-
Emerging Microbes & Infections Dec 2023The rapid evolution of SARS-CoV-2 Omicron sublineages mandates a better understanding of viral replication and cross-neutralization among these sublineages. Here we used...
The rapid evolution of SARS-CoV-2 Omicron sublineages mandates a better understanding of viral replication and cross-neutralization among these sublineages. Here we used K18-hACE2 mice and primary human airway cultures to examine the viral fitness and antigenic relationship among Omicron sublineages. In both K18-hACE2 mice and human airway cultures, Omicron sublineages exhibited a replication order of BA.5 ≥ BA.2 ≥ BA.2.12.1 > BA.1; no difference in body weight loss was observed among different sublineage-infected mice. The BA.1-, BA.2-, BA.2.12.1-, and BA.5-infected mice developed distinguishable cross-neutralizations against Omicron sublineages, but exhibited little neutralization against the index virus (i.e. USA-WA1/2020) or the Delta variant. Surprisingly, the BA.5-infected mice developed higher neutralization activity against heterologous BA.2 and BA.2.12.1 than that against homologous BA.5; serum neutralizing titres did not always correlate with viral replication levels in infected animals. Our results revealed a distinct antigenic cartography of Omicron sublineages and support the bivalent vaccine approach.
Topics: Humans; Animals; Mice; SARS-CoV-2; COVID-19; Melphalan; Antibodies, Viral; Antibodies, Neutralizing
PubMed: 36594261
DOI: 10.1080/22221751.2022.2161422 -
Annals of Hematology Aug 2023Despite the development of effective agents for multiple myeloma (MM), the management of patients with high-risk MM (HRMM) is challenging. High-dose treatment followed...
Busulfan plus melphalan versus high-dose melphalan as a conditioning regimen for autologous stem cell transplantation in multiple myeloma with high-risk features (KMM 2015).
Despite the development of effective agents for multiple myeloma (MM), the management of patients with high-risk MM (HRMM) is challenging. High-dose treatment followed by autologous stem cell transplantation (ASCT) is regarded as upfront treatment for transplant-eligible patients with HRMM. In the present study, we retrospectively investigated the efficacies of two conditioning regimens for upfront ASCT in newly diagnosed patients with MM and high-risk features: high-dose melphalan (HDMEL; 200 mg/m) and busulfan plus melphalan (BUMEL). In total, 221 patients underwent ASCT between May 2005 and June 2021; among these 221 patients, 79 had high-risk cytogenetic abnormalities. In patients with high-risk cytogenetics, BUMEL showed a tendency toward longer overall survival (OS) and progression-free survival (PFS) compared to HDMEL (median OS; not reached vs. 53.2 months; P = 0.091, median PFS; not reached vs. 31.7 months; P = 0.062). Additionally, multivariate analysis revealed that BUMEL was significantly associated with PFS (hazard ratio = 0.37, 95% confidence interval = 0.15-0.89, P = 0.026). We compared BUMEL with HDMEL in patients with other high-risk features, such as high lactate dehydrogenase level, extramedullary disease, and poor response to frontline therapy. Notably, among patients with less than very good partial response (VGPR) to frontline therapy, median PFS was significantly longer in the BUMEL group than in the HDMEL group (55.1 vs. 17.3 months, respectively; P = 0.011). These findings indicate that BUMEL may be an effective conditioning regimen for upfront ASCT in MM patients with high-risk cytogenetics; BUMEL may be more appropriate than HDMEL for patients with less than VGPR to frontline therapy.
Topics: Humans; Melphalan; Multiple Myeloma; Busulfan; Hematopoietic Stem Cell Transplantation; Retrospective Studies; Transplantation, Autologous; Antineoplastic Combined Chemotherapy Protocols; Transplantation Conditioning; Stem Cell Transplantation
PubMed: 37392367
DOI: 10.1007/s00277-023-05308-0 -
Lasers in Medical Science Oct 2023Photobiomodulation therapy (PBMT) is widely used in oncology settings, but lack of assessment standardization is the main barrier to optimization of clinical protocols....
