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The prognosis of central nervous system lymphoma (CNSL) remains poor, and attempts have been made to improve outcomes through autologous stem cell transplantation (ASCT) with thiotepa-based conditioning. We aimed to assess the outcomes of thiotepa/busulfan/cyclophosphamide (TBC) followed by ASCT in CNSL. An investigator-initiated, single-arm, phase II trial was conducted to evaluate the efficacy and safety of TBC/ASCT (NCT06625359). The conditioning dose was adjusted based on age and performance status (9-day or 8-day regimen). As this trial was terminated early after enrolling 17 patients, a retrospective cohort of CNSL treated with the same protocol was included. In total, 44 patients were included in the study and classified into 8-day and 9-day groups according to the TBC regimen received. In total, 25 patients (56.8%) had primary CNSL, and 19 patients (43.2%) received the 9-day regimens. Following ASCT, 33 patients (75.0%) achieved an objective response (32 complete response and 1 partial response). The 3-year progression-free survival (46.5% vs. 52.6%, P  = 0.49) and overall survival (60.5% vs. 73.7%, P  = 0.77) for 8-day and 9-day groups were comparable. The 1-year cumulative incidence of non-relapse mortality in the 8-day group showed a trend toward decrease compared to that in the 9-day group (4.6% vs. 21.1%, P  = 0.073). Our study demonstrates the efficacy of TBC/ASCT in CNSL in the Asian population. The conventional busulfan dose (9-day regimen) may be associated with higher toxicity, suggesting the potential need for a modified TBC regimen in Asian populations. Further studies are needed to identify the optimal thiotepa-based conditioning in CNSL.

Busulfan, an indispensable medicine in cancer treatment, can cause serious reproductive system damage to males as a side effect of its otherwise excellent therapeutic results. Its widespread use has also caused its accumulation in the environment and subsequent ecotoxicology effects. As a Chinese medicine, Wulingzhi (WLZ) has the effects of promoting blood circulation and improving female reproductive function. However, the potential effects of WLZ in male reproduction and in counteracting busulfan-induced testis damage, as well as its probable mechanisms, are still ambiguous. In this study, busulfan was introduced in a mouse model to evaluate its production of the testicular damage. The components of different WLZ extracts were compared using an untargeted metabolome to select extracts with greater efficacy, which were further confirmed in vivo. Here, we demonstrate abnormal spermatogenesis and low sperm quality in busulfan-injured testes. The WLZ extracts showed a strong potential to rehabilitate the male reproductive system; this effect was more prominent in room-temperature extracts. Additionally, both water and ethanol WLZ extracts at room temperature alleviated various busulfan-induced adverse effects. In particular, WLZ recovered spermatogenesis, re-activated arginine biosynthesis, and alleviated the increased oxidative stress and inflammation in the testis, ultimately reversing the busulfan-induced testicular injury. Collectively, these results suggest a promising approach to protecting the male reproductive system from busulfan-induced adverse side effects, as well as those of other similar anti-cancer drugs.

Background The increasing incidence of cancer and intestinal mucositis induced by chemotherapeutics are causing worldwide concern. Many approaches such as fecal microbiota transplantation (FMT) have been used to minimize mucositis. However, it is still unknown whether FMT from a donor with beneficial gut microbiota results in more effective intestinal function in the recipient. Recently, we found that alginate oligosaccharides (AOS) benefit murine gut microbiota through increasing “beneficial” microbes to rescue busulfan induced mucositis. Results In the current investigation, FMT from AOS-dosed mice improved small intestine function over FMT from control mice through the recovery of gene expression and an increase in the levels of cell junction proteins. FMT from AOS-dosed mice showed superior benefits over FMT from control mice on recipient gut microbiotas through an increase in “beneficial” microbes such as Leuconostocaceae and recovery in blood metabolome. Furthermore, the correlation of gut microbiota and blood metabolites suggested that the “beneficial” microbe Lactobacillales helped with the recovery of blood metabolites, while the “harmful” microbe Mycoplasmatales did not. Conclusion The data confirm our hypothesis that FMT from a donor with superior microbes leads to a more profound recovery of small intestinal function. We propose that gut microbiota from naturally produced AOS-treated donor may be used to prevent small intestinal mucositis induced by chemotherapeutics or other factors in recipients. 3fRPjgD1tu64W3SMZQXKgE Video Abstract

