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Transplantation and Cellular Therapy Nov 2021Reduced-intensity conditioning (RIC) regimens developed to extend the use of allogeneic hematopoietic stem cell transplantation (HSCT) to older patients have resulted in...
Reduced-intensity conditioning (RIC) regimens developed to extend the use of allogeneic hematopoietic stem cell transplantation (HSCT) to older patients have resulted in encouraging outcomes. We aimed to compare the 2 most commonly used RIC regimens, i.v. fludarabine with busulfan (FluBu) and fludarabine with melphalan (FluMel), in patients with myelodysplastic syndrome (MDS). Through the Center for International Blood and Marrow Transplant Research (CIBMTR), we identified 1045 MDS patients age ≥60 years who underwent first HSCT with a matched related or matched (8/8) unrelated donor using an RIC regimen. The CIBMTR's definition of RIC was used: a regimen that incorporated an i.v. busulfan total dose ≤7.2 mg/kg or a low-dose melphalan total dose ≤150 mg/m. The 2 groups, recipients of FluBu (n = 697) and recipients of FluMel (n = 448), were comparable in terms of disease- and transplantation-related characteristics except for the more frequent use of antithymocyte globulin or alemtuzumab in the FluBu group (39% versus 31%). The median age was 67 years in both groups. FluMel was associated with a reduced relapse incidence (RI) compared with FluBu, with a 1-year adjusted incidence of 26% versus 44% (P ≤ .0001). Transplantation-related mortality (TRM) was higher in the FluMel group (26% versus 16%; P ≤ .0001). Because the magnitude of improvement with FluMel in RI was greater than the improvement in TRM with FluBu, disease-free survival (DFS) was better at 1 year and beyond with FluMel compared with FluBu (48% versus 40% at 1 year [P = .02] and 35% versus 27% at 3 years [P = .01]). Overall survival was comparable in the 2 groups at 1 year (63% versus 61%; P = .4) but was significantly improved with FluMel compared with FluBu at 3 years (46% versus 39%; P = .03). Our results suggest that FluMel is associated with superior DFS compared with FluBu owing to reduced RI in older patients with MDS patients. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
Topics: Aged; Busulfan; Graft vs Host Disease; Humans; Melphalan; Middle Aged; Myelodysplastic Syndromes; Survival Analysis; Transplantation Conditioning; Vidarabine
PubMed: 34403791
DOI: 10.1016/j.jtct.2021.08.007 -
Frontiers in Chemistry 2021Gallic acid and catechin are the most abundant phenolic and flavonoid contents found in all plant extracts. The contents and the bioassay-guided fractionating substances...
Determination of Phenolics and Flavonoids of Some Useful Medicinal Plants and Bioassay-Guided Fractionation Substances of (A. Rich) Hochst Stem (Bark) Extract and Their Efficacy Against .
Gallic acid and catechin are the most abundant phenolic and flavonoid contents found in all plant extracts. The contents and the bioassay-guided fractionating substances of the (A. Rich) Hochst (Anacardiaceae) fraction played vital roles. The goals of the study were to determine the contents of some useful medicinal plants and the bioassay-guided fractionation substances of fraction compounds capable of acting against isolate using LC-MS/LC-HRMS (Dionex ultimate 3000 RS UPLC with Thermo Scientific Q Exactive Orbitrap Hybrid Tandem Mass Spectrometer). The Folin-Ciocalteu reagent procedure and flavonoid content determination were conducted spectrophotometrically. Bioassay-guided fractionation, chronological partitioning, and screening of the antibacterial action against were performed. The ethyl acetate fraction extracts of stem (bark) extract were analyzed using LC-MS/LC-HRMS. The gallic acid content increased tremendously in (L.) P.J.H. Hurter and Mabb (Fabaceae) pod extracts with curve fitting ( = 0.9958). Catechin content increase was significantly increased in stem (bark) extracts followed by that of pod extracts with curve fitting ( = 0.9993); they were all significantly different in the J.F. Gmel. and the (Poir.) Goyder leaves extracts at value <0.0001. Subsequently, 10 mg/ml of stem (bark) ethyl acetate fraction extract was the MIC, where no MBC was recorded and susceptible to the positive control with the highest inhibition zone, followed by the ethyl acetate fraction extract at 10 mg/ml (9.7 ± 0.0) at Turkey's < 0.0001. Vidarabine is one of the novel compounds, specifically having antimicrobial actions, found in the stem (bark). Reasonable amounts of phenolic and flavonoid contents determined the actions of the individual plant extract.
PubMed: 34386478
DOI: 10.3389/fchem.2021.670530 -
The Journal of Allergy and Clinical... Mar 2022Allogeneic hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis (HLH) disorders is associated with substantial morbidity and mortality.