Photobiomodulation therapy (PBMT) is widely used in oncology settings, but lack of assessment standardization is the main barrier to optimization of clinical protocols. This study analyzed three PBMT protocols for preventing oral and oropharyngeal mucositis (OM) in patients undergoing chemotherapy (CT) and/or hematopoietic stem cell transplantation (HSCT). This is a preliminary randomized blind clinical trial. Group 1 received intraoral prophylactic PBMT, Group 2 received intraoral and oropharyngeal PBMT, and Group 3 received intraoral, oropharyngeal, and extraoral PBMT. The applications were from the first day of CT to day + 10. Clinicodemographic data, CT regimens, types of HSCT, hematological exams, occurrence/severity of OM, odynophagia, and OM-related opportunistic infections were assessed. Sixty participants (age range: 18-74 years) were included; 70% of them underwent CT and 30% HSCT. About 43.3% of patients had OM, while odynophagia was reported by 23.3%. Both Groups 1 and 2 revealed better results. Multivariate analysis showed that HSCT directly influenced the occurrence of OM. Individuals who had undergone allogeneic HSCT were 1.93 times more likely to develop OM (p < 0.001). Group 3 exhibited a higher frequency of OM, albeit of lower grades. This group consisted of half the population who had undergone HSCT, had the highest percentage of melphalan use, and had the lowest mean leukocyte count. The three proposed protocols were effective in preventing and reducing OM, with good tolerance and no reported adverse effects. PBMT is a safe and effective approach to OM prophylaxis in adults undergoing CT/HSCT.
Topics: Adolescent; Adult; Aged; Humans; Middle Aged; Young Adult; Antineoplastic Agents; Hematopoietic Stem Cell Transplantation; Low-Level Light Therapy; Melphalan; Mucositis; Randomized Controlled Trials as Topic; Stomatitis
PubMed: 37889325
DOI: 10.1007/s10103-023-03916-w -
Methods in Molecular Biology (Clifton,... 2024Melphalan and busulfan are DNA-alkylating agents that are often used concurrently in hematopoietic stem cell transplant (HCT) conditioning regimens. Studies have...
Melphalan and busulfan are DNA-alkylating agents that are often used concurrently in hematopoietic stem cell transplant (HCT) conditioning regimens. Studies have demonstrated that this combination of alkylating agents is very effective and well-tolerated prior to HCT. This combination is widely used for acute leukemia, advanced lymphoid malignancies, and multiple myeloma. Our goal was to develop an assay for the rapid measurement of both compounds simultaneously in the hopes that rapidly measuring their concentrations could possibly shorten the length of hospital stay. It would also simplify specimen handling in the clinic and the laboratory, reduce the amount of blood drawn, and allow for rapid reporting of the drug levels, thereby facilitating rapid dose adjustments.This chapter describes a validated method that measures both compounds simultaneously. Melphalan and busulfan were extracted from plasma with methanol containing deuterated internal standards. Turbulent flow chromatography coupled with reversed-phase HPLC was used for separation, while the mass spectrometer was set in the positive ion mode. This method has proven accurate and rapid and allowed for timely dose adjustments. The assay was linear over the clinically relevant ranges; the analytical measurement range for busulfan and melphalan was 10-5000 ng/mL and 10-15,000 ng/mL, respectively. Specimens containing elevated drug levels were diluted yielding a final clinically reportable range of 10-25,000 ng/mL for busulfan and 10-75,0000 ng/mL for melphalan. This method is very suitable for simultaneous measurements of these drugs and is currently being used to support pharmacokinetic studies.
Topics: Busulfan; Tandem Mass Spectrometry; Melphalan; Drug Monitoring; Alkylating Agents; Chromatography, High Pressure Liquid
PubMed: 38036818
DOI: 10.1007/978-1-0716-3541-4_14 -
PloS One 2024Multiple myeloma (MM) is the second most prevalent hematologic malignancy which remains uncurable. Numerous drugs have been discovered to inhibit MM cells. Indisulam, an...