Adenosine deaminase (ADA) deficiency leads to severe combined immunodeficiency (SCID). Previous clinical trials showed that autologous CD34 + cell gene therapy (GT) following busulfan reduced-intensity conditioning is a promising therapeutic approach for ADA-SCID, but long-term data are warranted. Here we report an analysis on long-term safety and efficacy data of 43 patients with ADA-SCID who received retroviral ex vivo bone marrow-derived hematopoietic stem cell GT. Twenty-two individuals (median follow-up 15.4 years) were treated in the context of clinical development or named patient program. Nineteen patients were treated post-marketing authorization (median follow-up 3.2 years), and two additional patients received mobilized peripheral blood CD34 + cell GT. At data cutoff, all 43 patients were alive, with a median follow-up of 5.0 years (interquartile range 2.4–15.4) and 2 years intervention-free survival (no need for long-term enzyme replacement therapy or allogeneic hematopoietic stem cell transplantation) of 88% (95% confidence interval 78.7–98.4%). Most adverse events/reactions were related to disease background, busulfan conditioning or immune reconstitution; the safety profile of the real world experience was in line with premarketing cohort. One patient from the named patient program developed a T cell leukemia related to treatment 4.7 years after GT and is currently in remission. Long-term persistence of multilineage gene-corrected cells, metabolic detoxification, immune reconstitution and decreased infection rates were observed. Estimated mixed-effects models showed that higher dose of CD34 + cells infused and younger age at GT affected positively the plateau of CD3 + transduced cells, lymphocytes and CD4 + CD45RA + naive T cells, whereas the cell dose positively influenced the final plateau of CD15 + transduced cells. These long-term data suggest that the risk–benefit of GT in ADA remains favorable and warrant for continuing long-term safety monitoring. Clinical trial registration: NCT00598481 , NCT03478670 . Fifteen years’ follow-up of clinical development and real-world data from 43 patients show that gammaretroviral gene therapy for adenosine deaminase deficiency has a positive long-term efficacy profile, warranting continued safety monitoring of patients receiving gene therapy.

Optimal conditioning for adults with acute lymphoblastic leukemia (ALL) treated with haploidentical hematopoietic cell transplantation (haplo-HCT) and post-transplant cyclophosphamide has not been established so far. We retrospectively compared outcomes for two myeloablative regimens: fludarabine + total body irradiation (Flu-TBI, n = 117) and thiotepa + iv. busulfan + fludarabine (TBF, n = 119). Patients transplanted either in complete remission (CR) or with active disease were included in the analysis. The characteristics of both groups were comparable except for patients treated with TBF were older. In univariate analysis the incidence of non-relapse mortality (NRM) at 2 years was increased for TBF compared to Flu-TBI (31% vs. 19.5%, p = 0.03). There was a tendency towards reduced incidence of relapse after TBF (p = 0.11). Results of multivariate analysis confirmed a reduced risk of NRM using Flu-TBI (HR = 0.49, p = 0.03). In the analysis restricted to patients treated in CR1 or CR2, the use of Flu-TBI was associated with a decreased risk of NRM (HR = 0.34, p = 0.009) but an increased risk of relapse (HR = 2.59, p = 0.01) without significant effect on survival and graft-versus-host disease. We conclude that for haplo-HCT recipients with ALL, Flu-TBI may be preferable for individuals at high risk of NRM while TBF should be considered in cases at high risk of relapse.

