografts, of which 7 (31.8%) were grade 3-4 acute graft-versus-host disease. Eight patients (36.4%) developed chronic graft-versus-host disease, and three cases were extensive. Four patients (19%) relapsed after a median of 5.5 months, and three patients received donor lymphocyte infusion. The 3-year overall survival rate of the entire study population was 46.2%. The median overall survival was not reached in the myeloablative conditioning group; however, it was 11.9 months in the reduced-intensity conditioning group (p =0.3). According to the donor graft source, the median overall survival was 0.73 months in mismatched unrelated graft recipients, 12 months in matched sibling donors, and not reached in matched unrelated graft recipients (p = 0.03). The 3-year progression-free survival rate of patients who survived > 100 days was 74.7%. The effect of JAK-2 status, graft source, conditioning regimen or dynamic international prognostic scoring system on progression-free survival was not statistically significant. Conclusion: Given the poor prognosis of non-transplant recipients and the lack of non-transplant curative approaches, our results support the consideration of allogeneic hematopoietic stem cell transplantation for eligible patients with primary myelofibrosis.

Generic Lenalidomide Rivelime Versus Brand-name Revlimid® in the Treatment of Relapsed/Refractory Multiple Myeloma: A Retrospective Single-center Experience on Efficacy, Safety and Survival Outcome.

BACKGROUND: This study aimed to compare use of original brand-name lenalidomide (Revlimid®) vs. generic equivalent (Rivelime®) in terms of efficacy, safety and survival outcome in patients with relapsed/refractory multiple myeloma (RRMM) PATIENTS AND METHODS: A total of 184 patients RRMM (median age: 62 years, 60.9% were males) who received singlet, doublet or triplet lenalidomide-containing regimens including either Revlimid® (n=74) or Rivelime® (n=110) were included in this study. Treatment response was based on evaluation of objective response to treatment (ORR) including the sum of patients who achieved partial response (PR), very good partial responses (VGPR) or complete response (CR) to therapy. Progression-free survival (PFS), overall survival (OS) and safety data were also recorded. RESULTS: Revlimid® and Rivelime® groups were similar in terms of ORR (54.1 vs. 60.0%), CR (22.5 vs. 28.8%), VGPR (55.0 vs. 50.0%) and PR (22.5 vs. 21.2%) rates. Median (SE) PFS time were similar between Rivelime® vs. Revlimid® treated patients who were in the 2nd line (30.3(3.8) vs. 22.7(7.0) months, p=0.827) or 3rd line of therapy (38.1(12.1) vs. 20.1(0.9) months, p=0.147) at lenalidomide initiation. Two groups also had similar OS rate (83.8 vs. 73.6%) and OS time (mean 122.3 vs. 123.5 months). Side effects were manageable in both groups. CONCLUSION: In conclusion, replacing Revlimid® with its generic version Rivelime® in singlet, doublet or triplet lenalidomide containing RRMM regimens seems not to compromise the efficacy of treatment, and to yield a similarly improved response rates and survival outcome and no additional toxic effects, enabling a long-term therapy.

Eltrombopag for the Treatment of Poor Graft Function Following Haematopoietic Cell Transplantation: Real-Life Data

Background: Eltrombopag has an off-label indication for haematopoietic cell transplantation in patients experiencing delayed thrombocyte recovery and/or thrombocytopaenia. Aims: To present our centre's experience of using this agent not only for post- haematopoietic cell transplantation thrombocytopaenia but also for poor graft functioning in the post-haematopoietic cell transplantation setting. Study Design: Retrospective cross-sectional study. Methods: Thirty-nine patients who had persistent cytopaenia following haematopoietic cell transplantation and treated with eltrombopag at our centre between October 2011 and December 2021 were retrospectively identified. During this period, 9 (23.1%) and 30 (76.9%) patients who underwent allogeneic transplantations, respectively, received eltrombopag. Results: The female-to-male ratio was 12:27, and the median transplant age was 49 (18-70) years. Eight (20.5%) patients had isolated thrombocytopaenia, 19 (49.4%) had bi-lineage cytopaenia and 12 (30.1%) had pancytopaenia. Patients received a median of 50 mg/day (25-150 mg/day) of eltrombopagfor a median duration of 82 (24-386) days. Nine (23.1%) patients had autologous haematopoietic cell transplantation, and 30 (76.9%) had allogeneic haematopoietic cell transplantation (14 unrelated, 9 sibling and 7 haploidentical). The median donor age was 32 (20-67) years. The median follow-up was 16.4 (1.8-84.3) months. The median pre-treatment platelet count was 11x109/l (1-23), which increased to 41x109/l (6-150). The median platelet count increment was 29.5x109/l (p = 0.001). The pre-treatment median neutrophil count was 1.19x109/l (0.39-5.1), which increased to 2.35 x109/l (0.1-5.33) (p = 0.05), and the pre-treatment median haemoglobin was 8.3 (6.2-14) g/dl, which increased to 10 (6.2-14) g/dl (p = 0.001) with eltrombopag. No eltrombopag-related hepatotoxicity occurred; however, 1 (2.6%) patient failed to continue treatment because of two consecutive episodes of deep venous thrombosis. Six (15.4%) patients were unresponsive to eltrombopag and dependent on blood product transfusions. After a median time of 82 days, 61.5% of the patients discontinued eltrombopag successfully. Conclusion: The results confirmed that eltrombopag could provide a rapid, sustained response in patients with poor graft functioning after haematopoietic cell transplantation. This finding is essential given the high rate of non-relapse mortality caused by poor graft functioning after haematopoietic cell transplantation.