Multiple myeloma (MM) is the second most prevalent hematologic malignancy which remains uncurable. Numerous drugs have been discovered to inhibit MM cells. Indisulam, an aryl sulfonamide, has a potent anti-myeloma activity in vitro and in vivo. This study aims to explore the new mechanism of indisulam and investigate its potential use in combination with melphalan. We examined DNA damage in MM cells through various methods such as western blotting (WB), immunofluorescence, and comet assay. We also identified the role of topoisomerase IIα (TOP2A) using bioinformatic analyses. The impact of indisulam on the RNA and protein levels of TOP2A was investigated through qPCR and WB. Cell proliferation and apoptosis were assessed using CCK-8 assays, Annexin V/PI assays and WB. We predicted the synergistic effect of the combination treatment based on calculations performed on a website, and further explored the effect of indisulam in combination with melphalan on MM cell lines and xenografts. RNA sequencing data and basic experiments indicated that indisulam caused DNA damage and inhibited TOP2A expression by decreasing transcription and promoting degradation via the proteasome pathway. Functional experiments revealed that silencing TOP2A inhibited cell proliferation and induced apoptosis and DNA damage. Finally, Indisulam/melphalan combination treatment demonstrated a strong synergistic anti-tumor effect compared to single-agent treatments in vitro and in vivo. These findings suggest that combination therapies incorporating indisulam and melphalan have the potential to enhance treatment outcomes for MM.
Topics: Humans; Melphalan; Multiple Myeloma; Cell Line, Tumor; Sulfonamides
PubMed: 38593113
DOI: 10.1371/journal.pone.0299019 -
EBioMedicine Jan 2024The global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to approximately 500 million cases and 6 million deaths worldwide....
BACKGROUND
The global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to approximately 500 million cases and 6 million deaths worldwide. Previous investigations into the pathophysiology of SARS-CoV-2 primarily focused on peripheral blood mononuclear cells from patients, lacking detailed mechanistic insights into the virus's impact on inflamed tissue. Existing animal models, such as hamster and ferret, do not faithfully replicate the severe SARS-CoV-2 infection seen in patients, underscoring the need for more relevant animal system-based research.
METHODS
In this study, we employed single-cell RNA sequencing (scRNA-seq) with lung tissues from K18-hACE2 transgenic (TG) mice during SARS-CoV-2 infection. This approach allowed for a comprehensive examination of the molecular and cellular responses to the virus in lung tissue.
FINDINGS
Upon SARS-CoV-2 infection, K18-hACE2 TG mice exhibited severe lung pathologies, including acute pneumonia, alveolar collapse, and immune cell infiltration. Through scRNA-seq, we identified 36 different types of cells dynamically orchestrating SARS-CoV-2-induced pathologies. Notably, SPP1 macrophages in the myeloid compartment emerged as key drivers of severe lung inflammation and fibrosis in K18-hACE2 TG mice. Dynamic receptor-ligand interactions, involving various cell types such as immunological and bronchial cells, defined an enhanced TGFβ signaling pathway linked to delayed tissue regeneration, severe lung injury, and fibrotic processes.
INTERPRETATION
Our study provides a comprehensive understanding of SARS-CoV-2 pathogenesis in lung tissue, surpassing previous limitations in investigating inflamed tissues. The identified SPP1+ macrophages and the dysregulated TGFβ signaling pathway offer potential targets for therapeutic intervention. Insights from this research may contribute to the development of innovative diagnostics and therapies for COVID-19.
FUNDING
This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2020M3A9I2109027, 2021R1A2C2004501).
Topics: Animals; Cricetinae; Mice; Humans; COVID-19; SARS-CoV-2; Leukocytes, Mononuclear; Ferrets; Bronchi; Transforming Growth Factor beta; Mice, Transgenic; Disease Models, Animal; Lung; gamma-Globulins; Melphalan
PubMed: 38118400
DOI: 10.1016/j.ebiom.2023.104932 -
American Journal of Ophthalmology Apr 2024To evaluate changes in retinal microvascular density and choroidal vascularity in patients with retinoblastoma (RB) after intra-arterial chemotherapy (IAC).
PURPOSE
To evaluate changes in retinal microvascular density and choroidal vascularity in patients with retinoblastoma (RB) after intra-arterial chemotherapy (IAC).