Improving clinical outcomes among high risk Class III β thalassemia major patients (Class IIIHR) receiving an allogeneic SCT remains a challenge. From October, 2009 a treosulfan based regimen (TreoFluT) was used for all consecutive Class III patients (n = 50). The clinical outcomes were compared with the historical conventional busulfan (BuCy) based regimen (n = 139). Use of TreoFluT was associated with a significantly reduced incidence of sinusoidal obstruction syndrome (SOS) among Class IIIHR cases (78% to 30%; P = 0.000) and early TRM (46% to 13%; p = 0.005). There was also a trend towards better engraftment in the Class IIIHR subset (P = 0.055). However, the use of bone marrow (BM) as source of stem cells along with the TreoFluT regimen was associated with 50% early mixed chimerism which reduced to 8.5% with the use of a peripheral blood stem cell graft (PBSC). Use of a PBSC graft was not associated with a significant increase in the incidence of acute or chronic graft versus host disease (GVHD). The overall and event free survival was significantly better among the Class IIIHR subset with the use of TreoFluT Vs. BuCy (86.6 ± 7.3 Vs. 39.4 ± 6.8%; P = 0.002 and 77.8 ± 8.8 Vs. 32.4 ± 6.5%; P = 0.003 respectively). A TreoFluT conditioning regimen with a PBSC graft can significantly improve clinical outcomes of Class IIIHR patients.

In order to clarify injure mechanism of busulfan to spermatogenic function, we treated mice with busulfan, the testicular and epididymal weights and sperm concentration significantly decreased and the sperm malformation rate increased over time. Moreover, testicular interstitial cell infiltration, a smaller seminiferous tubule, and disorganized and shed spermatogenic cells were also observed by immunohistochemical, immunofluorescence detection after the busulfan treatment. Furthermore, the enzyme-linked absorbance assays showed serum interleukin (IL)-6, IL-1β, and tumor necrosis factor-apha levels (inflammatory factors) were significantly upregulated; blood-testis barrier (BTB)-related protein levels (e.g., N-Cadherin, occludin, and connexin 43) and vimentine gradually decreased. So we infer busulfan treatment induced orchitis, further disrupted the BTB and disrupted the spermatogenic microenvironment, then decreased vimentine and gradually damaged the cytoskeleton, which cause spermatogenic cells losing their supporting from sertoli cells, androgen regulation was also affected, which was detrimental to spermatogenesis. The study result will improve the efficiency and safety in spermatogonial stem cell transplant recipients.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the most effective salvage strategy for B-cell acute lymphoblastic leukemia (B-ALL). In this study, we explored the efficacy and safety of cladribine and medium-dose cytarabine intensified busulfan plus cyclophosphamide conditioning regimen (CBAC) for high-risk B-ALL patients at complete remission (CR) after chemotherapy undergoing allo-HSCT. And compared it with patients historical received traditional total body irradiation plus cyclophosphamide (TBI-Cy) regimen. The 3-year non-relapse mortality (NRM), cumulative incidence of relapse (CIR), disease-free survival (DFS) and overall survival (OS) of CBAC and TBI-Cy group were 15.0% vs. 11.1% ( p  = 0.576), 17.3% vs. 35.7% ( p  = 0.077), 67.7% vs. 53.2% ( p  = 0.235) and 74.3% vs. 66.8% ( p  = 0.482). Overall cohort multivariate analysis indicated TBI-Cy increased the risk of relapse after transplantation compared with CBAC (HR: 2.544, p  = 0.049). Subgroup analysis revealed that among cytogenetic high-risk patients, the CBAC group showed a trend of higher 3-year DFS (75.1% vs 52.6%, p  = 0.073). Among patients with minimal residual disease positive (MRD + ) at transplantation, the CBAC group showed higher 3-year DFS (60.0% vs 11.1%, p  = 0.018). In conclusion, CBAC conditioning regimen may reduce relapse without increasing NRM, improving the prognosis of high-risk B-ALL patients, especially those with cytogenetic high-risk factors or MRD + at transplantation.