BACKGROUND
Allogeneic hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis (HLH) disorders is associated with substantial morbidity and mortality.
OBJECTIVE
The effect of conditioning regimen groups of varying intensity on outcomes after transplantation was examined to identify an optimal regimen or regimens for HLH disorders.
METHODS
We studied 261 patients with HLH disorders transplanted between 2005 and 2018. Risk factors for transplantation outcomes by conditioning regimen groups were studied by Cox regression models.
RESULTS
Four regimen groups were studied: (1) fludarabine (Flu) and melphalan (Mel) in 123 subjects; (2) Flu, Mel, and thiotepa (TT) in 28 subjects; (3) Flu and busulfan (Bu) in 14 subjects; and (4) Bu and cyclophosphamide (Cy) in 96 subjects. The day 100 incidence of veno-occlusive disease was lower with Flu/Mel (4%) and Flu/Mel/TT (0%) compared to Flu/Bu (14%) and Bu/Cy (22%) (P < .001). The 6-month incidence of viral infections was highest after Flu/Mel (72%) and Flu/Mel/TT (64%) compared to Flu/Bu (39%) and Bu/Cy (38%) (P < .001). Five-year event-free survival (alive and engrafted without additional cell product administration) was lower with Flu/Mel (44%) compared to Flu/Mel/TT (70%), Flu/Bu (79%), and Bu/Cy (61%) (P = .002). The corresponding 5-year overall survival values were 68%, 75%, 86%, and 64%, and did not differ by conditioning regimen (P = .19). Low event-free survival with Flu/Mel is attributed to high graft failure (42%) compared to Flu/Mel/TT (15%), Flu/Bu (7%), and Bu/Cy (18%) (P < .001).
CONCLUSIONS
Given the high rate of graft failure with Flu/Mel and the high rate of veno-occlusive disease with Bu/Cy and Flu/Bu, Flu/Mel/TT may be preferred for HLH disorders. Prospective studies are warranted.
Topics: Busulfan; Cyclophosphamide; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Lymphohistiocytosis, Hemophagocytic; Melphalan; Thiotepa; Transplantation Conditioning; Vidarabine
PubMed: 34375618
DOI: 10.1016/j.jaci.2021.07.031 -
Transplantation and Cellular Therapy Nov 2021Compared to reduced-intensity conditioning regimen, myeloablative conditioning (MAC) for hematopoietic stem cell transplantation (HCT) reduces relapse but is avoided in...
Compared to reduced-intensity conditioning regimen, myeloablative conditioning (MAC) for hematopoietic stem cell transplantation (HCT) reduces relapse but is avoided in older patients because of higher non-relapse mortality (NRM). To meet the need for a myeloablative regimen for older patients, we developed a novel fludarabine and busulfan MAC regimen. We fractionated the dose of busulfan and gave it for 6 days over a 2-week period and demonstrated the feasibility and safety of this approach. However, the disease-specific efficacy of this regimen is not known. The purpose of this study was to estimate the efficacy of fractionated busulfan regimen by estimating diseases specific survival outcomes. The conditioning regimen consisted of busulfan and fludarabine. On days -13 and -12 before HCT, patients received 80 mg/m busulfan intravenously (IV) daily in an outpatient clinic. Additional chemotherapy was administered during inpatient treatment from day -6 through day -3, including fludarabine 40 mg/m and busulfan IV once daily. The dosing of busulfan was determined from pharmacokinetic analyses to achieve for the course a target area under the curve of 20,000 ± 12% μmol/min, which is close to the average exposure of myeloablative dose of busulfan. One hundred fifty patients with high-risk hematological malignancies up to 75 years were enrolled in this prospective phase II study. The objective was to evaluate NRM, relapse, survival, the rates of graft-versus-host disease (GVHD), and long-term complications. The median age of the patient population was 61 years (interquartile range, 55-67). The most common diagnoses were acute myeloid leukemia (AML; N = 59 [39.3%]), myelodysplastic syndrome (MDS; n = 29 [19.3%]), and myelofibrosis (MF; N = 22 [14.7%]). Most had an unrelated donor (n = 93 [62%]) and received peripheral blood graft (n = 110 [73.3%]). Over half had an HCT-specific comorbidity index of ≥3 (n = 79 [52.7%]). The median follow-up among survivors was 43.4 months (interquartile range, 38.9-50.4). In patients with AML in complete remission, MDS, and myelofibrosis, 3-year overall survival was 66.7% (95% confidence interval [CI], 50.2-88.5%), 43.6% (95% CI, 28.6-66.4%), and 59.1% (95% CI, 41.7-83.7%) respectively. The cumulative incidence of NRM was 22% (15.3%-28.7%), extensive chronic GVHD was 27% (95% CI, 20-34%), bronchiolitis obliterans was 4.7% (95% CI, 1.3-8.1%), and secondary malignancy was 8.7% (95% CI, 4.1-13.2%) at 3 years. Lengthening the duration of busulfan (fractionation) permits safe delivery of myeloablative conditioning in older patients, leading to prolonged survival. © 2021 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
Topics: Aged; Busulfan; Humans; Middle Aged; Myeloablative Agonists; Prospective Studies; Transplantation Conditioning; Vidarabine
PubMed: 34329753
DOI: 10.1016/j.jtct.2021.07.021 -
Transplantation and Cellular Therapy Nov 2021We have previously shown an advantage of a myeloablative conditioning regimen with reduced toxicity (Fludarabine 150 mg/m, Treosulfan 42 g/m, FluTreo) compared to a...
