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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 -
Chembiochem : a European Journal of... Jun 2024Only 0.016% of all known natural products contain an aziridine ring, but this unique structural feature imparts high reactivity and cytotoxicity to the compounds in...
Only 0.016% of all known natural products contain an aziridine ring, but this unique structural feature imparts high reactivity and cytotoxicity to the compounds in which it is found. Until 2021, no naturally occurring azirdine-forming enzymes had been identified. Since 2021, the biosynthetic enzymes for ~10% of known aziridine containing natural products have been identified and characterized. This article describes the recent advances in our understanding of enzyme-catalyzed aziridine formation in the context of historical means of azirdine formation through synthetic chemistry.
PubMed: 38830838
DOI: 10.1002/cbic.202400295 -
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 -
Advances in Experimental Medicine and... 2016DNA methyltransferases (MTases) uniquely combine the ability to recognize and covalently modify specific target sequences in DNA using the ubiquitous cofactor... (Review)
Review
DNA methyltransferases (MTases) uniquely combine the ability to recognize and covalently modify specific target sequences in DNA using the ubiquitous cofactor S-adenosyl-L-methionine (AdoMet). Although DNA methylation plays important roles in biological signaling, the transferred methyl group is a poor reporter and is highly inert to further biocompatible derivatization. To unlock the biotechnological power of these enzymes, two major types of cofactor AdoMet analogs were developed that permit targeted MTase-directed attachment of larger moieties containing functional or reporter groups onto DNA. One such approach (named sequence-specific methyltransferase-induced labeling, SMILing) uses reactive aziridine or N-mustard mimics of the cofactor AdoMet, which render targeted coupling of a whole cofactor molecule to the target DNA. The second approach (methyltransferase-directed transfer of activated groups, mTAG) uses AdoMet analogs with a sulfonium-bound extended side chain replacing the methyl group, which permits MTase-directed covalent transfer of the activated side chain alone. As the enlarged cofactors are not always compatible with the active sites of native MTases, steric engineering of the active site has been employed to optimize their alkyltransferase activity. In addition to the described cofactor analogs, recently discovered atypical reactions of DNA cytosine-5 MTases involving non-cofactor-like compounds can also be exploited for targeted derivatization and labeling of DNA. Altogether, these approaches offer new powerful tools for sequence-specific covalent DNA labeling, which not only pave the way to developing a variety of useful techniques in DNA research, diagnostics, and nanotechnologies but have already proven practical utility for optical DNA mapping and epigenome studies.
Topics: Aziridines; DNA; DNA Methylation; DNA Modification Methylases; Epigenomics; Humans; S-Adenosylmethionine; Staining and Labeling
PubMed: 27826850
DOI: 10.1007/978-3-319-43624-1_19 -
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 -
Cancer Treatment Reviews Feb 2016Leptomeningeal metastasis (LM), i.e. the seeding of tumor cells to the cerebrospinal fluid (CSF) and the leptomeninges, is a devastating and mostly late-stage... (Review)
Review
Leptomeningeal metastasis (LM), i.e. the seeding of tumor cells to the cerebrospinal fluid (CSF) and the leptomeninges, is a devastating and mostly late-stage complication of various solid tumors. Clinical signs and symptoms may include cranial nerve palsies, radicular symptoms, signs of increased intracranial pressure such as headache, nausea and vomiting, and cognitive dysfunction. In cases of suspected LM, the highest diagnostic sensitivity is provided by the combination of CSF cytology and contrast-enhanced MRI (cranial as well as complete spine). The therapeutic spectrum includes radiotherapy of the clinically involved region as well as systemic and intrathecal chemotherapy. The choice of treatment modalities depends on the type of LM (non-adherent tumor cells in the CSF vs. nodular contrast-enhancing tumor growth), additional systemic involvement (uncontrolled vs. controlled systemic disease) and additional involvement of the CNS parenchyma (LM as the only CNS involvement vs. LM+parenchymal CNS metastases). Larger contrast-enhancing nodular LM or symptomatic lesions of the spine may be treated with radiotherapy. In case of uncontrolled systemic disease, the treatment regimen should include systemic chemotherapy. The choice of systemic treatment should take into account the histology of the primary tumor. Intrathecal chemotherapy is most important in cases of LM of the non-adherent type. There are three substances for routine use for intrathecal chemotherapy: methotrexate, cytarabine, and thiotepa. Liposomal cytarabine shows advantages in terms of longer injection intervals, a sufficient distribution in the entire subarachnoid space after lumbar administration and improved quality-of-life. The role of new agents (e.g. rituximab and trastuzumab) for intrathecal therapy is still unclear.