Effect of CD34⁺ Total/Myeloid CD34⁺ Cell Progenitors and B-Lymphoid Progenitors Within the Bone Marrow Grafts on the Hematopoietic Recovery After Hematopoietic Stem Cell Transplantation.

OBJECTIVES: The influence of CD34⁺ cells on transplant outcomes following hematopoietic stem cell transplantation remains controversial. A minimum of 2.0 to 2.5 million CD34⁺ cells/kg of patient weight is requested for a rapid and durable engraftment. The aim of this study was to detect the ratio of CD34+ B-lymphoid progenitors (hematogones) in bone marrow grafts and investigate their effects on hematopoietic recovery after transplant. MATERIALS AND METHODS: Our study included 41 patients who received a bone marrow graft from their HLA-matched donor from 2016 through 2019. The CD34⁺ cell numbers within the graft were detected using Stem-Kit (Beckman Coulter). The ratio of CD34⁺ hematogones was determined either by their light scatter characteristics or by the detection of CD34, CD19, or CD10 coexpressing cells in a separate tube. RESULTS: The median number of CD34⁺ cells was 5.9 × 106/kg (0.8-14.3 × 106/kg). The CD34⁺ cells consisted of 71% (range, 35.7%-100%) and 29% (range, 5.7%-64.3%) myeloid and B-lymphoid progenitors, respectively. Percentage of CD34⁺ (P < .001) and total (P < .001) hematogones in correlation with donor age. Time of neutrophil engraftment was significantly longer (P = .039) when total infused CD34⁺ cell content was <3 × 106/kg. CONCLUSIONS: A remarkable population of hematogones within the CD34⁺ cell pool was detected in bone marrow grafts. Detection of the ratio of hematogones and most primitive stem cells (CD34⁺CD90⁺CD38⁻) may overall provide more information to build a better correlation between CD34⁺ cell content and the recovery of bone marrow.

Alpha-1-Antitrypsin Experience for Steroid-Resistant Acute Graft-Versus-Host Disease.

Steroid-refractory acute graft-versus-host disease (SR-aGVHD) treatment has a low response rate and a high risk of infection in allogeneic hematopoietic stem cell transplantation. The standard approach to be applied in this situation is uncertain. This study aims to evaluate the effectiveness and safety of alpha-1-antitrypsin (AAT). In the study, the results of five SR-aGVHD patients received AAT evaluated. Complete response was seen 2 of four patients with gastrointestinal (GI) aGVHD, partial response in one GI and one liver aGVHD. The overall response rate was 80%. AAT is an effective and safe treatment option in SR-aGVHD.

Pretransplant Consolidation Therapies Improve the Outcome of Myeloablative Allogeneic Transplantation in Adults with Ph-negative Acute Lymphoblastic Leukemia.