We have previously shown an advantage of a myeloablative conditioning regimen with reduced toxicity (Fludarabine 150 mg/m, Treosulfan 42 g/m, FluTreo) compared to a reduced-intensity regimen. We aimed to determine long-term safety and efficacy of FluTreo. We prospectively studied consecutive patients who received FluTreo in our center (2014-2019) on the basis of age (≥50 years), hematopoietic cell transplantation comorbidity index (HCT-CI) ≥2, or both. FluTreo recipients were then compared to a historical control group. We studied 68 FluTreo recipients, with a median age of 58.5 years and HCT-CI of 3. We calculated cumulative incidence (CI) of acute (grade 2-4) and moderate/severe chronic graft-versus-host disease (GVHD) (29.9% and 25%, respectively). The 3-year CI of treatment-related mortality was 19.1%, associated only with acute GVHD (P < .001). With a median follow-up of 27.3 (range 5.7-84.5) months in surviving patients, the 3-year overall survival (OS) was 56.6%, and disease-free survival (DFS) was 54.9%. Median survival has not yet been reached. Among pretransplantation and transplantation factors, only HCT-CI was associated with DFS and OS (P = .022 and P = .043, respectively). FluTreo recipients aged ≥50 with HCT-CI ≤ 2 had favorable DFS and OS compared with patients aged ≥50 with HCT-CI ≤2 after myeloablative conditioning. Our real-world study confirms that HCT with FluTreo expands the transplant population with favorable outcomes compared to previously used conditions. The choice of HCT in patients of a rather older age and comorbidity index needs to be revisited.
Topics: Aged; Busulfan; Comorbidity; Hematopoietic Stem Cell Transplantation; Humans; Middle Aged; Neoplasms; Transplantation Conditioning; Vidarabine
PubMed: 34320443
DOI: 10.1016/j.jtct.2021.07.020 -
Asian Pacific Journal of Cancer... Jul 2021Over-expression of anti-apoptotic proteins such as Bcl-2 and Mcl-1 is associated with resistance to chemotherapeutic agents such as fludarabine. Moreover, an inverse...
BACKGROUND
Over-expression of anti-apoptotic proteins such as Bcl-2 and Mcl-1 is associated with resistance to chemotherapeutic agents such as fludarabine. Moreover, an inverse relationship between miRNA-15a levels with Bcl-2 and Mcl-1 expression has been observed in CLL patients. In this study, the effect of miRNA-15a on apoptosis and sensitivity of the CLL cells to fludarabine was investigated.
METHODS
After treatments, the Mcl-1 and Bcl-2 expression levels were quantified by RT-qPCR. Trypan blue assay was used to explore the effects of miRNA-15a and fludarabine on cell proliferation. The cytotoxicity was measured using MTT assay and combination index analysis. Cell death was determined using cell death detection ELISA assay and caspase-3 activity assay Kits.
RESULTS
Results showed that miRNA-15a clearly decreased the mRNA levels of Bcl-2 and Mcl-1 in a time dependent manner, which led to CLL-II cell proliferation inhibition and enhancement of apoptosis (p < 0.05, relative to control). Transfection of the miRNA-15a synergistically reduced the cell survival rate and lowered the IC50 value of fludarabine. Furthermore, miRNA-15a significantly enhanced the apoptotic effect of fludarabine.
CONCLUSIONS
Our data propose that suppression of Bcl-2 and Mcl-1 by miRNA-15a can effectively inhibit the cell proliferation and sensitize CLL cells to fludarabine. Therefore, miRNA-15a can be considered as a potential therapeutic target in CLL resistant patients.
Topics: Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Cell Proliferation; Drug Resistance, Neoplasm; Leukemia, Lymphocytic, Chronic, B-Cell; MicroRNAs; Myeloid Cell Leukemia Sequence 1 Protein; Proto-Oncogene Proteins c-bcl-2; Tumor Cells, Cultured; Vidarabine
PubMed: 34319043
DOI: 10.31557/APJCP.2021.22.7.2191 -
AME Case Reports 2021In daily medical practice, scapular pain associated with cervical radiculopathy is commonly seen prior to the onset of pain of the upper extremity; however, the cause of...