Topics: Antineoplastic Agents; Cytarabine; Humans; Injections, Spinal; Meningeal Neoplasms; Methotrexate; Neoplasm Seeding; Neoplasm Staging; Radiotherapy; Thiotepa; Treatment Outcome
PubMed: 26827696
DOI: 10.1016/j.ctrv.2015.12.004 -
Mini Reviews in Medicinal Chemistry 2016Azaheterocyclic compounds are well-known to have diverse types of biological activity. Among them, azacyclopropanes, commonly referred as aziridines, occupy a prominent... (Review)
Review
Azaheterocyclic compounds are well-known to have diverse types of biological activity. Among them, azacyclopropanes, commonly referred as aziridines, occupy a prominent place in synthetic organic and medicinal chemistry due to its occurrence in natural resources, complexity involved in synthesis due to ring-strain, building blocks in organic synthesis, and its biological properties. Several novel compounds containing aziridine ring have been designed and synthesized recently by medicinal chemists for evaluating their biological profile. A number of compounds are reported as cysteine protease inhibitors, antibacterial, antifungal, anticancer, antileishmanial, and antimalarial agents. This review article summarizes the biological activity of such compounds. The preparation of such compounds is also described.
Topics: Animals; Anti-Infective Agents; Antineoplastic Agents; Aziridines; Chemistry Techniques, Synthetic; Chemistry, Pharmaceutical; Cysteine Proteinase Inhibitors; Drug Discovery; Fanconi Anemia; Humans; Malaria; Neoplasms; Tubulin Modulators
PubMed: 26156415
DOI: 10.2174/1389557515666150709122244 -
Organic & Biomolecular Chemistry Jun 2023Compounds featuring aziridine moieties are widely known and extensively reported in the literature. Due to their great potential from both synthetic and pharmacological... (Review)
Review
Compounds featuring aziridine moieties are widely known and extensively reported in the literature. Due to their great potential from both synthetic and pharmacological points of view, many researchers have focused their efforts on the development of new methodologies for the preparation and transformation of these interesting compounds. Over the years, more and more ways to obtain molecules bearing these three-membered functional groups, which are challenging due to their inherent reactivity, have been described. Among them, several are more sustainable. In this review, we report the recent advances in the biological and chemical evolution of aziridine derivatives, in particular, the variety of methodologies described for the synthesis of aziridines and their chemical transformations leading to the formation of interesting derivatives, such as 4-7 membered heterocycles of pharmaceutical interest due to their promising biological activities.
Topics: Aziridines
PubMed: 37218299
DOI: 10.1039/d3ob00424d -
International Journal of Molecular... Sep 2021Aziridination reactions represent a powerful tool in aziridine synthesis. Significant progress has been achieved in this field in the last decades, whereas highly... (Review)
Review
Aziridination reactions represent a powerful tool in aziridine synthesis. Significant progress has been achieved in this field in the last decades, whereas highly functionalized aziridines including 3-arylated aziridine-2-carbonyl compounds play an important role in both medical and synthetic chemistry. For the reasons listed, in the current review we have focused on the ways to obtain 3-arylated aziridines and on the recent advances (mainly since the year 2000) in the methodology of the synthesis of these compounds via aziridination.
Topics: Aziridines; Carboxylic Acids; Imines; Ketones; Molecular Structure; Stereoisomerism
PubMed: 34576025
DOI: 10.3390/ijms22189861