DESIGN
Retrospective clinical cohort study.
METHODS
This study included 12 unilateral RB eyes treated with IAC (RB tumor), 12 contralateral normal eyes (RB fellow), and 12 healthy controls. The macular retinal thickness and retinal microvascular structure, including the foveal avascular zone (FAZ) area, macular and peripapillary superficial vessel density (SVD), and deep vessel density (DVD), were measured by optical coherence tomography angiography (OCTA). The choroidal thickness (ChT) and choroidal vascularity, including total choroidal area (TCA), luminal area (LA), stromal area (SA), and choroidal vascularity index (CVI), were measured by spectral-domain optical coherence tomography (SD-OCT). A comparison among the 3 groups was conducted, and the correlations among the parameters were analyzed.
RESULTS
Among the 3 cohorts, the foveal retinal thickness, SVD, DVD, ChT, TCA, LA, SA, and CVI were significantly lower in RB tumor compared to RB fellow and the control eyes (all P < .01). There were no significant differences in the parameters between the contralateral and control eyes. The correlation analyses indicated a significant negative correlation between the total melphalan dose and foveal and parafoveal DVD, ChT, and LA.
CONCLUSIONS
The retinal microvascular density and choroidal vascularity were lower in unilateral RB treated with IAC, and seemed to be related to the total melphalan dose. There were no measurable changes in the contralateral eyes.
PubMed: 38615831
DOI: 10.1016/j.ajo.2024.04.007 -
Cureus Jan 2024Retinoblastoma necessitates urgent attention due to its potential fatality if untreated. Multiple treatment options are available and should be employed according to... (Review)
Review
Retinoblastoma necessitates urgent attention due to its potential fatality if untreated. Multiple treatment options are available and should be employed according to size, location, and the extent of dissemination. This review emphasizes the need for increased awareness, advanced diagnostic tools, and innovative treatment approaches, especially intravitreal chemotherapy (IVitC) to address the diverse manifestations and aggressive nature of retinoblastoma. Timely diagnosis and commitment to treatment are pivotal, as delays and reluctance to undergo enucleation contribute to unfavorable outcomes. The evolving treatment landscape, spanning from traditional interventions to modern targeted therapies such as intravitreal melphalan, holds promise for improved outcomes. While the intravitreal approach presents challenges, ongoing research aims to establish its definitive role in retinoblastoma treatment. In the treatment of retinoblastoma, IVitC raises considerations about side effects. The risk of tumor spread beyond the eye is rare, emphasising the potential of IVitC in carefully selected cases. Intravitreal injections exhibit fewer local adverse effects compared to intra-arterial chemotherapy, with careful measures reducing significant ocular complications. The evaluation of ocular toxicity, particularly with melphalan, underscores the importance of a nuanced approach to achieve the right balance between therapeutic efficacy and ocular safety. This comprehensive analysis of studies on IVitC and its ocular and systemic complications provides valuable insights for enhanced patient care. The review concludes with a focus on balancing safety and efficacy in local chemotherapeutic drugs, highlighting the need for thoughtful measures and continued research to optimise treatment modalities globally.
PubMed: 38410326
DOI: 10.7759/cureus.53012 -
Journal of Clinical Medicine Oct 2023Isolated limb perfusion (ILP) for soft tissue sarcomas (STS) is usually performed with tumor necrosis factor alpha (TNF-α) and melphalan. ILP regularly leads to a total...
BACKGROUND
Isolated limb perfusion (ILP) for soft tissue sarcomas (STS) is usually performed with tumor necrosis factor alpha (TNF-α) and melphalan. ILP regularly leads to a total blood loss (BLt) of 1.5-2 L/patient. Blood inflow from the central blood circulation to the limb is influenced by unstable pressure gradients and pain reactions after the administration of melphalan. With perioperative regional anesthesia (RA), pain levels can be reduced, and the pressure gradient stabilized resulting in a reduced BLt. The aim of this study was to compare the BLt with and without RA in patients with ILP during circulation of drugs.
