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Frontiers in Immunology 2024Severe congenital neutropenia (SCN) is caused by germline mutations, most commonly in , impacting neutrophil maturation and leading to high risk of life-threatening...
Severe congenital neutropenia (SCN) is caused by germline mutations, most commonly in , impacting neutrophil maturation and leading to high risk of life-threatening infections. Most patients with mutant SCN can achieve safe neutrophil counts with chronic Granulocyte-Colony Stimulating Factor (G-CSF). However, up to 10% of patients have neutropenia refractory to G-CSF and require allogeneic stem cell transplant. Traditional conditioning for these patients includes busulfan and cyclophosphamide which is associated with significant toxicities. We present five patients with SCN without myeloid malignancy transplanted using a reduced toxicity regimen of busulfan, fludarabine and thymoglobulin. 5 pediatric patients with SCN underwent matched sibling donor bone marrow transplant (MSD-BMT) between 2014-2022 on or per CHP14BT057 (NCT02928991), a prospective, single center trial testing elimination of cyclophosphamide from conditioning in pediatric patients with single lineage inherited BMF syndromes. All patients had MSDs and no evidence of MDS. Conditioning consisted of PK-adjusted busulfan, fludarabine, and thymoglobulin, with calcineurin inhibitor and mycophenolate mofetil GVHD prophylaxis. With median follow-up of 48.4 months, overall and event-free survival were 100%. There was no acute GVHD and one instance of chronic limited GVHD. Patients exhibited >95% donor myeloid chimerism at 5 years post-BMT. Two patients experienced CMV reactivation without end-organ disease, and no other viral reactivation or significant infections occurred. MSD-BMT with reduced toxicity myeloablation for SCN provides excellent outcomes while minimizing toxicity. These data suggest that busulfan, fludarabine, and ATG can be considered an efficacious, low-toxicity standard of care regimen for patients with SCN undergoing MSD-BMT.
Topics: Humans; Child; Bone Marrow Transplantation; Congenital Bone Marrow Failure Syndromes; Busulfan; Hematopoietic Stem Cell Transplantation; Siblings; Prospective Studies; Neutropenia; Cyclophosphamide; Graft vs Host Disease; Granulocyte Colony-Stimulating Factor
PubMed: 38469307
DOI: 10.3389/fimmu.2024.1369243 -
Stem Cell Reports Apr 2024Spermatogonial stem cell (SSC) transplantation is a valuable tool for studying stem cell-niche interaction. However, the conventional approach requires the removal of...
Spermatogonial stem cell (SSC) transplantation is a valuable tool for studying stem cell-niche interaction. However, the conventional approach requires the removal of endogenous SSCs, causing damage to the niche. Here we introduce WIN18,446, an ALDH1A2 inhibitor, to enhance SSC colonization in nonablated recipients. Pre-transplantation treatment with WIN18,446 induced abnormal claudin protein expression, which comprises the blood-testis barrier and impedes SSC colonization. Consequently, WIN18,446 increased colonization efficiency by 4.6-fold compared with untreated host. WIN18,446-treated testes remained small despite the cessation of WIN18,446, suggesting its irreversible effect. Offspring were born by microinsemination using donor-derived sperm. While WIN18,446 was lethal to busulfan-treated mice, cyclophosphamide- or radiation-treated animals survived after WIN18,446 treatment. Although WIN18,446 is not applicable to humans due to toxicity, similar ALDH1A2 inhibitors may be useful for SSC transplantation into nonablated testes, shedding light on the role of retinoid metabolism on SSC-niche interactions and advancing SSC research in animal models and humans.
Topics: Humans; Mice; Male; Animals; Spermatogonia; Semen; Testis; Fertility; Stem Cell Transplantation; Spermatogenesis
PubMed: 38458191
DOI: 10.1016/j.stemcr.2024.02.003 -
Frontiers in Oncology 2024Donor choosing remains to play a pivotal role in allogeneic hematopoietic stem cell transplantation (allo-HSCT). Numerous criteria beyond HLA compatibility impact the...
Determining the predictive impact of donor parity on the outcomes of human leukocyte antigen matched hematopoietic stem cell transplants: a retrospective, single-center study.
INTRODUCTION
Donor choosing remains to play a pivotal role in allogeneic hematopoietic stem cell transplantation (allo-HSCT). Numerous criteria beyond HLA compatibility impact the selection of a suitable donor.
