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Blood Nov 2023Secondary central nervous system (CNS) lymphoma (SCNSL) is a rare but clinically challenging scenario with historically disappointing outcomes. SCNSL refers to lymphoma...
Secondary central nervous system (CNS) lymphoma (SCNSL) is a rare but clinically challenging scenario with historically disappointing outcomes. SCNSL refers to lymphoma that has spread into the CNS concurrently with systemic disease or CNS relapse during or after frontline immunochemotherapy, presenting with or without systemic lymphoma. Diffuse large B-cell lymphoma (DLBCL) denotes the most common entity, but an increased incidence is observed in other histologies, such as Burkitt lymphoma and mantle-cell lymphoma. The incidence, timing in disease course, location, evidence supporting the use of CNS prophylaxis, and treatment pathways vary according to histology. No randomized data exist to delineate the best treatment approaches with current recommendations based on retrospective and single-arm studies. However, a regimen comprising immunochemotherapy, incorporating agents that cross the blood-brain barrier, followed by thiotepa-containing conditioning and autologous stem-cell transplant outlined in the international MARIETTA study demonstrated improvement in outcomes, representing a major accomplishment in the care of patients with DLBCL with SCNSL. Anti-CD19 chimeric antigen receptor T cell denotes a paradigm shift in the treatment of patients with systemic aggressive lymphomas, with emerging data also demonstrating efficacy without higher neurotoxicity in those with SCNSL. In this manuscript we discuss 5 clinical scenarios and review the evidence supporting our recommendations.
Topics: Humans; Adult; Retrospective Studies; Neoplasm Recurrence, Local; Lymphoma, Large B-Cell, Diffuse; Central Nervous System Neoplasms; Thiotepa; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37702537
DOI: 10.1182/blood.2023020168 -
JAMA Oncology Jul 2021Primary central nervous system lymphoma (PCNSL) requires induction and consolidation to achieve potential cure. High-dose therapy and autologous hematopoietic cell... (Observational Study)
Observational Study
IMPORTANCE
Primary central nervous system lymphoma (PCNSL) requires induction and consolidation to achieve potential cure. High-dose therapy and autologous hematopoietic cell transplant (AHCT) is an accepted and effective consolidation strategy for PCNSL, but no consensus exists on the optimal conditioning regimens.
OBJECTIVE
To assess the outcomes in patients with PCNSL undergoing AHCT with the 3 most commonly used conditioning regimens: thiotepa/busulfan/cyclophosphamide (TBC), thiotepa/carmustine (TT-BCNU), and carmustine/etoposide/cytarabine/melphalan (BEAM).
DESIGN, SETTING, AND PARTICIPANTS
This observational cohort study used registry data from the Center for International Blood and Marrow Transplant Research registry. The Center is a working group of more than 380 transplantation centers worldwide that contributed detailed data on HCT to a statistical center at the Medical College of Wisconsin, Milwaukee. The participant data were from 603 adult patients with PCNSL who underwent AHCT as initial, or subsequent, consolidation between January 2010 and December 2018. Patients were excluded if they had a non-Hodgkin lymphoma subtype other than diffuse large B-cell lymphoma, systemic non-Hodgkin lymphoma, or HIV; received an uncommon conditioning regimen; or were not in partial remission or complete remission prior to AHCT. Statistical analysis was performed from July 5, 2020, to March 1, 2021.
INTERVENTIONS
Patients received 1 of 3 conditioning regimens: TBC (n = 263), TT-BCNU (n = 275), and BEAM (n = 65).
MAIN OUTCOMES AND MEASURES
The primary outcome was progression-free survival. Secondary outcomes included hematopoietic recovery, incidence of relapse, nonrelapse mortality, and overall survival.
RESULTS
Of 603 patients, the mean age was 57 (range, 19-77) years and 318 (53%) were male. The 3-year adjusted progression-free survival rates were higher in the TBC cohort (75%) and TT-BCNU cohort (76%) compared with the BEAM cohort (58%) (P = .03) owing to a higher relapse risk in the BEAM cohort (hazard ratio [HR], 4.34; 95% CI, 2.45-7.70; P < .001). In a multivariable regression analysis, compared with the TBC cohort, patients who received TT-BCNU had a higher relapse risk (HR, 1.79; 95% CI, 1.07-2.98; P = .03), lower risk of nonrelapse mortality (NRM) (HR, 0.50; 95% CI, 0.29-0.87; P = .01), and similar risk of all-cause mortality more than 6 months after HCT (HR, 1.54; 95% CI, 0.93-2.55; P = .10). Age of 60 years or older, Karnofsky performance status less than 90, and an HCT-comorbidity index greater than or equal to 3 were associated with lower rates of survival across all 3 cohorts. Subgroup analyses demonstrated that patients aged 60 years and older had considerably higher NRM with TBC.
CONCLUSIONS AND RELEVANCE
In this cohort study, thiotepa-based conditioning regimen was associated with higher rates of survival compared with BEAM, despite higher rates of early toxic effects and NRM; these findings may assist clinicians in choosing between TBC or TT-BCNU based on patient and disease characteristics.
Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System; Cohort Studies; Cyclophosphamide; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma, Non-Hodgkin; Male; Middle Aged; Neoplasm Recurrence, Local; Thiotepa
PubMed: 33956047
DOI: 10.1001/jamaoncol.2021.1074 -
Organic & Biomolecular Chemistry Jan 2023As a type of readily available small strained-ring heterocycle, -aziridines may undergo catalytic desymmetrizing transformations to empower the rapid construction of... (Review)
Review
As a type of readily available small strained-ring heterocycle, -aziridines may undergo catalytic desymmetrizing transformations to empower the rapid construction of diverse nitrogen-containing structures bearing contiguous stereocenters, which have great relevance in natural product synthesis, drug development and the design and synthesis of chiral catalysts/ligands for asymmetric catalysis. This review outlines the advances achieved in the catalytic asymmetric desymmetrization of aziridines and highlights some promising avenues for further work in this realm.
Topics: Stereoisomerism; Aziridines; Catalysis; Ligands
PubMed: 36508282
DOI: 10.1039/d2ob01935c -
Chemical Communications (Cambridge,... Aug 2015(2,2,2-Trifluoroethyl)diphenylsulfonium triflate was found to be an efficient ylide reagent for the Johnson-Corey-Chaykovsky reaction to afford trifluoromethyl epoxides,...
(2,2,2-Trifluoroethyl)diphenylsulfonium triflate was found to be an efficient ylide reagent for the Johnson-Corey-Chaykovsky reaction to afford trifluoromethyl epoxides, cyclopropanes and aziridines. Interestingly, excellent but different diastereoselectivity was observed for these transformations. Both trifluoromethyl epoxides and cyclopropanes were obtained with trans-selectivity, whereas aziridines were obtained with cis-selectivity.
Topics: Aziridines; Cyclopropanes; Epoxy Compounds; Hydrocarbons, Fluorinated; Stereoisomerism
PubMed: 26189644
DOI: 10.1039/c5cc04991a -
Journal of the American Chemical Society Sep 2022-Symmetrical dirhodium(II) tetracarboxylates are highly efficient catalysts for the asymmetric intermolecular aziridination of substituted alkenes with sulfamates. The...
-Symmetrical dirhodium(II) tetracarboxylates are highly efficient catalysts for the asymmetric intermolecular aziridination of substituted alkenes with sulfamates. The reaction proceeds with high levels of efficiency and chemoselectivity to afford aziridines with excellent yields of up to 95% and enantiomeric excesses of up to 99%. The scope of the alkene aziridination includes mono-, di-, and trisubstituted olefins as well as the late-stage functionalization of complex substrates. The reaction can be performed on a gram-scale with a catalyst loading of 0.1 mol %. Our DFT study led us to propose a two-spin-state mechanism, involving a triplet Rh-nitrene species as key intermediate to drive the stereocontrolled approach and activation of the substrate.
Topics: Alkenes; Aziridines; Catalysis; Rhodium; Stereoisomerism
PubMed: 36094904
DOI: 10.1021/jacs.2c07337 -
Metal Ion Complexes with Pyrazoles, Aziridines and Diaziridines - Synthesis and Biological Activity.Current Medicinal Chemistry 2019Heterocyclic compounds containing nitrogen ions, like pyrazoles, aziridines, diaziridines and their metal ion complexes with Cu(II), Zn(II) and Ru(III) and others... (Review)
Review
Heterocyclic compounds containing nitrogen ions, like pyrazoles, aziridines, diaziridines and their metal ion complexes with Cu(II), Zn(II) and Ru(III) and others exhibit a wide range of biological activity, including mainly anti-inflammatory, antioxidant, anticancer, and antimicrobial properties. Biological significance of these molecules and thus their potential use in medicine has driven growing interest into their coordination chemistry. A knowledge of the relationship between the structure of chemical compounds and their activity is needed for the synthesis of the preparations possessing the most beneficial features. The choice of interposed substituents may improve biocidal and antitumor action, reduce the toxicity of the initial substance, or even completely eliminate its adverse effects for healthy tissues. The main aim of this review paper is to present the current state of knowledge concerning the synthesis and biological activity of complexes with small heterocyclic ligands containing transition metal ions.
Topics: Anti-Infective Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antioxidants; Aziridines; Coordination Complexes; Drug Discovery; Humans; Ions; Ligands; Molecular Structure; Pyrazoles; Structure-Activity Relationship; Transition Elements
PubMed: 29473492
DOI: 10.2174/0929867325666180221124447 -
Expert Opinion on Pharmacotherapy Nov 2017Bladder cancer is nowadays a common tumor. Non-muscle invasive bladder cancer (NMIBC) has still chances of recurrence and progression in spite of surgery and adjuvant... (Review)
Review
Bladder cancer is nowadays a common tumor. Non-muscle invasive bladder cancer (NMIBC) has still chances of recurrence and progression in spite of surgery and adjuvant treatments. New therapies are being developed to reduce these percentages with less adverse effects - Apaziquone (EO9) is an example. Areas covered: A literature search has been performed using Pubmed, UpToDate and Google verified information (mainly from Food and Drug Administration and Spectrum Pharmaceutics websites). We have included data from the most representative clinical trials and reviews published. Expert opinion: Apaziquone is considered a promising chemical agent if applied intravesically due mainly to its pharmacodynamics and safety profile. There is evidence for this with respect to adjuvant chemo ablative therapy and as a post-transurethral resection of bladder (TURB) single-dose regimen. As a result, new clinical phase III trials are needed both to evaluate its efficacy as an adjuvant therapy in the spectrum from intermediate- to high-risk non-muscle invasive bladder cancer and to select the most appropriate candidates and treatment schedule. As a conclusion, Apaziquone is a good candidate to become a better alternative as an adjuvant therapy for the treatment of NMIBC in the near future.