METHODS
Patients were treated according to the following protocol: After the establishment of limb circulation, ILP was started with the administration of TNF-α. Half the dose of melphalan was given as a bolus after 30 min, and the remaining dose was continuously administered in the following 30 min. The extremity was washed out after 90 min. ILP with perioperative RA (supraclavicular plexus block/peridural catheter) was performed prospectively in 17 patients and compared to a matched retrospective control group of 17 patients without RA. BLt was documented and perioperative anesthesiological data were analyzed for response rates after the application of melphalan (RaM).
RESULTS
BLt and RaM tended to be lower for the intervention group with RA if compared to the control group without RA in all analyses. The trend of lower BLt and RaM in ILP with RA was more pronounced for the upper extremity compared to the lower extremity. Results were not statistically significant.
CONCLUSION
These findings indicate that the use of RA can help to stabilize hemodynamic anesthetic management and reduce the BLt in ILP, especially during perfusion of the upper extremities.
PubMed: 37892681
DOI: 10.3390/jcm12206542 -
Transplantation and Cellular Therapy Aug 2023Second allogeneic hematopoietic stem cell transplantation (HSCT) is a treatment option for patients with acute leukemia who relapse after a first HSCT. Although...
Second allogeneic hematopoietic stem cell transplantation (HSCT) is a treatment option for patients with acute leukemia who relapse after a first HSCT. Although myeloablative conditioning (MAC) regimens before the first HSCT are considered superior to reduced- intensity conditioning (RIC) in terms of disease control in acute leukemia patients, the optimal conditioning regimen for the second allogeneic HSCT remains controversial. The most important prognostic factors are the remission disease phase at the time of the second HSCT and an interval >12 months from the first HSCT to the second HSCT. Total marrow irradiation (TMI) is an advanced high-precision radiation treatment that delivers therapeutic doses over extensively selected targets while substantially reducing radiation to vital organs compared to conventional total body irradiation (TBI). Here we report the results of a retrospective analysis of second allogeneic HSCT treated with TMI as an MAC regimen with the intent of limiting toxicity. We investigated the efficacy of high dose per fraction TMI in combination with thiotepa, fludarabine, and melphalan in 13 consecutive patients with acute leukemia who had relapsed after a first allogeneic HSCT treated between March 2018 and November 2021. Donor type was haploidentical in 10 patients, unrelated in 2 patients, and HLA-identical sibling in 1 patient. The conditioning regimen consisted of 8 Gy TMI in 5 patients on days -8 and -7 and 12 Gy TMI in 8 patients on days -9 to -7, plus thiotepa 5 mg/kg on day -6, fludarabine 50 mg/day on days -5 to -3, and melphalan 140 mg/day on day -2. The TMI was delivered at the dosage og 4 GY for 2 consecutive days (total = 8 GY) or for 3 consecutive days (total = 12 GY). The median patient age was 45 years (range, 19 to 70 years); 7 patients were in remission, and 6 had active disease at the time of their second allogeneic HSCT. The median time to a neutrophil count of >.5 × 10/L was 16 days (range, 13 to 22 days), and the median time to a platelet count of >20 × 10/L was 20 days (range, 14 to 34 days). All patients showed complete donor chimerism on day +30 post-transplantation. The cumulative incidence of grade I-II acute graft-versus-host disease (GVHD) was 43%, and that of chronic GVHD was 30%. The median duration of follow-up was 1121 days (range, 200 to 1540 days). Day +30 and +100 transplantation-related mortality (TRM) was 0. The overall cumulative incidence of TRM, relapse rate, and disease free-survival were 27%, 7%, and 67%, respectively. This retrospective study demonstrates the safety and efficacy of a hypofractionated TMI conditioning regimen in patients with acute leukemia undergoing second HSCT with encouraging outcomes in terms of engraftment, early toxicity, GVHD, and relapse.
Topics: Humans; Young Adult; Adult; Middle Aged; Aged; Retrospective Studies; Bone Marrow; Melphalan; Thiotepa; Leukemia, Myeloid, Acute; Hematopoietic Stem Cell Transplantation; Graft vs Host Disease; Acute Disease; Recurrence
PubMed: 37094701
DOI: 10.1016/j.jtct.2023.04.014