BACKROUND AND AIM: The benefit of pre-transplant consolidation in patients with acute lymphoblastic leukemia (ALL) who achieved first complete remission (CR1) has not yet been clearly demonstrated. Here, we aimed to investigate the relationship between the treatments received before transplantation and transplant outcome in Ph-ALL patients who underwent myeloablative allo-HSCT in CR1. PATIENTS AND METHODS: A total of 55, 32 (58.2%) men and 23 (41.8%) women, who underwent allo-HSCT with the diagnosis of Ph-ALL were evaluated retrospectively. All patients underwent to allo-HSCT with myeloablative conditioning regimen in the 1st CR from the available donor. RESULTS: In patients who received >2 consolidation, the 2-year and 3-year OS was 69% and 65%, respectively, while the 2-year and 3-year OS was 39% and 26%, respectively, in those who received < 2 consolidation (P =.03). RFS was similar in both groups (P = .8). One year- NRM was found 28% in patients who received ≥ 2 consolidations, and 37% in patients who received <2 consolidation (P =.06). L-asparaginase, high dose methotrexate, and cranial treatments given before transplantation had no effect on transplant outcomes (P > .05). CONCLUSION: Contrary to the belief that pre-transplant consolidation is not beneficial in ALL patients who proceed with allo-HCST in CR1, our results showed that consolidation treatments reduce NRM and improve the survival.

Hematopoietic stem cell transplantation for adolescents and adults with inborn errors of immunity: an EBMT IEWP study.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the gold standard curative therapy for infants and children with many inborn errors of immunity (IEI), but adolescents and adults with IEI are rarely referred for transplant. Lack of published HSCT outcome data outside small, single-center studies and perceived high risk of transplant-related mortality have delayed the adoption of HSCT for IEI patients presenting or developing significant organ damage later in life. This large retrospective, multicenter HSCT outcome study reports on 329 IEI patients (age range, 15-62.5 years at HSCT). Patients underwent first HSCT between 2000 and 2019. Primary endpoints were overall survival (OS) and event-free survival (EFS). We also evaluated the influence of IEI-subgroup and IEI-specific risk factors at HSCT, including infections, bronchiectasis, colitis, malignancy, inflammatory lung disease, splenectomy, hepatic dysfunction, and systemic immunosuppression. At a median follow-up of 44.3 months, the estimated OS at 1 and 5 years post-HSCT for all patients was 78% and 71%, and EFS was 65% and 62%, respectively, with low rates of severe acute (8%) or extensive chronic (7%) graft-versus-host disease. On univariate analysis, OS and EFS were inferior in patients with primary antibody deficiency, bronchiectasis, prior splenectomy, hepatic comorbidity, and higher hematopoietic cell transplant comorbidity index scores. On multivariable analysis, EFS was inferior in those with a higher number of IEI-associated complications. Neither age nor donor had a significant effect on OS or EFS. We have identified age-independent risk factors for adverse outcome, providing much needed evidence to identify which patients are most likely to benefit from HSCT.

Allogeneic hematopoietic stem cell transplantation for heavily pretreated patients with mycosis fungoides and Sezary syndrome.

Allogeneic hematopoietic stem cell transplantation (AHSCT) is a promising strategy for treatment of heavily pretreated mycosis fungoides/Sezary syndrome (MF/SS). Herein, we aimed to evaluate the outcomes of AHSCT for heavily pretreated patients with MF/SS retrospectively. This analysis included consecutive 19 patients with MF/SS who received 20 AHSCT between 2012-2021 in our transplant center. Eight patients have been previously reported. Fifteen patients had diagnosis of MF and referred to SS in five patients. In our cohort, all cases had advanced disease (stages IIB: n = 1, IIIA: n = 7; IIIB: n = 4, IVA: n = 4, and IVB: n = 3). Nine patients (47.4%) had developed large cell transformation. Only two patients received AHSCT in complete response, one very good partial response and two partial response while the others had progressive disease (n = 15) before transplant. Seven (35%) patients were alive at the time of analysis, with a median follow up of 10.5 months (range, 0.3-113 months) after AHSCT. Nine patients (47.4%) died without disease relapse or progression. Non-relapse mortality was 35.9% at 1 year and 26.9% at 3 years and thereafter. For all patients the probability of overall survival was 48.5% and 32.3% at 1- and 5-year post-transplant, respectively. AHSCT for MF/SS resulted in an estimated progression free survival of 45.4% at 1 year. Given the poor prognosis of patients not receiving transplants and in the absence of curative non-transplantation therapies, our results support that AHSCT is able to effectively rescue 32.3% of the population of transplant eligible, heavily pretreated patients in 5 years.

Autologous hematopoietic cell transplantation for relapsed multiple myeloma performed with cells procured after previous transplantation-study on behalf of CMWP of the EBMT.