Topics: Administration, Intravesical; Antineoplastic Agents; Aziridines; Chemotherapy, Adjuvant; Combined Modality Therapy; Disease Progression; Humans; Indolequinones; Neoplasm Recurrence, Local; Urinary Bladder Neoplasms
PubMed: 29034722
DOI: 10.1080/14656566.2017.1392510 -
Angewandte Chemie (International Ed. in... Jun 2023Aziridines are highly valued synthetic targets in organic and medicinal chemistry. The organocatalytic synthesis of such structures with broad substrate scope and good...
Aziridines are highly valued synthetic targets in organic and medicinal chemistry. The organocatalytic synthesis of such structures with broad substrate scope and good diastereoselectivity, however, is rare. Herein, we report a broadly applicable and diastereoselective synthetic method for the synthesis of trans-aziridines from imines and benzylic or alkyl halides utilizing sulfenate anions (PhSO ) as the catalyst. Substrates bearing heterocyclic aromatic groups, alkyl, and electron-rich and electron-poor aryl groups were shown to be compatible with this method (33 examples), giving good yields and high diastereoselectivities (trans : cis >20 : 1). Further functionalization of aziridines containing cyclopropyl or cyclobutyl groups was achieved through ring-opening reactions, with a cyclobutyl-substituted norephedrine derivative obtained through a four-step synthesis. We offer a mechanistic proposal involving reversible addition of the deprotonated benzyl sulfoxide to the imine to explain the high trans-diastereoselectivity.
Topics: Aziridines; Anions; Imines; Catalysis; Stereoisomerism
PubMed: 37068049
DOI: 10.1002/anie.202303069 -
Journal of Visualized Experiments : JoVE Jun 2022Nitrogen-containing heterocycle aziridines are synthetically very valuable for the preparation of azacyclic and acyclic molecules. However, it is very difficult and...
Nitrogen-containing heterocycle aziridines are synthetically very valuable for the preparation of azacyclic and acyclic molecules. However, it is very difficult and laborious to make aziridines in optically pure forms on a large scale to apply asymmetric synthesis of aza compounds. Fortunately, we successfully achieved both enantiomers (2R)- and (2S)-aziridine-2-carboxylates with the electron-donating α-methylbenzyl group at the ring nitrogen as non-activated aziridines. These starting aziridines have two distinct functional groups-highly reactive three-membered ring and versatile carboxylate. They are applicable in ring-opening or ring-transformation with aziridine and in functional group transformation to others from carboxylate. Both of these enantiomers were utilized in the preparation of biologically important amino acyclic and/or aza-heterocyclic compounds in an asymmetric manner. Specifically, this report describes the first expedient asymmetric synthesis of both enantiomers of 5, 6-dihydrouracil-type marine natural products biemamide B and D as potential TGF-β inhibitors. This synthesis consisted of regio- and the stereoselective ring-opening reaction of aziridine-2-carboxylate and subsequent formation of 4-aminoteterahydropyrimidine-2,4-dione. One more example in this protocol dealt a highly stereoselective Mukaiyama reaction of aziridine-2-carboxylate and silyl enol ether, following intramolecular aziridine ring-opening to provide easy and facile access to (-)-epiallo-isomuscarine.
Topics: Aza Compounds; Aziridines; Ethers; Nitrogen; Stereoisomerism
PubMed: 35758698
DOI: 10.3791/63705 -
Molecules (Basel, Switzerland) Feb 2019Small ring heterocycles, such as epoxides and aziridines, are present in several natural products and are also highly versatile building blocks, frequently involved in... (Review)
Review
Small ring heterocycles, such as epoxides and aziridines, are present in several natural products and are also highly versatile building blocks, frequently involved in the synthesis of numerous bioactive products and pharmaceuticals. Because of the potential for increased efficiency and selectivity, along with the advantages of environmentally benign synthetic procedures, multicomponent reactions (MCRs) have been explored in the synthesis and ring opening of these heterocyclic units. In this review, the recent advances in MCRs involving the synthesis and applications of epoxides and aziridines to the preparation of other heterocycles are discussed emphasizing the stereoselectivity of the reactions.
Topics: Aziridines; Biological Products; Epoxy Compounds; Green Chemistry Technology; Molecular Structure; Stereoisomerism
PubMed: 30754666
DOI: 10.3390/molecules24030630