METHODS
We evaluated the effect of donor parity on transplant outcomes in a large homogeneously treated population that received an HLA-matched allo-HSCT between 2010 and 2021 at our center. All patients were transplanted from a peripheral blood stem cell source following a myeloablative Busulfan-based conditioning and an identical protocol for graftversus-host disease (GVHD) prophylaxis regimen.
RESULTS
A total of 1103 allo-HSCT recipients were included. 188 (17%) had transplants from parous female donors, whereas 621 (56.30%) and 294 (26.70%) received transplants from male and nulliparous female donors, respectively. HSCTs from parous female donors compared to male and nulliparous females were associated with a significantly higher incidence of grade III-IV acute (a) GVHD (55.27% vs. 11.34 and 10.84%) and extensive chronic (c) GVHD (64.32% vs. 15.52 and 13.65%), as well as lower relapse incidence (RI).
DISCUSSION
This study finds that while parous female donors are associated with higher incidences of grade III-IV aGVHD and extensive cGVHD post-allo-HSCT, the advantages, such as a lower RI, outweigh the risks. The results of our study provide valuable insights for donor selection.
PubMed: 38454927
DOI: 10.3389/fonc.2024.1339605 -
The World Journal of Men's Health Feb 2024The leaves of var. acuta (PFA) are generally reported to have antioxidant, anti-allergic, anti-inflammatory, and antitumor effects and commonly used as a traditional...
PURPOSE
The leaves of var. acuta (PFA) are generally reported to have antioxidant, anti-allergic, anti-inflammatory, and antitumor effects and commonly used as a traditional medicine in East Asia. This study aimed to investigate the protective effect and antioxidant activity of PFA on busulfan-induced testicular dysfunction, histological damage, oxidative stress (OS), sperm quality, and hormone levels using a mouse model.
MATERIALS AND METHODS
C57BL/6 male mice were divided into four groups: control, busulfan-only treated, and varying concentrations of PFA (100 and 200 mg/kg) with busulfan. In the busulfan group, 40 mg/kg of busulfan was intraperitoneally injected to induce azoospermia. Mice were orally administered PFA for 35 consecutive days after busulfan administration. Samples were collected and assessed for testis/body weight, testicular histopathology, sperm quality, serum hormone levels, and OS to evaluate the effects of PFA treatment on spermatogenesis dysfunction induced by busulfan.
RESULTS
The busulfan-induced testicular dysfunction model showed reduced testis weight, adverse histological changes, significantly decreased sex hormones and sperm quality, and attenuated OS. These results indicate that PFA treatment significantly increased testis weight, testis/body weight, epididymal sperm count, motility, and testosterone level compared with busulfan alone. PFA treatment also attenuated the busulfan-induced histological changes. Furthermore, compared with mice treated with busulfan alone, PFA supplementation upregulated the testicular mRNA expression of the antioxidant enzymes () and 1 (), with a decrease in malondialdehyde (MDA) production and an increase in SOD and GPx activities.
CONCLUSIONS
This study shows that PFA exerts a protective effect against testicular damage by attenuating OS induced by busulfan. Our results suggest that PFA is a potentially relevant drug used to decrease the side effects induced by busulfan on testicular function and sperm during cancer chemotherapy.
PubMed: 38449453
DOI: 10.5534/wjmh.230254 -
Toxicology in Vitro : An International... May 2024Podocytes play a critical role in the formation and maintenance of the glomerular filtration barrier and injury to these cells can lead to a breakdown of the glomerular...
Podocytes play a critical role in the formation and maintenance of the glomerular filtration barrier and injury to these cells can lead to a breakdown of the glomerular barrier causing permanent damage leading to progressive chronic kidney disease. Matured podocytes have little proliferative potential, which makes them critical cells from a health perspective, but also challenging cells to maintain in vitro. Differentiating podocyte-like cells from induced pluripotent stem cells (iPSC) provides a novel and continuous source of cells. Here, we investigated the effect of a 24-h exposure to eight compounds, including the known glomerular toxins doxorubicin and pamidronate, on transcriptomic alterations in iPSC derived podocytes. Doxorubicin (50 nM), pamidronate (50 μM), sodium arsenite (10 μM), and cyclosporine A (15 μM) had a strong impact on the transcriptome, gentamicin (450 μg/ml), lead chloride (15 μM) and valproic acid (500 μM) had a mild impact and busulfan (50 μM) exhibited no impact. Gene alterations and pathways analysis provided mechanistic insight for example, doxorubicin exposure affected the p53 pathway and dedifferentiation, pamidronate activated several pathways including HIF1alpha and sodium arsenite up-regulated oxidative stress and metal responses. The results demonstrate the applicability of iPSC derived podocytes for toxicological and mechanistic investigations.