Autologous hematopoietic cell transplantation (auto-HCT) may be performed in multiple myeloma (MM) patients relapsing after a previous auto-HCT. For those without an adequate dose of stored stem cells, remobilization is necessary. This retrospective study included patients who, following disease relapse after the first auto-HCT(s), underwent stem cell remobilization and auto-HCT performed using these cells. There were 305 patients, 68% male, median age at salvage auto-HCT was 59 years. The median time to relapse after the first-line penultimate auto-HCT(s) was 30.6 months, the median follow-up after salvage auto-HCT 31 months. The 2- and 4-year non-relapse mortality (NRM) after the salvage auto-HCT was 5 and 9%, the relapse incidence 56 and 76%, respectively. Overall survival (OS) after 2 and 4 years was 76 and 52%, progression-free survival (PFS) 39 and 15%. In multivariable analysis an increasing interval between the penultimate auto-HCT and relapse was associated with better OS and PFS, later calendar year of salvage auto-HCT with better OS. In conclusion, salvage auto-HCT performed with cells remobilized after a previous auto-HCT was associated with acceptable NRM. The leading cause of failure was disease progression of MM, which correlated with a shorter interval from the penultimate auto-HCT to the first relapse.

Prospective Follow-up of Panel Reactive Antibodies From Diagnosis Until Completion of Therapy Including Allogeneic Stem Cell Transplantation Among Patients With Acute Leukemia.

OBJECTIVES: Existence of panel reactive antibodies is the limiting step in both solid-organ and hematopoietic stem cell transplantation. There are hypotheses related to panel reactive antibody formation, but there is no knowledge about its formation in acute leukemia at diagnosis and during the chemotherapy period, in which there is a strong myelosuppression and immunosuppression. We aimed to determine the panel reactive antibodies positivity in acute leukemia patients at diagnosis and during the entire therapy period, including stem cell transplantation. MATERIALS AND METHODS: In this single-center prospective study, we enrolled 35 patients with acute leukemia (8 with acute lymphoblastic leukemia, 27 with acute myeloid leukemia). Serum samples were obtained before induction therapy and every 3 months thereafter until the last follow-up or death, for a median of 369 days (minimum-maximum, 9-725 days). Panel reactive antibodies were defined with single-antigen bead assays on a Luminex platform. RESULTS: A total of 10 patients (29%) were found to have panel reactive antibodies at any time point. At diagnosis, 5 patients (14.3%) had antibodies of either class I (n = 2) or II (n = 1) or both (n = 2), and in 4 patients these persisted during median follow-up of 168 days (minimum-maximum, 9-322 days). Among the remaining 30 patients, an additional 5 (17%) developed de novo antibodies. Incidence rate of development of de novo antibodies was 5.5 per 10 000 person-days. There was no effect of transfusion load on the development of panel reactive antibodies. Differences in percentages in males versus females, blood type mismatch, and graftversus-host disease were higher in patients who had de novo antibodies after transplantation. Positivity at any time had no statistically significant effect on overall survival (P = .71). CONCLUSIONS: Panel reactive antibodies do not occur frequently in the acute leukemia setting despite intensive transfusions.

Blastic Plasmacytoid Dendritic Cell Neoplasm: Single Center Experience on a Rare Hematological Malignancy.

PURPOSE: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and poor prognostic hematological malignancy. There is still no standard treatment established for BPDCN patients. We aim to summarize the main clinical, biological features and treatment of 9 BPDCN patients. METHODS: Nine patients with BPDCN who had been diagnosed between July 2008 and December 2018 in Ankara University School of Medicine, were retrospectively evaluated. RESULTS: All patients (n = 9) were male, median age was 64 (21-80). Five patients (55.6%) had bone marrow infiltration, 5 patients (55.6%) cutaneous lesions, 6 patients (66.7%) lymph node involvement, 2 patients (22.2%) central nervous system involvement and 2 patients (22.2%) spleen involvement at time of diagnosis. Complex karyotype was observed in 2 patients. CHOP was given to 5 patients (55.6%), hyper-CVAD to 2 patients (22.2%), fludarabine, cyclophosphamide and mitoxantrone to 1 patient (11.1%) and cyclophosphamide, etoposide, methylprednisolone to 1 patient (11.1%) as first line chemotherapy. Four patients (44.4%) underwent allogeneic hematopoietic stem cell transplantation (AHSCT) in complete remission (CR) 1. Venetoclax was given to a transplant ineligible patient who had skin and lymph node involvement, with the off-label use. The median follow-up time was 15.9 months (3-48.6 months). Estimated median overall survival was 15.9 + 1.6 (95% CI 12.7-19.1) months. CONCLUSION: Intensive induction therapies followed by AHSCT in CR seems to be best approaches for patients with BPDCN. Thus, more effective treatment strategies particularly targeted therapies should be warranted to improve the survival of patients with this rare disease.