Simultaneous herpes zoster rash in the upper extremity and interscapular region that resembles innervation zone of the dorsal ramus of the cervical nerve root: a case report.
In daily medical practice, scapular pain associated with cervical radiculopathy is commonly seen prior to the onset of pain of the upper extremity; however, the cause of the scapular pain is uncertain. We report a case of herpes zoster with simultaneous skin rash in both the upper extremity and interscapular region, which corresponds to the painful scapular region in case of C8 cervical radiculopathy. A 71-year-old healthy woman complained of shoulder and scapular pain followed by a blistering skin rash on both the ulnar side of her upper extremity and intrascapular region on the right side. She was diagnosed with herpes zoster and was prescribed amenamevir as oral treatment with vidarabine ointment. After 1 year, she still had mild causalgia on her III-V fingers and needed oral treatment with pregabalin. To our knowledge, this is the first case report of a herpes zoster rash in the upper extremity and intrascapular region simultaneously. We speculate that the rash in the two regions is caused by the varicella zoster virus (VZV) traveling from the same ganglion, probably the C8 ganglion, considering the dermatome of the rash area in the upper extremity and the intrascapular region correspond to the innervation zone of the medial branches of the dorsal ramus of the cervical nerve root, which resembles the scapular region in case of cervical radiculopathy. This phenomenon implies the mechanism of scapular pain is related to cervical radiculopathy. Further case reports are needed to confirm this.
PubMed: 34312604
DOI: 10.21037/acr-21-1 -
Pathology Oncology Research : POR 2021The widespread application of fludarabine, cyclophosphamide, and rituximab combination is limited due to its toxicity, particularly the prolonged cytopenias. The study...
The widespread application of fludarabine, cyclophosphamide, and rituximab combination is limited due to its toxicity, particularly the prolonged cytopenias. The study aimed to compare the prolonged cytopenias depending on fitness and report real-life data on dose reduction measures and efficacy. According to our database, 120 and 14 patients were treated with FCR between 2011 and 2015 and between 2016 and 2019. Out of the first cohort, 34 patients were treated in subsequent lines. The complete and partial remission rate after first-line treatment was 79%, 16% in the first cohort and 86%, 14% in the second cohort, respectively; and 47%, 35% after non first-line treatment. Based on today's standards, only 37.5% of the patients were fit for FCR. The frequency of persistent cytopenia was 14%, and it was significantly associated with fitness ( (1) = 6.001, = 0.014 for all patients). The small number of FCR treated patients after 2016 shows how the availability of targeted therapies, mostly ibrutinib, in later lines changed the first-line choice. Recently, it is recommended first-line for fit patients with mutated and no aberrations. With this narrow indication, a decrease in the frequency of persistent cytopenias is predicted.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Female; Follow-Up Studies; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Molecular Targeted Therapy; Prognosis; Retrospective Studies; Rituximab; Survival Rate; Thrombocytopenia; Vidarabine
PubMed: 34257611
DOI: 10.3389/pore.2021.1609742 -
Viruses Jun 2021Herpes simplex viruses-1 and -2 (HSV-1 and -2) are two of the three human alphaherpesviruses that cause infections worldwide. Since both viruses can be acquired in the... (Review)
Review
Herpes simplex viruses-1 and -2 (HSV-1 and -2) are two of the three human alphaherpesviruses that cause infections worldwide. Since both viruses can be acquired in the absence of visible signs and symptoms, yet still result in lifelong infection, it is imperative that we provide interventions to keep them at bay, especially in immunocompromised patients. While numerous experimental vaccines are under consideration, current intervention consists solely of antiviral chemotherapeutic agents. This review explores all of the clinically approved drugs used to prevent the worst sequelae of recurrent outbreaks by these viruses.
Topics: Antiviral Agents; Biological Availability; DNA-Directed DNA Polymerase; Drug Resistance, Viral; Herpes Simplex; Herpesvirus 1, Human; Herpesvirus 2, Human; Humans; Nucleic Acid Synthesis Inhibitors; Virus Attachment; Virus Internalization
PubMed: 34202050
DOI: 10.3390/v13071228 -
Leukemia Jan 2022
Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cyclophosphamide; Follow-Up Studies; Humans; Immunoglobulin Heavy Chains; Immunoglobulin Variable Region; Integrin alpha4; Leukemia, Lymphocytic, Chronic, B-Cell; Mutation; Neoplasm Recurrence, Local; Prognosis; Rituximab; Survival Rate; Telomere Homeostasis; Tumor Suppressor Protein p53; Vidarabine
PubMed: 34148055
DOI: 10.1038/s41375-021-01322-1