Topics: Humans; Podocytes; Induced Pluripotent Stem Cells; Transcriptome; Xenobiotics; Pamidronate; Doxorubicin; Gene Expression Profiling; Sodium Compounds; Arsenites
PubMed: 38447685
DOI: 10.1016/j.tiv.2024.105804 -
Journal of Clinical and Experimental... Mar 2024Primary testicular lymphoma (PTL) frequently relapses in the central nervous system (CNS) despite prophylactic intrathecal chemotherapy, and the outcome for CNS...
Successful treatment of isolated central nervous system recurrence of primary testicular lymphoma by autologous stem cell transplantation using a conditioning regimen of thiotepa and busulfan.
Primary testicular lymphoma (PTL) frequently relapses in the central nervous system (CNS) despite prophylactic intrathecal chemotherapy, and the outcome for CNS recurrence of PTL is very poor. We report a case of isolated CNS recurrence of bilateral PTL. Our patient achieved complete response (CR) after rituximab-combination chemotherapy for PTL. Approximately five years later, isolated CNS recurrence of PTL occurred. Our patient achieved CR again after high-dose methotrexate therapy and autologous stem cell transplantation (ASCT) with a conditioning regimen of thiotepa and busulfan as a consolidation therapy. The secondary failure of platelet recovery, probably caused by busulfan, occurred after the platelet engraftment. Our patient has remained in CR for over three years. The treatment strategy for CNS recurrence of PTL is mainly whole-brain radiotherapy or high-dose methotrexate-based chemotherapy; however, CNS recurrence of PTL may occur again even after achieving CR. ASCT with a conditioning regimen of thiotepa and busulfan is the optimal consolidation therapy for secondary CNS lymphoma. To the best of our knowledge, this is the second reported case of a patient with isolated CNS recurrence of PTL successfully treated by ASCT with a conditioning regimen of thiotepa and busulfan as a consolidation therapy.
Topics: Humans; Thiotepa; Hematopoietic Stem Cell Transplantation; Busulfan; Methotrexate; Transplantation, Autologous; Antineoplastic Combined Chemotherapy Protocols; Neoplasm Recurrence, Local; Lymphoma; Central Nervous System; Combined Modality Therapy; Stem Cell Transplantation; Transplantation Conditioning
PubMed: 38417873
DOI: 10.3960/jslrt.23039 -
Journal of Clinical and Experimental... Mar 2024We report a case of therapy-related myelodysplastic syndrome (MDS), which developed 9 years after autologous peripheral blood stem cell transplantation (PBSCT) for...
We report a case of therapy-related myelodysplastic syndrome (MDS), which developed 9 years after autologous peripheral blood stem cell transplantation (PBSCT) for peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). A 65-year-old male was diagnosed with PTCL-NOS. After 6 cycles of the CHOP (cyclophosphamide [CPA], doxorubicin, vincristine, and prednisone) regimen, he achieved a first complete response (CR). He relapsed 33 months later and received salvage chemotherapy, which consisted of the CHASE regimen (CPA, high-dose cytarabine, dexamethasone, and etoposide). During the recovery phase of the first cycle of CHASE, his peripheral blood stem cells (PBSCs) were harvested and frozen in 2 bags. After 2 courses of CHASE, he underwent autologous PBSCT, which involved the use of the LEED preconditioning regimen (melphalan, CPA, etoposide, and dexamethasone) and one of the frozen bags. This resulted in a second CR. At 39 months after PBSCT, he relapsed with a tumor in his right arm. After it was resected, he received eight cycles of brentuximab vedotin and 45 Gy of involved-field irradiation concurrently and achieved a third CR. Nine years after autologous PBSCT, he was diagnosed with MDS with excess blasts 2 (MDS-EB-2). His disease progressed to acute myeloid leukemia after 2 courses of azacitidine therapy. He successfully underwent a second autologous PBSCT involving the busulfan and melphalan preconditioning regimen and the other frozen bag, which had been stored for 9 years. He has been in complete cytogenetic remission for 1 year since the second autologous PBSCT.
Topics: Male; Humans; Aged; Lymphoma, T-Cell, Peripheral; Etoposide; Melphalan; Transplantation, Autologous; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Leukemia, Myeloid, Acute; Dexamethasone; Myelodysplastic Syndromes; Hematopoietic Stem Cell Transplantation; Treatment Outcome; Combined Modality Therapy
PubMed: 38417872
DOI: 10.3960/jslrt.23054