Highlighting the Prognostic Importance of Measurable Residual Disease Among Acute Myeloid Leukemia Risk Factors

Objective: The optimal timing of measurable residual disease (MRD) evaluation in acute myeloid leukemia (AML) patients has not been well defined yet. We aimed to investigate the impact of MRD in pre- and post-allogeneic hematopoietic stem cell transplantation (AHSCT) periods on prognostic parameters. Materials and Methods: Seventy-seven AML patients who underwent AHSCT in complete morphological remission were included. MRD analyses were performed by 10-color MFC and 10-4 was defined as positive. Relapse risk and survival outcomes were assessed based on pre- and post-AHSCT MRD positivity. Results: The median age of the patients was 46 (range: 18-71) years, and 41 (53.2%) were male while 36 (46.8%) were female. The median follow-up after AHSCT was 12.2 months (range: 0.2-73.0). The 2-year overall survival (OS) in the entire cohort was 37.0%, with a significant difference between patients who were MRD-negative and MRD-positive before AHSCT, estimated as 63.0% versus 16.0%, respectively (p=0.005). MRD positivity at +28 days after AHSCT was also associated with significantly inferior 2-year OS when compared to MRD negativity (p=0.03). The risk of relapse at 1 year was 2.4 times higher (95% confidence interval: 1.1-5.6; p=0.04) in the pre-AHSCT MRD-positive group when compared to the MRD-negative group regardless of other transplant-related factors, including pre-AHSCT disease status (i.e., complete remission 1 and 2). Event-free survival (EFS) was significantly shorter in patients who were pre-AHSCT MRD-positive (p=0.016). Post-AHSCT MRD positivity was also related to an increased relapse risk. OS and EFS were significantly inferior among MRD-positive patients at +28 days after AHSCT (p=0.03 and p=0.019). Conclusion: Our results indicate the importance of MRD before and after AHSCT independently of other factors.

Understanding factors affecting human chondrocyte culturing: an experimental study.

Over the years, surgical strategies have been developed in hope of full regeneration of the injured cartilage. In our study, we aimed to develop an optimized chondrocyte culture isolation technique as an active ingredient of a standardized autologous chondrocte implantation product, which is able to maintain the phenotype along with the molecular features of the cartilage. We compared different enzymes, which suggested optimal performance with collagenase type II at 5 mg/ml concentration. Thereafter, we observed that COL2 and GAG expression is substantially reduced with passaging. There was a need to omit passaging to reach the optimal isolation method. We then tested various growth factors and media in order to maintain the natural character of chondrocytes. Our study also suggested the highest COL2 and GAG expressions with the highest recovery in the presence of Advanced DMEM. Autologous chondrocyte implantation manufacturing approval was recently received from the national competent authority, making it possible to utilize the process engineering protocol developed with this study at our Tissue and Cell Manufacturing Center as a part of the autologous chondrocyte implantation manufacturing standard operation procedure (SOP).

Thyroid dysfunctions in adult patients after allogeneic hematopoietic stem cell transplantation.

INTRODUCTION: Thyroid dysfunction (TD) is one of the major endocrinopathies shown after allogeneic hematopoietic stem cell transplantation over the long term. The incidence and the risk factors for TD have varied widely. PATIENTS AND METHODS: Two hundred and fifty-nine patients with pre-transplant normal thyroid function tests who survived at least 1 year after allo-HSCT between 2006-2016 were included in the study. RESULTS: Sixty-four patients (25%) developed TD at median of 34 months (range, 1-112 months). Hypothyroidism was detected in 32 patients (12%): 5 patients had primary hypothyroidism, and subclinical hypothyroidism occurred in 27 patients. 18 patients (7%) were diagnosed with hyperthyroidism: 2 patients (0.07%) were treated for primary hyperthyroidism, and 16 patients (6%) were followed for subclinical hyperthyroidism. Euthyroid sick syndrome occurred in 14 cases. None of the patients with thyroid dysfunction developed secondary thyroid malignancy. Receiving high-dose TBI (P = .001) was found to be significant risk for hypothyroidism; older age than median (P = .01) and pre-transplant active disease (P < .0001) were related to hyperthyroidism. CONCLUSIONS: Thyroid dysfunction, mostly hypothyroidism, is a long-term complication after allo-HSCT in 25% of patients. Older age, pre-transplant active disease, and receiving TBI are among the risk factors. Sustained long-term monitoring of thyroid function test should be considered post allo-HSCT.

Second autologous stem cell transplantation for relapsed/refractory Hodgkin lymphoma after a previous autograft: a study of the lymphoma working party of the EBMT.

The purpose of this study was to analyze the results of second autologous hematopoietic stem cell transplantation (ASCT2) for patients with relapsed/refractory Hodgkin lymphoma (HL) after a first transplantation (ASCT1). Outcomes for 56 patients receiving an ASCT2 registered in the EBMT database were analyzed. The 4-year cumulative incidences of non-relapse mortality and disease relapse/progression were 5% and 67%, respectively. The 4-year overall survival (OS) and progression-free survival (PFS) were 62% and 28%. In univariate analysis, relapse of HL within 12 months of ASCT1 was associated with a worse OS (35% versus 76%, p = 0.01) and PFS (19% versus 29%, p = 0.059). Chemosensitivity at ASCT2 predicted better outcomes (4-year OS 72% versus 29%, p = 0.002; PFS 31% versus 12%, p = 0.015). This series shows that ASCT2 is a safe procedure and a relatively effective option for patients with late relapses after ASCT1 and with chemosensitive disease who are not eligible for an allogeneic transplant.

Where is human-based cellular pharmaceutical R&D taking us in cartilage regeneration?

Lately, cellular-based cartilage joint therapies have gradually gained more attention, which leads to next generation bioengineering approaches in the development of cell-based medicinal products for human use in cartilage repair. The greatest hurdles of chondrocyte-based cartilage bioengineering are: (i) preferring the cell source; (ii) differentiation and expansion processes; (iii) the time necessary for chondrocyte expansion pre-implantation; and (iv) fixing the chondrocyte count in accordance with the lesion surface area of the patient in question. The chondrocyte presents itself to be the focal starting material for research and development of bioengineered cartilage-based medicinal products which promise the regeneration and restoration of non-orthopedic cartilage joint defects. Even though chondrocytes seem to be the first choice, inevitable complications related to proliferation, dedifferentation and redifferentiation are probable. Detailed studies are a necessity to fully investigate detailed culturing conditions, the chondrogenic strains of well-defined phenotypes and evaluation of the methods to be used in biomaterial production. Despite a majority of the current methods which aid amelioration of joint functionality, they are insufficient in fully restoring the natural structure and composition of the joint cartilage. Hence current studies have trended towards gene therapy, mesenchymal stem cells and tissue engineering practices. There are many studies addressing the outcomes of chondrocytes in the clinical scene, and many vital biomaterials have been developed for structuring the bioengineered cartilage. This study aims to convey to the audience the practical significance of chondrocyte-based clinical applications.

Mesenchymal stem cell transplantation in polytrauma: Evaluation of bone and liver healing response in an experimental rat model.

PURPOSE: Trauma is the most common cause of death of young people in the world. As known, mesenchymal stem cells (MSCs) accelerate tissue regeneration mechanisms. In our study, we aimed to investigate the effects of MSCs transplantation on the healing of liver and bone tissue by considering trauma secondary inflammatory responses. METHODS: 56 adult Wistar-albino rats were divided into two groups: the polytrauma (liver and bone) (n = 28), and the liver trauma group (n = 28). At 36 h and 5th day after surgery, both rats with polytrauma and with isolated liver injury received either intravenous (IV) or intraperitoneal (IP) injections of MSCs (one million cells per kg body weight). Untreated groups received IV and IP saline injections. At day 21 after surgery, liver, tibia and fibula of the subjects were excised and evaluated for histopathologic and histomorphometric examination. Additionally, whole blood count (white blood cells, hemoglobin and platelets), C-reactive protein (CRP), glucose, alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin, blood gas, and trauma markers interleukin-1B (IL-1B), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF alpha) levels were investigated. RESULTS: In general, MSC transplantations were well tolerated by the subjects. It was found that ALT, CRP, albumin were significantly lower in rats which received MSCs (p < 0.001). Inflammation of the liver and bone tissue in the MSC-injected rats were significantly lower than that of the untreated groups. CONCLUSIONS: Herewith we have shown that MSC infusion in posttraumatic rats leads to less aggressive and more effective consequences on liver and bone tissue healing. Human MSC treatment for trauma is still in early stages of development; thus standard protocols, and patient inclusion criteria should be established beforehand clinical trials.